Sylvant Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

SYLVANT^® (siltuximab) is indicated for:

• The treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV)-negative and human herpes virus-8 (HHV-8)-negative.

Pediatrics:

The safety and efficacy of SYLVANT^® have not been studied in pediatric patients.

CONTRAINDICATIONS

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS

General

Anaphylaxis

One case of anaphylaxis (1/82 [1.2%], grade 3) has occurred during infusion with SYLVANT^® in MCD studies. Appropriate personnel and medication should be available during infusion to treat anaphylaxis.

Treatment with SYLVANT^® should be immediately and permanently discontinued in patients who have severe infusion-related hypersensitivity reactions (e.g. anaphylaxis) (see WARNINGS AND PRECAUTIONS, Allergic and Infusion Reactions, and ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions).

Serious Infections

Infections, including localized infections, should be treated prior to administration of SYLVANT^®. Serious infections including pneumonia and sepsis were observed during clinical studies.

SYLVANT^® may mask signs and symptoms of acute inflammation including suppression of fever and of acute phase reactants such as C-reactive protein (CRP). Therefore, prescribers should diligently monitor patients receiving treatment in order to detect serious infections. Treat infections promptly, and do not administer further SYLVANT^® until the infection resolves.

Allergic and infusion reactions

Anaphylaxis has occurred during infusion with SYLVANT^® (see Anaphylaxis above).

In the MCD 2001clinical study, SYLVANT^® was associated with an infusion-related reaction or hypersensitivity reaction in 7.5% of patients treated with SYLVANT^® monotherapy vs. 0 % in the placebo group.

During IV infusion of SYLVANT^®, mild to moderate infusion reactions may improve following slowing of or stopping the infusion. In clinical trials of siltuximab monotherapy dosed at 11 mg/kg, 3.7% of patients in clinical trials required dose delay or interruption due to an infusion-related reaction.

The most common infusion related reactions reported in siltuximab-treated subjects (≥2 subjects) were pruritus, erythema, chest pain, and nausea. Upon resolution of the reaction, reinitiating the infusion at a lower infusion rate and therapeutic administration of antihistamines, acetaminophen, and corticosteroids may be considered. In the MCD2001 clinical study, 5.7% of subjects treated with siltuximab were administered antihistamines in association with an infusion-related reaction versus 0% in the placebo group, and 3.8% were administered corticosteroids in association with an infusion-related reaction versus 0% in the placebo group. For patients who do not tolerate the infusion following these interventions, SYLVANT^® should be discontinued.

Carcinogenesis and Mutagenesis

Immunomodulatory drugs may increase the risk of malignancy. On the basis of limited experience with siltuximab the present data do not suggest any increased risk of malignancy.

Cardiovascular

Hypertension has been reported as an adverse event in siltuximab clinical trials in MCD patients (13.4% vs 3.8% in the placebo group; 7.3% Grade 3 or 4 vs 0% in the placebo group).

Hypotension (grade 3 or higher) has been reported as an adverse event in clinical trials in MCD patients (1.2% vs 0% in the placebo group).

Endocrine and Metabolism

In patients treated with SYLVANT^®, elevations in triglycerides (13.4% vs 0% in the placebo group) and cholesterol (lipid parameters) (8.5% vs 0% in the placebo group) were reported as adverse events. In the MCD 2001 clinical study, 5.7% of SYLVANT^®-treated subjects were administered a lipid-modifying agent in association with an adverse event of hypertriglyceridemia of hypercholesterolemia (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions). Patients should be managed according to current clinical guidelines for management of hyperlipidemia.

In MCD studies, hyperuricemia was reported in 14.6% vs 0% in the placebo group (grade 3 or higher: 3.7% vs. 0). An increase in uric acid levels was reported in MCD studies (13.4% grade 4 vs 15.4% grade 4 in the placebo group).

Gastrointestinal

Gastrointestinal (GI) perforation has been reported in siltuximab clinical trials (0.75%) although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Advise patients of symptoms suggestive of GI perforation. Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation.

Hematologic

Polycythemia was reported as a serious adverse event in siltuximab clinical trials in MCD patients (1.2%).

Hepatic impairment

Following treatment with SYLVANT^® in clinical trials, transient or intermittent mild-to-moderate elevation of hepatic transaminases or other liver function tests such as bilirubin have been reported. SYLVANT^®-treated patients with known hepatic impairment as well as patients with elevated transaminase or bilirubin levels should be monitored.

Immune

In MCD clinical trials, grade 3 or grade 4 neutropenia was reported as an adverse event in 3/82 [3.7%] of siltuximab-treated patients versus 1/26 [3.8%] in placebo-treated patients.

Live, attenuated vaccines should not be given concurrently or within 4 weeks before initiating SYLVANT^® because clinical safety has not been established.

All clinical studies with SYLVANT^® excluded patients with clinically significant infections, including those known to be hepatitis B surface antigen positive. Two cases of reactivated hepatitis B have been reported when SYLVANT^® was administered concomitantly with high dose dexamethasone, and bortezomib, melphalan and prednisone in multiple myeloma patients.

SYLVANT^® did not bind to virally produced IL-6 in a nonclinical study. Patients should be tested to confirm they are not HIV or HHV-8 positive before treatment.

Renal impairment

Renal impairment was reported in 12.2% vs 0% in the placebo group (2.4% grade 3 or higher vs 0% in the placebo group).

Special Populations

Pregnant Women: There are no data from the use of SYLVANT^® in pregnant women.

No maternal or fetal toxicity was observed in cynomolgus monkeys after intravenous administration of siltuximab (see Product Monograph Part II: TOXICOLOGY, Reproductive and Developmental Toxicity). However, as with other immunoglobulin G antibodies, siltuximab crosses the placenta as observed in studies in monkeys.

It is not known whether siltuximab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SYLVANT^® should be given to a pregnant woman only if the benefit clearly outweighs the risk. Women of childbearing potential must use effective contraception during and for 3 months after treatment. Prescribers should also exercise caution when SYLVANT^® is administered with CYP3A4 substrates where a decrease in effectiveness would be undesirable e.g. oral contraceptives (see DRUG INTERACTIONS). As siltuximab crosses the placenta resulting in fetal exposure, infants born to women treated with SYLVANT^® may be at increased risk of infection, and caution is advised in the administration of live vaccines to these infants.

Effects of siltuximab on fertility have not been evaluated in human patients. In cynomolgus monkeys dosed intravenously with siltuximab, no histopathological changes were noted in the reproductive tissues. In mice dosed subcutaneously with an anti-mouse IL-6 monoclonal antibody, no effects on male or female fertility were observed (see Product Monograph Part II: TOXICOLOGY, Reproductive and Developmental Toxicity).

Nursing Women: It is not known whether siltuximab or its metabolites are excreted in human milk. Serum globulin levels were decreased in pregnant animals (GD 34 through lactation day 30) and in the offspring (lactation days 30-120) at both 10 mg and 50 mg/kg weekly IV doses.

Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from SYLVANT^®, including increased risk of infection, women should not breast-feed their infants while taking SYLVANT^®. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

No impact on male fertility was observed in animal studies at doses up to 100 mg/kg. Male patients and their female partners of childbearing potential must use effective contraceptive methods during treatment and for 3 months after all treatment has ended.

Pediatrics (< 18 years of age): The safety and efficacy of SYLVANT^® have not been studied in pediatric patients.

Geriatrics (> 65 years of age): Clinical studies did not include sufficient numbers of patients aged 65 and over (7%) to determine the effect of age on efficacy in the MCD population. No major age-related differences in pharmacokinetic (PK) or in safety profile were observed in clinical studies, but greater sensitivity of some older individuals cannot be ruled out (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

Monitoring and Laboratory Tests

Hematology laboratory tests (absolute neutrophil count, platelet count and hemoglobin) should be performed prior to each dose of SYLVANT^® therapy for the first 12 months and every 3 dosing cycles thereafter (see DOSAGE AND ADMINISTRATION). The prescriber should consider delaying treatment if the treatment criteria outlined in Table 1.5, DOSAGE AND ADMINISTRATION are not met, before administering SYLVANT^®.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Data from all patients treated with SYLVANT^® monotherapy (n=365) at various doses form the overall basis of the safety evaluation.

The most frequent ADRs (> 20% of patients) during treatment with SYLVANT^® in the MCD clinical trials were upper respiratory tract infection (37.8%), pruritus (29.3%), and maculo-papular rash (23.2%).

The most serious ADR associated with the use of SYLVANT^® was anaphylactic reaction (1.2%).

Adverse events leading to dose delay or interruption in MCD studies were reported in 32.9% (27/82) of siltuximab-treated subjects vs 19.2% (5/26) in the placebo group. Adverse events leading to discontinuation were reported in 18.3% (15/82) of siltuximab-treated subjects vs 38.5% (10/26) in the placebo group.

Infections

In the MCD clinical studies, SYLVANT^® was associated with upper respiratory tract infections in 37.8% of patients versus 15.4% of placebo-treated patients. Nasopharyngitis occurred in 13.4% of patients treated with siltuximab monotherapy, compared to 3.8% of placebo-treated patients.

Serious infections included pneumonia and sepsis.

Lipid parameters

In the MCD clinical studies, SYLVANT^® was associated with a higher incidence of hypertriglyceridemia compared with placebo-treated patients (13.4% versus 0%, respectively).

Infusion related reactions and hypersensitivity

In the MCD 2001clinical study, SYLVANT^® was associated with an infusion-related reaction or hypersensitivity reaction in 7.5% of patients treated with SYLVANT^® monotherapy.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse 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 drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

• In Study 1, a randomized placebo controlled Phase 2 study in MCD, 53 patients were randomized to the SYLVANT^® treatment arm and treated at the recommended dose, 11/mg/kg, every 3 weeks and 26 patients were randomized to the placebo arm. Of the 26 placebo-treated patients, 13 patients subsequently crossed-over to receive SYLVANT^®.
• In Study 2, a Phase 1 study, 16 of 37 patients with CD were treated with SYLVANT^®, at the recommended dose of 11 mg/kg every 3 weeks.

Table 1.1 reflects the frequencies of identified adverse drug reactions (ADRs) in Study 1.

Treatment-emergent adverse events reported in ≥3% of patients in the 82 MCD patients (Study 1 and Study 2) treated at the recommended dose of 11 mg/kg every 3 weeks are presented in Table 1.2.

Abnormal Hematologic Findings

Abnormal hematology parameters (Grade 3 and Grade 4) are provided in Table 1.3.

Studies with siltuximab monotherapy at 11 mg/kg

Treatment-emergent adverse events of Grade 3 or higher intensity were integrated from studies of siltuximab monotherapy administered at the target dose of 11 mg/kg in patients with various disease types (including MCD, malignant solid tumours, metastatic renal cell carcinoma, myelodysplastic syndrome, and smoldering multiple myeloma). In this safety population, Grade 3 or higher adverse events with at least a 5% incidence in siltuximab-treated subjects included: thrombocytopenia (5.9%), fatigue (5.9%), dyspnea (5.9%) and hypertension (7.8%) (Table 1.4).

Post-Market Adverse Drug Reactions

Not available.

DRUG INTERACTIONS

Overview

No formal drug-drug interaction studies have been conducted with SYLVANT^®.

Drug-Drug Interactions

In nonclinical studies, IL-6 is known to decrease the activity of cytochrome P450 (CYP450). Binding bioactive IL-6 by siltuximab may result in increased metabolism of CYP450 substrates, because CYP450 enzyme activity will normalize. Therefore, administering SYLVANT^® with CYP450 substrates that have a narrow therapeutic index has the potential to change drug therapeutic effects and toxicity due to alterations in the CYP450 pathways.

Upon initiation or discontinuation of SYLVANT^® in patients being treated with concomitant medications that are CYP450 substrates and have a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended. The dose of the concomitant medication should be adjusted as needed. The effect of SYLVANT^® on CYP450 enzyme activity can persist for several weeks after stopping therapy.

Prescribers should also exercise caution when SYLVANT^® is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, atorvastatin).

No physical biochemical compatibility studies have been conducted to evaluate the co-administration of SYLVANT^® with other agents.

Drug-Food Interactions

No formal drug-food interaction studies have been conducted with siltuximab.

Drug-Herb Interactions

No formal drug-food interaction studies have been conducted with siltuximab.

Drug-Laboratory Interactions

No formal drug-laboratory studies have been conducted with siltuximab.

Drug-Lifestyle Interactions

No formal drug-lifestyle interaction studies have been conducted with siltuximab.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Intravenous infusion (IV) of SYLVANT^® should be administered by qualified healthcare professionals. Comprehensive instructions for the intravenous infusion of SYLVANT^® are given in “Administration”.

• The SYLVANT^® therapy should be withheld if the patient has a severe infection or any severe non-hematological toxicity and can be restarted at the same dose after recovery.
• If the patient develops a severe infusion-related reaction, anaphylaxis, severe allergic reaction, or cytokine release syndrome related to SYLVANT^® infusion, further administration of SYLVANT^® should be discontinued.
• SYLVANT^® did not bind to virally produced IL-6 in a nonclinical study. Patients should be tested to confirm they are not HIV or HHV-8 positive before treatment.

Recommended Dose and Dosage Adjustment

SYLVANT^® 11 mg/kg is given over 1 hour as an intravenous infusion administered every 3 weeks until treatment failure.

Hematology laboratory tests should be performed prior to each dose of SYLVANT^® therapy for the first 12 months and every 3 dosing cycles thereafter. The prescriber should consider delaying treatment if the treatment criteria outlined in Table 1.5 are not met, before administering SYLVANT^®. Dose reduction is not recommended.

Missed Dose

If the patient misses a dose of SYLVANT^®, the patient should be directed to make another appointment to be administered SYLVANT^® as soon as possible.

Administration

Use aseptic technique.

1. 1. Calculate the dose, total volume of reconstituted SYLVANT^® solution required and the number of vials needed. The recommended needle for preparation is 21-gauge 1-½ inch (38mm). Infusion bags (250 mL) must contain Dextrose 5% and must be made of polyvinyl chloride (PVC), or polyolefin (PO), or polypropylene (PP), or polyethylene (PE). Alternatively PE bottles may be used.
2. 2.

   Allow the vial(s) of SYLVANT^® to come to room temperature over approximately 30 minutes. SYLVANT^® should remain at room temperature for the duration of the preparation.

   Reconstitution:

Gently swirl (do not shake or swirl vigorously) the reconstituted vials to aid the dissolution of the lyophilized powder. Do not remove the contents until all of the solids have been completely dissolved. The lyophilized powder should dissolve in less than 60 minutes. Inspect the vials for particulate matter and discoloration prior to dose preparation. Do not use the vials if visibly opaque or foreign particles and/or solution discoloration are present. Dilute the total volume of the reconstituted SYLVANT^® solution dose to 250 mL with sterile Dextrose 5% in Water, by withdrawing a volume equal to the volume of reconstituted SYLVANT^® from the Dextrose 5% in Water, 250 mL bag. Slowly add the total volume of reconstituted SYLVANT^® solution to the 250 mL infusion bag. Gently mix.

1. 3. The reconstituted product SYLVANT^® should be kept for no more than two hours prior to addition into the IV bag. The infusion should be completed within 6 hours of the addition of the reconstituted solution to the infusion bag. Administer the diluted solution over a period of 1 hour using administration sets lined with PVC, or polyurethane (PU), or PE containing a 0.2-micron inline polyethersulfone (PES) filter. SYLVANT^® does not contain preservatives; therefore do not store any unused portion of the infusion solution for reuse.
2. 4. No physical biochemical compatibility studies have been conducted to evaluate the co-administration of SYLVANT^® with other agents. Do not infuse SYLVANT^® concomitantly in the same intravenous line with other agents.
3. 5. Any unused product or waste material should be disposed of in accordance with local requirements.

OVERDOSAGE

Repeated dosing of 15 mg/kg every 3 weeks has been administered without additional adverse reactions.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Siltuximab is a human-mouse chimeric monoclonal antibody that forms high affinity, stable complexes with soluble bioactive forms of human interleukin-6 (IL-6). Siltuximab prevents the binding of human IL-6 to both soluble and membrane-bound IL-6 receptors (IL-6R), thus inhibiting the formation of the hexameric signaling complex with gp130 on the cell surface. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and

B-cells, lymphocytes, monocytes and fibroblasts, as well as malignant cells. IL-6 has been shown to be involved in diverse normal physiologic processes such as induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. Overproduction of IL-6, in chronic inflammatory diseases and malignancies has been linked to anemia and cachexia and has been hypothesized to play a central role in driving plasma cell proliferation and systemic manifestations in patients with CD.

Pharmacodynamics

In vitro, siltuximab dose-dependently inhibited the growth of an IL-6-dependent murine plasmacytoma cell line in response to human IL-6. In cultures of human hepatoma cells, IL-6- stimulated production of the acute phase protein serum amyloid A was dose-dependently inhibited by siltuximab. Similarly, in cultures of human Burkitt’s B-lymphoma cells, the production of immunoglobulin M (IgM) protein in response to IL-6 was dose-dependently inhibited by siltuximab.

Immunogenicity

As with all therapeutic proteins, there is potential for the generation of anti-drug antibodies (immunogenicity). The immunogenicity of siltuximab has been evaluated using antigen-bridging enzyme immunoassay (EIA) and electrochemiluminescence (ECL)-based immunoassay (ECLIA) methods.

In clinical studies including single-agent and combination studies 1 of 411 evaluable patients (having 1 or more immunogenicity samples obtained after their first siltuximab administration) tested positive for anti-siltuximab antibodies. Further immunogenicity analyses of the single positive sample revealed a low titer of anti-siltuximab antibodies with non-neutralizing capabilities. No evidence of altered toxicity profile was identified in the patient who developed antibodies to siltuximab.

Pharmacokinetics

Following the first administration of siltuximab ranging from 0.9 to 15 mg/kg, the area under the concentration-time curve (AUC) and maximal serum concentration (Cmax) increased in an approximately dose-proportional manner and clearance (CL) was independent of dose. During administration of siltuximab, serum concentrations increase through the end of infusion and then decline in a biphasic manner with an initial more rapid decrease in concentration followed by a slower elimination phase. Following the single-dose administration at the recommended dose regimen (11 mg/kg given once every 3 weeks), the clearance was 3.54 ± 0.44 mL/kg/day and half-life was 16.3 ± 4.2 days. Following the repeat dose administration at the recommended dose, siltuximab clearance was found to be time-invariant, and systemic accumulation was moderate (accumulation index of 1.7). In subjects with MCD, the mean CL after the first dose was higher (6.14 ± 2.96 mL/kg/day), however, consistent with the previously reported half-life after the first dose, serum concentrations reached steady-state levels by the sixth every 3-week infusion with mean (± SD) peak and trough concentrations of 332 ± 139 and 84 ± 66 mcg/mL, respectively.

Absorption: Absorption data are not available since all studies administered siltuximab as an IV infusion.

Distribution: Siltuximab is primarily localized to the circulatory system with limited extravascular tissue distribution.

Metabolism: As an IgG1қ mAb, siltuximab is presumably metabolized in the same manner as any other endogenous IgG (degraded into small peptides and amino acids via catabolic pathways), and is subject to similar elimination.

Excretion: No formal studies have been conducted.

Special Populations and Conditions

Pediatrics: The safety and efficacy of siltuximab have not been established in pediatric patients.

Geriatrics: Clinical studies did not include sufficient numbers of patients aged 65 and over (7%) to determine the effect of age on efficacy in the MCD population. No major age-related differences in pharmacokinetic (PK) or in safety profile were observed in clinical studies, but greater sensitivity of some older individuals cannot be ruled out.

Gender: No clinical effect on the clearance of siltuximab was observed in population pharmacokinetic analyses.

Ethnic origin: No clinical effect on the clearance of siltuximab was observed in population pharmacokinetic analyses.

Hepatic Insufficiency: No formal studies of siltuximab in subjects with hepatic impairment have been conducted. For subjects with baseline alanine transaminase ranging from 0.1 to 3.7 times the upper limit of normal, baseline bilirubin ranging from 1.71 to 42.75 mg/dL, baseline albumin ranging from 1.5 to 5.8 g/dL, there was no meaningful effect on siltuximab PK.

Renal Insufficiency: No formal studies of siltuximab in subjects with renal impairment have been conducted. For subjects with baseline calculated creatinine clearance of 12 mL/min or greater, there was no meaningful effect on siltuximab PK. In addition, there were no significant differences in PK for subjects with normal, Stage 2, and Stage 3 impaired renal function.

Genetic Polymorphism: No formal studies have been conducted.

STORAGE AND STABILITY

SYLVANT^® must be refrigerated at 2ºC to 8ºC. Do not use SYLVANT^® beyond the expiration date located on the carton and the vial. This product contains no preservative. Do not freeze. Protect from light.

SPECIAL HANDLING INSTRUCTIONS

Keep out of the sight and reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Each SYLVANT^® 8 mL or 30 mL vial is individually packaged in a carton. SYLVANT^® is supplied in a carton containing 1 vial.

For 100 mg presentation:

The product is supplied (as a sterile, single-use lyophilized dosage form) in an 8 mL Type 1 glass vial with an elastomeric closure and an aluminum seal with a flip-off button.

For 400 mg presentation:

The product is supplied (as a sterile, single-use lyophilized dosage form) in a 30 mL Type 1 glass vial with an elastomeric closure and an aluminum seal with a flip-off button.

Nonmedicinal ingredients include: L-histidine, L-histidine monohydrochloride monohydrate, polysorbate-80 and sucrose.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: siltuximab

Chemical name: Chimeric (human-murine) IgG1κ mAb

Physicochemical properties: Siltuximab is a chimeric (human-murine) IgG1κ mAb that specifically binds human IL-6 with high affinity and prevents its interaction with the IL-6 receptor, glycoprotein (GP) 80. The chimeric antibody contains the variable region of a murine anti human IL-6 mAb and the constant region from a human immunoglobulin gamma (IgG) 1 molecule.

A lyophilized formulation contains siltuximab at pH 4.9 to 5.6 after reconstitution of the lyophile.

CLINICAL TRIALS

Study demographics and trial design

Table 2.1 - Summary of patient demographics for clinical trials in Multicentric Castleman’s disease

Study 1

A Phase 2, multinational, randomized (2:1) double-blind, placebo-controlled study was conducted to assess the efficacy and safety of SYLVANT^® (11 mg/kg every 3 weeks) compared with placebo in combination with best supportive care in patients with MCD. Treatment was continued until treatment failure (defined as disease progression based on increase in symptoms, radiologic progression or deterioration in performance status), discontinuation of treatment, withdrawal from the study, unacceptable toxicity, or until 48 weeks after the last subject started study treatment, whichever occurred earlier. A total of 79 patients with symptomatic MCD were randomized and treated. Table 2.2 presents patient demographic and baseline characteristics for Study 1.

Table 2.2: Patient demographics and baseline characteristics

The primary endpoint of the study was durable tumor and symptomatic response, defined as tumour response (PR and CR based on modified International Working Group response criteria for malignant lymphoma) assessed by independent review and complete resolution or stabilization of prospectively collected MCD symptoms. Thirty-four MCD related signs and symptoms prospectively identified were collected and graded according to the NCI-CTCAE v 4, by investigators. A durable response was defined as tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure.

Study 1 demonstrated a statistically significant improvement in independently reviewed durable tumour and symptomatic response rate in the SYLVANT^® arm compared with the placebo arm (34% vs. 0%, respectively; 95% CI: 11.1, 54.8; p=0.0012).

Key efficacy results from Study 1 are summarized in Table 2.3.

Hemoglobin response was defined as a change from baseline of ≥ 15g/L at week 13. In the response evaluable population, 61.3% (19/31) of siltuximab-treated subjects had a hemoglobin increase of at least 15 g/L at week 13, versus 0% in the placebo group.

One-year survival rate was 100% in the SYLVANT^® arm and 92% in the placebo arm. Overall survival data was not mature at the time of analysis.

Subgroup analyses:

The primary endpoints on various subgroups including age (< 65 years and ≥ 65 years); race (White and Non-White); region (North America, Europe, and Asia-Pacific); baseline corticosteroid use (yes and no); prior therapy (yes and no); and MCD histology (plasmatic and mixed histology) consistently showed that the treatment effect favored the SYLVANT^® arm except no patients with hyaline vascular histology demonstrated a durable tumor and symptomatic response. However, a consistent treatment effect favouring SYLVANT^®-treated patients in the secondary endpoints of best tumour response and median time to treatment failure was shown in the hyaline vascular subgroup.

Study 2

In addition to Study 1, data are available in patients with Castleman’s disease from a single-arm Phase 1 study (Study 2). In this study, 16 out of 37 patients with MCD were treated with 11 mg/kg every 3 weeks. In these 16 patients with MCD treated with 11 mg/kg every 3 weeks for a median of 92 weeks (range 8.1, 252.3), overall tumour response rate by independent review was 43.8% with 6.3% complete response. Eleven of these patients have moved into a long-term extension study and have been treated for a median duration of 68 months (range 40.9, 85.1). All tumour responses were durable for > 18 weeks.

DETAILED PHARMACOLOGY

Clinical Pharmacokinetics

A population pharmacokinetic (PK) analysis was performed and a two-compartment model described the time course of serum siltuximab concentration following multiple intravenous (IV) administrations in 378 subjects with multicentric Castleman’s disease (MCD), Castleman’s disease (CD), renal cell carcinoma (RCC), non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), prostate cancer, ovarian cancer, and smoldering multiple myeloma (SMM) who received single-agent siltuximab at doses ranging from 0.9 to 15 mg/kg.

Body weight had a statistically significant impact on all siltuximab PK parameters (CL, VC, Q, and VP) and was the only clinically relevant covariate in the model. This supports a strategy of body weight-based dosing of siltuximab.

No formal studies of siltuximab in subjects with renal impairment have been conducted. In the population PK analysis, baseline CRCL was used as an indicator for renal function. Creatinine clearance was not found to be significant and therefore does not warrant dose adjustment. Therefore, CRCL at baseline was not assumed to have a clinically relevant effect on siltuximab PK in subjects with calculated CRCL values of 12 mL/min or greater.

No formal studies of siltuximab in subjects with hepatic impairment have been conducted. In the population PK analysis, baseline aspartate aminotransferase (AST), ALT, and ALB were considered in the evaluation of covariates on CL. Since AST and ALT were highly correlated, AST was not assessed as a covariate in the population PK analysis. For subjects with baseline ALT ranging from 0.1 to 3.7 U/L x upper limit of normal (ULN), there was no clinically relevant effect on siltuximab PK. In addition, for subjects with baseline ALB ranging from 1.5 to 5.8 g/dL, and baseline bilirubin ranging from 1.71 to 42.75 mg/dL, there was no clinically relevant effect on siltuximab PK. Clinical relevance of population PK analysis, however, needs to be evaluated concurrently with clinical efficacy and safety data.

No clinical drug interaction studies have been conducted.

Siltuximab PK parameter estimates based on non-compartmental analysis from study CNTO328MCD2001 are presented in table 2.4 below.

Clinical Pharmacodynamics

Rapid and sustained suppression of serum C-reactive protein (CRP) (a marker of interleukin-6 [IL-6] bioactivity) levels in subjects with MCD was observed only in the siltuximab group (not in the placebo group) in Study CNTO328MCD2001, which is indicative of in vivo neutralization of IL-6 bioactivity. The CRP suppression in MCD subjects treated with Chinese hamster ovary (CHO)-derived siltuximab in Study MCD2001 was consistent with that observed in MCD subjects treated with Sp2/0-derived siltuximab in an earlier study (C0328T03, Cohort 7b) at the target dose. Subjects with CD treated at the target dose of 11 mg/kg every 3 weeks in Study C0328T03 showed greater decrease of systemic CRP levels compared with those treated with 8.3 mg/kg every 3 weeks, supporting the clinical efficacy observations. Furthermore, the rapid and sustained CRP suppression observed at a dose of 11 mg/kg every 3 weeks was also observed at 15 mg/kg every 3 weeks in subjects with solid tumours. These results indicate that at the target dose of 11 mg/kg every 3 weeks, bioactive IL-6 is adequately suppressed. There was high intersubject variability of systemic IL-6 levels in Study MCD2001 (both complexed and non-complexed), which were not predictive of clinical response (durable tumour and symptomatic response or tumour response). Measurement of serum IL-6 concentrations during treatment cannot be used as a pharmacodynamic marker, as siltuximab-neutralized antibody-IL-6 complexes interfere with current immunological-based IL-6 quantification methods.

TOXICOLOGY

A summary of toxicology studies is provided in Table 2.5.

REFERENCES

Wong RS, Casper C, Munshi N, et al. A multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with multicentric Castleman’s disease. Blood (ASH Annual Meeting Abstracts) 2013. Abstract 505.