Ofatumumab With or Without Bendamustine for Patients With Mantle Cell Lymphoma Ineligible for Autologous Stem Cell Transplant

Study Overview
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Brief Summary
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This study is being done to understand how to treat Mantle Cell Lymphoma (MCL). The goals of treatment are to control the lymphoma with the least amount of side effects. In many cases, MCL is treated with an antibody plus chemotherapy. An antibody is a laboratory-produced substance created to attach to proteins on the cancer cells, eventually destroying them. Chemotherapy is medicine that specifically destroys cancer cells. The purpose of this study is to find out what effects, good and/or bad, the drugs Ofatumumab and Bendamustine have on this type of cancer. Patients in this study will either receive Ofatumumab alone, or Ofatumumab combined with Bendamustine.

Official Title
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Ofatumumab With or Without Bendamustine for Patients With Mantle Cell Lymphoma Ineligible for Autologous Stem Cell Transplant

Conditions
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Mantle Cell Lymphoma

Intervention / Treatment
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* Biological: Ofatumumab (This arm is closed)
* Other: Ofatumumab + Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Untreated, non-transplant eligible, newly diagnosed mantle cell lymphoma with measurable disease as determined by CT, and bone marrow biopsy. Age > or = to 65 years or > 18 year and ineligible for HDT/ASCT. Subjects must not be candidates for intensive high-dose chemotherapy, with or without an autologous stem cell transplant (ASCT), due to one or more of the following factors: Age ≥ 65 years Patients <65 years of age must be ineligible for HDT/ASCT on the basis of comorbidity, organ dysfunction or patient refusal for HDT/ASCT Comorbid disease, such as CAD, CHF, pulmonary dysfunction, liver or kidney dysfunction, precluding high dose therapy secondary to expected increased morbidity and mortality. poor performance status (KPS 70% or less) Ejection fraction <45% Impaired pulmonary function test with DLCO <50% expected Patient refusal Medical conditions which in the opinion of the treating physician and DMT preclude HDT/ASCT. Patients must have a serum creatinine clearance ≥ 40 mL/min (as per the Jelliffe method) or by 12-hour or 24-hour urine creatinine clearance. Patients must have ANC>1,000/mcl and Platelets>100,000/mcl (unless secondary to MCL). Patients must have a bilirubin level of < 2.0 mg/dl in the absence of a history of Gilbert's disease (or pattern consistent with Gilbert's). Negative serologies for Hepatitis B (HB) defined as a negative test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if negative, patient may be included but must undergo HBV DNA PCR testing at the beginning of treatment and throughout treatment duration, at least every 2 months. In addition patients will require treatment with Entacavir .5mg po qday per MSKCC institutional guidelines. No active co-morbid cardiac condition such as active CHF or CAD. KPS performance ≥ 70%. Histologically confirmed mantle cell lymphoma classified according to WHO criteria confirmed at MSKCC. No prior treatment for mantle cell lymphoma with the exception of corticosteroids for 7 days or less or 1 course of involved-field radiation. No prior malignancies within 5 yrs, unless treated early stage breast cancer, treated carcinoma in situ of the cervix, resected skin malignancies, or treated prostate cancer. Women who are pre-menopausal must have a negative serum pregnancy test. Subjects must agree to use appropriate contraception until 4 weeks after the completion of chemotherapy. Patients must be HIV negative, and have negative serologies for Hepatitis C. Exclusion Criteria: Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, hepatic involvement by MCL, or stable chronic liver disease per investigator assessment). Known pregnancy or breast-feeding. Medical illness unrelated to MCL within the prior one month that will preclude administration of chemotherapy safely. This includes patients with uncontrolled infection, chronic renal insufficiency, myocardial infarction within the past 6 months, unstable angina, active congestive heart failure, cardiac arrhythmias other than chronic atrial fibrillation and chronic active or persistent hepatitis.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: patients receiving Immunotherapy (This arm is closed)<br>The proposed study is a Simon 2 stage optimal study design investigating the activity of ofatumumab alone or in conjunction with Bendamustine for patients with MCL who are either not candidates for ASCT or aged 65 or older. The study design will allow for an estimation of the single agent response of ofatumumab in patients at low biologic risk for immediate disease progression. | Biological: Ofatumumab (This arm is closed)<br>* Ofatumumab Day 1 Week 1: 1000 mg, Day 2 week 1: 1000mg. Patients who exhibit a baseline leukocytosis ≥ 20,000 will receive 300 mg of ofatumumab on day 1, week 1. Thereafter, they can receive the 1000 mg dose Ofatumumab Day 1, Weeks 2-4: 1000 mg Will reassess 8-10 weeks after conclusion of treatment with CT CAP, and following this q 12 wks for 2 yrs, then q 6mo until POD or for a maximum of 5 years<br>|
| Experimental: patients receiving Chemoimmunotherapy<br>The proposed study is a Simon 2 stage optimal study design investigating the activity of ofatumumab alone or in conjunction with Bendamustine for patients with MCL who are either not candidates for ASCT or aged 65 or older. The combined regimen will assess the response rates of the combined chemo- immunotherapy program in patients with need for cytoreductive therapy, or high risk for disease progression. Patients with a leukemic phase only presentation of mantle cell lymphoma generally have clinically low-risk disease, regardless of mantle cell IPI calculations. Upon reciew with the principal investigator, these patients may be stratified to the immunotherapy only arm if clinically appropriate. | Other: Ofatumumab + Bendamustine<br>* Ofatumumab day 1 + Bendamustine 90 mg/m2 days 1 & 2 x 6 cycles q 28 days Cycle 1, day 1: Ofatumumab 1000 mg followed by Bendamustine 90 mg/m2. Patients who exhibit a leukocytosis ≥ 20,000 will receive 300 mg of ofatumumab on day 1, week 1. Thereafter, they can receive the 1000 mg dose. Cycle 1, day 2: Ofatumumab 1000mg followed by Bendamustine 90 mg/m2 Cycles 2-6: Ofatumumab 1000 mg day 1, Bendamustine 90 mg/m2 days 1 and 2 Will reassess 4-6 weeks after conclusion of treatment with CT CAP, and following this q 12 wks for 2 yrs, then q 6mo until POD or for a maximum of 5 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| single agent efficacy (as determined by response rate) | of the monoclonal antibody ofatumumab alone in low risk patients. Assessments prior to each cycle of immunotherapy or chemoimmunotherapy: (every 4 weeks) | 2 years | 
| the efficacy (as determined by response rate) of the combination ofatumumab + Bendamustine | in high risk patients. Assessments prior to each cycle of immunotherapy or chemoimmunotherapy: (every 4 weeks) | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | will be analyzed using Kaplan-Meier estimation, and logrank tests or Cox regression models when covariates are involved. | 2 years | 
| progression free survival (PFS) | will be analyzed using Kaplan-Meier estimation, and logrank tests or Cox regression models when covariates are involved. | 2 years | 
| Remission duration | (calculated from confirmation of CR to progression)will be analyzed using competing risks tools (with death as a competing risk for progression), and will be done on the subsets of patients who have CR or CR/PR. | 2 years | 
| Response duration | (calculated from confirmation of response (CR/PR) to progression. will be analyzed using competing risks tools (with death as a competing risk for progression), and will be done on the subsets of patients who have CR or CR/PR. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bendamustine HCL, Ofatumumab (GSK 1841157), Immunotherapy, Chemoimmunotherapy, 11-050