A Dose-Escalating Study of Obinutuzumab in Patients With B-lymphocyte Antigen (CD20+) Malignant Disease (GAUGUIN)
- Registration Number
- NCT00517530
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
The primary objective for the phase I part of the study is to investigate the safety and tolerability of escalating intravenous (IV) doses of obinutuzumab given as monotherapy in participants with CD20+ (tumor-infiltrating lymphocytic) Malignant Disease, including B-cell chronic lymphocytic leukemia (CLL) and Non-Hodgkin's Lymphoma (NHL). The primary objective for the phase II part of the study is to investigate the efficacy and safety of one dose of obinutuzumab in participants with relapsed/refractory CLL and NHL that is, in turn, either indolent (iNHL) or aggressive (aNHL).
It is an open label dose escalating study in phase I and open label in phase II, but the two doses in iNHL \& aNHL are randomized (to high or low dose of the same open label treatment). CLL was not randomized as only one dose level was used.
Participants with a response who might gain additional benefit from being treated again in the opinion of the investigator may be enrolled in a Retreatment Period.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 134
- Adult patients, >=18 years of age;
- Phase 1 only: CD20+ malignant disease (B-cell lymphoma or B-CLL);
- Phase 2 only: relapsed or refractory indolent NHL, relapsed or refractory aggressive NHL or relapsed or refractory B-CLL
- Have a clinical indication for treatment as determined by the investigator
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
- Life expectancy >12 weeks
- Prior use of any investigational antibody therapy or other agent within 6 months of study start;
- Prior use of any anti-cancer vaccine;
- Prior use of standard anti-lymphoma/leukemia therapy or radiation therapy within 4 weeks of enrollment;
- Prior use of MabThera (rituximab) within 8 weeks of study entry;
- Prior administration of radioimmunotherapy 3 months prior to study entry;
- Central nervous system (CNS) lymphoma.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase I, CLL Obinutuzumab Participants in this CLL arm received multiple ascending doses between 400 and 2000 mg via intravenous infusion of obinutuzumab. 400/400 mg - Phase II, iNHL Obinutuzumab Participants in this iNHL arm received an intravenous infusion of obinutuzumab 400 mg on Days 1 and 8 of Cycle 1 and obinutuzumab 400 mg on Day 1 of Cycles 2-8 for a maximum of 8 cycles and 9 infusions. Each cycle was 21 days. Phase I, NHL Obinutuzumab Participants in this NHL arm received multiple ascending doses between 50 and 2000 mg via intravenous infusion of obinutuzumab. 1600/800 mg - Phase II, iNHL Obinutuzumab Participants in this iNHL arm received an intravenous infusion of obinutuzumab 1600 mg on Days 1 and 8 of Cycle 1 and obinutuzumab 800 mg on Day 1 of Cycles 2-8 for a maximum of 8 cycles and 9 infusions. Each cycle was 21 days. 400/400 mg - Phase II, aNHL Obinutuzumab Participants in this aNHL arm received an intravenous infusion of obinutuzumab 400 mg on Days 1 and 8 of Cycle 1 and obinutuzumab 400 mg on Day 1 of Cycles 2-8 for a maximum of 8 cycles and 9 infusions. Each cycle was 21 days. 1600/800 mg - Phase II, aNHL Obinutuzumab Participants in this aNHL arm received an intravenous infusion of obinutuzumab 1600 mg on Days 1 and 8 of Cycle 1 and obinutuzumab 800 mg on Day 1 of Cycles 2-8 for a maximum of 8 cycles and 9 infusions. Each cycle was 21 days. Retreated Participants Obinutuzumab Participants who might benefit from retreatment who were allowed to be treated again via intravenous infusion of obinutuzumab at the request of the investigator. 1000/1000 mg - Phase II, CLL Obinutuzumab Participants in this CLL arm received an intravenous infusion of obinutuzumab 1000 mg on Days 1, 8, and 15 of Cycle 1 and obinutuzumab 1000 mg on Day 1 of Cycles 2-8 for a maximum of 8 cycles and 10 infusions. Each cycle was 21 days.
- Primary Outcome Measures
Name Time Method Percentage of Participants Who Experienced a Dose-limiting Toxicity in Phase I of the Study Baseline to 28 days after the last infusion of obinutuzumab (up to 6 months) Dose-limiting toxicities were defined as obinutuzumab-related adverse events occurring within the first 28 days of each administration of obinutuzumab, with the exception of B-cell depletion and lymphopenia which are expected outcomes of treatment with obinutuzumab.
Percentage of Participants With Best Overall Response in Phase II of the Study by Cutoff Date: 31 March 2012 (within 3 years, 4 months) Best overall response (BOR) was defined as the percentage of participants with a complete response (CR) or partial response (PR)
- Secondary Outcome Measures
Name Time Method Participants With Event-Free Survival (EFS) in Phase II of the Study by the end of the follow-up period in Phase II of the study (within 3 years, 4 months) EFS is defined as the time from start of treatment to disease progression/relapse, death or, in case of early withdrawal from the treatment period, the (end) date of last dose, whatever comes first.
Percentage of Participants With Complete Response (CR/CRu/CRi) in Phase II of the Study by Cutoff Date: 31 March 2012 (within 3 years, 4 months) A complete response was defined as the disappearance of all evidence of disease (NHL) and symptoms; normalization of biochemical abnormalities (NHL); regression of lymph nodes and nodal masses to normal size; decrease of nodes in the sum of the products of the greatest diameters (SPD); regression in size of the spleen and/or liver, should not be palpable, and disappearance of nodules related to lymphoma (CLL). Complete/unconfirmed (CRu) response includes NHL patients with one or more of the following: 1) a residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the SPD; 2) Indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural atypia). Complete Response with Incomplete Bone Marrow Recovery (CRi) was measured only in patients with CLL.
Progression-free Survival (PFS) in Phase II of the Study by the end of the follow-up period in Phase II of the study (within 3 years, 4 months) PFS was defined as the time from start of treatment to disease progression (PD) or death due to any cause, whichever occurred first. For non-Hodgkin's lymphoma participants, PD was defined as \>= 50% increase from nadir in the sum of the products of the greatest diameters (SPD) of any previously identified abnormal node for participants with a partial response or non-responders or the appearance of any new lesion during or at the end of therapy. For chronic lymphocytic leukemia participants, PD was defined as: (1) A \>= 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or the size of other lesions (eg, splenic or hepatic nodules); a lymph node with a short axis of \< 1.0 cm must increase by \>= 50% and to a size of 1.5×1.5 cm or \> 1.5 cm in the longest axis. (2) Appearance of any new lesion \> 1 cm in the short axis. (4) A new site that is positron emission tomography (PET)-positive with histological confirmation.
Percentage of Participants With Partial Response (PR) in Phase II of the Study by Cutoff Date: 31 March 2012 (within 3 years, 4 months) A PR was defined as a \>=50% decrease in SPD of the 6 largest nodes or nodal masses; no increase in size of other nodes, liver, or spleen; regression of splenic and hepatic nodules by \>=50% in their SPD or, for single nodules, in the long axis (CLL only); and no new disease sites.
Duration of Response by Disease Type in Phase II of the Study by the end of the follow-up period in Phase II of the study (within 3 years, 4 months) Duration of complete response was defined as the time from the first complete or partial response until disease progression (PD) or death, whichever occurred first. For non-Hodgkin's lymphoma participants, PD was defined as \>= 50% increase from nadir in the sum of the products of the greatest diameters (SPD) of any previously identified abnormal node for participants with a partial response or non-responders or the appearance of any new lesion during or at the end of therapy. For chronic lymphocytic leukemia participants, PD was defined as: (1) A \>= 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or the size of other lesions (eg, splenic or hepatic nodules); a lymph node with a short axis of \< 1.0 cm must increase by \>= 50% and to a size of 1.5×1.5 cm or \> 1.5 cm in the longest axis. (2) Appearance of any new lesion \> 1 cm in the short axis. (4) A new site that is PET-positive with histological confirmation.
Area Under the Concentration-time Curve of Obinutuzumab Administered on Day 1 of Cycle 1 in Phase I of the Study Day 1 of Cycle 1 Blood samples were taken on Day 1 (pre-infusion, end of infusion, 3-6 hours post-infusion) of Cycle 1. Nonlinear mixed-effects modeling (with NONMEM software) was used to analyze the pooled samples for dose-concentration-time data of obinutuzumab.
Pharmacodynamics: Participants With Peripheral B-cell Recovery After Having Had Depletion at End of Treatment During Phase II of the Study by the end of Phase II (within 3 years, 4 months) B-cell depletion was defined in two ways: definition 1 - decrease below 5% baseline level and definition 2 - decrease below 0.04 x 109/L. B-cell recovery was defined in two ways: definition 1 - return to at least 50% of baseline level and definition 2 - return to at least 0.08 x 109/L.
Percentage of Retreated Participants With Response by Cutoff Date: 25 November 2013 (within 4 years, 2 months) Patients who might benefit from retreatment were allowed to be treated again at the request of the investigator.
Maximum Plasma Concentration (Cmax) of Obinutuzumab in NHL Participants at Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 8 (over 168 days) Obinutuzumab serum pharmacokinetic (PK) parameters in NHL participants following ascending doses.