Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Behaviors and Mental Disorders

Rare Diseases

Lymphoma

Lymphoma, B-Cell

Aggression

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

B-cell Lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Etoposide

Carboplatin

Bendamustine Hydrochloride

Etoposide phosphate

Ofatumumab

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Level 1: Bendamustine 70mg/m\^2 Ofatumumab, Carboplatin, and Etoposide

Level -1: Bendamustine 50mg/m\^2 Ofatumumab, Carboplatin, and Etoposide

Level 2: Bendamustine 90mg/m\^2 Ofatumumab, Carboplatin, and Etoposide

Level 3: Bendamustine 120mg/m\^2 Ofatumumab, Carboplatin, and Etoposide

Phase II: Bendamustine at MTD from Phase I, Ofatumumab, Carboplatin, and Etoposide

Phase 1: Given via IV at the following dose levels:

* Level 1: 70 mg/m2
* Level -1: 50 mg/m2
* Level 2: 90 mg/m2
* Level 3: 120 mg/m2

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.

Bendamustine

Phase II

* Cycle 1: 300 mg via IV on Day 1 and 1000 mg via IV on Day 3
* Cycles 2 and 3: 1000 mg via IV on Day 1

Phase II: AUC 5 via IV on Day 2 of each cycle

Phase II: 100 mg/m2 via IV on Days 1, 2, and 3 of each cycle

CT Scan to assess disease after Cycle 2 (approximately 25 days) and 3-8 weeks post-treatment

CT Scan

PET Scan to assess disease after Cycle 2 (approximately 25 days) and 3-8 weeks post-treatment

PET Scan

For potential transplant candidates:

* Autologous STC: after 2 cycles of BOCE upon discretion of Thomas Jefferson University hematopoietic stem cell transplant group and in agreement with the study PI or her designee
* Allogeneic STC: after 2 cycles of BOCE upon discretion of Thomas Jefferson University hematopoietic stem cell transplant group and in agreement with the study PI or her designee

Stem Cell Transplant (STC)

Joanne Filicko-O'Hara, MD

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.

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.

Phase I/II Study of Bendamustine in Combination With Ofatumumab, Carboplatin and Etoposide

Phase I/II Study of Bendamustine in Combination With Ofatumumab, Carboplatin and Etoposide for Refractory or Relapsed Aggressive B-cell Lymphomas

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.

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).

To determine the overall frequency of response--overall response will include all subjects with complete response (CR) and partial response (PR). Based on the revised response criteria for malignant lymphoma \[Cheson 2007\]

CR= complete disappearance of all detectable clinical evidence of disease and disease related symptoms if present before therapy PR= \>/= 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of other nodes, liver or spleen;

Based on the revised response criteria for malignant lymphoma \[Cheson 2007\]

CR= complete disappearance of all detectable clinical evidence of disease and disease related symptoms if present before therapy PR= \>/= 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of other nodes, liver or spleen;

To determine 1 and 2 year progression-free survival \[Cheson 2007\] CR= complete disappearance of all detectable clinical evidence of disease and disease related symptoms if present before therapy PR= \>/= 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of other nodes, liver or spleen;

1 and 2 year overall survival for those who received Stem Cell Transplant (SCT) versus those who did not receive SCT

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.

To define safety and tolerability of the combination of ofatumumab, bendamustine, carboplatin and etoposide as measured by the number of dose modifications made to Bendamustine..

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

GlaxoSmithKline

Novartis

Sidney Kimmel Cancer Center at Thomas Jefferson University

adverse events are presented as a cumulative across both the Phase I and Phase II portions of the study to illustrate the overall safety of the combination of bendamustine, ofatumumab, carboplatin, and etoposide.

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Bendamustine: Phase 1: Given via IV at the following dose levels:

- Level 1: 70 mg/m2

Bendamustine 70 mg/m2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Bendamustine: Phase 1: Given via IV at the following dose levels:

- Level -1: 50 mg/m2

Bendamustine 50 mg/m2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Bendamustine: Phase 1: Given via IV at the following dose levels:

- Level 2: 90 mg/m2

Bendamustine 90 mg/m2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Bendamustine: Phase 1: Given via IV at the following dose levels:

- Level 3: 120 mg/m2

Bendamustine 120 mg/m2

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.

Ofatumumab: Phase II

* Cycle 1: 300 mg via IV on Day 1 and 1000 mg via IV on Day 3
* Cycles 2 and 3: 1000 mg via IV on Day 1

Carboplatin: Phase II: AUC 5 via IV on Day 2 of each cycle

Etoposide: Phase II: 100 mg/m2 via IV on Days 1, 2, and 3 of each cycle

Bendamustine at MTD

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide 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.

Ofatumumab: Phase II

* Cycle 1: 300 mg via IV on Day 1 and 1000 mg via IV on Day 3
* Cycles 2 and 3: 1000 mg via IV on Day 1

Carboplatin: Phase II: AUC 5 via IV on Day 2 of each cycle

Etoposide: Phase II: 100 mg/m2 via IV on Days 1, 2, and 3 of each cycle

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Bendamustine at 50mg/m2 was the dose level -1. No dose limiting toxicities were noted in the first Bendamustine dose level (70mg/m2) so a reduction to 50mg/m2 was not needed and therefore no patients were enrolled at the dose level -1.

Joanna Filicko-O'Hara, MD

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Bendamustine: Phase 1: Given via IV at the following dose levels:

* Level 1: 70 mg/m2
* Level -1: 50 mg/m2
* Level 2: 90 mg/m2
* Level 3: 120 mg/m2

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.

Ofatumumab: Phase II

* Cycle 1: 300 mg via IV on Day 1 and 1000 mg via IV on Day 3
* Cycles 2 and 3: 1000 mg via IV on Day 1

Carboplatin: Phase II: AUC 5 via IV on Day 2 of each cycle

Etoposide: Phase II: 100 mg/m2 via IV on Days 1, 2, and 3 of each cycle

Bendamustine, Ofatumumab, Carboplatin, and Etoposide (BOCE)

Patients enrolled on the Phase 1 portion of the study

Phase I: Maximum-Tolerated Dose of Bendamustine in Combination With Ofatumumab, Carboplatin and Etoposide (BOCE)

Patients who received MTD in phase 1 and the phase 2 patients were evaluated in combined analysis.

Overall Frequency of Response With Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide at Maximum Tolerated Dose (MTD)

For the Phase 1 analysis, participants who received doses of Bendamustine below the MTD were combined for the statistical analysis.

Phase I: Overall Frequency of Response

Phase 2

Phase 1

one subject withdrew voluntarily and was not analyzed. The patients enrolled into Phase I portion were combined into one analysis group to compare the two phases of the study.

Overall Complete Response (CR) and Partial Response (PR) Rate

Patients who achieved a complete or partial response. median progression free survival was not achieved in patients undergoing transplant. This population is patients who received the Maximum Tolerated Dose in both Phase I and Phase II. One patient withdrew and was not included in the analysis.

Overall Progression-Free Survival

Did not receive transplant

Received transplant

One patient withdrew and was not included in the analysis. For the purpose of this analysis, patients in both phases were combined into two groups based on whether or not the patient received a transplant.

Total Overall Survival for Transplant vs Non-transplant

one subject withdrew voluntarily and was not analyzed. patients from both Phase I and Phase II were analyzed cumulatively for the purpose of analyzing the patients who received a transplant

Overall Proportion of Patients Who Are Able to Undergo Stem Cell Transplant (SCT)

one subject withdrew voluntarily and was not analyzed. As no dose modifications were needed during the study, results of analysis are provided based on the overall patients enrolled to the study.

Overall Safety and Tolerability of the Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Bendamustine:

- Level 1: 70 mg/m2

Bendamustine 70mg/m^2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Bendamustine:

- Level -1: 50 mg/m2

Bendamustine 50mg/m^2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Bendamustine:

- Level 2: 90 mg/m2

Bendamustin 90mg/m^2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Bendamustine:

- Level 3: 120 mg/m\^2

Bendamustine 120mg/m^2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Bendamustine:

Phase II at the MTD

Spots Global Cancer Trial Database for stem cell transplant (stc)