Vincristine Sulfate Liposome Injection (Marqibo®), Bendamustine and Rituximab-Phase I Trial in Indolent B-cell Lymphoma

Study Overview
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Brief Summary
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This study evaluates addition of Vincristine Sulfate Liposome Injection (Marqibo®) to the standard regimen of Bendamustine and Rituximab in adult patients with indolent B-cell lymphoma. This is a dose-escalation study.

Detailed Description
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Bendamustine-rituximab is a standard chemotherapy regimen for treatment of many indolent B-cell lymphomas, but most patients experience a recurrence of the lymphoma. Vincristine sulfate has been a traditional component of chemotherapy regimens in non-Hodgkin lymphoma and it is possible that adding it to the bendamustine-rituximab regimen might provide a better quality of remissions or longer duration of remissions with acceptable toxicity. This is a phase 1, single-center, open-label, single-arm trial in patients with indolent B-cell non-Hodgkin lymphoma otherwise appropriate for bendamustine-rituximab as initial or subsequent line of therapy. Patients will receive the of rituximab and bendamustine in combination with escalating doses of vincristine sulfate liposome injection (Marqibo®). The objective of this study is to assess safety of this combination by establishing the maximum tolerated dose of vincristine sulfate liposome injection (Marqibo®) in the combination.

Official Title
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BrUOG 326: A Phase I Dose-Escalation Study of Vincristine Sulfate Liposome Injection (Marqibo®) in Combination With Bendamustine and Rituximab (BRiM) in Indolent Non-Hodgkin Lymphoma

Conditions
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Lymphoma, Non-Hodgkin, Lymphoma, Follicular, Lymphoma, Mantle-Cell, Lymphoma, Small-Cell, Waldenstrom Macroglobulinemia, Lymphoma, B-Cell, Marginal Zone

Intervention / Treatment
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* Drug: Rituximab
* Drug: Bendamustine
* Drug: Vincristine sulfate liposome injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed indolent B-cell non-Hodgkin lymphoma. Radiological measurable disease. Previous treatment for lymphoma is allowed, with the exception of use of bendamustine within 6 months or any prior use of vincristine sulfate liposome injection Eastern Cooperative Oncology Group performance status 0 or 1; Life expectancy of at least 6 months; Adequate organ and marrow function; Women of child-bearing potential and men must agree to use adequate contraception. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: History of allergic reactions attributed to any drug used in the study. Any lymphoma-directed therapy within 4 weeks. Any prior treatment with vincristine sulfate liposome injection. Prior treatment with bendamustine or vincristine sulfate within 180 days of enrollment. Patients who are receiving any other investigational agents with the exception of endocrine therapy for breast or prostate cancer. Central nervous system involvement. Peripheral sensory or motor neuropathy. History of a demyelinating condition. Positive test for the Human Anti-Chimeric Antibody (HACA). Patients receiving any medications or substances that are strong inhibitors or inducers of Cytochrome P450, family 3, subfamily A (CYP3A) enzyme are ineligible. Uncontrolled intercurrent illness. Prisoners. Pregnant or breast-feeding women. Known Human Immunodeficiency Virus (HIV) or active Hepatitis B infection Any prior or active cancer, which in the opinion of the investigator would preclude safe participation in this 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
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vincristine sulfate liposome injection 1.8 mg/m^2<br>Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | Drug: Rituximab<br>* 375 mg/m2 I.V. on Day 1 of each cycle<br>* Other names: Rituxan, anti-CD20 antibody;Drug: Bendamustine<br>* 90 mg/m2 I.V. on Day 1 and 2 of each cycle<br>* Other names: Treanda;Drug: Vincristine sulfate liposome injection<br>* Dose per dose escalation protocol, I.V. on Day 2 of each cycle<br>* Other names: Marqibo;|
| Experimental: Vincristine sulfate liposome injection 1.95 mg/m^2<br>Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | Drug: Rituximab<br>* 375 mg/m2 I.V. on Day 1 of each cycle<br>* Other names: Rituxan, anti-CD20 antibody;Drug: Bendamustine<br>* 90 mg/m2 I.V. on Day 1 and 2 of each cycle<br>* Other names: Treanda;Drug: Vincristine sulfate liposome injection<br>* Dose per dose escalation protocol, I.V. on Day 2 of each cycle<br>* Other names: Marqibo;|
| Experimental: Vincristine sulfate liposome injection 1.98 mg/m^2<br>Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | Drug: Rituximab<br>* 375 mg/m2 I.V. on Day 1 of each cycle<br>* Other names: Rituxan, anti-CD20 antibody;Drug: Bendamustine<br>* 90 mg/m2 I.V. on Day 1 and 2 of each cycle<br>* Other names: Treanda;Drug: Vincristine sulfate liposome injection<br>* Dose per dose escalation protocol, I.V. on Day 2 of each cycle<br>* Other names: Marqibo;|
| Experimental: Vincristine sulfate liposome injection 2.04 mg/m^2<br>Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | Drug: Rituximab<br>* 375 mg/m2 I.V. on Day 1 of each cycle<br>* Other names: Rituxan, anti-CD20 antibody;Drug: Bendamustine<br>* 90 mg/m2 I.V. on Day 1 and 2 of each cycle<br>* Other names: Treanda;Drug: Vincristine sulfate liposome injection<br>* Dose per dose escalation protocol, I.V. on Day 2 of each cycle<br>* Other names: Marqibo;|
| Experimental: Vincristine sulfate liposome injection 2.10 mg/m^2<br>Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | Drug: Rituximab<br>* 375 mg/m2 I.V. on Day 1 of each cycle<br>* Other names: Rituxan, anti-CD20 antibody;Drug: Bendamustine<br>* 90 mg/m2 I.V. on Day 1 and 2 of each cycle<br>* Other names: Treanda;Drug: Vincristine sulfate liposome injection<br>* Dose per dose escalation protocol, I.V. on Day 2 of each cycle<br>* Other names: Marqibo;|
| Experimental: Vincristine sulfate liposome injection 2.14 mg/m^2<br>Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | Drug: Rituximab<br>* 375 mg/m2 I.V. on Day 1 of each cycle<br>* Other names: Rituxan, anti-CD20 antibody;Drug: Bendamustine<br>* 90 mg/m2 I.V. on Day 1 and 2 of each cycle<br>* Other names: Treanda;Drug: Vincristine sulfate liposome injection<br>* Dose per dose escalation protocol, I.V. on Day 2 of each cycle<br>* Other names: Marqibo;|
| Experimental: Vincristine sulfate liposome injection 2.19 mg/m^2<br>Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | Drug: Rituximab<br>* 375 mg/m2 I.V. on Day 1 of each cycle<br>* Other names: Rituxan, anti-CD20 antibody;Drug: Bendamustine<br>* 90 mg/m2 I.V. on Day 1 and 2 of each cycle<br>* Other names: Treanda;Drug: Vincristine sulfate liposome injection<br>* Dose per dose escalation protocol, I.V. on Day 2 of each cycle<br>* Other names: Marqibo;|
| Experimental: Vincristine sulfate liposome injection 2.22 mg/m^2<br>Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | Drug: Rituximab<br>* 375 mg/m2 I.V. on Day 1 of each cycle<br>* Other names: Rituxan, anti-CD20 antibody;Drug: Bendamustine<br>* 90 mg/m2 I.V. on Day 1 and 2 of each cycle<br>* Other names: Treanda;Drug: Vincristine sulfate liposome injection<br>* Dose per dose escalation protocol, I.V. on Day 2 of each cycle<br>* Other names: Marqibo;|
| Experimental: Vincristine sulfate liposome injection 2.24 mg/m^2<br>Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | Drug: Rituximab<br>* 375 mg/m2 I.V. on Day 1 of each cycle<br>* Other names: Rituxan, anti-CD20 antibody;Drug: Bendamustine<br>* 90 mg/m2 I.V. on Day 1 and 2 of each cycle<br>* Other names: Treanda;Drug: Vincristine sulfate liposome injection<br>* Dose per dose escalation protocol, I.V. on Day 2 of each cycle<br>* Other names: Marqibo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | Determined as the median of the marginal posterior distribution using data from all available patients | Up to 6 cycles of treatment (approximately 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Completed Six Cycles of Study Treatment |  | Up to 6 cycles of treatment (approximately 6 months) | 
| Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 6 cycles of treatment (approximately 6 months) | 
| Complete Response Rate | The number of patients achieving complete response during treatment on study | Up to 6 cycles of treatment (approximately 6 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bendamustine, Rituximab, Vincristine sulfate, Vincristine sulfate liposome injection, Phase I, Escalation With Overdose Control