A Dose-Escalating Study of Obinutuzumab in Patients With B-lymphocyte Antigen (CD20+) Malignant Disease (GAUGUIN)

Study Overview
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Brief Summary
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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.

Official Title
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An Open-label, Multicentre, Nonrandomized, Dose-escalating Phase I/II Study, With a Randomized Phase II Part, to Investigate the Safety and Tolerability of RO5072759 Given as Monotherapy in Patients With CD20+ Malignant Disease.

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I, NHL<br>Participants in this NHL arm received multiple ascending doses between 50 and 2000 mg via intravenous infusion of obinutuzumab. | Drug: Obinutuzumab<br>* Obinutuzumab was provided in single-dose glass vials as a freeze-dried powder.<br>* Other names: GA101;|
| Experimental: Phase I, CLL<br>Participants in this CLL arm received multiple ascending doses between 400 and 2000 mg via intravenous infusion of obinutuzumab. | Drug: Obinutuzumab<br>* Obinutuzumab was provided in single-dose glass vials as a freeze-dried powder.<br>* Other names: GA101;|
| Experimental: 400/400 mg - Phase II, iNHL<br>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. | Drug: Obinutuzumab<br>* Obinutuzumab was provided in single-dose glass vials as a freeze-dried powder.<br>* Other names: GA101;|
| Experimental: 1600/800 mg - Phase II, iNHL<br>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. | Drug: Obinutuzumab<br>* Obinutuzumab was provided in single-dose glass vials as a freeze-dried powder.<br>* Other names: GA101;|
| Experimental: 400/400 mg - Phase II, aNHL<br>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. | Drug: Obinutuzumab<br>* Obinutuzumab was provided in single-dose glass vials as a freeze-dried powder.<br>* Other names: GA101;|
| Experimental: 1600/800 mg - Phase II, aNHL<br>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. | Drug: Obinutuzumab<br>* Obinutuzumab was provided in single-dose glass vials as a freeze-dried powder.<br>* Other names: GA101;|
| Experimental: 1000/1000 mg - Phase II, CLL<br>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. | Drug: Obinutuzumab<br>* Obinutuzumab was provided in single-dose glass vials as a freeze-dried powder.<br>* Other names: GA101;|
| Experimental: Retreated Participants<br>Participants who might benefit from retreatment who were allowed to be treated again via intravenous infusion of obinutuzumab at the request of the investigator. | Drug: Obinutuzumab<br>* Obinutuzumab was provided in single-dose glass vials as a freeze-dried powder.<br>* Other names: GA101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced a Dose-limiting Toxicity in Phase I of the Study | 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. | Baseline to 28 days after the last infusion of obinutuzumab (up to 6 months) | 
| Percentage of Participants With Best Overall Response in Phase II of the Study | Best overall response (BOR) was defined as the percentage of participants with a complete response (CR) or partial response (PR) | by Cutoff Date: 31 March 2012 (within 3 years, 4 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR/CRu/CRi) in Phase II of the Study | 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. | by Cutoff Date: 31 March 2012 (within 3 years, 4 months) | 
| Percentage of Participants With Partial Response (PR) in Phase II of the Study | 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. | by Cutoff Date: 31 March 2012 (within 3 years, 4 months) | 
| Progression-free Survival (PFS) in Phase II of the Study | 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. | by the end of the follow-up period in Phase II of the study (within 3 years, 4 months) | 
| Duration of Response by Disease Type in Phase II of the Study | 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. | by the end of the follow-up period in Phase II of the study (within 3 years, 4 months) | 
| Participants With Event-Free Survival (EFS) in Phase II of the Study | 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. | by the end of the follow-up period in Phase II of the study (within 3 years, 4 months) | 
| Pharmacodynamics: Participants With Peripheral B-cell Recovery After Having Had Depletion at End of Treatment During Phase II of the Study | 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. | by the end of Phase II (within 3 years, 4 months) | 
| Percentage of Retreated Participants With Response | Patients who might benefit from retreatment were allowed to be treated again at the request of the investigator. | by Cutoff Date: 25 November 2013 (within 4 years, 2 months) | 
| Maximum Plasma Concentration (Cmax) of Obinutuzumab in NHL Participants | Obinutuzumab serum pharmacokinetic (PK) parameters in NHL participants following ascending doses. | at Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 8 (over 168 days) | 
| Area Under the Concentration-time Curve of Obinutuzumab Administered on Day 1 of Cycle 1 in Phase I of the Study | 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. | Day 1 of Cycle 1 |