Phase I/II Study of Bendamustine in Combination With Ofatumumab, Carboplatin and Etoposide for Refractory or Relapsed 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.
Interventional
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase I: Maximum-Tolerated Dose of Bendamustine in Combination with Ofatumumab, Carboplatin and Etoposide (BOCE)
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.
Through 50 days
Yes
Elena Gitelson, MD, PhD
Principal Investigator
Thomas Jefferson University
United States: Institutional Review Board
11D.404
NCT01458366
November 2011
October 2017
Name | Location |
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Thomas Jefferson University | Philadelphia, Pennsylvania 19107-6541 |