Clinical Trials /

Bendamustine + Obinutuzumab Induction With Obinutuzumab Maintenance in Untreated Mantle Cell Lymphoma

NCT03311126

Description:

This is a phase II single-arm, open-label, multicenter study evaluating the efficacy and safety of the combination of induction chemoimmunotherapy with bendamustine and obinutuzumab (BO) followed by consolidation therapy and maintenance therapy with obinutuzumab in subjects who have not received prior cytotoxic chemotherapy for their MCL (i.e., prior single agent rituximab is permitted, prior involved-field radiotherapy is permitted).

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Bendamustine + Obinutuzumab Induction With Obinutuzumab Maintenance in Untreated Mantle Cell Lymphoma
  • Official Title: Bendamustine + Obinutuzumab Induction Chemoimmunotherapy With Risk-adapted Obinutuzumab Maintenance Therapy in Previously Untreated Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: UW16086
  • SECONDARY ID: 2017-0609
  • SECONDARY ID: NCI-2017-01729
  • SECONDARY ID: A534260
  • SECONDARY ID: SMPH\MEDICINE\HEM-ONC
  • NCT ID: NCT03311126

Conditions

  • Mantle Cell Lymphoma
  • Non-hodgkin Lymphoma
  • Non Hodgkin Lymphoma

Interventions

DrugSynonymsArms
BendamustineBendamustine + Obinutuzumab (BO)
ObinutuzumabGA101, RO5072759Bendamustine + Obinutuzumab (BO)

Purpose

This is a phase II single-arm, open-label, multicenter study evaluating the efficacy and safety of the combination of induction chemoimmunotherapy with bendamustine and obinutuzumab (BO) followed by consolidation therapy and maintenance therapy with obinutuzumab in subjects who have not received prior cytotoxic chemotherapy for their MCL (i.e., prior single agent rituximab is permitted, prior involved-field radiotherapy is permitted).

Detailed Description

      This is a phase II single-arm, open-label, multicenter study evaluating the efficacy and
      safety of the combination of induction chemoimmunotherapy with bendamustine and obinutuzumab
      (BO) followed by consolidation therapy and maintenance therapy with obinutuzumab in subjects
      who have not received prior cytotoxic chemotherapy for their MCL (i.e., prior single-agent
      rituximab is permitted, prior involved-field radiotherapy is permitted). Therapy for
      individual subjects will be risk-adapted based on results of minimal residual disease (MRD)
      testing performed after the consolidation phase. The study will be carried out at the
      University of Wisconsin Carbone Cancer Center (UWCCC) and participating community and
      academic practice sites within the Wisconsin Oncology Network (WON). There will be 6-10 sites
      participating in this study.

      The subject participation will include a screening period, treatment period, and a follow-up
      period. The induction chemoimmunotherapy regimen consists of bendamustine and obinutuzumab
      for 4-6 cycles, followed by consolidation and maintenance therapy with obinutuzumab in
      subjects achieving an objective response to induction therapy (i.e., complete or partial
      response; stable disease with objective evidence of tumor shrinkage. Subjects who are
      MRD-negative (determined by MRD testing on bone marrow and PB) after consolidation therapy
      will omit maintenance therapy.

      Subjects will undergo disease reassessment after C4 of induction BO chemoimmunotherapy, after
      obinutuzumab consolidation therapy, and after C4 and C8 of maintenance obinutuzumab. MRD
      testing will be done after C2 of induction (PB only), after consolidation (BMA and PB), and
      post-maintenance or EOT (PB only).
    

Trial Arms

NameTypeDescriptionInterventions
Bendamustine + Obinutuzumab (BO)ExperimentalInduction chemoimmunotherapy (28 day cycles): Bendamustine 90 mg/m2 IV days 1 & 2 every 28 days X 4-6 cycles Obinutuzumab: Cycle 1: 100 mg IV day 1, 900 mg IV day 2, 1000 mg IV days 8 & 15 Cycles 2-6: 1000 mg IV day 1 Consolidation phase: Obinutuzumab 1000 mg IV weekly X 4 doses Maintenance phase (8 week cycles): Obinutuzumab 1000 mg IV on day 1 of cycles 1-8
  • Bendamustine
  • Obinutuzumab

Eligibility Criteria

        Inclusion Criteria:

          1. Age ≥18 years at the time of signing the informed consent document.

          2. Histologically confirmed mantle cell lymphoma (confirmation of cyclin D1 positivity on
             diagnostic biopsy).

          3. Subjects must have at least one bi-dimensionally measurable lesion; one of the
             measurements must be ≥1.5 cm in one direction

          4. No prior cytotoxic chemotherapy; prior therapy with single-agent rituximab is
             permitted. Prior involved-field radiotherapy to symptomatic nodal sites of involvement
             is also permitted.

          5. Prior therapy with rituximab is permitted, even in the setting of rituximab-refractory
             disease.

          6. Must meet one of the following criteria:

               1. Not eligible for more intensive cytotoxic chemotherapy or consolidative
                  autologous stem cell transplant based on one or more of the following:

                    -  Clinically significant heart or lung comorbidities, as reflected by at least
                       1 of the following:

                         -  LVEF ≤ 50%

                         -  Chronic stable angina or congestive heart failure controlled with
                            medication

                         -  NYHA class III or IV heart failure

                         -  Symptomatic chronic pulmonary disease or requirement for intermittent
                            or continuous oxygen therapy

                    -  Presence of other medical comorbidity or limitation in functional status
                       which the investigator judges to be incompatible with an acceptable risk to
                       the subject with the use of intensive chemotherapy. The associated
                       comorbidity or functional limitation must be clearly documented in the
                       medical record at the time of enrollment.

                  OR

               2. Subject has been informed of the risks and benefits of intensive chemotherapy and
                  autologous stem cell transplant for treatment of mantle cell lymphoma and has
                  refused this option. This discussion must be clearly documented in the medical
                  record at the time of enrollment.

          7. ECOG performance status of ≤2 at study entry.

          8. Laboratory test results within these ranges:

               1. Absolute neutrophil count ≥1500/µL.

               2. Platelet count ≥100,000/µL.

               3. Subjects with neutrophils <1500/µL or platelets <100,000/µL with splenomegaly or
                  extensive bone marrow involvement as the etiology for their cytopenias are
                  eligible.

               4. Subjects must have adequate renal function with a creatinine clearance of ≥40
                  mL/min as determined by the Cockcroft-Gault calculation.

               5. Total bilirubin ≤2X upper limit laboratory normal (ULN); subjects with
                  nonclinically significant elevations of bilirubin due to Gilbert's disease are
                  not required to meet these criteria.

               6. Serum transaminases AST (SGOT) and ALT (SGPT) ≤5X ULN.

               7. Serum alkaline phosphatase ≤5X ULN.

          9. Disease-free of prior malignancies for ≥2 years with the exception of basal or
             squamous cell skin carcinoma, carcinoma "in situ" of the breast or cervix, or
             localized prostate cancer (treated definitively with hormone therapy, radiotherapy, or
             surgery).

         10. Life expectancy of at least 3 months.

         11. Understand and voluntarily sign an informed consent document.

        Exclusion Criteria:

          1. Subjects are not eligible if there is a prior history or current evidence of central
             nervous system or leptomeningeal involvement.

          2. Concurrent use of other anti-cancer agents or treatments.

          3. Any serious medical condition, laboratory abnormality, or psychiatric illness that
             would prevent the subject from signing the informed consent document or complying with
             the protocol treatment.

          4. Prior malignancy, except for adequately treated basal cell or squamous cell skin
             cancer, in situ cervical or breast cancer, or other cancer from which the subject has
             been disease free for at least 2 years.

          5. Severe or life-threatening anaphylaxis or hypersensitivity reaction when previously
             exposed to rituximab or other mAb therapy.

          6. Known to be positive for HIV or infectious hepatitis (type B or C).

          7. Pregnant or breast-feeding females.

          8. Any condition, including the presence of laboratory abnormalities, which places the
             subject at unacceptable risk if he/she were to participate in the study or confounds
             the ability to interpret data from the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS) at 2 years
Time Frame:Up to 2 years
Safety Issue:
Description:For each patient, progression-free survival (PFS) will be defined as the number of days from C1D1 of induction chemoimmunotherapy to the day patient experiences an event of disease progression or death, whichever occurs first. If a patient has not experienced an event at the time of analysis, patient's data will be censored at the date of the last available evaluation. The 2-year PFS probability will be estimated using the Kaplan-Meier method. From the date of C1D1 of induction therapy to the date of progression or death; in the absence of progression or death, subjects will be followed for a minimum of 24 months after completion of study-related treatment.

Secondary Outcome Measures

Measure:Minimal Residual Disease (MRD) status
Time Frame:At the end of Cycle 2 of induction therapy (each cycle is 28 days), following consolidation phase of therapy (after 6 cycles of induction, consolidation is 4 weekly doses of obinutuzumab), and within 30 days of completing protocol therapy
Safety Issue:
Description:MRD defined as reduction to >=10^-6 fold reduction in the IgVH unique clone of MCL (mantle cell lymphoma) by NGS (next generation sequencing). MRD status will be evaluated after 2 cycles of induction chemoimmunotherapy with bendamustine and obinutuzumab, after 4 cycles of consolidation with obinutuzumab, and after an additional 8 cycles of maintenance with obinutuzumab. MRD status will be summarized using frequency and proportion with 95% confidence intervals. MRD status will be collected on peripheral blood after cycle 2 of induction therapy, on peripheral blood and bone marrow aspirate after consolidation obinutuzumab, and peripheral blood after maintenance therapy completion.
Measure:Estimate the concordance rate between peripheral blood (PB) and bone marrow aspirates (BMA) in predicting MRD status.
Time Frame:At the end of Cycle 2 of induction therapy (each cycle is 28 days), following consolidation phase of therapy (after 6 cycles of induction, consolidation is 4 weekly doses of obinutuzumab), and within 30 days of completing protocol therapy
Safety Issue:
Description:Concordance between PB and BMA in predicting MRD negative status will be summarized by percent of subjects in which MRD status is concordant (i.e., both positive in the PB and BMA or both negative in the PB and BMA).
Measure:Determine objective response rates (CR + PR) with induction BO in previously untreated MCL using the Lugano classification for response in lymphoma
Time Frame:At the end of induction cycle 4 (each cycle is 28 days), after consolidation therapy (post-induction, consolidation is 4 weekly doses Obinutuzumab), and after Cycles 4 and 8 of Maintenance Obinutuzumab (each cycle is 8 weeks)
Safety Issue:
Description:Lugano criteria will be used to assess radiographic response by CT and/or PET imaging. Imaging for response assessment will be performed after 4 cycles of induction therapy, after consolidation obinutuzumab, and after cycles 4 and 8 of maintenance obinutuzumab. Bone marrow biopsy will be performed verify complete responses.
Measure:Overall Survival (OS)
Time Frame:Up to 2 years
Safety Issue:
Description:For a given subject, OS will be defined as the number of days from C1D1 of the induction chemoimmunotherapy to the day the subject dies. Survival times of subjects who are still alive at the end of the follow-up period will be censored. OS will be summarized using point estimate of the median OS, along with the 95% confidence interval.
Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 during therapy induction BO chemoimmunotherapy and obinutuzumab consolidation and maintenance
Time Frame:Up to 25 months (until 30 days after completion of final dose of study-related treatment)
Safety Issue:
Description:Count of toxicities from the initiation of study treatment until 30 days following the last administration of study treatment or study discontinuation/termination; after this period, only SAES that are possibly, probably, or definitely attributed will be reported. For a given subject, toxicities will be assessed from the time of C1D1 of study therapy until 30 days after completion of final dose of study-related treatment.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Wisconsin, Madison

Last Updated

November 18, 2019