Summary Basis of Decision for Gazyva

Clinical Pharmacology

Gazyva (obinutuzumab) is a recombinant monoclonal humanized and glycoengineered Type II anti-CD20 antibody of the Immunoglobulin G1 (IgG1) isotype. It specifically targets the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B and mature B-lymphocytes, but not on haematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissue. Glycoengineering of the Fc part of Gazyva results in higher affinity for FcγRIII receptors on immune effector cells such as natural killer cells, and macrophages and monocytes as compared to non-glycoengineered antibodies.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the dosing regimen of Gazyva for the recommended indication.

For further details, please refer to the Gazyva Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Gazyva was evaluated primarily in one Phase III study (BO21004/CLL11), a randomized, three arm, open-label, active control, randomized, multicentre study. The study population included patients with previously untreated CD20+ chronic lymphocytic leukemia (CLL) requiring treatment who also had coexisting medical conditions and/or reduced renal function as measured by a creatinine clearance (CrCl) <70 mL/min. The BO21004/CLL11 study assessed Gazyva in combination with chlorambucil (GClb) versus (vs.) rituximab in combination with chlorambucil (RClb) vs. chlorambucil (Clb) alone.

Study BO21004/CLL11 was designed to include two stages. Stage 1 compared GClb vs. Clb, and RClb vs. Clb. Stage 2 compared GClb vs. RClb. Stage 1 was split into Stage 1a (GClb vs. Clb) and Stage 1b (RClb vs. Clb) as the two primary analysis time points. This Summary Basis of Decision focuses on the efficacy from the primary efficacy analysis of GClb vs. Clb (referred to as the Stage 1a analysis). Efficacy results from Stage 1b and Stage 2 of study BO21004/CLL11 will be submitted to Health Canada when they become available.

Prior to the start of enrolment in the BO21004/CLL11 study, six patients entered a safety run-in phase with GClb to assess the safety of the combination therapy. After the formal safety review of the six run-in patients were met, a total of 356 patients were randomized in Stage 1 to GClb, RClb or Clb alone in a 2:2:1 ratio. Randomization was stratified by Binet stage and region. Main diagnosis and criteria for inclusion were documented CD20+ B-cell chronic lymphocytic leukemia (B-CLL) according to National Cancer Institute (NCI) criteria, previously untreated CLL requiring treatment according to the NCI criteria and total cumulative illness rating scale score >6 or creatinine clearance <70 mg/min.

The majority of patients enrolled in the Stage 1a were Caucasian, 60% male and 40% female. The median age was 73 years (39-88). Sixty-five percent of patients had a creatinine clearance <70 mL/min and 76% had multiple coexisting medical conditions. Twenty-two percent of patients were Binet stage A, 42% were stage B and 36% were Stage C. The baseline characteristics were in general comparable between the two treatment arms.

The BO21004/CLL11 study design for Stage 1a consisted of patients in the GClb treatment arm [Number of patients (n) = 238] to receive Gazyva 1,000 mg by intravenous (IV) infusion on Day 1, Day 8 and Day 15 of the first cycle followed by treatment on the first day of five subsequent cycles (total of 6 cycles, 28 days each). All patients in the Clb treatment arm (n = 118) received oral chlorambucil 0.5 mg/kg body weight on Day 1 and Day 15 for all treatment cycles (1 to 6). At the clinical cut off on July 11, 2012, the median observation time in the GClb arm was 14.5 months and 13.6 months in the Clb arm.

The primary efficacy endpoint for this study was progression-free survival (PFS) as assessed by the primary investigator. Progression-free survival (PFS) was also assessed by an Independent Review Committee (IRC). The regulatory decision for this submission was made based on the IRC assessment. The secondary endpoints included, end of treatment response, best overall response, event-free survival, duration of response, disease-free survival, time to new anti-leukemic therapy, and overall survival. The secondary endpoints were not adjusted for multiplicity and therefore were not considered confirmatory.

The final Stage 1a analysis results of PFS (at the specified clinical cut-off date) showed that the median PFS assessed by the IRC was 23.0 months in the GClb arm vs. 11.1 months in the Clb arm with a hazard ratio of 0.16 [95% Confidence Interval (CI): 0.11, 0.24] and log-rank p-value <0.0001. The median PFS assessed by the investigator was 23.0 months vs. 10.9 months, thus consistent with the IRC assessment.

The results of the key secondary endpoints, which include end of treatment response rate, duration of response, time to new anti-leukemic treatment and molecular remission were in support and consistent with the PFS results in CLL patients receiving Gazyva therapy. However, there was no adjustment for multiplicity for the secondary endpoints: the results are considered not confirmatory. The overall survival time could not be estimated in either of the treatment arms due to the low number of deaths at the data cut-off point. Overall survival will continue to be followed.

In conclusion, Gazyva (obinutuzumab) in combination with chlorambucil demonstrated a statistically significant and clinically relevant improvement in median progression-free survival (PFS) in previously untreated elderly CLL patients with comorbidities in comparison to chlorambucil alone. All response related assessments are in support of the benefit of Gazyva in combination with chlorambucil over chlorambucil alone.

For more information, refer to the Gazyva Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Gazyva was evaluated in 660 Gazyva-treated patients based on the clinical safety data provided from the Stage 1a analysis of the Phase III BO21004/CLL11 study described previously in the Clinical Efficacy section, along with four supporting Phase I/II studies. The adverse drug reactions (ADRs) described in this section focus primarily on safety issues identified during treatment and follow-up based on the pivotal Phase III BO21004/CLL11 study, in which Gazyva was given in combination with chlorambucil (Clb) compared to chlorambucil (Clb) alone.

The majority of patients in Stage 1a of the BO21004/CLL11 study experienced at least one adverse event (AE) of any grade up to the clinical cut-off date, which includes combined treatment and safety follow-up periods. A total of 93% of patients in the GClb treatment arm experienced AEs compared to 82% of patients receiving only Clb. Most AEs experienced by patients were Grade 1-2 and occurred primarily during the treatment period. The higher incidence of AEs reported in the GClb treatment arm was attributed largely to the addition of AEs known to be associated with the mechanism of action of Gazyva.

The most common (≥10%) treatment-related ADRs observed in the Stage 1a analysis were infusion reactions, neutropenia, thrombocytopenia, nausea, anemia, diarrhea, and pyrexia. Severe infusion reactions (Grade 3-4) were experienced by 21% of patients, 8% of patients experienced an event leading to discontinuation. The most frequently reported symptoms of infusion reactions (>20%) included nausea, chills, hypotension, pyrexia, vomiting, dyspnea, flushing, hypertension, headache, tachycardia, and diarrhea. Respiratory and cardiac symptoms such as, bronchospasm, larynx and throat irritation, wheezing, laryngeal edema and atrial fibrillation have also been reported as symptoms associated with an infusion reaction. A serious warnings and precaution statement has been inserted in the Gazyva Product Monograph suggesting patients be monitored closely during infusion, given Gazyva can cause severe and life-threatening infusion reactions.

In Stage 1a of the BO21004/CLL11 study, serious adverse events (SAEs) were more frequent in the GClb arm (37%) compared to the Clb arm (32%) and occurred more frequently during the treatment period than the follow-up period. Serious infection was the most frequently reported SAE (10% GClb vs. 14% Clb), with pneumonia being the most common event.

In the GClb arm of the BO21004/CLL11 study, 13% of patients had at least one AE that led to withdrawal of Gazyva. Infusion reaction was the most frequent cause of Gazyva discontinuation.

At the clinical cut-off date (11 July 2012), a total of 22 randomized patients had died: 9/118 patients (7.6%) in the Clb arm and 13/238 patients (5.5%) in the GClb arm.

There were 16 deaths caused by AEs. During treatment, 6/116 patients (5%) in the Clb arm and 5/240 patients (2%) in the GClb arm died because of an adverse event (AE). In the Clb arm, 3 patients died because of an infection and the three other deaths were due to intracranial hemorrhage, pancreatitis and respiratory failure. In the GClb arm, deaths were due to cerebrovascular accident, hemorrhagic stroke, colon cancer, squamous cell carcinoma and subdural hematoma. During follow up, 2/86 patients (2%) in the Clb arm died due to an adverse event (pneumonia, septic shock) and 3/199 (2%) patients in the GClb arm died (unknown cause, general physical health deterioration, and myocardial infarction). Other reported deaths were due to disease progression.

Adverse Events of Particular Interest

Gazyva therapy is associated with CD20-directed cytolytic antibody class adverse drug reactions, such as Hepatitis B virus reactivation (HBV) and progressive multifocal leukoencephalopathy (PML). The most common adverse events that occurred in a large proportion of patients treated with Gazyva were infusion reactions and bone marrow suppression; both AEs can be serious and/or severe. Adverse events that were infrequent, however important and could be fatal or serious AEs, included tumor lysis syndrome, cardiovascular events, infections, and thrombocytopenia. Although with an unknown relationship, fatal hemorrhagic events have been reported in patients receiving Gazyva in first treatment cycle. A significant proportion of patients developed anti-obinutuzumab antibodies during treatment and/or follow-up period. Clinical or pharmacokinetic consequences of these antibodies have not been fully investigated.

Hepatitis B Virus Reactivation and Progressive Multifocal Leukoencephalopathy

Hepatitis B virus reactivation and PML are two known risks for patients receiving anti-CD20 antibodies. No HBV reactivation or PML were reported in the clinical studies submitted for this submission. However, cases of HBV reactivation and PML have been reported with Gazyva therapy from other clinical studies conducted in patients with lymphoma.

Tumor Lysis Syndrome

In the Phase III BO21004/CLL11 (Stage 1a update, cut-off date 09 May 2013) study, TLS occurred in 4% (10 patients) randomized to the GClb treatment arm with 1% of these events defined as serious (Grade 3-4). In comparison, only 1% (1 patient) in the Clb treatment arm developed TLS (Grade 2). The higher incidence of patients with TLS in the GClb treatment arm is expected given the Gazyva mode of action of inducing a more rapid cell lysis with the initiation of therapy. None of the patients in either treatment arm were withdrawn from the BO21004/CLL11 study due to TLS. Also, none of the TLS events resulted in a fatal outcome (Grade 5).

Patients with higher tumor burden and/or higher circulating lymphocyte count (>25 x 10⁹/L are known to be at a greater risk to develop TLS and should receive adequate tumor lysis prophylaxis with uricostatics and hydration starting 12-24 hours prior to the infusion of Gazyva.

Cardiovascular

Cardiovascular events including cardiac arrhythmias, cardiac failure, and myocardial infarction occurred in 8% of patients in the GClb treatment arm compared to 5% in the Clb treatment arm, 5% and 3% during treatment, and 4% vs. 2% during the follow-up period respectively. In the GClb treatment arm, 3/240 patients vs. 1/116 patients in the Clb arm experienced Grade 3-4 cardiac disorders during the treatment period. These cardiac events may occur as part of an infusion reaction, may be fatal, and may worsen an existing cardiovascular disease. Patients with a history of cardiac disease should be monitored closely when administered Gazyva.

Anti-obinutuzumab Antibodies

Anti-obinutuzumab antibodies were tested in 70 previously untreated CLL patients within the BO21004/CLL11 study. Nine out of 70 (13%) patients tested positive for anti obinutuzumab antibodies at one or more time points during the treatment period and/or 12 month follow-up period. Neutralization activity of anti-obinutuzumab antibodies was not assessed. Clinical or pharmacokinetic consequences of these antibodies have not been investigated.

Hematologic

Across all submitted clinical studies and safety updates with Gazyva, four fatal hemorrhagic events (cerebrovascular accident, alveolar pulmonary hemorrhage, subdural hematoma, and hemorrhagic stroke) during Cycle 1 have been reported in CLL patients treated with Gazyva. A clear relationship between fatal hemorrhagic events and Gazyva has not been established.

Other Adverse Events of Interest

Neutropenia

Grade 3 or 4 neutropenia occurred in more than one third of patients receiving Gazyva (with normal neutrophils at baseline). Febrile neutropenia, worsening existing neutropenia and prolonged (lasting more than 28 days) or late onset neutropenia (occurring 28 days or later after completion of treatment) were also observed. As such, blood cell counts in patients receiving Gazyva should be closely monitored with regular laboratory tests.

Thrombocytopenia

Gazyva in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia, in 11% of patients in study BO21004/CLL11. In 5% of patients, Gazyva caused acute thrombocytopenia occurring within 24 hours following Gazyva infusion. Fatal hemorrhagic events such as cerebrovascular accident, alveolar pulmonary haemorrhage, subdural hematoma, and hemorrhagic stroke during Cycle 1 have been reported in CLL patients treated with Gazyva. A clear relationship between thrombocytopenia and hemorrhagic events has not been established. As a result, frequent monitoring of all patients receiving Gazyva, especially during Cycle 1, for thrombocytopenia and hemorrhagic events, is highly recommended.

B-Cell Depletion

Due to the mechanism of action of Gazyva, anti-CD20 antibody induced B-cell depletion with Gazyva is expected. The majority of patients that had their B-cell assessed had prolonged peripheral B-cell depletion following the last dose of Gazyva.

For more information, refer to the Gazyva Product Monograph, approved by Health Canada and available through the Drug Product Database.