Product Monograph - Calquence (Astrazeneca Canada, Tablet)

Recent Major Label Changes

1 Indications	2026-10
4 Dosage and Administration, 4.2 Recommended Dose and Dosage Adjustment	2026-10
7 Warnings and Precautions	2026-10
7 Warnings and Precautions, 7.1.4 Geriatrics	2025-09

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ..................................................................................................... 3

Table of Contents ........................................................................................................................ 3

Part 1: Healthcare Professional Information ............................................................................ 6

1.
Indications ............................................................................................................................ 6
1.1. Pediatrics .................................................................................................................. 6
1.2. Geriatrics .................................................................................................................. 6
2. Contraindications ................................................................................................................ 6
3. Serious Warnings and Precautions Box ........................................................................... 7
4.
Dosage and Administration ................................................................................................ 7
4.1. Dosing Considerations ............................................................................................. 7
4.2. Recommended Dose and Dosage Adjustment ........................................................ 7
4.4. Administration ......................................................................................................... 13
4.5. Missed Dose ........................................................................................................... 14
5. Overdose ............................................................................................................................ 14
6. Dosage Forms, Strengths, Composition and Packaging ............................................... 14
7.
Warnings and Precautions ............................................................................................... 14
Carcinogenesis and Genotoxicity ........................................................................................ 14
Cardiovascular ..................................................................................................................... 15
Driving and Operating Machinery ........................................................................................ 15
Hematologic ......................................................................................................................... 15
Hemorrhage ......................................................................................................................... 15
Hepatic ............................................................................................................................... 16
Immune ............................................................................................................................... 16
Monitoring and Laboratory Tests ......................................................................................... 17
7.1. Special Populations ................................................................................................ 17
7.1.1 Pregnancy ........................................................................................................... 17
7.1.2 Breastfeeding ...................................................................................................... 17
7.1.3 Pediatrics ............................................................................................................. 17
7.1.4 Geriatrics ............................................................................................................. 17
8.
Adverse Reactions ............................................................................................................ 17
8.1. Adverse Reaction Overview ................................................................................... 17
8.2. Clinical Trial Adverse Reactions ............................................................................. 18
8.3. Less Common Clinical Trial Adverse Reactions .................................................... 27
8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ................................................................................................................. 29
9.
Drug Interactions ............................................................................................................... 32
9.1. Serious Drug Interactions ....................................................................................... 32
9.2. Drug Interactions Overview .................................................................................... 32
9.4. Drug-Drug Interactions ........................................................................................... 33
9.5. Drug-Food Interactions ........................................................................................... 34
9.6. Drug-Herb Interactions ........................................................................................... 34
9.7. Drug-Laboratory Test Interactions .......................................................................... 34
10.
Clinical Pharmacology ...................................................................................................... 34
10.1. Mechanism of Action .............................................................................................. 34
10.2. Pharmacodynamics ................................................................................................ 35
10.3. Pharmacokinetics ................................................................................................... 35
11. Storage, Stability, and Disposal ....................................................................................... 37

Part 2: Scientific Information ................................................................................................... 38

13. Pharmaceutical Information ............................................................................................. 38
14.
Clinical Trials ..................................................................................................................... 39
14.1. Clinical Trials by Indication ..................................................................................... 39
Previously Untreated Chronic Lymphocytic Leukemia (CLL) – Fixed Duration Therapy (AMPLIFY) ........................................................................................................................... 39
Previously Untreated CLL (ELEVATE-TN) .......................................................................... 43
Previously Treated CLL (ASCEND) ..................................................................................... 47
Previously Untreated Mantle Cell Lymphoma (MCL) (ECHO) ............................................. 50
Previously Treated MCL (ACE-LY-004) ............................................................................... 53
14.2. Comparative Bioavailability Studies ....................................................................... 54
15. Microbiology ...................................................................................................................... 55
16. Non-Clinical Toxicology .................................................................................................... 55
17. Supporting Product Monographs .................................................................................... 56

Patient Medication Information ............................................................................................... 57

Part 1: Healthcare Professional Information

1. Indications

Chronic Lymphocytic Leukemia (CLL)

CALQUENCE^®(acalabrutinib tablets) is indicated:

in combination with venetoclax for the treatment of patients with previously untreated CLL.
in combination with venetoclax and obinutuzumab for the treatment of patients with previously untreated CLL.
- Marketing authorization with conditions was based on the primary efficacy endpoint of progression-free survival (PFS) (see 14 Clinical Trials). Continued approval for this indication may be contingent upon verification and description of clinical benefit in subsequent analyses.
in combination with obinutuzumab or as monotherapy for the treatment of patients with previously untreated CLL.
as monotherapy for the treatment of patients with CLL who have received at least one prior therapy.

Mantle Cell Lymphoma (MCL)

CALQUENCE is indicated:

in combination with bendamustine and rituximab for the treatment of adult patients with previously untreated MCL who are ineligible for autologous stem cell transplant.
as monotherapy for the treatment of patients with MCL who have received at least one prior therapy.

1.1. Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Geriatrics (≥65 years of age): No clinically relevant differences in safety or efficacy were observed between patients ≥65 years and those younger than 65 years. See 7.1 Special Populations.

2. Contraindications

CALQUENCE (acalabrutinib) is contraindicated in patients who are hypersensitive to acalabrutinib or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition and Packaging.

3. Serious Warnings and Precautions Box

Treatment with CALQUENCE should be initiated and supervised by a qualified physician experienced in the use of anticancer therapies. Concomitant use of CALQUENCE with a strong CYP3A inhibitor should be avoided (see 9 Drug Interactions). Serious Hemorrhage: Monitor for bleeding and manage appropriately (see 7 Warnings and Precautions, Hemorrhage).

4. Dosage and Administration

4.1. Dosing Considerations

Avoid concomitant use with strong CYP3A4 inhibitors (see 9 Drug Interactions).
Avoid concomitant use with strong CYP3A4 inducers (see 9 Drug Interactions).
Consider the benefit-risk of withholding CALQUENCE for at least 3 days pre-and post-surgery.

4.2. Recommended Dose and Dosage Adjustment

The recommended dose of CALQUENCE for patients with CLL or MCL is 100 mg (1 tablet) twice daily.

CALQUENCE doses should be separated by approximately 12 hours.

CLL

In patients with previously untreated CLL, CALQUENCE can be used in combination with venetoclax or in combination with venetoclax and obinutuzumab for a fixed duration of treatment. Start CALQUENCE at Cycle 1 (each cycle is 28 days) for a total of 14 cycles. Start venetoclax at Cycle 3 as per the dose ramp-up schedule (see Table 1). Administer venetoclax for a total of 12 cycles. If CALQUENCE is given in combination with venetoclax and obinutuzumab, start obinutuzumab at Cycle 2 with 100 mg on Day 1 followed by 900 mg which may be administered on Day 1 or Day 2, and 1000 mg on Day 8 and Day 15. For Cycles 3 to 7, administer obinutuzumab 1000 mg on Day 1. Administer obinutuzumab for a total of 6 cycles. For details of the combination regimen, see 14 Clinical Trials.

Table 1 Venetoclax dose ramp-up schedule

Cycle - Week	Venetoclax daily dose
Cycle 3 - Week 1	20 mg
Cycle 3 - Week 2	50 mg
Cycle 3 - Week 3	100 mg
Cycle 3 - Week 4	200 mg
Cycle 4 - Week 1	400 mg
Subsequent dosing up to and including Cycle 14	400 mg

In patients with previously untreated CLL, CALQUENCE can be used as monotherapy or in combination with obinutuzumab. Treatment with CALQUENCE should continue until disease progression or unacceptable toxicity. Start CALQUENCE at cycle 1 (each cycle is 28 days).

Start obinutuzumab at cycle 2 for a total of 6 cycles. Consult the obinutuzumab Product Monograph for recommended dosing information. For details of the combination regimen, see 14 Clinical Trials.

In patients with CLL who have received at least one prior therapy, CALQUENCE is used as monotherapy until disease progression or unacceptable toxicity.

MCL

In patients with previously untreated MCL, CALQUENCE is used in combination with bendamustine and rituximab. Start CALQUENCE at cycle 1 (each cycle is 28 days). Start bendamustine and rituximab at cycle 1 for 6 cycles. Bendamustine (90 mg/m²) is administered intravenously over 30 minutes on Days 1 and 2 of each cycle. Rituximab (375 mg/m²) is administered intravenously on Day 1 of each cycle. For patients achieving a response, treatment with rituximab (375 mg/m²) continues for a maximum of an additional 12 doses every other cycle. Treatment with CALQUENCE should continue until disease progression or unacceptable toxicity. For details of the combination regimen, see 14 Clinical Trials.

In patients with MCL who have received at least one prior therapy, CALQUENCE is used as monotherapy until disease progression or unacceptable toxicity.

Dosage Adjustment

Recommended dose modifications of CALQUENCE for Grade ≥3 adverse reactions in patients receiving CALQUENCE monotherapy or in combination with obinutuzumab are provided in Table 2.

Table 2 Recommended Dose Adjustments for Adverse Reactions in patients receiving CALQUENCE monotherapy or CALQUENCE in combination with obinutuzumab

Adverse Reaction^a	Adverse Reaction Occurrence	Dose Modification (Starting dose = 100 mg twice daily)
Grade ≥3 non-hematologic toxicities, or Grade 3 thrombocytopenia with significant bleeding, or Grade 4 thrombocytopenia, or Grade 4 neutropenia lasting longer than 7 days	First and second	Interrupt CALQUENCE Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE therapy may be resumed at 100 mg twice daily
	Third	Interrupt CALQUENCE Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE therapy may be resumed at a reduced dose of 100 mg once daily
	Fourth	Discontinue CALQUENCE

^aAdverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse

Events (NCI CTCAE) version 4.03.

Recommended dose modification of CALQUENCE for Grade ≥ 3 adverse reactions in patients receiving CALQUENCE in combination with venetoclax with or without obinutuzumab are listed in Table 3.

Table 3 Recommended dose modifications for adverse reactions in patients receiving CALQUENCE in combination with venetoclax with or without obinutuzumab

Adverse Reaction^a	Adverse Reaction Occurrence	Dose Modification
Grade 3 or 4 neutropenia with or without fever and/or infection; Grade 4 neutropenia lasting more than 7 days	First occurrence	Interrupt CALQUENCE and/or venetoclax.^b Once toxicity resolves to Grade ≤1 or baseline, restart CALQUENCE and/or venetoclax at same dose.
	Second occurrence	Interrupt CALQUENCE and/or venetoclax.^b Once toxicity resolves to Grade ≤1 or baseline, restart CALQUENCE at same dose and venetoclax at one lower dose level^c.
	Subsequent occurrence	Interrupt CALQUENCE and/or venetoclax until toxicity resolves to Grade ≤1 or baseline.^b Clinical judgment of the treating physician should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with CALQUENCE in combination with venetoclax.
Grade 3 or 4 thrombocytopenia and/or bleeding^d	First occurrence	Interrupt CALQUENCE and/or venetoclax, and delay obinutuzumab (if clinically indicated). When bleeding resolves and thrombocytopenia is Grade ≤1 or baseline without transfusion support for 5 consecutive days, restart CALQUENCE and/or venetoclax at same dose. Continue obinutuzumab as per schedule (if applicable).
Grade 3 or 4 thrombocytopenia and/or bleeding^d	Second occurrence	Interrupt CALQUENCE and venetoclax, delay obinutuzumab (if clinically indicated) until resolution of bleeding and thrombocytopenia resolves to Grade ≤1 or baseline. Restart CALQUENCE at same dose and/or restart venetoclax at one lower
dose level^c. Continue obinutuzumab as per schedule (if applicable).
			Subsequent occurrences of severe thrombocytopenia	Interrupt CALQUENCE and venetoclax, delay obinutuzumab (if clinically indicated) until resolution of bleeding and thrombocytopenia resolves to Grade ≤1 or baseline. Restart CALQUENCE at a reduced frequency of 100 mg once daily and/or venetoclax at one lower dose level^c. Continue obinutuzumab as per schedule (if applicable). For recurrent severe thrombocytopenia in spite of dose reduction and/or symptomatic bleeding, the clinical judgment of the treating physician should guide the management plan.
Grade 3 or 4 tumour lysis syndrome (TLS), first episode and subsequent episodes	First and subsequent episodes	If a patient experiences blood chemistry changes suggestive of TLS, the following day’s venetoclax and CALQUENCE dose should be withheld. If resolved within 24-48 hours of last dose, treatment can be resumed at the same dose. Obinutuzumab should be delayed until TLS resolves (if applicable). For events of clinical TLS or blood chemistry changes requiring more than 48 hours to resolve, venetoclax should be resumed at one lower dose level^c. When resuming treatment after interruption due to TLS, monitor for TLS and provide prophylaxis.
Grade 3 other non-hematologic events^e	First occurrence	Interrupt CALQUENCE and/or venetoclax and delay obinutuzumab (if applicable) until toxicity resolves to Grade ≤1. Restart CALQUENCE and/or venetoclax at same dose.
Grade 3 other non-hematologic events^e	Second occurrence	Interrupt CALQUENCE and/or venetoclax and delay obinutuzumab (if applicable) until toxicity resolves to Grade ≤1. Clinical judgment of the treating physician should guide the management plan of
each patient based on the individual benefit/risk assessment for treatment with CALQUENCE in combination with venetoclax and obinutuzumab (if applicable).
Grade 4 other non-hematologic events^e	First occurrence	Interrupt CALQUENCE and/or venetoclax and delay obinutuzumab (if applicable) until toxicity resolves to Grade ≤1. Restart CALQUENCE at a reduced frequency of 100 mg once daily and/or venetoclax at one lower dose level^c.
Grade 4 other non-hematologic events^e	Second occurrence	Interrupt CALQUENCE and/or venetoclax and delay obinutuzumab (if applicable) until toxicity resolves to Grade ≤1. Clinical judgment of the treating physician should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with CALQUENCE in combination with venetoclax and obinutuzumab (if applicable).

^aAdverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

^bGrowth factor may be used at physician discretion.

^cSee table 1 for details on venetoclax dose reduction.

^dPlatelets may be used at physician discretion.

^eCertain treatment-emergent non-hematologic adverse events (e.g., venous thromboembolic events) may be managed and become clinically stable following medical intervention but may not improve to Grade ≤1 according to the NCI CTCAE definitions. In such cases, if a patient is clinically stable, resumption of CALQUENCE, venetoclax and obinutuzumab (if applicable) may be possible based on clinical judgement of the treating physician.

Recommended dose modifications of CALQUENCE and bendamustine for Grade ≥3 adverse reactions in patients receiving CALQUENCE in combination with bendamustine and rituximab are listed in Table 4.

Table 4 Recommended dose modifications for adverse reactions in patients receiving CALQUENCE in combination with bendamustine and rituximab

Adverse reaction^a

Bendamustine dose modification^b

CALQUENCE dose modification

Adverse reaction^a

Bendamustine dose modification^b

CALQUENCE dose modification

Neutropenia

If Grade 3 or Grade 4 neutropenia:

Interrupt bendamustine.

Once toxicity has resolved to Grade ≤2 or baseline level, bendamustine may be

If Grade 4 neutropenia^clasting longer than 7 days then interrupt CALQUENCE.

Once toxicity has resolved to Grade ≤2 or baseline level, CALQUENCE may be resumed at starting dose (1^stadverse reaction

resumed at 70 mg/m².

Discontinue bendamustine if additional dose reduction is required.

occurrence) or at a reduced frequency of 100 mg once daily (2^ndand 3^rdadverse reaction occurrence).

Discontinue CALQUENCE at 4^thadverse reaction occurrence.

Thrombocytopenia

If Grade 3 or Grade 4 thrombocytopenia:

Interrupt bendamustine.

Once toxicity has resolved to Grade 2 or baseline level, bendamustine may be resumed at 70 mg/m².

Discontinue bendamustine if additional dose reduction is required.

If Grade 3 thrombocytopenia^dwith significant bleeding or Grade 4^ethen interrupt CALQUENCE.

Once toxicity has resolved to Grade ≤2 or baseline level, CALQUENCE may be resumed at starting dose (1^stadverse reaction occurrence) or at a reduced frequency of 100 mg once daily (2^ndoccurrence).

Discontinue CALQUENCE at 3^rdadverse reaction occurrence.

Other hematologic:

Grade 4^for unmanageable Grade 3 toxicity

Interrupt bendamustine.

Once toxicity has resolved to Grade ≤2 or baseline level, bendamustine may be resumed at 70 mg/m².

Discontinue bendamustine if additional dose reduction is required.

Interrupt CALQUENCE.

Discontinue CALQUENCE at 4^thadverse reaction occurrence.

Non-hematologic toxicities: ≥Grade 3

Interrupt bendamustine.

Once toxicity has resolved to Grade 1 or baseline level, bendamustine may be resumed at 70 mg/m².

Discontinue bendamustine if additional dose reduction is required.

Interrupt CALQUENCE.

Once toxicity has resolved to Grade 2 or baseline, CALQUENCE may be resumed at starting dose (1^stadverse reaction occurrence) or at a reduced frequency of 100 mg once daily (2^ndadverse reaction occurrence).

Discontinue CALQUENCE at 3^rdadverse reaction occurrence.

^aAdverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

^bFor any toxicities not listed in this table refer to the bendamustine Product Monograph.

^cdefined as absolute neutrophil count less than 0.5 x 10⁹/L.

^ddefined as a platelet count between 25 to 50 x 10⁹/L.

^edefined as platelet count less than 25 x 10⁹/L.

^fGrade 4 lymphopenia is an expected outcome for treatment with bendamustine and rituximab. Dose modification due to lymphopenia is expected only if considered clinically important, e.g. associated recurrent infections.

Recommended dose modifications of CALQUENCE for use with CYP3A inhibitors is provided in Table 5.

Table 5 Use with CYP3A inhibitors

	Co-administered Drug		Recommended CALQUENCE Use
CYP3A Inhibitors	Strong CYP3A inhibitors	Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for up to seven days), interrupt CALQUENCE.
	Moderate CYP3A inhibitors	100 mg once daily. Patients should be monitored for adverse reactions.
	Mild CYP3A inhibitors	No dose adjustment. Patients should be monitored for adverse reactions.

Special Populations

Pediatrics (<18 years of age): Health Canada has not authorized an indication for pediatric use.

Geriatrics (≥65 years of age): No dose adjustment is necessary based on age (see 10 Clinical Pharmacology).

Renal Impairment: No dose adjustment is recommended in patients with mild to moderate renal impairment (eGFR ≥30 mL/min/1.73m²as estimated by MDRD (modification of diet in renal disease equation)).

The pharmacokinetics and safety of CALQUENCE in patients with severe renal impairment (eGFR <30 mL/min/1.73m²) or end-stage renal disease have not been studied (see 10 Clinical Pharmacology).

Hepatic Impairment: No dose adjustment is recommended in patients with mild or moderate hepatic impairment (Child-Pugh A, Child-Pugh B, or total bilirubin between 1.5-3 times the upper limit of normal [ULN] regardless of aspartate aminotransferase [AST] levels).

Avoid the administration of CALQUENCE in patients with severe hepatic impairment (Child-Pugh C or total bilirubin >3 times ULN regardless of AST levels) (see 10 Clinical Pharmacology).

4.4. Administration

CALQUENCE should be swallowed whole with water at approximately the same time each day. CALQUENCE can be taken with or without food. The tablet should not be chewed, crushed, dissolved, or divided.

4.5. Missed Dose

If a patient misses a dose of CALQUENCE by more than 3 hours, instruct the patient to take the next dose at its regularly scheduled time. Extra tablets of CALQUENCE should not be taken to make up for a missed dose.

5. Overdose

There is no specific treatment for CALQUENCE overdose and symptoms of overdose have not been established. In the event of an overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6. Dosage Forms, Strengths, Composition and Packaging

Table 6 Dosage Forms, Strengths, and Composition

Description

CALQUENCE (acalabrutinib) 100 mg tablet is an orange, 7.5 x 13 mm, oval, biconvex tablet, debossed with ‘ACA 100’ on one side and plain on the reverse.

Packaging

CALQUENCE 100 mg tablets are provided in white high-density polyethylene (HDPE) plastic bottles, containing desiccant, with a child-resistant closure containing 60 tablets.

CALQUENCE (acalabrutinib tablets) is also available as 100 mg acalabrutinib capsules. Do not substitute CALQUENCE tablets with CALQUENCE capsules without prior consideration of the CALQUENCE capsules Product Monograph, Dosage and Administration section regarding drug interactions with gastric acid reducing agents.

7. Warnings and Precautions

See 3 Serious Warnings and Precautions Box.

Carcinogenesis and Genotoxicity

Second Primary Malignancies

Second primary malignancies, including skin and other solid tumours, have been reported more frequently in patients treated with CALQUENCE than in patients treated in the control arms of clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer,

Route of Administration	Dosage Form / Strength/Composition	Non-medicinal Ingredients
Oral	100 mg acalabrutinib (as acalabrutinib maleate) tablet	Copovidone, hypromellose, iron oxide red (E172), iron oxide yellow (E172), Low-substituted hydroxypropyl cellulose, mannitol, macrogol 3350, microcrystalline cellulose, purified water, sodium stearyl fumarate, titanium dioxide and triglycerides (medium-chain).

reported in 8.4% of patients followed by other solid tumors (7.4%) (including melanoma, lung cancer, gastrointestinal cancers and genitourinary cancers) and hematologic malignancies (0.7%). Monitor patients for the development of second cancers and advise protection from the sun.

Cardiovascular

Patients with severe cardiovascular disease were excluded from CALQUENCE clinical studies.

Atrial Fibrillation

In clinical studies of patients with hematologic malignancies who were treated with CALQUENCE (N=2,339), events of atrial fibrillation or atrial flutter were reported in 6% of patients, including Grade 3 or 4 events in 2.1% of patients. The risk of these events may be increased in patients with risk factors, such as pre-existing cardiovascular disease, hypertension, previous history of atrial fibrillation, and infection/pneumonia. Monitor all patients for symptoms of cardiac arrhythmia (e.g., palpitations, light-headedness, syncope, chest discomfort, or dyspnea) and manage appropriately.

Driving and Operating Machinery

CALQUENCE has no or negligible influence on the ability to drive and use machines. However, during treatment with CALQUENCE in clinical trials, fatigue and dizziness have been reported. Patients who experience these symptoms should observe caution when driving or operating a vehicle or potentially dangerous machinery.

Hematologic

Cytopenias

Grade 3 or higher cytopenias including absolute neutrophil count decreased (35%), absolute lymphocyte count decreased (22%), platelets decreased (11%) and hemoglobin decreased (9%), occurred in patients with hematologic malignancies treated with CALQUENCE (see 8 Adverse Reactions). Monitor complete blood counts regularly during CALQUENCE treatment (see 7 Warnings and Precautions, Monitoring and Laboratory Tests). Interrupt treatment, reduce the dose, or discontinue treatment as necessary (see 4.2 Recommended Dose and Dosage Adjustment, Dosage Adjustment).

Hemorrhage

Serious hemorrhagic events, including fatal events, have been reported in patients with hematologic malignancies (N=2,339) treated with CALQUENCE in clinical trials.

Major hemorrhagic events (serious or Grade 3 or higher bleeding events or any central nervous system bleeding events) occurred in 4.5% of patients. Overall, bleeding events including bruising and petechiae of any grade, occurred in 40% of patients with hematological malignancies.

The mechanism for the bleeding events is not well understood.

Patients receiving antithrombotic agents concomitantly with CALQUENCE may be at increased risk of hemorrhage. Patients were excluded from CALQUENCE clinical trials if they required warfarin or other vitamin K antagonists, or if they had a recent history of stroke or intracranial hemorrhage. In clinical trials, major hemorrhagic events were reported in 2.9% of patients taking CALQUENCE with other antithrombotic agents, and in 5.2% of patients taking CALQUENCE without any concomitant antithrombotic agents.

Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE (see 9.4 Drug-Drug Interactions). Monitor all patients for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for at least 3 days pre- and post-surgery.

Hepatic

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE.

Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.

Immune

Infections

Serious and fatal infections (bacterial, viral or fungal) have occurred in patients with hematologic malignancies treated with CALQUENCE. The most frequently reported Grade 3 or higher infection was pneumonia.

Monitor patients for signs and symptoms of infection and treat promptly.

Serious and/or fatal COVID-19 infection has occurred, particularly when CALQUENCE is used in combination with venetoclax and obinutuzumab. Appropriate monitoring and prophylaxis, as indicated, together with careful patient selection taking into account the risk of infection, are essential to optimise the benefit-risk profile of CALQUENCE.

Opportunistic infections

Cases of progressive multifocal leukoencephalopathy (PML), including fatal events, have been reported in patients treated with CALQUENCE in clinical trials. Patients should be monitored for symptoms (chills, weakness, confusion), and appropriate therapy should be instituted as indicated.

Infections due to hepatitis B virus (HBV) reactivation have been reported in patients treated with CALQUENCE in clinical trials. Patients should be monitored for signs and symptoms (jaundice, abdominal pain, weakness, fatigue, nausea, and vomiting), and appropriate therapy should be instituted as indicated.

Cases of herpes zoster have occurred in patients treated with CALQUENCE. Consider prophylaxis in patients who are at increased risk for herpes zoster infection. Monitor patients taking CALQUENCE for signs and symptoms of herpes zoster and treat as medically appropriate.

Other opportunistic infections, including aspergillosis, fungal pneumonia, and Pneumocystis Jiroveci Pneumonia have also been reported. Consider prophylaxis in patients who are at increased risk for opportunistic infections.

Monitoring and Laboratory Tests

Monitor complete blood counts as per routine clinical practice.
Monitor for symptoms (e.g., palpitations, dizziness, syncope, chest pain, dyspnoea) of atrial fibrillation and atrial flutter and obtain an electrocardiogram (ECG) as appropriate.
Monitor patients for secondary cancers, including appearance of skin cancers.
Monitor patients for signs and symptoms of infection and treat as medically appropriate.
Monitor patients for signs of bleeding.
Monitor for liver test abnormalities and clinical signs and symptoms of hepatic toxicity.

7.1. Special Populations

7.1.1 Pregnancy

CALQUENCE should not be used during pregnancy and women of childbearing potential should be advised to avoid becoming pregnant while receiving CALQUENCE. There are insufficient clinical data on CALQUENCE use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Based on findings from animal studies, there may be a risk to the fetus from exposure to acalabrutinib during pregnancy. Administration of acalabrutinib to pregnant rabbits at exposures 4 times the human exposure at the recommended dose was associated with reduced fetal growth (see 16 Non-Clinical Toxicology). Dystocia was observed in a rat study involving dosing animals from implantation throughout gestation, parturition and lactation at exposures >2.3 times the human AUC at the recommended dose (see 16 Non-Clinical Toxicology).

7.1.2 Breastfeeding

It is not known whether acalabrutinib is excreted in human milk. There are no data on the effect of acalabrutinib on the breast-fed infant or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. A risk to the suckling child cannot be excluded. Breast-feeding mothers are advised not to breast-feed during treatment with CALQUENCE and for 2 weeks after receiving the last dose.

7.1.3 Pediatrics

Pediatrics (<18 years of age): The safety and efficacy of CALQUENCE in children and adolescents aged less than 18 years have not been established; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (≥65 years of age): No dose adjustment is necessary based on age (see 10 Clinical Pharmacology). Of the 2,339 patients in clinical trials of CALQUENCE, 62.3% were 65 years of age or older, and 18.9% were 75 years of age or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 years and those younger than 65 years.

8. Adverse Reactions

8.1. Adverse Reaction Overview

The overall safety profile of CALQUENCE is based on pooled data from patients with hematologic malignancies receiving CALQUENCE (N=2,339) as monotherapy or in combination with other agents. The median duration of CALQUENCE exposure was 26.2 months.

The most common (≥10%) adverse reactions of any grade reported in this pooled safety population of patients receiving CALQUENCE were infection, diarrhea, headache, leukopenia, neutropenia, musculoskeletal pain, bruising, nausea, fatigue, rash, arthralgia, second primary malignancies, anemia, constipation, hemorrhage/hematoma, vomiting, abdominal pain, thrombocytopenia, and dizziness.

The most frequently reported (≥2%) serious adverse reactions in patients receiving CALQUENCE were pneumonia (6.8%), COVID-19 pneumonia (5.5%), COVID-19 (4.2%), pyrexia (2.6%), and anemia (2.2%).

Dose reductions and interruptions due to adverse reactions in patients receiving CALQUENCE were reported in 6.8% and 55% of patients, respectively. The most frequently reported adverse reaction leading to dose reduction (≥1%) was neutropenia (1.1%). The most frequently reported adverse reactions leading to dose interruption (≥1%) were neutropenia (12.8%), COVID-19 (6.4%), pneumonia (4.6%), diarrhea (3.8%), thrombocytopenia (2.9%), neutrophil count decreased (2.9%), COVID-19 pneumonia (2.7%), pyrexia (2.5%), vomiting (2.4%), nausea (2.1%), anemia (1.8%), upper respiratory tract infection (1.7%), ALT increased (1.6%), herpes zoster (1.5%), AST increased (1.3%), headache (1.2%), febrile neutropenia (1.2%), urinary tract infection (1.1%), respiratory tract infection (1.1%), rash (1.1%), fatigue (1.0%) and platelet count decreased (1.0%).

Discontinuation due to adverse reactions were reported in 18.8% of the patients. The most frequent adverse reactions leading to treatment discontinuation (≥1%) were COVID-19 (1.6%) and COVID-19 pneumonia (1.6%). The median dose intensity was 98.3%.

Lymphocytosis

Upon initiation of CALQUENCE, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count [ALC] increased ≥50% from baseline and a post baseline assessment ≥5 x 10⁹/L) has occurred in 47% (N=1,100/2,339) of patients. The median time to onset of lymphocytosis was 1.1 weeks and the median duration of lymphocytosis was 6.1 weeks.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Previously Untreated Chronic Lymphocytic Leukemia (CLL) – AMPLIFY

The safety of CALQUENCE in patients with previously untreated CLL has been studied in a 3-arm, randomized, multi-centre, open-label Phase 3 trial (AMPLIFY). CALQUENCE plus venetoclax, CALQUENCE plus venetoclax and obinutuzumab, or Investigator’s choice of chemoimmunotherapy, either FCR (fludarabine plus cyclophosphamide plus rituximab) or BR (bendamustine plus rituximab) were administered to 867 patients with previously untreated CLL (see 14 Clinical Trials).

In the CALQUENCE plus venetoclax arm, adverse events led to dose reduction of CALQUENCE in 5.8% of patients, and discontinuation of CALQUENCE in 7.6% of the patients. The median dose intensity was 99.5% for CALQUENCE in patients receiving CALQUENCE in combination with venetoclax.

In the CALQUENCE plus venetoclax and obinutuzumab arm, adverse events led to dose reduction of CALQUENCE in 6.3% of patients, and discontinuation of CALQUENCE in 13.7% of the patients. The median dose intensity was 98.1% for CALQUENCE in patients receiving CALQUENCE in combination with venetoclax and obinutuzumab.

The adverse reactions described in Table 7 reflect exposure to CALQUENCE in the CALQUENCE plus venetoclax and CALQUENCE plus venetoclax and obinutuzumab arms with a median duration of exposure of 12.9 months in each arm in patients with previously untreated CLL. The tabulated adverse reactions were reported in ≥5% of patients in either CALQUENCE-containing treatment arm.

Table 7 Adverse Reactions in ≥5% (All Grades) of Patients with Chronic Lymphocytic Leukemia (CLL) in the AMPLIFY Trial

System Organ Class Preferred term	CALQUENCE + venetoclax (N=291)		CALQUENCE + venetoclax + obinutuzumab (N=284)	Investigator’s choice of fludarabine + cyclophosphamide + rituximab or bendamustine + rituximab (N=259)
System Organ Class Preferred term	CALQUENCE + venetoclax (N=291)		CALQUENCE + venetoclax + obinutuzumab (N=284)	Investigator’s choice of fludarabine + cyclophosphamide + rituximab or bendamustine + rituximab (N=259)
All Grades^a(%)	Grade ≥3 (%)	All Grades^a(%)	Grade ≥3 (%)	All Grades^a(%)	Grade ≥3 (%)
All Grades^a(%)	Grade ≥3 (%)	All Grades^a(%)	Grade ≥3 (%)	All Grades^a(%)	Grade ≥3 (%)
Blood and lymphatic system disorders
Leukopenia^b	37	33	52	48	54	46
Neutropenia^b	37	32	50	46	51	43
Anemia^b	7	4	5	2	10	7
Thrombocytopenia^b	6	2	12	9	15	11
Gastrointestinal disorders
Diarrhea	33	2	36	1	11	0.4
Nausea	15	0	22	0.7	36	0
Constipation	7	0.3	8	0	12	0.4
Abdominal pain^b	8	1	8	0.7	4	0.8
Vomiting	5	0	7	0	12	0
General disorders and administration site conditions
Fatigue	15	0.3	14	0	14	0.8
Infections and Infestations
Infection^b	51	12	54	24	32	10
COVID-19	19	3	20	7	2	2
Upper respiratory tract infection^b	14	0.3	11	0	8	0
Pneumonia	4	1	5	4	3	2
COVID-19 pneumonia	7	5	12	12	3	3
Musculoskeletal and connective tissue disorders
Arthralgia	13	1	11	0.4	3	0
Musculoskeletal pain^b	24	0.7	22	1	13	0.8
Neoplasms benign, malignant and unspecified
Second Primary Malignancy (SPM)^b	5	2	4	2	0.8	0
SPM excluding non-melanoma skin	3	2	2	1	0.4	0
Non-melanoma skin malignancy	3	0	2	0.4	0.4	0
Nervous system disorders
Headache	35	1	28	0.4	8	0.4
Dizziness	5	0	7	0	3	0
Skin and subcutaneous tissue disorders
Bruising^b	21	0	22	0	2	0
Rash^b	12	0.3	16	1	13	0.8
Vascular disorders
Hemorrhage/ Hematoma^b	9	1	8	1	2	0

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

^bIncludes multiple ADR terms:

Leukopenia: includes leukopenia, leukocyte count decreased and other related terms.

Neutropenia: includes neutropenia, febrile neutropenia, neutrophil count decreased and other related terms.

Anemia: includes anemia, hemoglobin decreased and other related terms.

Thrombocytopenia: includes thrombocytopenia, platelet count decreased and other related terms.

Abdominal pain: includes all terms containing 'abdominal pain'.

Infection: includes any adverse reactions containing infection.

Upper respiratory tract infection: includes all terms containing ‘upper respiratory tract infection’, ‘nasopharyngitis’, ‘rhinitis’, ‘laryngitis’, ‘tonsillitis’, ‘sinusitis’, ‘rhinovirus infection’, ‘human rhinovirus test positive’; and excludes rhinitis allergic, allergic sinusitis, reflux laryngitis and epiglottitis.

Musculoskeletal pain: includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.

Second Primary Malignancy: includes terms related to malignant neoplasms including cutaneous neoplasms.

Bruising: includes all terms containing 'bruise', 'contusion', 'petechia', or 'ecchymosis'.

Rash: includes all terms containing 'rash'.

Hemorrhage/hematoma: includes all terms containing 'hemorrhage' or 'hematoma'.

Previously Untreated Chronic Lymphocytic Leukemia (CLL) – ELEVATE-TN

The safety of CALQUENCE in patients with previously untreated CLL has been studied in a 3-arm, randomized, multi-centre, open-label Phase 3 trial (ELEVATE-TN). CALQUENCE plus obinutuzumab, CALQUENCE monotherapy, or obinutuzumab plus chlorambucil were administered to 526 patients with previously untreated CLL (see 14 Clinical Trials).

In the CALQUENCE plus obinutuzumab arm, adverse events led to regimen discontinuation in 11% of patients, and dose reduction of CALQUENCE in 7% of patients. In the CALQUENCE monotherapy arm, adverse events led to discontinuation in 10% and dose reduction in 4% of patients.

The adverse reactions described in Table 8 reflect exposure to CALQUENCE in the CALQUENCE plus obinutuzumab and CALQUENCE monotherapy arms with a median duration of exposure of 27.7 months in patients with previously untreated CLL. The median duration of exposure in the obinutuzumab plus chlorambucil arm was 5.6 months. The tabulated adverse reactions were reported in ≥5% of patients in either CALQUENCE-containing treatment arm, and are considered at least possibly related to study drug.

Table 8 Adverse Reactions in ≥5% (All Grades) of Patients with Chronic Lymphocytic Leukemia (CLL) in the ELEVATE-TN Trial

System organ class/ preferred term^a	Acalabrutinib plus Obinutuzumab N=178		Acalabrutinib Monotherapy N=179	Obinutuzumab plus Chlorambucil N=169
System organ class/ preferred term^a	Acalabrutinib plus Obinutuzumab N=178		Acalabrutinib Monotherapy N=179	Obinutuzumab plus Chlorambucil N=169
All Grades^b(%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
All Grades^b(%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
Blood and lymphatic system disorders^c
Neutropenia^c	33	32	12	11	49	46
Thrombocytopenia^c	15	9	10	3	15	13
Anemia^c	13	6	16	7	12	7
Gastrointestinal disorders
Diarrhea	39	5	35	1	21	2
Nausea	20	0	22	0	31	0
Constipation	14	0	11	0	10	1
Vomiting	14	1	12	1	11	1
Abdominal pain^c	12	2	10	0	9	0
General disorders and administration site conditions
Fatigue	28	2	18	1	17	1
Pyrexia	13	0	7	1	21	1
Edema peripheral	12	1	9	1	7	0
Asthenia	10	1	5	0	6	1
Infections and Infestations
Infection^c	69	21	65	14	44	8
Upper respiratory tract infection	21	2	18	0	8	1
Lower respiratory tract infection (including pneumonia)^c	15	7	10	2	5	0
Urinary tract infection	12	1	12	2	5	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain^c	37	2	32	1	16	2
Arthralgia	22	1	16	1	5	1
Neoplasms benign, malignant and unspecified
Second Primary Malignancy (SPM)^c	11	4	8	1	4	2
SPM excluding non-melanoma skin	6	3	3	1	2	1
Non-Melanoma Skin Malignancy	5	1	6	0	2	1
Nervous system disorders
Headache	40	1	37	1	12	0
Dizziness	18	0	12	0	6	0
Skin and subcutaneous tissue disorders
Bruising^c	34	0	26	0	5	0
Rash^c	22	2	19	1	7	1
Vascular disorders
Hemorrhage/Hematoma^c	13	1	9	1	4	0

^aBased on MedDRA version 21.1.

^bPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

^cIncludes multiple ADR terms:

Neutropenia: includes neutropenia, neutrophil count decreased.

Thrombocytopenia: includes thrombocytopenia, platelet count decreased.

Anemia: includes anemia, red blood cell decreased.

Abdominal pain: includes abdominal pain, abdominal pain upper, and abdominal pain lower.

Musculoskeletal pain: includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, neck pain, pain in extremity, myalgia, spinal pain, bone pain.

Infection: includes any adverse reactions involving infection.

Lower respiratory infection: includes lower respiratory tract infection, pneumonia.

Second Primary Malignancy: includes any adverse reactions involving malignancy.

Bruising: includes bruise, contusion, and ecchymosis.

Rash: includes rash, dermatitis, and other related terms.

Hemorrhage/Hematoma: includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis and epistaxis.

Tumour Lysis Syndrome

Tumour lysis syndrome (TLS) was reported in 3 (2%) patients treated with CALQUENCE plus obinutuzumab. No patients experienced TLS in the CALQUENCE monotherapy arm.

Previously Treated Chronic Lymphocytic Leukemia (CLL) – ASCEND

The safety of CALQUENCE in patients with previously treated CLL has been studied in a randomized, multi-centre, open-label, Phase 3 trial (ASCEND) in 307 patients with relapsed or refractory CLL. Patients were treated with CALQUENCE monotherapy or investigator’s choice of either idelalisib plus rituximab or bendamustine plus rituximab (see 14 Clinical Trials).

In the CALQUENCE arm, adverse events led to discontinuation in 10% and dose reduction in 4% of patients.

The adverse reactions described in Table 9 reflect exposure to CALQUENCE with a median duration of 15.7 months, exposure to idelalisib with a median duration of 11.5 months, exposure to rituximab with a median duration of 5.5 months, and exposure to bendamustine with a median duration of 5.6 months in patients with relapsed or refractory CLL. The tabulated adverse reactions were reported in ≥5% of patients in the CALQUENCE arm, and are considered at least possibly related to study drug.

Table 9 Adverse Reactions in ≥5% (All Grades) of Patients with Chronic Lymphocytic Leukemia (CLL) in the ASCEND Trial

System organ class/ preferred term^a	Acalabrutinib N=154	Idelalisib plus Rituximab N=118		Bendamustine plus Rituximab N=35
System organ class/ preferred term^a	Acalabrutinib N=154	Idelalisib plus Rituximab N=118		Bendamustine plus Rituximab N=35
All Grades^b(%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
All Grades^b(%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
Blood and lymphatic system disorders^c
Neutropenia^c	21	18	51	47	37	34
Thrombocytopenia^c	14	5	17	8	17	3
Anemia^c	15	12	9	7	11	9
Cardiac disorders
Atrial Fibrillation/Flutter^c	5	1	3	1	3	3
Gastrointestinal disorders
Diarrhea	18	1	47	24	14	0
Nausea	7	0	13	1	20	0
Constipation	7	0	8	0	14	6
Abdominal pain^c	8	0	9	1	3	0
General disorders and administration site conditions
Pyrexia	12	1	18	7	17	3
Fatigue	10	1	9	0	23	3
Asthenia	5	1	4	1	9	3
Infections and Infestations
Infection^c	57	15	65	28	49	11
Upper respiratory tract infection	14	2	14	3	11	3
Lower respiratory tract infection (including pneumonia)^c	12	5	13	10	6	3
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain^c	15	1	15	2	3	0
Arthralgia	8	1	6	0	3	0
Neoplasms benign, malignant and unspecified
Second Primary Malignancy (SPM)^c	12	4	3	0	3	3
SPM excluding non-melanoma skin	7	3	3	0	3	3
Non-Melanoma Skin Malignancy	7	1	1	0	0	0
Nervous system disorders
Headache	22	1	6	0	0	0
Dizziness	6	0	3	0	0	0
Skin and subcutaneous tissue disorders
Bruising^c	12	0	3	0	0	0
Rash^c	7	0	16	3	9	0
Vascular disorders
Hemorrhage/Hematoma^c	13	1	4	1	6	3

^aBased on MedDRA version 21.1.

^bPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

^cIncludes multiple ADR terms:

Neutropenia: Includes Neutropenia, Neutrophil count decreased

Anemia: Includes anemia, red blood cell decreased,

Thrombocytopenia: Includes Thrombocytopenia, Platelet count decreased

Abdominal pain: Includes abdominal pain, abdominal pain upper, and abdominal pain lower.

Musculoskeletal pain: Includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal pain and bone pain

Infection: Includes any adverse reactions involving infection

Lower respiratory tract infection: Includes lower respiratory tract infection, Pneumonia

Second primary malignancy: Includes any adverse reactions involving malignancy

Bruising: Includes bruise, contusion, and ecchymosis

Rash: Includes rash, dermatitis, and other related terms

Hemorrhage/Hematoma: Includes hemorrhage, hematoma, Hemoptysis, Hematuria, Menorrhagia, hemarthrosis, and epistaxis

Tumour Lysis Syndrome

TLS was reported in 1 patient treated with CALQUENCE and 1 patient treated with idelalisib plus rituximab, with an incidence of 1% in both arms. The one patient experiencing TLS treated with CALQUENCE had Grade 3 TLS and bulky disease.

Previously untreated mantle cell lymphoma (MCL) – ECHO

The safety of CALQUENCE in patients with previously untreated MCL has been studied in a randomized, multi-centre, double blind, placebo-controlled Phase 3 trial (ECHO) in 598 patients. Patients were treated with CALQUENCE in combination with bendamustine plus rituximab or placebo in combination with bendamustine plus rituximab (see 14 Clinical Trials). The median duration of CALQUENCE exposure in patients treated with CALQUENCE in combination with bendamustine and rituximab was 28.6 months. The median duration of exposure to placebo in combination with bendamustine and rituximab was 24.6 months.

Table 10 Adverse reactions in ≥5% (All Grades) of patients with MCL in ECHO

System organ class/ preferred term^a	Acalabrutinib + Bendamustine and Rituximab (N=297)	Placebo + Bendamustine and Rituximab (N=297)
All Grades^b (%)	Grade ≥3 (%)	All Grades^b (%)	Grade ≥3 (%)
Blood and lymphatic system disorders
Leukopenia^c	59	53	61	55
Neutropenia^c	55	50	56	47
Anemia^c	24	9	21	10
Thrombocytopenia^c	23	10	21	8
Cardiac disorders
Atrial Fibrillation/Flutter^c	7	4	4	2
Nervous system disorders
Headache	30	1	14	1
Dizziness	15	1	15	0.3
Gastrointestinal disorders
Nausea	43	1	38	1
Diarrhea	37	3	28	2
Vomiting	26	1	14	1
Constipation	25	1	25	0.3
Abdominal pain^c	12	2	13	1
General disorders and administration site conditions
Fatigue	29	3	24	4
Asthenia	10	1	10	1
Infections and Infestations
Infection^c	78	40	71	34
COVID-19	31	9	21	7
Upper respiratory tract infection^c	30	1	29	1
Pneumonia	16	9	13	6
COVID-19 pneumonia	16	13	12	10
Herpes zoster	10	1	5	0.7
Musculoskeletal and connective tissue disorders
Arthralgia	18	1	17	1
Musculoskeletal Pain^c	34	4	24	1
Neoplasms benign, malignant and unspecified
Second Primary Malignancy^c	18	7	15	7
SPM excluding non-melanoma skin^c	10	5	11	7
Non-Melanoma Skin Malignancy^c	11	2	7	2
Skin and subcutaneous tissue disorders
Bruising^c	14	0.3	8	0
Rash^c	39	10	26	2
Vascular disorders
Hemorrhage/Hematoma^c	16	1	8	2

^aBased on MedDRA version 26.1

^bPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

^cIncludes multiple ADR term:

Leukopenia: includes leukopenia, leukocyte count decreased and other related terms

Neutropenia: includes neutropenia, febrile neutropenia, neutrophil count decreased and other related terms.

Anemia: includes anemia, hemoglobin decreased and other related terms.

Thrombocytopenia: includes thrombocytopenia, platelet count decreased and other related terms.

Atrial fibrillation/ flutter: includes atrial fibrillation and atrial flutter.

Abdominal pain: includes all terms containing 'abdominal pain'.

Infection: includes any adverse reactions containing infection.

Upper respiratory tract infection: includes all terms containing ‘upper respiratory tract infection’, ‘nasopharyngitis’, ‘rhinitis’, ‘laryngitis’, ‘tonsillitis’, ‘sinusitis’, ‘rhinovirus infection’, ‘human rhinovirus test positive’; includes pharyngitis, pharyngitis streptococcal, and pharyngitis bacterial; and excludes rhinitis allergic, allergic sinusitis, reflux laryngitis and epiglottitis.

Musculoskeletal pain: includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain.

Second Primary Malignancy: includes terms related to malignant neoplasms including cutaneous neoplasms.

SPM excluding non-melanoma skin: includes terms related to malignant neoplasms excluding non-melanoma cutaneous neoplasms.

Non-melanoma skin malignancy: includes malignant cutaneous neoplasms excluding melanoma.

Bruising: includes all terms containing 'bruise', 'contusion', 'petechia', or 'ecchymosis'.

Rash: includes all terms containing 'rash'.

Hemorrhage/hematoma: includes all terms containing 'hemorrhage' or 'hematoma'.

Previously treated Mantle Cell Lymphoma (MCL) – ACE-LY-004

The safety of CALQUENCE in patients with MCL has been studied in 124 patients at a dose of 100 mg twice daily in a single-arm Phase 2 trial (ACE-LY-004). The median dose intensity was 99%.

The frequencies of treatment-emergent adverse events reported (regardless of causality) in the ACE-LY-004 study have been included in Table 11. The median duration of CALQUENCE treatment in patients with MCL (ACE-LY-004) was 17.3 months.

Table 11 Treatment-Emergent Adverse Events reported at ≥10% incidence (frequencies reported regardless of causality) in ACE-LY-004 Study (100 mg twice daily)

System organ class/ preferred term^a	Acalabrutinib (N=124)
System organ class/ preferred term^a	Acalabrutinib (N=124)
All CTCAE^bGrades (%)	CTCAE Grade ≥3^c (%)
All CTCAE^bGrades (%)	CTCAE Grade ≥3^c (%)
Blood and lymphatic system disorders
Anemia	13	10
Neutropenia	10	10
Gastrointestinal disorders
Diarrhea	36	3
Nausea	19	2
Constipation	15	0
Vomiting	15	2
Abdominal pain^d	15	2
General disorders and administration site conditions
Asthenia	17	2
Fatigue	28	2
Pyrexia	16	0
Infections and infestations
Sinusitis	12	0
Upper respiratory tract infection	10	0
Musculoskeletal and connective tissue disorders
Myalgia	21	2
Nervous system disorders
Headache	38	2
Dizziness	12	0
Respiratory, thoracic and mediastinal disorders
Cough	22	0
Dyspnoea	10	2
Skin and subcutaneous tissue disorders
Bruising^d	21	0
Rash^d	19	2
^aBased on MedDRA version 20.1. ^bAdverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. ^cAll events were Grade 3, except one Grade 4 intracranial hemorrhage and one Grade 5 intracranial hematoma. ^dAEs based on grouping of individual preferred terms (PTs): Abdominal pain: Any PT containing ‘abdominal pain’ Bruising: Any PT containing ‘bruise’, ‘contusion’, ‘petechiae’, or ‘ecchymosis’ Rash: Any PT containing ‘rash’

Contusion, a common finding in B cell malignancies, was reported at a lower rate in the ACE-LY-004 population (13%) than in the overall safety analysis (N=2,339) population (17%), while myalgia was reported at a higher rate in the ACE-LY-004 population (21%) than in the overall safety analysis (10%) population. Overall, the most commonly reported AEs were consistent between the ACE-LY-004 and overall safety analysis populations.

8.3. Less Common Clinical Trial Adverse Reactions

Chronic Lymphocytic Leukemia (CLL)

The following less common clinical trial adverse reactions were reported in the AMPLIFY study in ≥1 but <5% of patients with previously untreated CLL treated with CALQUENCE:

Cardiac disorders: atrial fibrillation/flutter^*

General disorders and administration site conditions: asthenia

Metabolism and nutrition disorders: tumour lysis syndrome

Respiratory, thoracic and mediastinal disorders: epistaxis

*AEs based on grouping of individual preferred terms: including ‘atrial fibrillation’ and ‘atrial flutter’.

The following less common clinical trial adverse reactions were reported in patients with previously untreated CLL (ELEVATE-TN study), or in patients with previously treated CLL (ASCEND study), at a frequency of ≥1 but <5% in either study, and are considered at least possibly related to study drug.

Blood and lymphatic system disorders: lymphocytosis, febrile neutropenia

Endocrine and metabolism: tumour lysis syndrome

Mantle Cell Lymphoma (MCL)

The following treatment-emergent adverse events (regardless of causality) have been reported in the ACE-LY-004 study (100 mg twice daily) in ≥5 - <10% of patients.

Eye disorders: lacrimation increased, vision blurred

Gastrointestinal disorders: stomatitis

General disorders and administration site conditions: peripheral oedema

Infections and infestations: bronchitis, nasopharyngitis, pneumonia

Injury, poisoning and procedural complications: fall

Metabolism and nutrition disorders: decreased appetite

Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscle spasms, musculoskeletal pain, pain in extremity

Nervous system disorders: paraesthesia, memory impairment

Psychiatric disorders: insomnia

Respiratory, thoracic and mediastinal disorders: epistaxis

Skin and subcutaneous tissue disorders: erythema

Vascular disorders: hemorrhage/hematoma*, hypotension

*AEs based on grouping of individual preferred terms: any preferred term containing ‘hemorrhage’ or ‘hematoma’

The following less common clinical trial adverse reactions were reported in patients with previously untreated MCL (ECHO study) in ≥1 - <5% of patients.

Metabolism and nutrition disorders: tumour lysis syndrome

Respiratory, thoracic and mediastinal disorders: epistaxis

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Previously Untreated CLL:

Table 12 Treatment-Emergent Hematological Laboratory Abnormalities for Patients receiving CALQUENCE in combination with venetoclax with or without obinutuzumab in AMPLIFY

Laboratory Abnormalities^a,b	CALQUENCE + venetoclax		CALQUENCE + venetoclax + obinutuzumab		Investigator’s choice of fludarabine + cyclophosphamide + rituximab or bendamustine + rituximab
	All Grades (%)	Grade ≥3^a (%)	All Grades (%)	Grade ≥3^a (%)		All Grades (%)	Grade ≥3^a (%)
Absolute neutrophil count decreased	78.3	38.3	82.4	54.2		80.2	52.7
Hemoglobin decreased	34.8	6.6	46.1	3.9		55.8	8.1
Leukocytes decreased	77.6	21.4	87.3	25.7		87.2	46.5
Platelets decreased	42.9	5.2	54.9	13.7		58.5	15.1

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

^bPercentages are based on the number of patients per treatment group with a baseline value and at least one post-baseline value on treatment for each specific lab test.

Table 13 Treatment-Emergent Chemistry Laboratory Abnormalities for Patients receiving CALQUENCE in combination with venetoclax with or without obinutuzumab in AMPLIFY

Laboratory Abnormalities^a,b	CALQUENCE + venetoclax		CALQUENCE + venetoclax + obinutuzumab		Investigator’s choice of fludarabine + cyclophosphamide + rituximab or bendamustine + rituximab
	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)		All Grades (%)	Grade ≥3 (%)
ALT increased	24.9	2.8	32.6	2.5		25.6	0.4
AST increased	21.8	1.4	23.0	1.1		26.4	1.2
Bilirubin increased	12.8	0.3	7.8	0.4		8.6		0
Uric acid increased	24.9	24.9	23.3	23.3		23.3	23.3

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

^bPercentages are based on the number of patients per treatment group with a baseline value and at least one post-baseline value on treatment for each specific lab test.

Table 14 Hematologic Laboratory Abnormalities in ≥20% of Patients with Chronic Lymphocytic Leukemia (CLL) in the ELEVATE-TN Trial

Laboratory Abnormalities^a	CALQUENCE plus Obinutuzumab N=178					CALQUENCE Monotherapy N=179
Laboratory Abnormalities^a	All Grades (%)		Grade ≥3 (%)		All Grades (%)		Grade ≥3 (%)		All Grades (%)		Grade ≥3 (%)
Absolute Neutrophil Count decreased		53		35		24		13		76		47
Hemoglobin decreased		48		8		44		6		49		11
Platelets decreased		48		12		28		3		60		15

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 based on laboratory measurements.

Table 15 Chemistry Laboratory Abnormalities (≥15% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN)

Laboratory Abnormalities ^a,b	CALQUENCE plus Obinutuzumab N=178		CALQUENCE Monotherapy N=179	Obinutuzumab plus Chlorambucil N=169
All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
ALT increase	30	7	20	1	36	6
AST increase	38	5	17	1	60	8
Bilirubin increase	13	1	15	1	11	1
Uric acid increase	29	29	22	22	37	37

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

^bExcludes electrolytes.

Increases in creatinine of 1.5 to 3 times the upper limit of normal (ULN) occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.

Previously Treated CLL:

Table 16 Hematologic Laboratory Abnormalities^ain ≥20% of Patients with CLL in the ASCEND Trial

Hematologic Laboratory Abnormalities	CALQUENCE N=154		Idelalisib plus Rituximab N=118	Bendamustine plus Rituximab N=35
All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
Absolute Lymphocyte Count increased	26	20	22	17	3	3
Absolute Neutrophil Count decreased	47	25	79	51	80	40
Hemoglobin decreased	46	13	42	4	54	11
Platelets decreased	25	4	36	11	51	6

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 based on laboratory measurements and adverse reactions.

Table 17 Chemistry Laboratory Abnormalities (≥10% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ASCEND)

Laboratory Abnormalities ^a,b	CALQUENCE N=154		Idelalisib plus Rituximab N=118	Bendamustine plus Rituximab N=35
All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)	All Grades (%)	Grade ≥3 (%)
ALT increase	15	2	59	23	26	3
AST increase	13	1	48	13	31	3
Bilirubin increase	13	1	16	2	26	11
Uric acid increase	15	15	11	11	23	23

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

^bExcludes electrolytes.

Increases in creatinine of 1.5 to 3 times the ULN occurred in 1.3% of patients.

Previously Untreated Mantle Cell Lymphoma:

Table 18 Hematological Laboratory Abnormalities for Patients Receiving CALQUENCE in Combination with Bendamustine and Rituximab (BR) in ECHO Trial

Hematological Laboratory Abnormalities	CALQUENCE + BR N=297			Placebo + BR N=297
	All Grades (%)	Grade ≥3^a (%)	All Grades (%)		Grade ≥3^a (%)
Absolute lymphocyte count decreased	98	87	97		89
Absolute neutrophil count decreased	76	56	77		51
Hemoglobin decreased	80	11	65		11
Leukocyte decreased	88	49	90		46
Platelets decreased	69	18	60		16

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Table 19 Chemistry Laboratory Abnormalities for Patients Receiving CALQUENCE in Combination with Bendamustine and Rituximab (BR) in ECHO Trial

Laboratory Abnormalities	CALQUENCE + BR N=297			Placebo + BR N=297
	All Grades (%)	Grade ≥3^a (%)	All Grades (%)		Grade ≥3^a (%)
Albumin decrease	38	3	33		1
ALT increase	44	7	41		2
AST increase	53	5	50		3
Bilirubin increase	19	2	12		2
Creatinine increase	41	3	33		2
Phosphate decrease	36	4	29		5
Potassium decrease	29	7	23		6
Potassium increase	40	2	38		3
Uric acid increase	45	45	40		40

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Previously Treated Mantle Cell Lymphoma:

Table 20 Treatment-Emergent Hematological Laboratory Abnormalities in ACE-LY-004 Study (N=124)

Hematological

Adverse Reaction^a

All Grades

(%)

Grade ≥3

(%)

Absolute neutrophil count decreased

Hemoglobin decreased

Platelets decreased

^aPer National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

9. Drug Interactions

9.1. Serious Drug Interactions

Concomitant use of CALQUENCE with a strong CYP3A inhibitor should be avoided (see 3 Serious Warnings and Precautions Box and 4.1 Dosing Considerations)

9.2. Drug Interactions Overview

Co-administration of CALQUENCE with strong CYP3A inhibitors may increase acalabrutinib plasma concentrations. Consider alternative therapies that do not have strong inhibition of CYP3A activity in order to prevent an increased risk of toxicity with CALQUENCE.

Co-administration of CALQUENCE with strong CYP3A inducers decreases acalabrutinib plasma concentrations. Consider alternative therapies that do not strongly induce CYP3A activity in order to prevent a reduction of CALQUENCE activity.

Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g. methotrexate)

by inhibition of intestinal BCRP.

9.4. Drug-Drug Interactions

The drugs listed below are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 21 Established or Potential Drug-Drug Interactions

Non-proprietary names of the drug products	Source of evidence	Effect	Clinical comment
CYP3A inhibitors (e.g. itraconazole, erythromycin, fluconazole, diltiazem)	CT, T	Co-administration with a strong CYP3A inhibitor (200 mg itraconazole once daily for 5 days) increased acalabrutinib C_maxand AUC by 3.7-fold and 5.1-fold, respectively, in healthy subjects (N=17). PBPK simulations with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) showed that co-administration increased acalabrutinib C_max, and AUC by 2 to almost 3-fold.	Consider alternative therapies that do not strongly inhibit CYP3A activity. Alternatively, if the strong CYP3A inhibitors (e.g. ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir, posaconazole, voriconazole) will be used short-term, interrupt CALQUENCE. When CALQUENCE is co-administered with moderate CYP3A inhibitors, reduce the acalabrutinib dose to 100 mg once daily.
CYP3A Inducers (e.g. phenytoin, rifampin, carbamazepine)	CT	Co-administration of a strong CYP3A inducer (600 mg rifampin once daily for 9 days) decreased acalabrutinib C_maxand AUC by 68% and 77%, respectively, in healthy subjects (N=24).	Strong inducers of CYP3A activity (e.g. phenytoin, rifampin, carbamazepine) should be avoided during treatment with CALQUENCE.
Antithrombotic agents	T	Use of CALQUENCE in patients receiving antithrombotic agents may increase the risk of bleeding.	Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE (see 7 Warnings and Precautions, Hemorrhage).

Legend: C = Case Study; CT = Clinical Trial; PBPK = Physiologically based pharmacokinetic modelling; T = Theoretical

Clinical Studies

Effect of Gastric Acid Reducing Medications on acalabrutinib

No clinically significant differences in acalabrutinib (given as acalabrutinib maleate) pharmacokinetics were observed when used concomitantly with rabeprazole, a proton pump inhibitor. Acalabrutinib tablet can be co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists, antacids).

In Vitro Studies

Effects of acalabrutinib and its active metabolite, ACP-5862, on CYP3A Substrates

CYP3A Substrates

Based on in vitro data and PBPK modelling, no interaction with CYP substrates is expected at the clinically relevant concentration (see 10 Clinical Pharmacology).

Effects of acalabrutinib and ACP-5862 on Drug Transport Systems

BCRP Substrates

Based on in vitro data, clinically relevant drug-drug interactions with BCRP substrates via inhibition of intestinal BCRP transport activity cannot be discounted (see 10 Clinical Pharmacology).

MATE1 substrates

ACP-5862, may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1 (see 10 Clinical Pharmacology).

9.5. Drug-Food Interactions

CALQUENCE tablets may be administered with or without food.

9.6. Drug-Herb Interactions

Avoid St. John’s wort which may unpredictably decrease acalabrutinib plasma concentrations.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

Acalabrutinib is a potent, highly selective small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), with minimal off-target kinase activity. Bruton’s tyrosine kinase is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in B-cell survival and proliferation, and is required for cellular adhesion, trafficking, and chemotaxis. Acalabrutinib was selected to exhibit high potency against BTK and few interactions with other kinases.

Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to irreversible inactivation of BTK (IC50 ≤ 5 nM) with minimal off-target interactions. In a screen of >380 mammalian wild-type kinases, the only additional kinase interactions at clinically relevant concentrations of acalabrutinib and ACP-5862 were with non-receptor tyrosine kinase (BMX) and erb-b2 receptor tyrosine kinase 4 (ERBB4), with 3- to 4-fold less potency than with BTK.

In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signalling proteins CD86 and CD69, inhibited malignant B-cell proliferation and tumour growth in mouse xenograft models, and had minimal activity on other immune cells (T cells and NK cells).

Acalabrutinib redistributes CLL cells from the lymph nodes into the peripheral blood. Additionally, acalabrutinib increases mitochondrial BCL-2 dependence of CLL cells in vivo, rendering CLL cells more susceptible to apoptosis induced by venetoclax, a BCL-2 inhibitor. In preclinical models, combination treatment of acalabrutinib and venetoclax may provide complementary activity.

10.2. Pharmacodynamics

In patients with B-cell malignancies dosed with 100 mg CALQUENCE twice daily, median steady state BTK occupancy of ≥95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval.

Cardiac Electrophysiology

In a randomized, double-blind, double-dummy, placebo- and positive-controlled, 4-way crossover ECG assessment study, single dose administration of acalabrutinib 100 mg and 400 mg (4X maximum recommended single dose) was not demonstrated to have a clinically meaningful effect on the QTcF interval, the QRS duration, or the PR interval in healthy subjects (N=44).

10.3. Pharmacokinetics

Table 22 Pharmacokinetic Parameters of acalabrutinib and its active metabolite, ACP-5862, following administration of CALQUENCE 100mg twice daily

Cmax

(ng/mL)^a

Tmax

(h)^b

t½

(h)^a

AUC24h

(ng•h/mL)^a

CL/F

(L/h)^a

Vd/F

(L)^a

acalabrutinib

563 (29%)

0.5

(0.2, 3.0)

1.4 (50%)

1843 (38%)

71 (35%)

101 (52%)

ACP-5862*

451 (52%)

0.75

(0.5, 4.0)

6.6 (32%)

3947 (43%)

13 (42%)

67 (32%)

^ageometric mean (percentage coefficient of variation) is shown.

^bmedian (range) is shown.

The pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862, were studied in healthy subjects and patients with B-cell malignancies. Acalabrutinib exhibits dose-proportionality, and both acalabrutinib and ACP-5862 exhibit almost linear PK across a dose range of 75 to 250 mg. Population PK modeling suggests that the PK of acalabrutinib and ACP-5862 does not differ significantly in patients with different B-cell malignancies. At the recommended dose of 100 mg twice daily in patients with B-cell malignancies (including, MCL and CLL), the geometric mean (% coefficient of variation [CV]) daily area under the plasma concentration over time curve (AUC_24h) and maximum plasma concentration (C_max) for acalabrutinib were 1843 (38%) ng•h/mL and 563 (29%) ng/mL, respectively, and for ACP-5862 were 3947 (43%) ng•h/mL and 451 (52%) ng/mL, respectively.

CALQUENCE tablets and CALQUENCE capsules have been demonstrated to be bioequivalent and have equivalent oral bioavailability except when administered concomitantly with proton pump inhibitors and other acid reducing agents.

Absorption The absolute bioavailability of acalabrutinib was 25%. The median [min, max] time to peak acalabrutinib plasma concentrations (T_max) was 0.5 [0.2, 3.0] hours, and 0.75 [0.5, 4.0] hours for ACP-5862. In healthy subjects, administration of CALQUENCE (1 x 100 mg tablet) with a high-fat, high-calorie meal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat, and 39 grams protein) did not affect the mean AUC as compared to dosing under fasted conditions, although C_maxwas decreased by 54% and T_maxwas delayed by 1-2 hours. CALQUENCE tablets may be administered with or without food. CALQUENCE is available as a capsule or tablet formulation with equivalent oral bioavailability except when administered concomitantly with proton pump inhibitors or acid reducing agents.

Distribution Reversible binding of acalabrutinib to human plasma protein was 97.5% and for ACP-5862 was 98.6%. The in vitro mean blood-to-plasma ratio was 0.8 for acalabrutinib and 0.7 for ACP-5862. The geometric mean (%CV) apparent steady state volume of distribution (V_ss/F) was 101 (52%) L for acalabrutinib and 67 (32%) L for ACP-5862.

Metabolism In vitro, acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent by glutathione conjugation and amide hydrolysis. ACP-5862 was identified as the major metabolite in plasma with a geometric mean exposure (AUC) that was approximately 2- to 3-fold higher than the exposure of acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib with regard to BTK inhibition.

In vitro, acalabrutinib is a weak inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C19, CYP2D6, UGT1A1, and UGT2B7. ACP-5862 is a weak inhibitor of CYP2C8, CYP2C9 and CYP2C19, but does not inhibit CYP1A2, CYP2B6, CYP2D6, CYP3A4/5, UGT1A1, and UGT2B7 in vitro. Acalabrutinib is a weak inducer of CYP1A2, CYP2B6 and CYP3A4 mRNA; ACP-5862 weakly induces CYP3A4.

In vitro, acalabrutinib and its active metabolite, ACP-5862, are substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Acalabrutinib is not a substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OATP1B1 and OATP1B3, in vitro. ACP-5862 is not a substrate of OATP1B1 or OATP1B3.

Acalabrutinib and ACP-5862 do not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3, and MATE2-K at clinically relevant concentrations.

Acalabrutinib may inhibit intestinal BCRP transport activity, while ACP-5862 may inhibit MATE1 at clinically relevant concentrations (see 9 Drug Interactions).

Elimination The geometric mean (%CV) terminal elimination half-life (t_1/2) was 1.4 (50%) hours for acalabrutinib and 6.6 (32%) hours for ACP-5862.

The geometric mean (%CV) apparent oral clearance (CL/F) was 71 (35%) L/hr for acalabrutinib and 13 (42%) L/hr for ACP-5862, with similar PK between patients and healthy subjects based on population PK analysis.

Following administration of a single 100 mg radiolabelled [¹⁴C]-acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine, with less than 2% of the dose excreted as unchanged acalabrutinib in urine and feces.

Special populations and conditions

Based on population PK analysis, age, sex, race (Caucasian, Black or African American), and body weight did not have clinically meaningful effects on the PK of acalabrutinib and its active metabolite, ACP-5862.

Pediatrics No pharmacokinetic studies were performed with acalabrutinib in patients under 18 years of age.
Geriatrics Based on population pharmacokinetic analysis, age (42 to 90 years) did not have a clinically meaningful effect on the PK of acalabrutinib.
Hepatic Insufficiency Acalabrutinib is metabolized in the liver. In dedicated hepatic impairment studies, compared to subjects with normal liver function (N=6), acalabrutinib exposure (AUC) was increased by 1.9-fold, 1.5-fold and 5.3-fold in subjects with mild (N=6) (Child-Pugh A), moderate (N=6) (Child-Pugh B), and severe (N=8) (Child-Pugh C) hepatic impairment, respectively. Based on a population PK analysis, no clinically relevant difference was observed between subjects with mild (N=79) or moderate (N=6) hepatic impairment (total bilirubin between 1.5 to 3 times ULN and any AST) relative to subjects with normal (N=651) hepatic function (total bilirubin and AST within ULN).
Renal Insufficiency Acalabrutinib undergoes minimal renal elimination. A PK study in patients with renal impairment has not been conducted. Based on population PK analysis, no clinically relevant PK difference was observed in 433 patients with mild renal impairment (eGFR between 60 and 89 mL/min/1.73m²as estimated by MDRD), 110 patients with moderate renal impairment (eGFR between 30 and 59 mL/min/1.73m²) relative to 204 patients with normal renal function (eGFR greater than or equal to 90 mL/min/1.73m²). The pharmacokinetics of acalabrutinib has not been characterized in patients with severe renal impairment (eGFR less than 29 mL/min/1.73m²) or renal impairment requiring dialysis. Patients with creatinine levels greater than 2.5 times the institutional ULN were not included in the clinical trials (see 4 Dosage and Administration).
Storage, Stability, and Disposal

Store CALQUENCE at room temperature, between 15°C-30°C, in original bottle.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: Acalabrutinib maleate

Chemical name: 4-{8-Amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (2Z)-2-butenedioic acid hydrate (1:1:1)

Molecular formula and molecular mass: C₂₆H₂₃N₇O₂.C₄H₄O₄.H₂O , 599.59 (acalabrutinib free base is 465.51)

Structural formula:

Physicochemical properties: Acalabrutinib maleate (as acalabrutinib maleate monohydrate) is a white to pale brown powder with pH-dependent solubility. It is freely soluble in water at pH values below 3 and practically insoluble at pH values above 6.

14. Clinical Trials

14.1. Clinical Trials by Indication

Previously Untreated Chronic Lymphocytic Leukemia (CLL) – Fixed Duration Therapy (AMPLIFY)

Table 23 Summary of patient demographics for clinical trial in patients with previously untreated CLL – fixed duration treatment

Study #

Trial design

Dosage, route of administration and duration

Study subjects (n)

Mean age (Range)

Sex

AMPLIFY

(ACE-CL-311)

Randomized (1:1:1), open-label, Phase 3 Study

Arm A:

CALQUENCE plus venetoclax^a

Arm B:

CALQUENCE plus venetoclax and obinutuzumab^b

Arm C:

Investigator’s choice of chemoimmunotherapy:

fludarabine plus cyclophosphamide plus rituximab (FCR)^c
bendamustine plus rituximab (BR)^d

291

286

290

Total:

N=867

(26-86)

M: 64.5%

F: 35.5%

^aCALQUENCE 100 mg was administered twice daily starting on Cycle 1 Day 1 for a total of 14 cycles, or until disease progression or unacceptable toxicity. On Cycle 3 Day 1 patients started the venetoclax 5-week dose ramp-up schedule, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Venetoclax was administered for a total of 12 cycles. Each cycle was 28 days.

^bCALQUENCE 100 mg was administered twice daily starting on Cycle 1 Day 1 for a total of 14 cycles, or until disease progression or unacceptable toxicity. On Cycle 3 Day 1 patients started the venetoclax 5-week dose ramp-up schedule, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Venetoclax was administered for a total of 12 cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on Day 1, followed by 900 mg which may be administered on Day 1 or 2), 8 and 15 of Cycle 2 followed by 1000 mg on Day 1 of Cycles 3-7. Each cycle was 28 days.

^cFludarabine (25 mg/m²) and cyclophosphamide (250 mg/m²) were administered on Days 1-3 up to a maximum of 6 cycles. Rituximab was administered at a dose of 375 mg/m²on Day 1 Cycle 1 and 500 mg/m²on Day 1 of Cycles 2-6. Each cycle was 28 days.

^dBendamustine 90 mg/m²was administered on Days 1 and 2 up to maximum of 6 cycles. Rituximab was administered at a dose of 375 mg/m²on Day 1 Cycle 1 and 500 mg/m²on Day 1 of Cycles 2-6. Each cycle was 28 days.

The safety and efficacy of CALQUENCE in combination with venetoclax with or without obinutuzumab in previously untreated CLL was evaluated in a randomised, multi-centre, open-label Phase 3 study (AMPLIFY) of 867 patients. Patients were randomized 1:1:1 to receive CALQUENCE plus venetoclax, CALQUENCE plus venetoclax and obinutuzumab, or Investigator’s choice of chemoimmunotherapy, either FCR (fludarabine plus cyclophosphamide plus rituximab) or BR (bendamustine plus rituximab).

Patients were stratified by age (>65 years or ≤65 years), IGHV mutational status (mutated versus unmutated), Rai stage (high risk [≥3] versus non-high risk [<3]) and geographic region (North America versus Europe versus other).

AMPLIFY included patients previously untreated for CLL without del(17p) or TP53 mutation that were 18 years of age and older. The trial allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists. The study enrolled patients during the COVID-19 pandemic (March 2020 – May 2023).

The demographics and baseline disease characteristics, including complex karyotypes and unmutated IGHV, were well balanced between the study arms (see Table 24).

Table 24 Summary of patient demographics and disease baseline characteristics for patients with previously untreated CLL – fixed duration treatment (AMPLIFY)

	AV N=291	AVO N=286	FCR/BR N=290
Age, years; median (range)	61 (31-84)	61 (29-81)	61 (26-86)
Male; %	61.2	69.2	63.1
Caucasian; %	91.1	86.7	86.9
ECOG performance status 0-1; %	90.0	95.1	90.3
Median time from diagnosis to randomization (months)	28.5	26.1	29.6
Bulky disease with nodes ≥5 cm; %	38.8	35.0	42.8
Cytogenetics/FISH Category; %
11q deletion	17.5	19.6	15.9
Complex karyotype (≥3 abnormalities)	15.5	16.1	14.5
Unmutated IGHV; %	57.4	59.1	59.3
Rai stage; %
0	1.0	0.3	1.4
I	16.2	21.3	21.4
II	35.7	37.8	33.4
III	23.7	17.8	20.3
IV	23.4	22.7	23.4

AV = acalabrutinib plus venetoclax; AVO = acalabrutinib plus venetoclax and obinutuzumab; BR = bendamustine plus rituximab; FCR = fludarabine plus cyclophosphamide and rituximab

The primary endpoint was IRC-assessed PFS of AV arm versus investigator’s choice of chemoimmunotherapy (FCR/BR) arm as assessed by IWCLL 2018 criteria. Additional efficacy endpoints included IRC-assessed PFS of AVO arm versus FCR/BR arm and OS in both AV arm versus FCR/BR arm and AVO arm versus FCR/BR arm.

With a median follow-up of 41.3 months, IRC-assessed PFS indicated a 35% statistically significant reduction in risk of disease progression or death in patients treated with AV compared to FCR/BR.

At the time of primary analysis, the OS HR was 0.33 [95% CI (0.18, 0.56)] for the AV arm compared to the FCR/BR arm, with a total of 60 death events (10% maturity): 18 (6.2%) in AV arm and 42 (14.5%) in FCR/BR arm.

With a median follow-up of 42.0 months, IRC-assessed PFS indicated a 58% statistically significant reduction in risk of disease progression or death in patients treated with AVO compared to FCR/BR.

At the time of primary analysis, the OS HR was 0.76 [95% CI (0.49, 1.18)] for the AVO arm compared to the FCR/BR arm, with a total of 79 death events (14% maturity): 37 (12.9%) in AVO arm and 42 (14.5%) in FCR/BR arm.

Efficacy results are presented in Table 25. The Kaplan-Meier curve for IRC-PFS is shown in Figure 1 and the Kaplan-Meier curves for OS is shown in Figure 2.

Table 25 Efficacy results from the AMPLIFY Trial in Patients with Previously Untreated CLL (ITT population) – fixed duration treatment


Progression-free survival^a
	Number of events (%)				89 (30.6)				56 (19.6)			95 (32.8)
					PD, n (%)			77 (26.5)					23 (8.0)	66 (22.8)
					Death events (%)				12 (4.1)			33 (11.5)		29 (10.0)
	Median (95% CI), months			NC (51.1, NC)				NC (NC, NC)			47.6 (43.3, NC)
	HR^c(95% CI)		0.65 (0.49, 0.87)				0.42 (0.30, 0.59)						-
	p-value					0.0038				˂0.0001			-
	PFS rate
		12 months estimate (95% CI), %	94.8 (91.5, 96.8)				91.5 (87.6, 94.2)				88.3 (83.6, 91.7)
		24 months estimate (95% CI), %	87.6 (83.1, 90.9)				87.1 (82.6, 90.5)				79.0 (73.2, 83.6)
		36 months estimate (95% CI), %	76.5 (71.0, 81.1)				83.1 (78.1, 87.1)				66.5 (59.8, 72.3)
Overall Survival
	Death events (%)					18 (6.2)			37 (12.9)			42 (14.5)
	HR^c(95% CI)		0.33 (0.18, 0.56)				0.76 (0.49, 1.18)						-
	OS rate
		12 months estimate (95% CI), %	97.2 (94.5, 98.6)				93.0 (89.3, 95.4)				91.9 (87.8, 94.6)
		24 months estimate (95% CI), %	95.5 (92.4, 97.4)				89.1 (84.9, 92.2)				88.3 (83.7, 91.7)
		36 months estimate (95% CI), %	94.1 (90.7, 96.3)				87.7 (83.2, 91.0)				85.9 (81.0, 89.6)

AV = acalabrutinib plus venetoclax; AVO = acalabrutinib plus venetoclax and obinutuzumab; BR = bendamustine plus rituximab; FCR = fludarabine plus cyclophosphamide and rituximab; NC = Not calculable; HR = Hazard Ratio; PD = progressive disease

^aPer IRC assessment.

^bApproximately 50% of patients were planned to be treated with FCR and 50% treated with BR per investigator’s choice.

^cBased on stratified Cox-Proportional-Hazards model. Stratified by randomization stratification factors: age (>65 years or ≤65 years), IGHV mutational status (mutated versus unmutated), Rai stage (high risk [≥3] versus non-high risk) and geographic region (North America and Western Europe versus other).

Figure 1 Kaplan-Meier Curve of IRC-Assessed Progression-Free Survival in Patients with Previously Untreated CLL (AMPLIFY) (ITT Population) – fixed duration treatment

The benefit of CALQUENCE in combination with venetoclax versus the FCR/BR arm on PFS risk reduction was consistent across all clinically relevant subgroups, including higher risk CLL patients (unmutated IGHV) with a PFS HR of 0.69 [95% CI (0.48, 0.97)].

The benefit of CALQUENCE in combination with venetoclax and obinutuzumab versus the FCR/BR arm on PFS risk reduction was consistent across all clinically relevant subgroups, including higher risk CLL patients (unmutated IGHV) with a PFS HR of 0.35 [95% CI (0.23, 0.53)].

Figure 2 Kaplan-Meier Curve of Overall Survival in Patients with Previously Untreated CLL (AMPLIFY) (ITT Population) – fixed duration treatment

Previously Untreated CLL (ELEVATE-TN)

Table 26 Summary of patient demographics for clinical trials in patients with previously untreated CLL

Study #

Trial design

Dosage, route of administration and duration

Study subjects (n)

Mean age (Range)

Sex

ELEVATE-TN

(ACE-CL-007)

Randomized (1:1:1), open-label, Phase 3 Study

Arm A:

obinutuzumab + chlorambucil^a

Arm B:

CALQUENCE 100 mg orally twice daily + obinutuzumab^b,

Arm C:

CALQUENCE monotherapy, 100 mg orally twice daily^c

177

179

Total:

N=535

(41-91)

M: 61%

F: 39%

^aObinutuzumab and chlorambucil were administered for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on

Day 2), 8 and 15 of Cycle 1 followed by 1000 mg on Day 1 of Cycles 2 up to 6. Chlorambucil 0.5 mg/kg was administered on Days 1 and 15 of Cycles 1 up to 6. Each cycle was 28 days.

^bCALQUENCE 100 mg was administered twice daily starting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1000 mg on Day 1 of Cycles 3 up to 7. Each cycle was 28 days.

^cCALQUENCE monotherapy: CALQUENCE 100 mg was administered twice daily until disease progression or unacceptable toxicity.

The safety and efficacy of CALQUENCE in patients with previously untreated CLL were evaluated in a randomized, multi-centre, open-label Phase 3 study (ELEVATE-TN) of 535 patients. Patients were randomized to receive either CALQUENCE plus obinutuzumab, CALQUENCE monotherapy, or obinutuzumab plus chlorambucil.

Patients 65 years of age or older or between 18 and 65 years of age with coexisting medical conditions were included in ELEVATE-TN. The trial also allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists. Key inclusion criteria included confirmed diagnosis of CD20+ CLL and active disease that met ≥1 of the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for requiring treatment. Key exclusion criteria included prior systemic treatment of CLL, known central nervous system (CNS) lymphoma or leukemia, and known prolymphocytic leukemia or Richter’s syndrome.

Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and geographic region (North America and Western Europe versus Other). At baseline, the majority of patients (84%) were ≥65 years old, 94% of patients had an ECOG score of 0 or 1, 32% presented with lymph nodes ≥5 cm, 47% had Rai stage III or IV disease, 9% had 17p deletion, 11% had TP53 mutation, 63% of patients had an unmutated IGHV, and 18% had 11q deletion. The median time from initial CLL diagnosis to randomization was 27.6 months. Baseline demographic and disease characteristics were similar between treatment arms.

The primary endpoint was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) in the CALQUENCE + obinutuzumab arm compared with the obinutuzumab + chlorambucil arm. PFS was defined as the time from the date of randomization to the date of first IRC-assessed disease progression or death due to any cause. The assessment of progressive disease was per IWCLL 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis. Secondary endpoints included PFS as assessed by IRC in the CALQUENCE monotherapy arm compared with the obinutuzumab + chlorambucil arm, and ORR as assessed by IRC per IWCLL 2008 criteria.

With a median follow-up of 28.3 months in the ELEVATE-TN trial, PFS by IRC indicated a 90% statistically significant reduction in the risk of a PFS event for previously untreated CLL patients in the CALQUENCE plus obinutuzumab arm compared to obinutuzumab plus chlorambucil arm (HR=0.10 [95% CI: 0.06–0.17]; p<0.0001). At the time of analysis, median overall survival was not reached in any arm, with fewer than 10% of patients experiencing an event.

Efficacy results are presented in Table 27. The Kaplan-Meier curves for PFS are shown in Figure 3.

Table 27 Results from the ELEVATE-TN Trial in Patients with Previously Untreated CLL (Intention to Treat Population)

Efficacy Parameter	CALQUENCE plus Obinutuzumab N=179	CALQUENCE Monotherapy N=179	Obinutuzumab plus Chlorambucil N=177
Progression-Free Survival (PFS)^a
Number of events, n (%)	14 (7.8%)	26 (14.5%)	93 (52.5%)
Disease progression, n (%)	9 (5%)	20 (11.2%)	82 (46.3%)
Death events, n (%)	5 (2.8%)	6 (3.4%)	11 (6.2%)
Median (95% CI), months	NR	NR (34.2, NR)	22.6 (20.2, 27.6)
HR^b(95% CI)	0.10 (0.06, 0.17)^c	0.20 (0.13, 0.30)^d	--
p-value	p<0.0001	p<0.0001	--
Overall Response Rate (ORR)^e,f
n (%) (95% CI)	168 (93.9%) (89.3, 96.5)	153 (85.5%) (79.6, 89.9)	139 (78.5%) (71.9, 83.9)
p-value	<0.0001	0.0763	--
CR, n(%)^g	24 (13.4%)	1 (0.6%)	8 (4.5%)
PR, n(%)^h	144 (80.4%)	152 (84.9%)	131 (74%)

CI=Confidence Interval; CR=Complete Response; CRi=Complete Response with incomplete marrow recovery; HR=Hazard Ratio; NR=Not Reached; ORR=Overall Response Rate; PR=Partial Response; nPR=nodular Partial Response.

^aIndependent Review Committee (IRC) assessment per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis.

^bBased on stratified Cox-Proportional Hazards model.

^cCALQUENCE + obinutuzumab compared to obinutuzumab + chlorambucil.

^dCALQUENCE monotherapy compared to obinutuzumab + chlorambucil.

^eORR: (CR + CRi + nPR + PR).

^fPer IRC assessment.

^gIncludes 1 patient in the CALQUENCE + obinuzumab arm with CRi.

^hPR = PR + nPR; 1 patient with nPR in the CALQUENCE + obinutuzumab arm, 2 patients with nPR in the CALQUENCE monotherapy arm, and 3 patients with nPR in the obinutuzumab + chlorambucil arm.

Figure 3 Kaplan-Meier Curve of IRC-Assessed Progression-Free Survival in Patients with Previously Untreated CLL (ELEVATE-TN) (ITT Population)

The PFS benefit for CALQUENCE with or without obinutuzumab was consistent in the following subgroups: <65 and ≥65 years of age, patients with and without 17p deletion, patients with and without TP53 mutation, patients with and without 11q deletion, patients with unmutated IGHV, patients with and without advanced disease (Rai stage 0-II and stage III-IV), and patients with and without bulky lymphadenopathy (<5cm and ≥5cm).

Previously Treated CLL (ASCEND)

Table 28 Summary of patient demographics for clinical trials in patients with CLL who have received at least one prior therapy

Study #

Trial design

Dosage, route of administration and duration

Study subjects (n)

Mean age (Range)

Sex

ASCEND

(ACE-CL-309)

Randomized (1:1), open-label, Phase 3 Study

Arm A:

CALQUENCE 100 mg orally twice daily^a

Arm B (Investigator’s Choice):

-Idelalisib + rituximab (IR)^b

-Bendamustine + rituximab (BR)^c

155

Total

N=310

(32-90)

M: 67%

F: 33%

^aCALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity.

^bIdelalisib plus a rituximab product (IR): Idelalisib 150 mg orally approximately every 12 hours until disease progression or unacceptable toxicity, in combination with 8 infusions of a rituximab product (375 mg/m²intravenously on Day 1 of Cycle 1, followed by 500 mg/m²every 2 weeks for 4 doses and then every 4 weeks for 3 doses), with a 28-day cycle length.

^cBendamustine plus a rituximab product (BR): Bendamustine 70 mg/m²intravenously (Day 1 and 2 of each 28-day cycle), in combination with a rituximab product (375 mg/m²intravenously on Day 1 of Cycle 1, then 500 mg/m²on Day 1 of subsequent cycles), for up to 6 cycles.

The safety and efficacy of CALQUENCE in patients with relapsed or refractory CLL were evaluated in a randomized, multi-centre, open-label Phase 3 study (ASCEND) of 310 patients who received at least one prior therapy. Patients were randomized to receive CALQUENCE monotherapy or investigator’s choice of either idelalisib plus rituximab (IR) or bendamustine plus rituximab (BR).

Key inclusion criteria included diagnosis of CD20+ CLL, ≥1 prior systemic therapy for CLL, active disease that met ≥1 of the IWCLL 2008 criteria for requiring treatment. The trial allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists. The trial excluded patients with known CNS lymphoma or leukemia, transformed disease, prolymphocytic leukemia, or previous treatment with a Bruton’s Tyrosine Kinase inhibitor, venetoclax, or a phosphoinositide-3 kinase inhibitor.

Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and number of prior therapies (1 to 3 versus ≥4). The median time from diagnosis to randomization was 79 months. At baseline, about two-thirds (63%) of patients were ≥65 years of age, 87% had an ECOG score of 0 or 1, 49% had tumour bulk ≥5cm, 42% had Rai stage III or IV disease, 16% had 17p deletion, 24% had TP53 mutation, 78% had an unmutated IGHV, and 27% had an 11q deletion. The CALQUENCE arm had a median of 1 prior therapy (range 1-8), with 47% having at least 2 prior therapies. The investigator’s choice arm had a median of 2 prior therapies (range 1-10), with 57% having at least 2 prior therapies.

In the CALQUENCE arm, the median treatment duration was 15.7 months, with 86% of patients treated for at least 1 year. In the control arm (IR/BR), the median treatment duration was 11.5 months for idelalisib, 5.6 months for bendamustine and 5.5 months for rituximab.

The primary endpoint was PFS as assessed by IRC. PFS was defined as the time from the date of randomization to the date of first IRC-assessed disease progression or death due to any cause. The assessment of progressive disease was per the IWCLL 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis. IRC-assessed ORR per IWCLL 2008 criteria was a secondary endpoint.

At a median follow-up of 16.1 months in the ASCEND trial which enrolled patients with CLL who had received at least one prior therapy, PFS as assessed by IRC indicated a 69% statistically significant reduction in the risk of a PFS event for patients who received CALQUENCE compared to patients who received the investigator’s choice of therapy (HR=0.31 [95% CI: 0.20-0.49], p<0.0001). At the time of analysis, overall survival had not been reached in any arm. Efficacy results are presented in Table 29. The Kaplan-Meier curve for PFS is shown in Figure 4. The difference in overall response rate between the two arms did not reach statistical significance.

Table 29 Results from the ASCEND Trial in Patients with Previously Treated CLL (ITT population)


Progression-Free Survival (PFS)^a
	Number of events (%)			27 (17.4)								68 (43.9)
	Disease Progression, n (%)			19 (12.3)								59 (38.1)
	Death events (%)				8 (5.2)								9 (5.8)
	Median (95% CI), months^b					NR				16.5 (14.0, 17.1)
	HR^c(95% CI)							0.31 (0.20, 0.49)
	P-value								<0.0001
Overall Response Rate (ORR)^d,e
	n (%) (95% CI)		126 (81.3) (74.4, 86.6)								117 (75.5) (68.1, 81.6)
	ORR Difference, % (95% CI)	5.8 (-3.3, 14.9)												--
	P-value				0.2248									--
	CR, n(%)						0					2 (1.3%)
	PR, n(%)		126 (81.3%)								115 (74.2%)

CI=Confidence Interval; CR=Complete Response; CRi=Complete Response with incomplete blood count recovery; HR=hazard ratio; nPR=nodular Partial Response; NR=not reached; PR=partial response ^aIndependent Review Committee (IRC) assessment per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis.

^bKaplan-Meier estimate.

^cBased on stratified Cox-Proportional-Hazards model.

^dPer IRC assessment.

^eORR: (CR + CRi + nPR + PR); there were no patients with CRi or nPR.

Figure 4 Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL Who Have Received At Least One Prior Therapy (ASCEND) (ITT Population)

The PFS benefit of CALQUENCE was consistent in the following subgroups: <65 and ≥65 years of age, patients with and without 17p deletion, patients with and without 11q deletion, patients with or without TP53 mutation, patients with mutated and unmutated IGHV, patients with and without advanced disease (Rai stage 0-II and stage III-IV), and patients with and without bulky lymphadenopathy (<5cm and ≥5cm).

Previously Untreated Mantle Cell Lymphoma (MCL) (ECHO)

Table 30 Summary of patient demographics for clinical trial in patients with previously untreated MCL

Study #

Study Design

Dosage, route of administration and duration a,b,c

Study subjects (n)

Mean age (Range)

Sex

ECHO

(ACE-LY-308)

Randomized, double blind, placebo controlled, multicenter Phase 3 study

CALQUENCE 100 mg orally twice daily plus bendamustine and rituximab

Placebo plus bendamustine and rituximab

299

Total: N=598

71 (65-86)

M: 71%

F: 29%

^aCALQUENCE or placebo was administered twice daily from Day 1 of Cycle 1, continuously, until disease progression or unacceptable toxicity.

^bBendamustine, 90 mg/m², was intravenously administered over 30 minutes on Days 1 and 2 of each of six 28-day cycles; and rituximab, 375 mg/m², was intravenously administered on Day 1 of each cycle of six 28-day cycles. CALQUENCE or placebo in combination with bendamustine plus rituximab was administered for a maximum of 6 treatment cycles.

^cAfter the first 6 cycles, patients achieving a response (PR or CR) received rituximab maintenance at 375 mg/m²on Day 1 of every other cycle starting the Cycle 8 for maximum of 12 additional doses up to Cycle 30. Patients randomised to placebo + BR arm, who had confirmed progressive disease were eligible to cross over to CALQUENCE monotherapy at 100 mg twice daily dose until their second disease progression or unacceptable toxicity.

The safety and efficacy of CALQUENCE in patients with previously untreated MCL were evaluated in ECHO, a randomised, double-blind, placebo controlled, multicentre Phase 3 study. ECHO included 598 patients 65 years of age and older with confirmed MCL that was previously untreated. Patients were randomized 1:1 to receive CALQUENCE in combination with bendamustine and rituximab, or placebo in combination with bendamustine and rituximab.

Key exclusion criteria included history of CNS lymphoma or leptomeningeal disease, significant cardiovascular disease, or patients for whom the goal of therapy is tumour debulking before stem cell transplant. Patient randomisation was stratified by geographic region (North America versus Western Europe versus Other) and simplified MIPI (Mantle Cell Lymphoma International Prognostic Index) score (0-3 [low] versus 4-5 [intermediate] versus 6-11 [high]). The study enrolled patients during the COVID-19 pandemic.

The demographics and baseline disease characteristics, including bulky disease (≥5 cm), high-risk score by simplified MIPI, advanced disease (bone marrow involvement or extranodal disease and blastoid or pleomorphic histology), were well balanced between study arms (see Table 31).

Table 31 Patient Demographics and Baseline Disease Characteristics, ECHO (Full Analysis Set)

	CALQUENCE + bendamustine and rituximab N=299	Placebo + bendamustine and rituximab N=299
Age, median (range), y	71 (65–85)	71 (65–86)
≥75 y, n (%)	84 (28.1)	77 (25.8)
Male, n (%)	214 (71.6)	209 (69.9)
ECOG PS, n (%)
1	129 (43.1)	132 (44.1)
2	12 (4.0)	23 (7.7)
Tumor bulk ≥5 cm, n (%)	112 (37.5)	113 (37.8)
Ann Arbor Stage IV disease, n (%)	251 (83.9)	263 (88)
Extranodal disease, n (%)	264 (88.3)	277 (92.6)
Bone marrow involvement, n (%)	211 (70.6)	218 (72.9)
Blastoid/pleomorphic histology, n (%)	41 (13.7)	38 (12.7)
Simplified MIPI score, n (%)
Low risk [0-3]	99 (33.1)	101 (33.8)
Intermediate risk [4-5]	128 (42.8)	125 (41.8)
High risk [6-11]	72 (24.1)	73 (24.4)
Ki-67 ≥30%, n (%)	139 (46.5)	147 (49.2)

The primary endpoint was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) per Lugano Classification for NHL in patients with previously untreated MCL. Additional efficacy endpoints were Investigator-assessed (INV) PFS, INV- and IRC-assessed overall response rate (ORR), IRC- and INV-assessed duration of response (DOR) and overall survival (OS).

With a median follow-up of 46.1 months in the CALQUENCE + BR arm and 44.4 months in the Placebo + BR arm, IRC-assessed PFS demonstrated 27% statistically significant reduction in risk of disease progression or death in patients treated with CALQUENCE + BR compared to Placebo + BR. Within the placebo arm, 88 (29.4%) patients received at least one subsequent anti-MCL therapy of which 76 (86.4%) received a BTKi as subsequent treatment.

At the time of PFS analysis, median OS had not been reached in any arm with a total of 203 deaths: 97 (32.4%) in the CALQUENCE + BR arm, 106 (35.5%) in the Placebo + BR arm suggesting no detriment for patients in the CALQUENCE + BR arm [HR=0.86, 95% CI 0.65,1.13]. Efficacy results are presented in Table 32. The Kaplan-Meier curves for PFS are shown in Figure 5.

Table 32 Efficacy Results in Patients with previously untreated MCL in ECHO

	CALQUENCE + BR N=299	Placebo + BR N=299
	CALQUENCE + BR N=299	Placebo + BR N=299
PFS^a
			Median (95% CI)	66.4 (55.1, NE)					49.6 (36.0, 64.1)
			HR (95% CI) (stratified)^b			0.73 (0.57, 0.94)
			p-value^c				0.0160
ORR^a
			ORR (CR + PR), n (%)		272 (91.0)					263 (88.0)
			95% CI		87.3, 93.8					83.9, 91.3
					CR, n (%)			199 (66.6)			160 (53.5)
					PR, n (%)			73 (24.4)			103 (34.4)
			ORR difference (vs PBR arm)					3.0%
			p-value				0.2196
DOR^a
DOR^a			Median (95% CI), months	63.5 (52.5, NE)					53.8 (37.6, 66.1)

HR = hazard ratio, CR = complete response, PBR = placebo plus bendamustine + rituximab, PR = partial response, NE = not evaluable

^aIRC-assessed.

^bStratified by randomization stratification factors: Geographic Regions (North American, Western Europe, Other) and simplified MIPI Score (Low risk [0 to 3], Intermediate risk [4 to 5], High Risk [6 to 11]) as collected via IXRS. Estimated based on stratified Cox Proportional Hazards model for hazard ratio (95% CI).

^cEstimated based on stratified log-rank test for p-value.

Figure 5 Kaplan-Meier Curve of IRC-Assessed PFS in patients with previously untreated MCL (ECHO)

Previously Treated MCL (ACE-LY-004)

Table 33 Summary of patient demographics for clinical trial in patients with MCL who have received at least one prior therapy

Study #

Trial design

Dosage, route of administration and duration

Study subjects (n)

Mean age (Range)

Sex

ACE-LY-004

Open-label, multi-centre, single-arm Phase 2 Study

CALQUENCE 100 mg orally twice daily until disease progression or unacceptable toxicity

124

68 (range 42 to 90) years

M: 80%

F: 20%

The safety and efficacy of CALQUENCE in patients with MCL were evaluated in an open-label, multi-centre, single-arm Phase 2 study (ACE-LY-004) of 124 previously treated patients.

In Study ACE-LY-004, the median age was 68 (range 42 to 90) years, 80% were male and 74% were Caucasian. At baseline, 93% of patients had an ECOG performance status of 0 or 1. The median time since diagnosis was 46 months and the median number of prior treatments was 2 (range 1 to 5), including 18% with prior stem cell transplant. The majority of patients (95%) had previously received rituximab as a single agent or part of a regimen. Common prior regimens included CHOP-based regimen (52%), cytarabine (34%), bendamustine and rituximab-based regimens (22%), and Hyper-CVAD (21%). At baseline, 24% and 76% of patients had refractory and relapsed disease, respectively, and 37% of patients had at least one tumour with a longest diameter ≥5 cm, 73% had extra nodal involvement including 51% with bone marrow involvement. The Simplified MCL International Prognostic Index (MIPI) score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 44% and high in 17% of patients, and 75% of patients had Ann Arbor Stage IV disease.

Patients were to receive CALQUENCE 100 mg orally twice daily until disease progression or unacceptable toxicity. The median duration of treatment was 17.3 months and the median dose intensity was 98.7%. The median duration of follow-up was 26.3 months.

The trial did not include patients who received prior treatment with BTK inhibitors.

The primary endpoint was investigator-assessed overall response rate (ORR) per the Lugano classification for non-Hodgkin’s lymphoma (NHL). Duration of Response (DoR) was an additional outcome measure.

The efficacy analysis for patients with MCL who have received at least one prior therapy was conducted at a median follow-up of 26.3 months, and the results are summarized below and presented in Table 34. At time of analysis, 39.5% of patients remained on study. The ORR was 80.6% with a median time to documented response of 1.9 months and a median DoR of 25.7 months.

Table 34 Efficacy Results of Study ACE-LY-004 (N=124) in Patients with Mantle Cell Lymphoma Who Have Received At Least One Prior Therapy

Efficacy Parameter	Investigator Assessed^an (%) (95% CI^b)
Overall Response Rate (ORR)^c
Overall Response Rate	100 (80.6%) (72.6, 87.2)
Complete Response	53 (42.7%) (33.9, 51.9)
Partial Response	47 (37.9%) (29.3, 47.1)
Stable Disease	11 (8.9%) (4.5, 15.3)
Progressive Disease	10 (8.1%) (3.9, 14.3)
Duration of Response (DoR)
Median (months)	25.7 (17.5, NE)

CI=Confidence Interval; NE=Not Estimable

^aPer Lugano classification for non-Hodgkin’s lymphoma.

^b95% exact binomial confidence interval.

^cNon-Evaluable: 3 patients were non-evaluable due to inadequate post-baseline disease assessment.

14.2. Comparative Bioavailability Studies

A randomized, multi-centre, open-label, single dose, two-way, cross-over, comparative bioavailability study of CALQUENCE 100 mg tablets and CALQUENCE 100 mg capsules was conducted in 66 healthy, adult male subjects under fasting conditions. Comparative bioavailability data from 63 subjects that were included in the statistical analysis are presented in the following table.

Table 35 Summary Table of Comparative Bioavailability Data

Acalabrutinib (1 x 100 mg) Geometric Mean Arithmetic Mean (CV %)
Parameter	Test¹	Reference²	% Ratio of Geometric Means	90% Confidence Interval
AUC_T (ng·h/mL)	563.9 599.5 (2.81)	566.8 605.8 (2.71)	98.8	93.6 – 104.2
AUC_I (ng·h/mL)	567.8 603.7 (2.80)	572.2 610.6 (2.73)	98.6	93.4 – 104.0
Cmax (ng/mL)	537.2 581.6 (2.52)	535.7 606.8 (2.16)	100.4	90.8 – 111.0
Tmax3 (h)	0.52 (0.23 – 2.97)	0.58 (0.47 – 3.98)
T½4 (h)	1.64 (1.39)	2.24 (0.79)

¹CALQUENCE (acalabrutinib as acalabrutinib maleate) tablets, 100 mg (AstraZeneca Canada Inc.).

²CALQUENCE (acalabrutinib as acalabrutinib base) capsules, 100 mg (AstraZeneca Canada Inc.).

³Expressed as the median (range) only.

⁴Expressed as the arithmetic mean (CV %) only.

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

General toxicology

Daily oral administration of acalabrutinib for up to 6 months duration in rats and 9 months in dogs, was tolerated at exposure levels that exceed human therapeutic exposures at the recommended dose (2.5-fold in rats, 8.2-fold in dogs, based on AUC).

Kidney, liver and heart were identified as the target organs of toxicities in rats and dogs. In rats, liver and kidney findings were observed at exposures 4.2 times the total clinical exposures. More severe toxicities including cardiac findings were observed in both species at exposures ≥6.8 times the total clinical exposure. Reversibility was demonstrated for liver and kidney findings in both species. Reversibility for the heart findings could not be assessed as these findings were only observed at doses above the maximum tolerated dose (MTD).

Toxicology species were exposed to relevant metabolites of acalabrutinib, including the active metabolite ACP-5862.

Genotoxicity

Acalabrutinib was not mutagenic in a bacterial reverse mutation assay, in an in vitro chromosome aberration assay, or in an in vivo mouse bone marrow micronucleus assay.

Carcinogenicity

Carcinogenicity studies have not been conducted with acalabrutinib.

Reproductive and developmental toxicology

No effects on fertility were observed in male or female rats at exposures 10 or 9 times the human AUC exposure at the recommended dose, respectively.

In a combined fertility and embryofetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No effects on embryofetal development and survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 9 times the AUC in patients at the recommended dose of 100 mg twice daily. The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma.

In an embryofetal study in pregnant rabbits, acalabrutinib was administered orally at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Acalabrutinib produced no maternal toxicity and no evidence of teratogenicity or fetal development, growth, or survival at doses of 50 mg/kg/day (approximately equivalent to the human AUC exposure at the recommended dose). Decreased fetal body weight and delayed ossification were observed at exposure levels that produced maternal toxicity (doses ≥100 mg/kg/day), which were 2.4 times greater than the human exposure levels at the recommended dose.

In a rat reproductive study involving dosing animals from implantation throughout gestation, parturition and lactation, dystocia (prolonged /difficult labor) was observed at exposures >2.3-times the clinical exposure at 100 mg twice daily.

17. Supporting Product Monographs

1. CALQUENCE^®(capsules, 100 mg), submission control number 231228, Product Monograph, AstraZeneca Canada Inc. (2019-11-28)

Rx or OTC	Prescription (Rx)?
DIN	02535696
Schedule(s)	PRESCRIPTION
Active ingredient(s)	Acalabrutinib (acalabrutinib maleate) 100 MG
Dosage form(s)	Tablet
Route(s) of administration	Oral
Drug class (WHO ATC)	L Antineoplastic and immunomodulating agents L01 Antineoplastic agents L01E Protein kinase inhibitors, antineoplastic and immunomodulating agents L01EL Bruton's tyrosine kinase (BTK) inhibitors L01EL02 Acalabrutinib
Company	ASTRAZENECA CANADA INC
Current status	Marketed
Current status date	May 1, 2023

Calquence (Astrazeneca Canada, Tablet) Product Monograph

Product Monograph - Calquence (Astrazeneca Canada, Tablet)

Recent Major Label Changes

1. Indications

Chronic Lymphocytic Leukemia (CLL)

Mantle Cell Lymphoma (MCL)

1.1. Pediatrics

1.2. Geriatrics

2. Contraindications

3. Serious Warnings and Precautions Box

4. Dosage and Administration

4.1. Dosing Considerations

4.2. Recommended Dose and Dosage Adjustment

Table 1 Venetoclax dose ramp-up schedule

Dosage Adjustment

Table 2 Recommended Dose Adjustments for Adverse Reactions in patients receiving CALQUENCE monotherapy or CALQUENCE in combination with obinutuzumab

Table 4 Recommended dose modifications for adverse reactions in patients receiving CALQUENCE in combination with bendamustine and rituximab

Table 5 Use with CYP3A inhibitors

Special Populations

4.4. Administration

4.5. Missed Dose

5. Overdose

6. Dosage Forms, Strengths, Composition and Packaging

Table 6 Dosage Forms, Strengths, and Composition

Description

Packaging

7. Warnings and Precautions

Carcinogenesis and Genotoxicity

Cardiovascular

Driving and Operating Machinery

Hematologic

Hemorrhage

Hepatic

Immune

Monitoring and Laboratory Tests

7.1. Special Populations

7.1.1 Pregnancy

7.1.2 Breastfeeding

7.1.3 Pediatrics

7.1.4 Geriatrics

8. Adverse Reactions

8.1. Adverse Reaction Overview

8.2. Clinical Trial Adverse Reactions

Previously Untreated Chronic Lymphocytic Leukemia (CLL) – AMPLIFY

Table 7 Adverse Reactions in ≥5% (All Grades) of Patients with Chronic Lymphocytic Leukemia (CLL) in the AMPLIFY Trial

Previously Untreated Chronic Lymphocytic Leukemia (CLL) – ELEVATE-TN

Table 8 Adverse Reactions in ≥5% (All Grades) of Patients with Chronic Lymphocytic Leukemia (CLL) in the ELEVATE-TN Trial

Previously Treated Chronic Lymphocytic Leukemia (CLL) – ASCEND

Table 9 Adverse Reactions in ≥5% (All Grades) of Patients with Chronic Lymphocytic Leukemia (CLL) in the ASCEND Trial

Previously untreated mantle cell lymphoma (MCL) – ECHO

Table 10 Adverse reactions in ≥5% (All Grades) of patients with MCL in ECHO

Previously treated Mantle Cell Lymphoma (MCL) – ACE-LY-004

8.3. Less Common Clinical Trial Adverse Reactions

Chronic Lymphocytic Leukemia (CLL)

Mantle Cell Lymphoma (MCL)

Injury, poisoning and procedural complications: fall

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Table 14 Hematologic Laboratory Abnormalities in ≥20% of Patients with Chronic Lymphocytic Leukemia (CLL) in the ELEVATE-TN Trial

Table 15 Chemistry Laboratory Abnormalities (≥15% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ELEVATE-TN)

Table 16 Hematologic Laboratory Abnormalitiesa in ≥20% of Patients with CLL in the ASCEND Trial

Table 17 Chemistry Laboratory Abnormalities (≥10% Any Grade), New or Worsening from Baseline in Patients Receiving CALQUENCE (ASCEND)

Table 18 Hematological Laboratory Abnormalities for Patients Receiving CALQUENCE in Combination with Bendamustine and Rituximab (BR) in ECHO Trial

Table 19 Chemistry Laboratory Abnormalities for Patients Receiving CALQUENCE in Combination with Bendamustine and Rituximab (BR) in ECHO Trial

Table 20 Treatment-Emergent Hematological Laboratory Abnormalities in ACE-LY-004 Study (N=124)

9. Drug Interactions

9.1. Serious Drug Interactions

9.2. Drug Interactions Overview

9.4. Drug-Drug Interactions

Table 21 Established or Potential Drug-Drug Interactions

Clinical Studies

Effect of Gastric Acid Reducing Medications on acalabrutinib

In Vitro Studies

Effects of acalabrutinib and its active metabolite, ACP-5862, on CYP3A Substrates

CYP3A Substrates

Effects of acalabrutinib and ACP-5862 on Drug Transport Systems

BCRP Substrates

MATE1 substrates

9.5. Drug-Food Interactions

9.6. Drug-Herb Interactions

Table 16 Hematologic Laboratory Abnormalities^ain ≥20% of Patients with CLL in the ASCEND Trial