A Study Comparing RO5072759 (GA101) 1000 mg Versus 2000 mg in Patients With Previously Untreated Chronic Lymphocytic Leukemia (GAGE)

Lymphocytic Leukemia, Chronic Clinical Trial

Official title:

An Open-label, Multicenter, Randomized Phase II Trial Comparing the Efficacy, Safety, and Pharmacokinetics of GA101 1000 mg Versus 2000 mg in Patients With Previously Untreated Chronic Lymphocytic Leukemia

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01414205
• Other study ID #: GAO4768g
• Secondary ID: GO25677
• Status: Active, not recruiting
• Phase: Phase 2
• First received: August 10, 2011
• Last updated: May 22, 2014
• Start date: October 2011
• Est. completion date: March 2016

Study information

• Verified date: May 2014
• Source: Genentech, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This open-label, multicenter, randomized study will compare the efficacy, safety and pharmacokinetics of RO5072759 (GA101) 1000 mg versus 2000 mg in patients with previously untreated chronic lymphocytic leukemia. The randomization scheme will ensure approximately equal sample sizes in the two treatment dose arms for the following stratification factors: 1) tumor burden at baseline (high or low); and 2) Rai stage at baseline (study entry; I/II or III/IV). Tumor burden will be assessed on the basis of the presence or absence of at least one nodal mass >/= 5 cm in the baseline computed tomography (CT) scan. Patients will be randomized to receive a maximum of 8 cycles of GA101: 1000mg intravenous (iv) infusion, on days 1 (split dose 100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of cycle 1 and day 1 of cycles 2 - 8 on 21 day cycles or maximum of 8 cycles of GA101 2000mg iv infusion, on days 1 (split dose 100 mg on Day 1, 900 mg on Day 2, 1000 mg on Day 3), 8 and 15 of cycle 1 and day 1 of cycles 2 - 8 on 21 day cycles.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 80
• Est. completion date: March 2016
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Cluster of differentiation antigen 20 (CD20)-positive B-cell chronic lymphocytic leukemia [per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines]

• Rai Stage III/IV or Binet Stage C disease, or Rai Stage I/II or Binet Stage B disease that requires treatment according to IWCLL guidelines

• No previous treatment for CLL chemotherapy, radiotherapy or immunotherapy; no previous rituximab treatment for autoimmune hemolytic anemia (AIHA) or Idiopathic thrombocytopenic purpura (ITP); prior use of steroids for AIHA or ITP is allowed

• Eastern Cooperative Oncology Group performance status of 0, 1 or 2

Exclusion Criteria:

• Transformation of CLL to aggressive B-cell malignancy

• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy

• Evidence of severe, uncontrolled concomitant disease

• Known active infection or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks before the start of Cycle 1

• Seropositive for human immunodeficiency virus (HIV)

• Positive for chronic hepatitis B infection (defined as positive HBsAg serology)

• Positive for hepatitis C (hepatitis C virus [HCV] antibody serology testing)

• Pregnant or lactating women

• Concurrent (or within 7 days prior to fist dose of study treatment) systemic corticosteroid use, except for low-dose corticosteroid therapy used to treat illness other than lymphoma

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphocytic Leukemia, Chronic

Intervention

Drug:
• Obinutuzumab
Obinutuzumab (RO5072759) Repeating intravenous dose.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Genentech, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR)	ORR was defined as the percentage of participants with complete response (CR), CR with incomplete marrow recovery (Cri) or partial response (PR) as assessed by the investigator according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines two months after last treatment. CR required: blood lymphocytes < 4 x 10^9/Liter (L), absence of lymphadenopathy (= 1.5 centimeter (cm) in long axis by Computed Tomography), no hepatomegaly or splenomegaly, absence of disease, Neutrophils > 1.5 x 10^9/L, Platelets > 100 x 10^9/L, Hemoglobin >11 g/dL, bone marrow normal and lymphoid nodules absent. CRi was CR with incomplete marrow recovery. PR required: 50% decrease in peripheral blood lymphocyte count, 50% reduction in lymphadenopathy, 50% reduction of liver and/or spleen enlargement if enlarged at baseline, Neutrophils > 1.5 x 10^9/L or > 50% of pretreatment value, Platelets > 100 x 10^9/L or 50% of pretreatment value and Hemoglobin > 11 g/dL or > 50% of pretreatment value.	Week 32	No
Secondary	Progression-free Survival (PFS)	PFS was defined as the time from the randomization to the first occurrence of progression or death, whichever occurred first.	up to 3.5 years	No
Secondary	Duration of Response	Duration of response was defined as the first occurrence of a documented, objective response until the first occurrence of relapse or progression or death from any cause.	up to 3.5 years	No
Secondary	Overall Survival (OS)	OS was defined as the time from randomization until death from any cause.	up to 3.5 years	No
Secondary	Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)	An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. A SAE was any AE that was one of the following: fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product or considered a significant medical event by the investigator.; Additional information about AEs can be found in the Adverse Event Section	Randomization to Clinical data cut-off: 27 April 2013 (Up to 1.5 years)	No
Secondary	Percentage of Participants With Adverse Events of Interest	Adverse Events of interest for this study were: serious infusion related reactions during or within 24 hours of infusion, serious neutropenia, serious infection, tumor lysis syndrome and Hepatitis B reactivation.	Randomization to Clinical data cut-off: 27 April 2013 (Up to 1.5 years)	No
Secondary	Percentage of Participants With Adverse Events Leading to Study Discontinuation	An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution.	Randomization to Clinical data cut-off: 27 April 2013 (Up to 1.5 years)	No
Secondary	PK Parameter: Maximum Serum Concentration (Cmax)	Blood was collected for Pharmacokinetic (PK) Parameter Cmax after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in micrograms per milliliter (µg/mL).	Day 148 (at end of infusion)	No
Secondary	PK Parameter: Area Under the Serum Concentration-Time Curve Between Dosing Interval Tau (AUCt )	Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in day times micrograms per milliliter (day*µg/mL).	Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)	No
Secondary	PK Parameter: Clearance at Steady State (CLss)	Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). CLss is reported in milliliters per day (mL/day).	Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)	No
Secondary	PK Parameter: Volume of Distribution at Steady State (Vss)	Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). Vss is reported in liters.	Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)	No
Secondary	PK Parameter: Terminal Half-Life (t1/2)	Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). T1/2 was reported in Days.	Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)	No
Secondary	Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion	Blood was sent to a central laboratory for the evaluation of cluster of differentiation 19 (CD19) by flow cytometry. B-cell depletion was defined as a CD19 result < 0.07 × 10^9/L after at least one dose of study drug has been administered.	Randomization to Clinical data cut-off: 27 April 2013 (Up to 1.5 years)	No
Secondary	Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery	Blood was sent to a central laboratory for the evaluation of cluster of differentiation 19 (CD19) by flow cytometry. B-cell recovery was defined as a CD19 result = 0.07 × 10^9/L, where CD19 was previously depleted. B-cell recovery was only considered possible following the last dose of study treatment. The number of participants with B-cell recovery from End of Treatment to 6 months of Follow-up is reported in two categories: Recovery with Progressive Disease (PD) [PD before B-cell recovery or PD within 45 days after recovery] or Recovery without PD. PD required one of the following: 50% increase in the absolute number of circulating lymphocytes, Appearance of new palpable lymph nodes, 50% increase in the longest diameter of any previous site of lymphadenopathy, 50% increase in the enlargement of the liver and/or spleen or Transformation to a more aggressive histology.	Randomization to Clinical data cut-off: 27 April 2013 (Up to 1.5 years)	No