slow accrual

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 Mantle Cell Lymphoma (MCL) (i.e., prior single agent rituximab is permitted, prior involved-field radiotherapy is permitted).

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 end of treatment (EOT) (PB only).

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:

        • Left ventricular ejection fraction (LVEF) ≤ 50%
        • Chronic stable angina or congestive heart failure controlled with medication
        • New York Heart Association (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. Eastern Cooperative Oncology Group (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

up to 36 months