Bendamustine in Combination With Ofatumumab, Carboplatin and Etoposide for Refractory or Relapsed Aggressive B-Cell Lymphomas
The Phase I part of the study will apply to identify dose-limiting toxicities (DLT) and to define maximum-tolerated dose (MTD) for a new chemoimmunotherapy combination of bendamustine, ofatumumab, carboplatin, and etoposide in patients with Non Hodgkin's lymphoma whose disease has progressed or has recurred after prior chemotherapy.
The Phase II part of the study will be a single-arm, open-label study in which all patients will receive combination bendamustine, ofatumumab, carboplatin and etoposide at the MTD dose defined in phase I.
This study hopes to identify a life-prolonging therapy for patients with Non-Hodgkin's Lymphoma whose disease has progressed or has recurred after prior chemotherapy. The hypothesis is that the proposed combination of chemotherapy is well-tolerated and is efficacious for the treatment of relapsed/refractory aggressive B cell lymphomas.
Procedure: CT Scan
Procedure: PET Scan
Genetic: Stem Cell Transplant (STC)
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Study of Bendamustine in Combination With Ofatumumab, Carboplatin and Etoposide for Refractory or Relapsed Aggressive B-cell Lymphomas|
- Phase I: Maximum-Tolerated Dose of Bendamustine in Combination with Ofatumumab, Carboplatin and Etoposide (BOCE) [ Time Frame: Through 50 days ] [ Designated as safety issue: Yes ]To determine the maximum-tolerated dose of bendamustine in combination with ofatumumab, carboplatin and etoposide for patients with refractory or relapsed aggressive B cell lymphomas. Toxicity levels will be assessed after every cycle until a dose-limiting toxicity (DLT) is found. Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria (CTCAE version 4.0). DLT will be defined as any grade 4 infection, or grade >/= 3 non-hematologic toxicity that persists for 7 days or more.
- Phase II: Overall Frequency of Response with Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide [ Time Frame: At 25 days and 3-8 weeks post-treatment ] [ Designated as safety issue: No ]To determine the overall frequency of response with combination bendamustine, ofatumumab, carboplatin, and etoposide for refractory or relapsed aggressive B-cell lymphomas. Overall response is determined as cumulative Complete Response (CR) and Partial Response (PR).
- Phase I: Overall Frequency of Response [ Time Frame: CT and PET scans after Cycle 2 (approximately 25 days) and 3-8 weeks post-treatment ] [ Designated as safety issue: No ]To determine the overall frequency of response--overall response will include all subjects with complete response (CR) and partial response (PR).
- Phase II: Complete Response (CR) and Partial Response (PR) Rate [ Time Frame: CT and PET scans after Cycle 2 (approximately 25 days) and 3-8 weeks post-treatment ] [ Designated as safety issue: No ]Assessed per the 2007 Revised Cheson Criteria for NHL (33)
- Phase II: Progression-Free Survival [ Time Frame: At 1 and 2 years ] [ Designated as safety issue: No ]To determine 1 and 2 year progression-free survival
- Phase II: Overall Survival [ Time Frame: At 1 and 2 years ] [ Designated as safety issue: No ]To determine 1 and 2 year overall survival.
- Phase II: Proportion of Patients Who Are Able to Undergo Stem Cell Transplant (SCT) [ Time Frame: At 3 years ] [ Designated as safety issue: No ]To determine the proportion of patients who are able to undergo stem cell transplant among transplant-eligible patients. Patients can receive SCT after Cycle 2.
- Phase II: Safety and Tolerability of the Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide [ Time Frame: After each cycle (after approximately 3 days, 25 days, and 50 days) ] [ Designated as safety issue: Yes ]
To define safety and tolerability of the combination of ofatumumab, bendamustine, carboplatin and etoposide.
Determined through dose modifications for bendamustine according to patient's toxicity levels:
- Initial 120 mg/m2 dose decreased to 90 mg/m2
- Initial 90 mg/m2 dose decreased to 70 mg/m2
- Initial 70 mg/m2 dose decreased to 50 mg/m2
- Initial 50 mg/m2 dose decreased to Withdrawn from study
|Study Start Date:||November 2011|
|Estimated Study Completion Date:||October 2017|
|Estimated Primary Completion Date:||October 2016 (Final data collection date for primary outcome measure)|
Experimental: Bendamustine, Ofatumumab, Carboplatin, and Etoposide (BOCE)
Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Phase 1: Given via IV at the following dose levels:
Phase II: Given via IV on Days 1 and 2 of each cycle at the maximum-tolerated dose level found in the Phase I portion of the study.
Other Names:Drug: Ofatumumab
Other Names:Drug: Carboplatin
Phase II: AUC 5 via IV on Day 2 of each cycle
Other Names:Drug: Etoposide
Phase II: 1000 mg/m2 via IV on Days 1, 2, and 3 of each cycle
Other Names:Procedure: CT Scan
CT Scan to assess disease after Cycle 2 (approximately 25 days) and 3-8 weeks post-treatment
Other Name: X-ray computed tomographyProcedure: PET Scan
PET Scan to assess disease after Cycle 2 (approximately 25 days) and 3-8 weeks post-treatment
Other Names:Genetic: Stem Cell Transplant (STC)
For potential transplant candidates:
Fifty percent of patients with aggressive B cell non-Hodgkin lymphomas are expected to relapse after initial standard chemotherapy. There is no standard salvage regimen for patients with relapsed or refractory disease and at least 75% of patients are expected to succumb to their condition with the commonly used therapy. The recent CORAL study was evaluating the most frequently used rescue regimens R-ICE (rituximab, ifosfamide, carboplatin, etoposide) vs. R-DHAP (rituximab, dexamethasone, high-dose cytarabine and cisplatin) for relapsed aggressive lymphomas, the overall response (OR) was 83% and 3 year event-free survival (EFS) was 47% for "rituximab naïve" patients. In contrast, OR was 51% and 3 year EFS was only 21% in patients who had relapsed after a rituximab containing regimen. There was no significant difference between R-ICE and R-DHAP (in 3-year EFS or overall survival). This study confirmed that rituximab containing rescue was less effective in those patients who had received prior rituximab. Currently, there is virtually no relapsed B-cell lymphoma patients who had not received a rituximab containing induction; therefore, novel strategies are needed to overcome rituximab resistance and to improve overall poor outcome in the relapsed setting. Ofatumumab is a human IgG1 monoclonal anti-CD20 antibody which binds to different CD20 epitopes and is presumed to destroy B cells that are insensitive to rituximab due to their low CD20-expression due to its higher binding avidity and higher antibody and complement dependent cytotoxicity. It was approved by FDA for the treatment of patients with refractory Chronic Lymphocytic Leukemia (CLL). It is being actively studied in low grade and aggressive CD20 positive lymphomas. Bendamustine is an alkylator/purine analogue hybrid cytotoxic compound that has demonstrated single agent activity in lymphomas refractory to other alkylating agents, such as cyclophosphamide. Weidmann et al (2002) demonstrated single agent activity and safety of bendamustine at the dose of 120mg/m2 (day 1, 2) in relapse/refractory aggressive lymphomas. This study had an ORR of 44% in 18 patients. Non-hematological toxicity was mild (13% grade 3 and 0 grade 4). Bendamustine has shown impressive activity and a favorable safety profile when used in combination with rituximab and other cytotoxic drugs: Weide R et al (2007) studied bendamustine (90 mg/m2 day 1, 2) in combination with rituximab and mitoxantrone in 57 patients' with indolent lymphomas and mantle cell lymphoma (MCL). ORR was 92% in follicular and 78% in MCL Vacirca et al presented interim safety analysis of bendamustine (120mg/m2, day 1, 2) and rituximab combination in aggressive B cell lymphomas at 2010 ASCO meeting (in 76 cycles 1 grade 4 neutropenia and 9 additional grade 3 events). Thus, bendamustine combinations are effective and can be given safely in patients with relapsed lymphomas.
The investigators propose a novel R-ICE-like salvage combination regimen in which rituximab is substituted with ofatumumab and ifosfamide with bendamustine in combination with carboplatin and etoposide for refractory or relapsed aggressive B cell lymphomas. The investigators hope to avoid the substantial ifosfamide mediated urinary bladder toxicity (incidence of grade 3 and 4 hemorrhagic cystitis 8-12%) and neurologic toxicity (10-30%: somnolence, confusion, psychosis and seizure) by substituting ifosfamide for bendamustine. The proposed regimen is convenient and can be administered on the outpatient basis which presents an additional benefit to the patients and to the providers. The investigators propose a phase I/II clinical trial and will first determine safety and toxicity of escalating dose bendamustine in combination with fixed doses of ofatumumab, carboplatin and etoposide. The investigators recognize that the commonly used doses of bendamustine in lymphoid malignancies range from 70-120 mg/m2. The investigators will determine maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of the combination by using dose escalation of bendamustine from 70mg/m2 in a standard 3 by 3 design. The investigators will then assess efficacy of the combination regimen in relapsed and refractory aggressive B-cell lymphomas.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01458366
|Contact: Mark Weiss, MD||215-955-8874|
|Contact: Clinical Research Management Office||215-955-1661|
|United States, Pennsylvania|
|Thomas Jefferson University||Recruiting|
|Philadelphia, Pennsylvania, United States, 19107|
|Contact: Mark Weiss, MD 215-955-8874|
|Contact: Clinical Research Management Office 215-955-1661|
|Sub-Investigator: S. Onder Alpdogan, MD|
|Sub-Investigator: Renu Bajaj, PhD|
|Sub-Investigator: Avnish K Bhatia, MD|
|Sub-Investigator: Matthew Carabasi, MD|
|Sub-Investigator: Andrew E Chapman, DO|
|Sub-Investigator: Jerald Gong, MD|
|Sub-Investigator: Dolores Grosso, DNP, CRNP|
|Sub-Investigator: Margaret Kasner, MD|
|Sub-Investigator: Atrayee Basu-Mallick, MD|
|Sub-Investigator: Joanne Filicko-O'Hara, MD|
|Sub-Investigator: Neal Flomenberg, MD|
|Sub-Investigator: Ubaldo Martinez Outschoorn, MD|
|Sub-Investigator: Michael J Ramirez, MD|
|Sub-Investigator: Lewis J Rose, MD|
|Sub-Investigator: John L Wagner, MD|
|Principal Investigator: Mark Weiss, MD|
|Sub-Investigator: Allison M Zibelli, MD|
|Principal Investigator:||Mark Weiss, MD||Thomas Jefferson University|