Leukemias, lymphomas, and other hematologic cancers:
Indications for: GAZYVA
In combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In combination with bendamustine followed by Gazyva monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen. In combination with chemotherapy followed by Gazyva monotherapy, for the treatment of previously untreated stage II bulky, III or IV follicular lymphoma in patients achieving at least a partial remission.
Chronic Lymphocytic Leukemia
Efficacy was evaluated in a 3-arm, open-label, active-controlled, randomized trial (CLL11; ClinicalTrials.gov Identifier: NCT01010061) in 781 patients with previously untreated CD20+ CLL requiring treatment who had coexisting medical conditions or reduced renal function as measured by ClCr <70mL/min (median age, 73 years, 62% male, 95% White).
Patients were treated with chlorambucil control (Arm 1), Gazyva in combination with chlorambucil (Arm 2), or rituximab product in combination with chlorambucil (Arm 3). The safety and efficacy of Gazyva was evaluated in a Stage 1 comparison of Arm 1 vs Arm 2 in 356 patients and a Stage 2 comparison of Arm 2 vs Arm 3 in 663 patients.
In Stage 1, median progression free survival (PFS) in the Gazyva combination arm was 27.2 months vs 11.2 months in the chlorambucil alone arm (median observation time, 22.8 months). Overall response rate and median duration of response was 78.2% and 22.4 months for the Gazyva combo arm and 33.1% and 4.7 months for chlorambucil alone arm. The hazard ratio [HR] for overall survival (OS) was 0.41 (95% CI, 0.23-0.74).
In Stage 2, median PFS was 26.7 months in the Gazyva arm vs 14.9 months in the rituximab + chlorambucil arm with a median observation time of 18.7 months (HR, 0.42; 95% CI, 0.33-0.54, P <.0001). Overall response rate and median duration of response was 79.6% and 19.6 months for the Gazyva combo arm and 66.3% and 9.7 months for the rituximab combo arm.
The efficacy of Gazyva was evaluated in an open-label, randomized study that included 335 patients with follicular lymphoma (FL) who had no response to or had progressed during or within 6 months of rituximab product or a rituximab product-containing regimen (ClinicalTrials.gov Identifier: NCT01059630).
Patients were randomly assigned to receive either bendamustine alone or Gazyva in combination with bendamustine for 6 cycles, each of 28 days duration. Median PFS in the bendamustine arm was 13.8 months and was not reached in the Gazyva plus bendamustine arm (PFS HR, 0.48; 95% CI, 0.34-0.68; P <.0001), with a median observation time of 21.1 months.
The final analysis included 171 patients randomly assigned to bendamustine alone and 164 to Gazyva in combination with bendamustine. There were 66 deaths (40.2%) reported in the Gazyva arm and 85 deaths (51.3%) in the bendamustine arm (OS HR, 0.71; 95% CI, 0.51-0.98), with an overall median observation time of 52.2 months (range, 0-100.9 months).
The phase 3 study evaluated the safety and efficacy of Gazyva + chemotherapy followed by Gazyva alone for up to 2 years, compared with rituximab + chemotherapy followed by rituximab alone for up to 2 years; the chemotherapy (CHOP, CVP or bendamustine) regimen was chosen by each study site prior to study enrollment. Of the total patients with previously untreated NHL, 1,202 had advanced follicular lymphoma (stage II bulky, III or IV).
Results showed superior PFS in patients treated with the Gazyva-based regimen vs patients treated with the rituximab-based regimen. The Gazyva-based regimen significantly reduced the risk of disease worsening or death by 28% vs the rituximab-based regimen (HR, 0.72; 95% CI, 0.56-0.93; P =.0118). Overall response rate (ORR), a secondary endpoint, was 91% of the Gazyva cohort and 88% of the rituximab cohort.
See full labeling. Premedicate (eg, glucocorticoid, APAP, antihistamine) before each infusion. Provide prophylactic hydration and antihyperuricemics to those at risk for TLS. Give by IV infusion for 6 treatment cycles (28 days duration). CLL: Cycle 1 (Day 1): 100mg at 25mg/hr over 4 hours; (Day 2): 900mg at 50mg/hr if no infusion-related reaction (IRR) occurred previously, and can be increased at 50mg/hr every 30mins to max 400mg/hr; if an IRR occurred, give at 25mg/hr and can be increased up to 50mg/hr every 30mins to max 400mg/hr; (Days 8 and 15): 1000mg at 100mg/hr if no IRR occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr; if an IRR occurred, give at 50mg/hr and can be increased at 50mg/hr every 30mins to max 400mg/hr. Cycles 2–6 (Day 1): 1000mg at 100mg/hr if no IRR occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr; if an IRR occurred, give at 50mg/hr and can be increased at 50mg/hr every 30mins to max 400mg/hr. FL: Relapsed/refractory: give with bendamustine for six 28-day cycles; Previously untreated: give with either bendamustine for six 28-day cycles, with CVP for eight 21-day cycles, or with CHOP for six 21-day cycles followed by two additional 21-day cycles of Gazyva monotherapy. Cycle 1 (Day 1): 1000mg at 50mg/hr, can be increased at 50mg/hr every 30mins to max 400mg/hr; (Days 8 and 15): 1000mg at 100mg/hr if no IRR (or a Grade 1 IRR) occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr; if Grade ≥2 IRR occurred previously, give at 50mg/hr and can be increased at 50mg/hr every 30mins to max 400mg/hr. Cycles 2–6 or 2–8 (Day 1): 1000mg at 100mg/hr if no IRR (or a Grade 1 IRR) occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr; if Grade ≥2 IRR occurred previously, give at 50mg/hr and can be increased at 50mg/hr every 30mins to max 400mg/hr; followed by Gazyva monotherapy (every 2months for up to 2yrs): 1000mg at 100mg/hr if no IRR (or a Grade 1 IRR) occurred previously, and increased by 100mg/hr increments every 30mins to max 400mg/hr; if Grade ≥2 IRR occurred previously, give at 50mg/hr and can be increased at 50mg/hr every 30mins to max 400mg/hr. In FL patients (if no Grade ≥3 IRR during Cycle 1, may administer Gazyva as a shorter, approx. 90min infusion from Cycle 2 onwards): 100mg/hr for 30mins, then 900mg/hr for approx. 60mins; if Grade 1–2 IRR with ongoing symptoms or Grade ≥3 IRR occurs during previous 90min infusion, administer all subsequent infusions at standard infusion rate. Management of infusion reactions, premedication: see full labeling.
Hepatitis B virus (HBV) reactivation. Progressive multifocal leukoencephalopathy (PML).
Risk of hepatitis B virus (HBV) reactivation; immediately discontinue and any concomitant chemotherapy if occurs. Screen for HBV infection prior to initiation; if positive evidence, monitor and consider antiviral therapy. Discontinue treatment and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressives if progressive multifocal leukoencephalopathy (PML) develops. Monitor closely for infusion-related reactions; reduce infusion rate, interrupt, or permanently discontinue based on severity. Preexisting cardiac or pulmonary conditions: monitor more frequently during and post-infusion period for severe reactions. Risk of TLS in high tumor burden, high circulating lymphocyte count (>25 x 109/L), or renal impairment. Active infection: do not administer. History of recurring or chronic infections. Risk of neutropenia; monitor for signs of infection. Severe or prolonged neutropenia, give antimicrobial prophylaxis until resolved to Grade 1 or 2; consider antiviral and antifungal prophylaxis. Monitor for thrombocytopenia and hemorrhagic events esp. during the 1st cycle and if clinically indicated; if Grade 3 or 4 thrombocytopenia, obtain platelet counts more frequently until resolved; transfusion of blood products may be necessary. Risk of disseminated intravascular coagulation (may be serious). Monitor coagulation parameters, platelet counts, signs/symptoms of bleeding or thrombosis. Permanently discontinue if hypersensitivity reaction is suspected. Hepatic or renal impairment (CrCl <30mL/min). Embryo-fetal toxicity. Advise females of reproductive potential to use effective contraception during and for 6 months after the last dose. Pregnancy: risk of fetal B-cell depletion. Nursing mothers: not recommended (during and for 6 months after the last dose).
CD20-directed cytolytic monoclonal antibody.
Concomitant live viral vaccines: not recommended during treatment and until B-cell recovery (esp. neonates/infants if exposed to Gazyva in utero). Consider withholding antihypertensives for 12hrs prior to, during, and for 1hr after infusion until BP is stable. Consider withholding drugs that may increase bleeding risk (eg, platelet inhibitors, anticoagulants) esp. during 1st cycle.
Infusion reactions, neutropenia, fatigue, thrombocytopenia, diarrhea, cough, constipation, pyrexia, upper RTI, arthralgia, sinusitis, asthenia, UTI, headache, insomnia, pneumonia, decreased appetite, alopecia, pruritus.
Half-life: 25.5 days (CLL); 35.3 days (NHL).
Generic Drug Availability:
Single-use vial (40mL)—1