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A phase I dose-finding trial of recombinant interleukin-21 and rituximab in relapsed and refractory low grade B-cell lymphoproliferative disorders.

ABSTRACT: We conducted a phase I study to determine the safety, maximum-tolerated dose (MTD), and efficacy of weekly bolus recombinant human interleukin-21 (rIL-21) plus rituximab in patients with indolent B-cell malignancies.One week after a lead-in rituximab dose, cohorts of three patients were treated with 30, 100, or 150 ?g/kg rIL-21 weekly for four weeks, concurrent with four weekly doses of rituximab. Patients with stable disease or better were eligible for a second course of therapy.Twenty-one patients with relapsed small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL, n = 11), follicular lymphoma (n = 9), or marginal zone lymphoma (n = 1) were enrolled, with 19 completing at least one course of therapy. The MTD for rIL-21 was 100 ?g/kg, based on observed toxicities including nausea, vomiting, diarrhea, hypotension, edema, and hypophosphatemia. Clinical responses were seen in 8 of 19 evaluable patients (42%; 3 CR/CRu, 5 PR), with 4 of longer duration than the patient's previous response to rituximab-based treatment (median 9 months vs. 3 months).Outpatient therapy of indolent B-cell malignancies with rituximab and weekly rIL-21 was well tolerated and clinically active, with durable complete remissions in a small subset of patients. Additional studies of rIL-21 and anti-CD20 antibodies in lymphoma and SLL/CLL are warranted.

SUBMITTER: Timmerman JM

PROVIDER: S-EPMC5027960 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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A phase I dose-finding trial of recombinant interleukin-21 and rituximab in relapsed and refractory low grade B-cell lymphoproliferative disorders.

Timmerman John M JM Byrd John C JC Andorsky David J DJ Yamada Reiko E RE Kramer Janet J Muthusamy Natarajan N Hunder Naomi N Pagel John M JM

Clinical cancer research : an official journal of the American Association for Cancer Research 20120814 20

<h4>Purpose</h4>We conducted a phase I study to determine the safety, maximum-tolerated dose (MTD), and efficacy of weekly bolus recombinant human interleukin-21 (rIL-21) plus rituximab in patients with indolent B-cell malignancies.<h4>Experimental design</h4>One week after a lead-in rituximab dose, cohorts of three patients were treated with 30, 100, or 150 μg/kg rIL-21 weekly for four weeks, concurrent with four weekly doses of rituximab. Patients with stable disease or better were eligible fo ...[more]

PMID: 22893631

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Project description:Background:Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL). Patients and methods:BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50-1200?mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy. Results:Sixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n?=?4) or respiratory failure (n?=?1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800?mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3?months [95% confidence interval (CI) 10.4-NR], not yet reached, and 10.7?months (95% CI 4.3-21.0), respectively. Conclusions:This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL. Trial registered:Clinicaltrials.gov, NCT01594229.

Project description:LESSONS LEARNED:Clofarabine can be active in relapsed and refractory lymphoid malignancies on a weekly dosing schedule.Responses were seen in patients with T-cell lymphomas, including cutaneous T-cell lymphoma, but not in patients with aggressive B-cell lymphomas. BACKGROUND:Clofarabine is a second-generation purine nucleoside analog currently approved for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. In adults, clofarabine has been investigated in several phase I and II trials as a single agent and in combination for relapsed or refractory acute leukemia. These studies have shown that clofarabine has activity and an acceptable safety profile in patients with hematological malignancies. In this phase I dose escalation trial, clofarabine was evaluated in patients with relapsed or refractory, low-grade or intermediate-grade, B-cell or T-cell lymphoma. METHODS:The starting dose of 10 mg/m2 per week was administered intravenously (IV) for 3 consecutive weeks every 28 days, and doses were escalated in cohorts of three. The study objectives were to determine the maximum tolerated dose (MTD), characterize and quantify the toxicity profile, and determine the overall response rate of clofarabine administered once a week for 3 weeks and repeated every 4 weeks. Eligible patients were over the age of 18, had a histologically confirmed low-grade or intermediate-grade B-cell or T-cell lymphoma, and must have previously been treated with one standard chemotherapy regimen, excluding single-agent rituximab. The primary objectives included in statistical analyses were MTD, toxicity, and overall response rate (ORR). Four patients were enrolled in cohort 1 (clofarabine 10 mg/m2), four in cohort 2 (clofarabine 15 mg/m2), three in cohort 3 (clofarabine 20 mg/m2), two in cohort 4 (clofarabine 30 mg/m2), and one in cohort 5 (clofarabine 40 mg/m2) (Table 2). RESULTS:MTD was not reached in the study. The most common toxicity observed was myelosuppression. A total of four (29%) patients experienced grade 3 leukopenia, with three (21%) patients experiencing grade 4 neutropenia. The myelosuppression was not considered to be a dose-limiting toxicity, as it resolved within 7 days.Fourteen patients were enrolled: 10 patients with T-cell non-Hodgkin lymphoma (NHL) and 4 patients with B-cell NHL (see Table 1). All 14 patients received at least one dose of clofarabine and were evaluable for response. One patient with cutaneous T-cell lymphoma (CTCL) had a partial response; five (36%) had stable disease, and eight patients (57%) had no response. The one patient with a response had stage III erythroderma and was treated in the 10 mg/m2 cohort; a nodal complete response by positron emission tomography scan was observed with a partial response of the skin. CONCLUSION:In this study, weekly administration of clofarabine was demonstrated to be safe and associated with minimal hematologic toxicity at doses ranging from 10-40 mg/m2. In prior studies when dosed daily for 5 consecutive days, the MTD was shown to be 4 mg/m2. Weekly dosing within this dose range did not result in dose modifications, and the MTD was not reached. Clinical efficacy was observed in one patient with CTCL who was treated in the lowest-dose cohort.

Dataset Information

A phase I dose-finding trial of recombinant interleukin-21 and rituximab in relapsed and refractory low grade B-cell lymphoproliferative disorders.

Publications

A phase I dose-finding trial of recombinant interleukin-21 and rituximab in relapsed and refractory low grade B-cell lymphoproliferative disorders.

Similar Datasets

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