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

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Mantle Cell Lymphoma, Non-hodgkin Lymphoma, Non Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Bendamustine
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years at the time of signing the informed consent document. Histologically confirmed mantle cell lymphoma (confirmation of cyclin D1 positivity on diagnostic biopsy). Subjects must have at least one bi-dimensionally measurable lesion; one of the measurements must be ≥1.5 cm in one direction 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. Prior therapy with rituximab is permitted, even in the setting of rituximab-refractory disease. Must meet one of the following criteria: 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 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. ECOG performance status of ≤2 at study entry. Laboratory test results within these ranges: Absolute neutrophil count ≥1500/µL. Platelet count ≥100,000/µL. 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. Subjects must have adequate renal function with a creatinine clearance of ≥40 mL/min as determined by the Cockcroft-Gault calculation. 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. Serum transaminases AST (SGOT) and ALT (SGPT) ≤5X ULN. Serum alkaline phosphatase ≤5X ULN. 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). Life expectancy of at least 3 months. Understand and voluntarily sign an informed consent document. Exclusion Criteria: Subjects are not eligible if there is a prior history or current evidence of central nervous system or leptomeningeal involvement. Concurrent use of other anti-cancer agents or treatments. 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. 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. Severe or life-threatening anaphylaxis or hypersensitivity reaction when previously exposed to rituximab or other mAb therapy. Known to be positive for HIV or infectious hepatitis (type B or C). Pregnant or breast-feeding females. 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

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bendamustine + Obinutuzumab (BO)<br>Induction 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 | Drug: Bendamustine<br>* Bendamustine is a chemotherapeutic agent that has dual functional properties of both an alkylating agent and a nitrogen mustard. Through these unique cytostatic properties, bendamustine is able to inhibit DNA transcription, replication, and repair. Bendamustine is approved in the U.S. for treatment of CLL and for indolent B cell NHLs progressing during or within 6 months of rituximab or a rituximab - containing regimen.<br>Drug: Obinutuzumab<br>* Obinutuzumab is a glycoengineered, humanized, type II anti-CD20 mAb.<br>* Other names: RO5072759;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) at 2 years | 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. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimal Residual Disease (MRD) status | 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. | 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 | 
| Estimate the concordance rate between peripheral blood (PB) and bone marrow aspirates (BMA) in predicting MRD status. | 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). | 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 | 
| Determine objective response rates (CR + PR) with induction BO in previously untreated MCL using the Lugano classification for response in lymphoma | 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. | 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) | 
| Overall Survival (OS) | 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. | Up to 2 years | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 during therapy induction BO chemoimmunotherapy and obinutuzumab consolidation and maintenance | 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. | Up to 25 months (until 30 days after completion of final dose of study-related treatment) |