Phase II Single-arm "Window-of-opportunity" Study of a Combination of Obinutuzumab (GA-101) and Venetoclax (ABT-199) in Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)
Overview
- Phase
- Phase 2
- Intervention
- Venetoclax
- Conditions
- Lymphoma, Large B-Cell, Diffuse
- Sponsor
- Arbeitsgemeinschaft medikamentoese Tumortherapie
- Enrollment
- 22
- Locations
- 6
- Primary Endpoint
- Clinical activity and tolerability
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
The purpose of this study is to evaluate the clinical activity and tolerability of a combination of obinutuzumab plus venetoclax in patients with relapsed or refractory diffuse large B-cell lymphoma.
Detailed Description
The study will have a 6 patient run-in phase to determine safety and to adjust treatment. Once the sixth patient has completed 21 days of treatment, withdrawn due to toxicity, or died, a formal review will be undertaken by the sponsor (AGMT). Enrolment will be halted until review is completed. If one (1) treatment related death is reported or three (3) or more patients experience CTC grade 4 events other than neutropenia, anemia, or thrombocytopenia, the study will be stopped for further recruitment. If the stopping criteria are not met, enrollment will be continued. A futility analysis will be conducted when the first 10 patients have been evaluated for response: If at least 2 patients had an objective response (CR or PR), the study will be continued. The combination treatment will be repeated for up to 3 cycles. The first response assessment (including PET-CT) will be performed after the first cycle of obinutuzumab-venetoclax and patients with at least stable disease (SD) or better will be given another 2 cycles of therapy and then have assessment after a total of 3 cycles. Patients with complete or partial remission (CR, PR) after 3 cycles of therapy will either go on to transplant or receive 9 further cycles of the combination therapy (if transplant ineligible). Patients with progressive disease at any time-point or stable disease after 3 cycles will be taken off study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Diffuse large B-cell lymphoma (DLBCL)
- •with histologically confirmed relapse within 12 months after having achieved a PR or CR with initial R-anthracycline containing therapy, or
- •with refractoriness to initial R-anthracycline containing therapy (not achieving at least a partial response)
- •Bcl-2 protein expression detected by immunohistochemistry.
- •Adequate organ function,
- •At least one bi-dimensionally measurable lesion on CT scan defined as \> 1.5 cm in its longest dimension.
- •Confirmed availability of archival or freshly biopsied tumor tissue meeting protocol-defined-specifications prior to study enrolment.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or
- •Adequate hematologic function (unless caused by underlying disease, as established by extensive bone marrow involvement or as a result of hypersplenism secondary to the involvement of the spleen by lymphoma per the investigator)
Exclusion Criteria
- •Patient has received any other investigational treatment within 28 days before study entry.
- •Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of obinutuzumab or venetoclax.
- •DLBCL transformed from other malignancies or CD20 negative DLBCL.
- •Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 4 weeks prior to Cycle 1 Day
- •Ongoing corticosteroid use \> 30 mg/day of prednisone or equivalent. Patients who received corticosteroid treatment with ≤ 30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks duration prior to randomization (Cycle 1 Day 1). Patients may have received a brief (\< 7 days) course of systemic steroids (≤ 100 mg prednisone equivalent) prior to initiation of study therapy for control of lymphoma-related symptoms.
- •ECOG performance status ≥
- •Female patients who are pregnant or breast-feeding.
- •Acute or uncontrolled chronic infections.
- •Known diagnosis of HIV
- •Known cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of PML.
Arms & Interventions
Treatment
Obinutuzumab is given in a 21 day cycle intravenously starting at 1000 mg on day 1, 8 and 15 in cycle 1 and on day 1 of each following cycle Venetoclax is given orally at a dose of 800mg daily from day 1 of the first cycle.
Intervention: Venetoclax
Treatment
Obinutuzumab is given in a 21 day cycle intravenously starting at 1000 mg on day 1, 8 and 15 in cycle 1 and on day 1 of each following cycle Venetoclax is given orally at a dose of 800mg daily from day 1 of the first cycle.
Intervention: Obinutuzumab
Outcomes
Primary Outcomes
Clinical activity and tolerability
Time Frame: After 3 cycles of treatment (9 weeks)
Objective response rate (complete or partial responses; best response) defined by PET/CT scan and bone marrow examination examination after 3 cycles.
Secondary Outcomes
- Genetically/biomarker defined subgroups(72 weeks after last patient last visit)
- Safety: Incidence of dose-limiting toxicities(9 weeks induction plus maximum of 27 weeks consolidation)
- Response duration(From first documented response until end of follow up (max 108 weeks))
- Progression-free survival(72 weeks after last patient last visit)
- Overall survival(72 weeks after last patient last visit)
- Ability to proceed to further stem cell transplantation(After 3 cycles of treatment (9 weeks))