Product Monograph - Calquence (Astrazeneca Canada, Capsule)
RECENT MAJOR LABEL CHANGES
INDICATIONS (1) 11-2019
DOSAGE AND ADMINISTRATION, Recommended dose and dosage
adjustment (4.2) 11-2019
WARNINGS AND PRECAUTIONS, Cardiovascular (7) 11-2019
WARNINGS AND PRECAUTIONS, Hemorrhage (7) 11-2019
WARNINGS AND PRECAUTIONS, Immune (7) 11-2019
WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests (7) 11-2019
WARNINGS AND PRECAUTIONS, Pregnant Women (7.1.1) 11-2019
TABLE OF CONTENTS
RECENT MAJOR LABEL CHANGES ........................................................................................ 2
TABLE OF CONTENTS ............................................................................................................. 2
PART I: HEALTH PROFESSIONAL INFORMATION ................................................................. 4
1 INDICATIONS ................................................................................................................. 4
1.1 Pediatrics ............................................................................................................... 4
1.2 Geriatrics ............................................................................................................... 4
2 CONTRAINDICATIONS .................................................................................................. 4
3 SERIOUS WARNINGS AND PRECAUTIONS BOX ........................................................ 4
4 DOSAGE AND ADMINISTRATION ................................................................................ 5
4.1 Dosing Considerations ........................................................................................... 5
4.2 Recommended Dose and Dosage Adjustment ....................................................... 5
4.3 Administration ........................................................................................................ 7
4.4 Missed Dose .......................................................................................................... 7
5 OVERDOSAGE ............................................................................................................... 7
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ......................... 7
7 WARNINGS AND PRECAUTIONS ................................................................................. 8
7.1 Special Populations ............................................................................................. 10
7.1.1 Pregnant Women .............................................................................................10
7.1.2 Breast-feeding ..................................................................................................10
7.1.3 Pediatrics .........................................................................................................10
7.1.4 Geriatrics ..........................................................................................................10
8 ADVERSE REACTIONS ............................................................................................... 10
8.1 Adverse Reaction Overview ................................................................................. 10
8.2 Clinical Trial Adverse Reactions........................................................................... 11
8.3 Less Common Clinical Trial Adverse Reactions ................................................... 16
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................... 17
9 DRUG INTERACTIONS ................................................................................................ 20
9.1 Serious Drug Interactions Box ............................................................................. 20
9.2 Overview .............................................................................................................. 20
9.3 Drug-Drug Interactions ......................................................................................... 21
9.4 Drug-Food Interactions ........................................................................................ 22
9.5 Drug-Herb Interactions ......................................................................................... 22
10 ACTION AND CLINICAL PHARMACOLOGY ............................................................... 22
10.1 Mechanism of Action ........................................................................................ 22
10.2 Pharmacodynamics .......................................................................................... 23
10.3 Pharmacokinetics ............................................................................................. 23
11 STORAGE, STABILITY AND DISPOSAL ..................................................................... 25
12 SPECIAL HANDLING INSTRUCTIONS ........................................................................ 25
PART II: SCIENTIFIC INFORMATION ..................................................................................... 26
13 PHARMACEUTICAL INFORMATION ........................................................................... 26
14 CLINICAL TRIALS ........................................................................................................ 26
14.1 Trial Design and Study Demographics ............................................................. 26
14.2 Study Results ................................................................................................... 30
15 NON-CLINICAL TOXICOLOGY .................................................................................... 35
PATIENT MEDICATION INFORMATION ................................................................................. 37
PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
CALQUENCE (acalabrutinib) is indicated:
- in combination with obinutuzumab or as monotherapy for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL)
- as monotherapy for the treatment of patients with CLL who have received at least one prior therapy
- for the treatment of patients with mantle cell lymphoma (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 WARNINGS AND PRECAUTIONS, Special Populations.
2 CONTRAINDICATIONS
CALQUENCE is contraindicated in patients who are hypersensitive to acalabrutinib or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION and PACKAGING section of the Product Monograph.
3 SERIOUS WARNINGS AND PRECAUTIONS BOX
Serious Warnings and Precautions
- 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 DRUG INTERACTIONS).
- Serious Hemorrhage: Monitor for bleeding and manage appropriately (see WARNINGS AND PRECAUTIONS, Hemorrhage).
4 DOSAGE AND ADMINISTRATION
4.1 Dosing Considerations
- Avoid concomitant use with strong CYP3A4 inhibitors (see DRUG INTERACTIONS).
- Avoid concomitant use with strong CYP3A4 inducers (see DRUG INTERACTIONS).
- Avoid concomitant use with proton pump inhibitors (see 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
Recommended Dose
The recommended dose of CALQUENCE for patients with CLL or MCL is 100 mg (1 capsule) twice daily.
Doses should be separated by approximately 12 hours.
In patients with previously untreated CLL, CALQUENCE can be used as monotherapy or in combination with obinutuzumab. 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 CLINICAL TRIALS.
Treatment with CALQUENCE should continue until disease progression or unacceptable toxicity.
Dosage Adjustment
Recommended dose modifications of CALQUENCE for Grade ≥3 adverse reactions are provided in Table 1.
Table 1 Recommended Dose Adjustments for Adverse Reactionsa
| Adverse Reaction | 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 | |
a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse
Events (NCI CTCAE) version 4.03.
Recommended dose modifications of CALQUENCE for use with CYP3A inhibitors and gastric acid reducing agents are provided in Table 2.
Table 2 Use with CYP3A Inhibitors and Gastric Acid Reducing Agents
| 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. | ||
| Gastric Acid Reducing Agents | Proton Pump Inhibitors | Avoid concomitant use. | |
| H2-Receptor Antagonists | Take CALQUENCE 2 hours before taking a H2-receptor antagonist. | ||
| Antacids | Separate dosing by at least 2 hours. | ||
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 ACTION AND CLINICAL PHARMACOLOGY).
Renal Impairment: No dose adjustment is recommended in patients with mild to moderate renal impairment (eGFR ≥30 mL/min/1.73m2 as 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 ACTION AND 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 ACTION AND CLINICAL PHARMACOLOGY).
4.3 Administration
CALQUENCE should be swallowed whole with water at approximately the same time each day. CALQUENCE can be taken with or without food. The capsule should not be chewed, dissolved, or opened.
4.4 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 capsules of CALQUENCE should not be taken to make up for a missed dose.
5 OVERDOSAGE
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 management of a suspected drug overdose, contact your regional poison control centre. |
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
Table 3 Dosage Forms, Strengths, Composition and Packaging
Description
Size 1 hard gelatine capsule with a yellow body and blue cap, marked in black ink with ‘ACA 100 mg’
Packaging
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
| Oral | 100 mg acalabrutinib capsule | Ammonium hydroxide, black iron oxide, colloidal silicon dioxide, FD&C Blue 2 (Indigotine/Indigo carmine), gelatine, magnesium stearate, microcrystalline cellulose, partially pregelatinized starch (maize), propylene glycol, shellac, sodium starch glycolate (Type A), titanium dioxide, and yellow iron oxide. |
White high density polyethylene (HDPE) plastic bottle, capped with a child-resistant closure containing 60 capsules.
7 WARNINGS AND PRECAUTIONS
Please see the Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.
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=1029), events of atrial fibrillation or atrial flutter were reported in 4.1% of patients, including Grade 3 events in 1.1% 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.
Carcinogenesis and Mutagenesis
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 skin cancer, reported in 6% of patients. Advise protection from the sun.
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
Treatment-emergent Grade 3 or 4 neutropenia (including febrile neutropenia), anemia, and thrombocytopenia, based on laboratory measurements, occurred in patients with hematologic malignancies treated with CALQUENCE (see ADVERSE REACTIONS). Monitor complete blood counts regularly during CALQUENCE treatment (see Monitoring and Laboratory Tests). Interrupt treatment, reduce the dose, or discontinue treatment as necessary (see DOSAGE AND ADMINISTRATION, Dosage Adjustment).
Hemorrhage
Serious hemorrhagic events, including fatal events, have been reported in patients with hematologic malignancies (n=1029) 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 3.3% of patients. Overall, bleeding events including bruising and petechiae of any grade, occurred in 44% 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 3.8% of patients taking CALQUENCE with other antithrombotic agents, and in 3.0% of patients taking CALQUENCE without any concomitant antithrombotic agents.
Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE (see DRUG INTERACTIONS, Drug-Drug Interactions, Antithrombotic agents). Monitor all patients for signs of bleeding.
Consider the benefit-risk of withholding CALQUENCE for at least 3 days pre- and post-surgery.
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 4 infection was pneumonia.
Monitor patients for signs and symptoms of infection and treat promptly.
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.
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 echocardiogram (ECG) as appropriate.
- Monitor patients for the appearance of skin cancers.
- Monitor patients for signs and symptoms of infection and treat as medically appropriate.
- Monitor patients for signs of bleeding.
Sexual Health
Fertility
There are no data on the effect of CALQUENCE on human fertility.
7.1 Special Populations
7.1.1 Pregnant Women
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 foetal growth (see 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 NON-CLINICAL TOXICOLOGY).
7.1.2 Breast-feeding
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 ACTION AND CLINICAL PHARMACOLOGY). Of the 1029 patients in clinical trials of CALQUENCE, 68% were 65 years of age or older, and 24% 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 1029 patients with hematologic malignancies receiving CALQUENCE as monotherapy (n=820) or in combination with obinutuzumab (n=209).
The most common (≥20%) adverse reactions (ARs) of any grade reported in in this pooled safety population of patients receiving CALQUENCE were infection, headache, diarrhea, musculoskeletal pain, bruising, fatigue, nausea, and rash.
The most frequently reported (≥2%) serious adverse reaction was pneumonia (5%).
Dose reductions and interruptions due to adverse events (AEs) were reported in 5% and 39% of patients, respectively. Discontinuation due to AEs were reported in 10% of the patients. The median dose intensity was 99%.
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 54% (N=552/1029) of patients. The median time to onset of lymphocytosis was 1.1 weeks and the median duration of lymphocytosis was 7 weeks.
8.2 Clinical Trial Adverse Reactions
Because clinical trials are conducted under very specific conditions, the reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse event information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Chronic Lymphocytic Leukemia (CLL)
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 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 4 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 4 Adverse Reactions in ≥5% (All Grades) of Patients with Chronic Lymphocytic Leukemia (CLL) in the ELEVATE-TN Trial.
| System Organ Class Preferred Terma | CALQUENCE plus Obinutuzumab N=178 | CALQUENCE Monotherapy N=179 | Obinutuzumab plus Chlorambucil N=169 | |||
|---|---|---|---|---|---|---|
| All Gradesb (%) | Grade ≥3 (%) | All Grades (%) | Grade ≥3 (%) | All Grades (%) | Grade ≥3 (%) | |
| Blood and lymphatic system disordersc | ||||||
| Neutropeniac | 33 | 32 | 12 | 11 | 49 | 46 |
| Thrombocytopeniac | 15 | 9 | 10 | 3 | 15 | 13 |
| Anemiac | 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 painc | 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 | ||||||
| Infectionc | 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 painc | 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 | ||||||
| Bruisingc | 34 | 0 | 26 | 0 | 5 | 0 |
| Rashc | 22 | 2 | 19 | 1 | 7 | 1 |
| Vascular disorders | ||||||
| Hemorrhage/Hematomac | 13 | 1 | 9 | 1 | 4 | 0 |
a Based on MedDRA version 21.1.
b Per 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 epitstaxis.
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 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 5 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 5 Adverse Reactions in ≥5% (All Grades) of Patients with Chronic Lymphocytic Leukemia (CLL) in the ASCEND Trial.
| System Organ Class Preferred Terma | CALQUENCE N=154 | Idelalisib plus Rituximab N=118 | Bendamustine plus Rituximab N=35 | |||
|---|---|---|---|---|---|---|
| All Gradesb (%) | Grade ≥3 (%) | All Grades (%) | Grade ≥3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
| Blood and lymphatic system disordersc | ||||||
| Neutropeniac | 21 | 18 | 51 | 47 | 37 | 34 |
| ThrombocytopeniaC | 14 | 5 | 17 | 8 | 17 | 3 |
| Anemiac | 15 | 12 | 9 | 7 | 11 | 9 |
| Cardiac disorders | ||||||
| Atrial Fibrillation/Flutterc | 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 painc | 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 | ||||||
| Infectionc | 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 |
| 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 |
| Musculoskeletal and connective tissue disorders | ||||||
| Musculoskeletal Painc | 15 | 1 | 15 | 2 | 3 | 0 |
| Arthralgia | 8 | 1 | 6 | 0 | 3 | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| Bruisingc | 12 | 0 | 3 | 0 | 0 | 0 |
| Rashc | 7 | 0 | 16 | 3 | 9 | 0 |
| Vascular disorders | ||||||
| Hemorrhage/Hematomac | 13 | 1 | 4 | 1 | 6 | 3 |
a Based on MedDRA version 21.1.
b Per 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.
Mantle Cell Lymphoma (MCL)
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 6. The median duration of CALQUENCE treatment in patients with MCL (ACE-LY-004) was 17.3 months.
Table 6 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 Terma | CALQUENCE (N=124) | ||||
|---|---|---|---|---|---|
All CTCAEb Grades (%) | CTCAE Grade ≥3c (%) | ||||
| 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 Paind | 15 | 2 | |||
| System Organ Class Preferred Terma | CALQUENCE (N=124) |
|---|
All CTCAEb Grades (%) | CTCAE Grade ≥3c (%) | |
|---|---|---|
| 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 | ||
| Bruisingd | 21 | 0 |
| Rashd | 19 | 2 |
a Based on MedDRA version 20.1. b Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. c All events were Grade 3, except one Grade 4 intracranial hemorrhage and one Grade 5 intracranial hematoma. d AEs 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=1029) population (20%), 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 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’
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data
Hematological and chemistry abnormalities are shown below.
Previously Untreated CLL:
Table 7 Hematologic Laboratory Abnormalities in ≥20% of Patients with Chronic Lymphocytic Leukemia (CLL) in the ELEVATE-TN Trial
| Laboratory Abnormalitiesa | 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 (%) | |||||||
| 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 | ||||||
a Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 based on laboratory measurements.
Table 8 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 (%) | |
| Uric acid increase | 29 | 29 | 22 | 22 | 37 | 37 |
| ALT increase | 30 | 7 | 20 | 1 | 36 | 6 |
| AST increase | 38 | 5 | 17 | 1 | 60 | 8 |
| Bilirubin increase | 13 | 1 | 15 | 1 | 11 | 1 |
a Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
b Excludes electrolytes.
Increases in creatinine of 1.5 to 3 times the upper level 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 9 Hematologic Laboratory Abnormalitiesa in ≥20% of Patients with CLL in the ASCEND Trial
Hematologic Laboratory Abnormalities | CALQUENCE N=154 | Idelalisib plus Rituximab N=118 | Bendamustine plus Ritixumab N=35 | |||||||||
| All Grades (%) | Grade ≥3 (%) | All Grades (%) | Grade ≥3 (%) | All Grades (%) | Grade ≥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 | ||||||
| Absolute Lymphocyte Count increased | 26 | 20 | 22 | 17 | 3 | 3 | ||||||
a Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 based on laboratory measurements and adverse reactions.
Table 10 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 (%) | |
| Uric acid increase | 15 | 15 | 11 | 11 | 23 | 23 |
| ALT increase | 15 | 2 | 59 | 23 | 26 | 3 |
| AST increase | 13 | 1 | 48 | 13 | 31 | 3 |
| Bilirubin increase | 13 | 1 | 16 | 2 | 26 | 11 |
a Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. b Excludes electrolytes. Increases in creatinine of 1.5 to 3 times the ULN occurred in 1.3% of patients. | ||||||
Mantle Cell Lymphoma:
Table 11 Treatment-Emergent Hematological Laboratory Abnormalities in ACE-LY-004 Study (N=124)
Hematological Adverse Reactiona | All Grades (%) | Grade ≥3 (%) |
|---|---|---|
| Absolute neutrophil count decreased | 36 | 13 |
| Hemoglobin decreased | 42 | 6 |
| Platelets decreased | 44 | 11 |
a Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
9 DRUG INTERACTIONS
9.1 Serious Drug Interactions Box
9.2 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.
Serious Drug Interactions
Concomitant use of CALQUENCE with a strong CYP3A inhibitor should be avoided (see DOSAGE AND ADMINISTRATION, Concomitant use of CYP3A Inhibitors).
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.
Increase in gastric pH may decrease acalabrutinib concentrations. Avoid use with proton pump inhibitors. If antacids are used, it is recommended to separate dosing of CALQUENCE by 2 hours. CALQUENCE should be taken 2 hours before the administration of H2 receptor antagonists.
9.3 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).
Active substances that may increase acalabrutinib plasma concentrations
CYP3A Inhibitors
Co-administration with a strong CYP3A inhibitor (200 mg itraconazole once daily for 5 days) increased acalabrutinib Cmax and AUC by 3.7-fold and 5.1-fold, respectively, in healthy subjects (N=17).
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.
Physiologically based pharmacokinetic (PBPK) simulations with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) showed that co-administration increased acalabrutinib Cmax, and AUC by 2- to almost 3-fold. When CALQUENCE is co-administered with moderate CYP3A inhibitors, reduce the acalabrutinib dose to 100 mg once daily.
Active substances that may decrease acalabrutinib plasma concentrations
CYP3A Inducers
Co-administration of a strong CYP3A inducer (600 mg rifampin once daily for 9 days) decreased acalabrutinib Cmax and 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.
Gastric Acid Reducing Medications
Acalabrutinib solubility decreases with increasing pH. Co-administration of acalabrutinib with an antacid (1 g calcium carbonate) decreased acalabrutinib AUC by 53% in healthy subjects. Co-administration with a proton pump inhibitor (40 mg omeprazole for 5 days), decreased acalabrutinib AUC by 43%.
If treatment with an acid reducing agent is required, consider using an antacid (e.g., calcium carbonate) or an H2-receptor antagonist (e.g., ranitidine or famotidine). For use with antacids, separate dosing by at least 2 hours. For H2-receptor antagonists, CALQUENCE should be taken 2 hours before their administration.
Due to the long-lasting effect of proton pump inhibitors, separation of doses with proton pump inhibitors may not eliminate the interaction with CALQUENCE.
Active substances whose plasma concentrations may be altered by CALQUENCE
CYP3A Substrates
Based on in vitro data and PBPK modelling, no interaction with CYP substrates is expected at the clinically relevant concentration (see ACTION AND CLINICAL PHARMACOLOGY).
Effects of acalabrutinib and its active metabolite, 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 ACTION AND CLINICAL PHARMACOLOGY).
ACP-5862, may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1 (see ACTION AND CLINICAL PHARMACOLOGY).
Antithrombotic agents
Use of CALQUENCE in patients receiving antithrombotic agents may increase the risk of bleeding (see WARNINGS AND PRECAUTIONS, Hemorrhage).
9.4 Drug-Food Interactions
In healthy subjects, administration of a single 75 mg dose of CALQUENCE from a developmental formulation 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 Cmax was decreased by 73% and Tmax was delayed by 1-2 hours.
In healthy subjects, administration of acalabrutinib with acidic beverages such as orange juice and grapefruit juice decreased AUC by 40% and 17%, respectively, compared to when administered with water.
9.5 Drug-Herb Interactions
Avoid St. John’s wort which may unpredictably decrease acalabrutinib plasma concentrations.
10 ACTION AND 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).
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
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 (AUC24h) and maximum plasma concentration (Cmax) 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.
Absorption: The absolute bioavailability of acalabrutinib was 25%. The median [min, max] time to peak acalabrutinib plasma concentrations (Tmax) was 0.9 [0.5, 1.9] hours, and 1.6 [0.9, 2.7] hours for ACP-5862.
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 (Vss/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 DRUG INTERACTIONS).
Elimination: The geometric mean (%CV) terminal elimination half-life (t1/2) was 1 (59%) hour for acalabrutinib and was 3.5 (24%) 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 faeces 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, 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/1.73m2 as 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 DOSAGE AND ADMINISTRATION).
11 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.
12 SPECIAL HANDLING INSTRUCTIONS
Not applicable.
PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
Proper/Common name: Acalabrutinib
Chemical name: 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-N-(pyridine-2-yl)benzamide
Molecular formula and molecular mass: C26H23N7O2; 465.51
Structural formula:
Physicochemical properties: Acalabrutinib is a white to yellow 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 Trial Design and Study Demographics
Previously Untreated Chronic Lymphocytic Leukemia (CLL)
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.
Table 12 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 + chlorambucila Arm B: CALQUENCE 100 mg orally twice daily + obinutuzumabb, Arm C: CALQUENCE monotherapy, 100 mg orally twice dailyc | 179 179 177 Total: N=535 | 70 (41-91) | M: 61% F: 39% |
a Obinutuzumab 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.
b CALQUENCE 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.
c CALQUENCE monotherapy: CALQUENCE 100 mg was administered twice daily until disease progression or unacceptable toxicity.
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 subjects (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 (Cheson 2012). 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.
Previously Treated CLL
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).
Table 13 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 dailya Arm B (Investigator’s Choice): -Idelalisib + rituximab (IR)b or -Bendamustine + rituximab (BR)c | 155 155 Total N= 310 | 67 (32-90) | M: 67% F: 33% |
a CALQUENCE 100 mg approximately every 12 hours until disease progression or unacceptable toxicity.
b Idelalisib 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/m2 intravenously on Day 1 of Cycle 1, followed by 500 mg/m2 every 2 weeks for 4 doses and then every 4 weeks for 3 doses), with a 28-day cycle length.
c Bendamustine plus a rituximab product (BR): Bendamustine 70 mg/m2 intravenously (Day 1 and 2 of each 28-day cycle), in combination with a rituximab product (375 mg/m2 intravenously on Day 1 of Cycle 1, then 500 mg/m2 on Day 1 of subsequent cycles), for up to 6 cycles.
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 (Cheson 2012). IRC-assessed ORR per IWCLL 2008 criteria was a secondary endpoint.
Mantle Cell Lymphoma
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 (Table 14).
Table 14 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% |
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 subject 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.
14.2 Study Results
Previously Untreated Chronic Lymphocytic Leukemia (CLL)
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 15. The Kaplan-Meier curves for PFS are shown in Figure 1.
Table 15 Efficacy 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 | 22.6 |
| Efficacy Parameter | CALQUENCE plus Obinutuzumab N=179 | CALQUENCE Monotherapy N=179 | Obinutuzumab plus Chlorambucil N=177 |
|---|---|---|---|
| (34.2, NR) | (20.2, 27.6) | ||
| HRb (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.
a Independent Review Committee (IRC) assessment per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012).
b Based on stratified Cox-Proportional Hazards model.
c CALQUENCE + obinutuzumab compared to obinutuzumab + chlorambucil.
d CALQUENCE monotherapy compared to obinutuzumab + chlorambucil.
e ORR: (CR + CRi + nPR + PR).
f Per IRC assessment.
g Includes 1 patient in the CALQUENCE + obinuzumab arm with CRi.
h PR = 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 1 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
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 16. The Kaplan-Meier curve for PFS is shown in Figure 2. The difference in overall response rate between the two arms did not reach statistical significance.
Table 16 Efficacy Results from the ASCEND Trial in Patients with Previously Treated CLL (ITT population)
CALQUENCE monotherapy N=155 | Investigator’s choice of idelalisib + rituximab or bendamustine + rituximab N=155 | ||||||||||||||
| 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), monthsb | NR | 16.5 (14.0, 17.1) | |||||||||||||
| HRc (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.
a Independent Review Committee (IRC) assessment per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012).
b Kaplan-Meier estimate.
c Based on stratified Cox-Proportional-Hazards model.
d Per IRC assessment.
e ORR: (CR + CRi + nPR + PR); there were no patients with CRi or nPR.
Figure 2 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).
Mantle Cell Lymphoma
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 17. 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 17 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 Assesseda n (%) (95% CIb) |
|---|---|
| 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
a Per Lugano classification for non-Hodgkin’s lymphoma (Cheson et al. 2014, J.Clin.Oncol.32:3059- 3068).
b 95% exact binomial confidence interval.
c Non-Evaluable: 3 subjects were non-evaluable due to inadequate post-baseline disease assessment.
15 NON-CLINICAL TOXICOLOGY
Carcinogenicity
Carcinogenicity studies have not been conducted with acalabrutinib.
Genotoxicity/Mutagenicity
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.
Repeat-dose toxicity
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.
Reproductive 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 embryofoetal 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 foetal rat plasma.
In an embryofoetal 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 foetal development, growth, or survival at doses of 50 mg/kg/day (approximately equivalent to the human AUC exposure at the recommended dose). Decreased foetal 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.