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"The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).


CLL is a blood and bone ma"...



Mechanism Of Action

Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. Upon binding to CD20, obinutuzumab mediates B-cell lysis through (1) engagement of immune effector cells, (2) by directly activating intracellular death signaling pathways and/or (3) activation of the complement cascade. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.


In clinical trials in patients with CLL, GAZYVA caused CD19 B-cell depletion (defined as CD19 B-cell counts < 0.07 x 109/L). Initial CD19 B-cell recovery was observed in some patients approximately 9 months after the last GAZYVA dose. At 18 months of follow up, some patients remain B-cell depleted. Although the depletion of B-cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B-cells in solid organs or in malignant deposits. B-cell depletion has not been shown to be directly correlated to clinical response.

Cardiac Electrophysiology

The potential effects of GAZYVA on the QTc interval have not been studied.


Based on a population pharmacokinetic (pop-PK) analysis, the geometric mean (CV%) volume of distribution of obinutuzumab at steady state is approximately 3.8 (23) L.

The elimination of obinutuzumab is comprised of a linear clearance pathway and a timedependent non-linear clearance pathway. As GAZYVA treatment progresses, the impact of the time-dependent pathway diminishes in a manner suggesting target mediated drug disposition (TMDD). Based on a pop-PK analysis, the geometric mean (CV%) terminal obinutuzumab clearance and half-life are approximately 0.09 (46%) L/day and 28.4 (43%) days, respectively.

Specific Populations

Age: Age did not affect the pharmacokinetics of GAZYVA.

Body Weight: Volume of distribution and steady state clearance both increased with body weight, however, the expected change in exposure does not warrant a dose modification.

Renal Impairment: Based on the population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) > 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr < 30 mL/min.

Hepatic impairment: GAZYVA has not been studied in patients with hepatic impairment.

Clinical Studies

Chronic Lymphocytic Leukemia

GAZYVA was evaluated in a three arm, open-label, active control, randomized, multicenter trial (Study 1) in patients with previously untreated CD20+ chronic lymphocytic leukemia requiring treatment and had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CrCl) < 70 mL/min. Patients with CrCl < 30 mL/min, active infections, positive hepatitis B (HBsAg or anti-HBc positive, patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable) and hepatitis C serology, or immunization with live virus vaccine within 28 days prior to randomization were excluded from the trial. Patients were treated with chlorambucil control (Arm 1), GAZYVA in combination with chlorambucil (Arm 2) or rituximab in combination with chlorambucil (Arm 3). The safety and efficacy of GAZYVA was evaluated in a comparison of Arm 1 vs. Arm 2 in 356 patients. Data comparing Arm 2 vs. Arm 3 are not available at this time.

The majority of patients received 1000 mg of GAZYVA on days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of GAZYVA was divided between day 1 (100 mg) and day 2 (900 mg) [see DOSAGE AND ADMINISTRATION], which was implemented in 45 patients. Chlorambucil was given orally at 0.5 mg/kg on day 1 and day 15 of all treatment cycles (1 to 6).

In Study 1, the median age was 73 years, 60% were male, and 95% were Caucasian. Sixty-eight percent had a CrCl < 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 median estimated CrCl was 61 mL/min. Eighty-one percent of patients treated with GAZYVA in combination with chlorambucil received all 6 cycles compared to 67% of patients in the chlorambucil alone arm.

The median progression free survival (PFS) in the GAZYVA in combination with chlorambucil arm was 23.0 months and 11.1 months in the chlorambucil alone arm (median observation time 14.2 months) as assessed by independent review and is consistent with investigator assessed PFS. Efficacy results are shown in Table 5 and the Kaplan-Meier curve for PFS is shown in Figure 1.

Table 5 : Efficacy Results for Study 1

Endpoint GAZYVA + Chlorambucil Chlorambucil
Median Progression-Free Survivala 23.0 months 11.1 months
(HR 0.16 [0.11; 0.24], p-value < 0.0001 stratified log-rank test)
Overall Response Rateb 75.9% 32.1%
Complete Response 27.8% 0.9%
Median Duration of Response 15.2 months 3 . 5 months
a As defined by independent review. Investigator assessed PFS was consistent with data from independent review.
b As defined as best overall response rate (ORR=CR+PR)

Figure 1: Kaplan-Meier Curve of Progression-Free Survival in Patients with CLL in Study 1

Kaplan-Meier Curve of Progression-Free Survival in Patients with CLL - Illustration

Last reviewed on RxList: 7/14/2014
This monograph has been modified to include the generic and brand name in many instances.


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