This phase I/Ib trial studies the side effects and best dose of carfilzomib when given together with rituximab, ifosfamide, carboplatin, and etoposide and to see how well it works in treating patients with stage I-IV diffuse large B-cell lymphoma that has returned (relapsed) or that has not responded to treatment (refractory). Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, also work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving carfilzomib with rituximab, ifosfamide, carboplatin, and etoposide may be a better treatment for diffuse large B-cell lymphoma.
PRIMARY OBJECTIVES: * I. To estimate the maximum tolerated dose (MTD) and examine the dose-limiting toxicities of carfilzomib when administered in combination with rituximab, ifosfamide, carboplatin, and etoposide (C-R-ICE) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). (Phase I) * II. To assess the toxicity of dose regimen using the Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 4.0). (Phase I) * III. To evaluate the safety of carfilzomib (given at maximum tolerated dose \[MTD\] as determined in Phase I of this study) in combination with R-ICE salvage therapy in relapsed/refractory DLBCL patients. (Phase Ib) * IV. To achieve an overall response rate (complete response \[CR\] and partial response \[PR\]) of 70% after 3 cycles of C-R-ICE in patients between the ages of 18 to 75 with relapsed/refractory cluster of differentiation (CD)20-positive DLBCL previously treated with rituximab-based immunochemotherapy (e.g., rituximab, cyclophosphamide, doxorubicin, vincristine \[vincristine sulfate\], and prednisone \[R-CHOP\], rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin \[REPOCH\], rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine \[R-HyperCVAD\], etc.) induction. (Phase Ib) SECONDARY OBJECTIVES: * I. To determine the feasibility of successful mobilization of autologous stem cells (i.e., minimum of 2 x 10\^6 CD34+ cells/kg should be collected) to be used for autologous stem cell transplant (ASCT) * II. To determine toxicities associated with C-R-ICE salvage therapy * III. To determine the time to progression (TTP), progression-free survival (PFS), and overall survival (OS) followed by ASCT; disease-free survival in CR patients. * IV. To determine the pharmacokinetics/pharmacodynamics relationship between carfilzomib's degree of proteasome inhibition and response rate along with the time course of thrombocytopenia * V. To study differences in clinical outcomes between germinal center B-cell-like (GCB) and non-GCB relapsed/refractory DLBCL following therapy with carfilzomib and R-ICE * VI. Correlative translational research studies to include: phenotypic/genotypic analysis and functional activity (i.e., antibody-dependent cellular cytotoxicity \[ADCC\] and complement-mediated cytotoxicity \[CMC\]) of patient's peripheral blood mononuclear "effector" cells (PBMC), as well as ex vivo analysis of sensitivity of primary tumor cells to various combinations of carfilzomib versus bortezomib +/- rituximab; enzymatic assay for chymotrypsin-like activity to determine the degree of proteasome inhibition in primary DLBCL patient samples and patient PBMC specimens; explorative analysis to identify potential factors predictive of response to therapy will be performed. OUTLINE: This is a phase I, dose-escalation study of carfilzomib, followed by a phase Ib study. Patients receive carfilzomib intravenously (IV) over 10-30 minutes on days 1, 2, 8, and 9; rituximab IV over 3-8 hours on day 3; etoposide IV over 1 hour on days 4-6; carboplatin IV over 1 hour on day 5; and ifosfamide IV over 24 hours on day 5. Treatment repeats every 21-28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 2 years, and then annually for 2 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
29
Given IV
Given IV
Given IV
Given IV
Correlative studies
Correlative studies
Given IV
Roswell Park Cancer Institute
Buffalo, New York, United States
Overall Response Rate (PR + CR)
Overall response rate (CR and PR) after 3 cycles of C R ICE in patients age of 18 to 75 with relapsed/refractory CD20-positive DLBCL treated with rituximab-based immunochemotherapy (e.g., R-CHOP, R-EPOCH, R-HyperCVAD, etc.) induction. Response was based on a Modified Cheson Criteria with Complete response (CR): All lesions with a longest diameter ≤ 15 mm or short axis ≤ 10 mm (Not palpable during the clinical examination, No visible nodule on imaging, And disappearance of all non-nodal target lesions Or in case of hypermetabolic disease on the baseline PET scan, negative PET scan whatever the appearance of lesions on CT) and Partial Response (PR): ≥ 50 % of sum of the products of the diameters (SPD) of target lesions or in the case of hypermetabolic lesions on the baseline PET scan, persistence of at least one PET-positive site without progression of other lesions on CT (≥ 50 % of SPD of target lesions (or longest diameter if a single nodule) No clinically enlarged liver or spleen)
Time frame: The time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented, assessed up to 12 weeks
MTD Defined as the Dose of Carfilzomib Added to Standard R-ICE Chemotherapy Which, if Exceeded, Would Put the Patient at an Undesirable Risk of Medically Unacceptable Dose-limiting Toxicities (Phase I)
Time frame: 28 days
Complete Response Rate According to the International Working Group Response Criteria as Reported by the Revised Cheson Criteria
Efficacy rates were estimated using simple relative frequencies. Complete response rate after 3 cycles of C R ICE in patients age of 18 to 75 with relapsed/refractory CD20-positive DLBCL treated with rituximab-based immunochemotherapy (e.g., R-CHOP, R-EPOCH, R-HyperCVAD, etc.) induction. Response was based on a Modified Cheson Criteria with Complete response (CR): All lesions with a longest diameter ≤ 15 mm or short axis ≤ 10 mm (Not palpable during the clinical examination, No visible nodule on imaging, And disappearance of all non-nodal target lesions Or in case of hypermetabolic disease on the baseline PET scan, negative PET scan whatever the appearance of lesions on CT) and Partial Response (PR): ≥ 50 % of sum of the products of the diameters (SPD) of target lesions or in the case of hypermetabolic lesions on the baseline PET scan, persistence of at least one PET-positive site without progression of other lesions on CT (≥ 50 % of SPD of target lesions (or longest diameter if a si
Time frame: Up to 5 years
Overall Survival
The estimated distributions of overall survival will be obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed. It is assumed a priori that any drop out times will be non-informative in terms of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric demographic/baseline variables will be compared in regards to time-to-event distributions using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.
Time frame: From the start of treatment until death for any reason, assessed up to 5 years
Pharmacokinetics (PK)/Pharmacodynamics (PD) of Carfilzomib and Standard R-ICE Combination Therapy in Adult Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma
A population PK/PD structural model will be developed for carfilzomib based on degree of proteasome inhibition in relation to efficacy and toxicity endpoints in the proposed study using NONMEM. This model will describe the potential relationship between carfilzomib exposure in relation to proteasome inhibition to the time course of thrombocytopenia and neutropenia as indicators of pharmacodynamics response.
Time frame: Pre-dose, just prior to the end of the infusion; and at 15 minutes, 30 minutes, 1, 2, 4, 6 hours post infusion on course 1, day 1, then at 24 hours post course 1 infusion on course 1, day 2 (prior to day 2 infusion)
Progression-free Survival
The estimated distributions of progression-free survival will be obtained using the Kaplan-Meier method. Corresponding confidence intervals using the methodology of Brookmeyer and Crowley will be computed. It is assumed a priori that any drop out times will be non-informative in terms of the censoring mechanism. Groups defined by levels of categorical or dichotomized numeric demographic/baseline variables will be compared in regards to time-to-event distributions using the log-rank test. Cox proportional hazards model regression will be utilized for multivariate analyses.
Time frame: Up to 5 years
Toxicity of the Addition of Carfilzomib to R-ICE at the MTD, Assessed by the CTEP Version 4.0 of the NCI CTCAE
Count of participants that experienced serious adverse events assessed by the CTEP version 4.0 of the NCI CTCAE
Time frame: Up to 5 years
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