Clinical Trials /

Combination of Obinutuzumab and Venetoclax in Relapsed or Refractory DLBCL

NCT02987400

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination of Obinutuzumab and Venetoclax in Relapsed or Refractory DLBCL
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: AGMT_NHL-15B
  • SECONDARY ID: 2016-001760-10
  • NCT ID: NCT02987400

Conditions

  • Lymphoma, Large B-Cell, Diffuse

Interventions

DrugSynonymsArms
VenetoclaxGA-101Treatment
ObinutuzumabGazyvaroTreatment

Purpose

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      Once the sixth patient has completed 21 days of treatment, withdrawn due to toxicity, or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.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalObinutuzumab 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.
  • Venetoclax
  • Obinutuzumab

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 2.

          -  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 1.

          -  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 ≥ 3.

          -  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.

          -  Symptomatic neurologic disease compromising normal activities of daily living or
             requiring medications.

          -  Any sensory or motor peripheral neuropathy greater than or equal to Grade 2.

          -  Known history of any of the following cardiovascular conditions:

               -  myocardial infarction within 2 years of study entry,

               -  New York Heart Association (NYHA) Class III or IV heart failure,

               -  evidence of current uncontrolled cardiovascular conditions, including cardiac
                  arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic
                  evidence of acute ischemia or active conduction system abnormalities,

               -  recent evidence (within 6 months before first dose of study drug) of a
                  left-ventricular ejection fraction <50% .

          -  Diagnosed or treated for another malignancy within 3 years before the first dose or
             previously diagnosed with another malignancy and have evidence of residual disease.

          -  Patients with transformed lymphoma.

          -  Primary CNS lymphoma.

          -  Vaccination with live vaccines within 28 days prior to treatment.

          -  History of other malignancy that could affect compliance with the protocol or
             interpretation of results (Patients with a history of curatively treated basal or
             squamous cell carcinoma or Stage 1 melanoma of the skin or in situ carcinoma of the
             cervix are eligible).

          -  Patients with a malignancy that has been treated with surgery alone with curative
             intent will also be excluded, unless the malignancy has been in documented remission
             without treatment for ≥ 3 years prior to enrollment.

          -  Evidence of significant, uncontrolled concomitant diseases that could affect
             compliance with the protocol or interpretation of results or that could increase risk
             to the patient.

          -  Significant pulmonary disease (including obstructive pulmonary disease and history of
             bronchospasm).

          -  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
             (excluding fungal infections of nail beds) at study enrollment, or any major episode
             of infection requiring treatment with IV antibiotics or hospitalization (relating to
             the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1.

          -  Requires the use of warfarin (because of potential drug-drug interactions that may
             potentially increase the exposure of warfarin).

          -  Received the following agents within 7 days prior to the first dose of venetoclax:

               -  CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin

               -  Strong CYP3A inducers such as rifampin, carbamazepine

          -  Consumed grapefruit, grapefruit products, Seville oranges (including marmalade
             containing Seville oranges) or star fruit within 3 days prior to the first dose of
             venetoclax.

          -  Clinically significant history of liver disease, including viral or other hepatitis,
             current alcohol abuse, or cirrhosis.

          -  Presence of positive test results for Hepatitis B, Hepatitis C and CMV.

          -  Recent major surgery (within 6 weeks prior to the start of Cycle 1 Day 1), other than
             for diagnosis.

          -  Any of the following abnormal laboratory values:

               -  Calculated creatinine clearance < 50 mL/min with the use of the 24-hour
                  creatinine clearance or modified Cockcroft-Gault equation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical activity and tolerability
Time Frame:After 3 cycles of treatment (9 weeks)
Safety Issue:
Description:Objective response rate (complete or partial responses; best response) defined by PET/CT scan and bone marrow examination examination after 3 cycles.

Secondary Outcome Measures

Measure:Safety: Incidence of dose-limiting toxicities
Time Frame:9 weeks induction plus maximum of 27 weeks consolidation
Safety Issue:
Description:Incidence of dose-limiting toxicities of the combination treatment.
Measure:Response duration
Time Frame:From first documented response until end of follow up (max 108 weeks)
Safety Issue:
Description:
Measure:Progression-free survival
Time Frame:72 weeks after last patient last visit
Safety Issue:
Description:
Measure:Overall survival
Time Frame:72 weeks after last patient last visit
Safety Issue:
Description:
Measure:Ability to proceed to further stem cell transplantation
Time Frame:After 3 cycles of treatment (9 weeks)
Safety Issue:
Description:Assessed by number of eligible patients reaching transplant
Measure:Genetically/biomarker defined subgroups
Time Frame:72 weeks after last patient last visit
Safety Issue:
Description:Identification of genetically/biomarker defined subgroups regarding response and survival

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Arbeitsgemeinschaft medikamentoese Tumortherapie

Trial Keywords

  • DLBCL
  • GA-101
  • ABT-199
  • relapsed DLBCL
  • refractory DLBCL
  • AGMT
  • Diffuse large B-cell lymphoma
  • window of opportunity

Last Updated

January 8, 2019