FL |MCL

Triple combination idelalisib, lenalidomide, and rituximab deemed ‘excessively toxic’ in Mantle Cell and Follicular Lymphoma patients

Professor Sonali Smith, from the University of Chicago, Chicago, and colleagues published in The Lancet Haematology the results of the Alliance for Clinical Trials in Oncology A051201 and A051202 phase I trials. The goal of these trials were to assess the maximum tolerated dose of the combination of lenalidomide, rituximab, and idelalisib in patients with either FL or MCL. The rationale for the triplet combination was that the doublet combinations of idelalisib-rituximab and lenalidomide-rituximab were previously shown to be safe and effective, and the authors wanted to assess if the addition of a PI3K inhibitor could enhance efficacy while being safe.

Key Highlights:

  • MCL: Dose Level 0 = 15mg lenalidomide daily D1–21 each cycle, 150mg idelalisib twice daily, 375mg/m2 rituximab once weekly in cycle 1, then D1 cycle 4, 6, 8, and 10
  • FL: Dose Level 0 = 10mg lenalidomide daily D1–21 each cycle, 150mg idelalisib twice daily, 375mg/m2 rituximab on D8, 15, and 22 in cycle 1, then D1 of each cycle
  • Results:
  • Patients recruited = 11; MCL = 3, FL = 8, all had prior rituximab therapy
  • Eight patients ended treatment due to AE (100% of MCL pts, 62.5% of FL pts), 3 referred to intensive care, no treatment-related deaths
  • Five patients met the criteria for having reached dose-limiting toxicity (2 MCL pts, 3 FL pts)
  • AE onset was typically seen 9–20 days after initiation of treatment
  • No MCL pts responded to this treatment, SD = 1, PD = 2
  • FL: ORR = 45%; CR = 1, PR = 4, SD = 1, PD = 2
  • FL: estimated mPFS = 8.3 months, with 7.4-month median follow-up

The authors concluded that this triple combination of rituximab, idelalisib, and lenalidomide is ‘excessively toxic’, and send a warning that investigating combination therapies should only be performed within the context of clinical trials where patients should be closely monitored. The toxicity data presented in this study supports similar toxicities seen in another trial in R/R indolent lymphomas (NCT01088048).

Abstract:

Background. A new generation of biological and targeted agents might potentially replace traditional cytotoxic agents in lymphoma. Lenalidomide plus rituximab was felt to be a safe and promising backbone based on available data. Idelalisib is an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor that has promising activity as a monotherapy in refractory indolent lymphomas. The primary objective of these two trials was to determine the maximum tolerated dose of lenalidomide in combination with rituximab and idelalisib in relapsed follicular and mantle cell lymphoma. Methods. A051201 (mantle cell lymphoma) and A051202 (follicular lymphoma) were phase 1 trials. Patients with histologically documented relapsed mantle cell lymphoma who had not received previous lenalidomide or idelalisib (A051201) were started with oral lenalidomide 15 mg on days 1–21 in a 28 day cycle, oral idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m2 weekly during cycle 1. Patients with histologically documented relapsed follicular lymphoma and time to progression 6 months or longer from last rituximab-containing regimen (A051202) were started with oral lenalidomide 10 mg on days 1–21 every 28 days and oral idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m2 on cycle 1, day 8, day 15, day 22, and cycle 2, day 1. The primary endpoints of the studies were safety and tolerability of combining idelalisib with lenalidomide and rituximab in patients with relapsed mantle cell lymphoma (A051201) and relapsed follicular lymphoma (A051202). All analyses were by intention to treat. The trials were registered at ClinicalTrials.gov, number NCT01838434 (A051201) and number NCT01644799 (A051202). Findings. Between July 9, 2013, and Sept 30, 2014, 11 patients (three with mantle cell lymphoma and eight with follicular lymphoma) were enrolled. Among the first eight patients, four experienced unexpected dose-limiting toxicities: grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash. Symptom onset was 9–20 days after treatment initiation, coinciding with rituximab infusions. Both studies were amended to remove rituximab, but two of three additional patients had grade 3 rashes and one had grade 3 AST elevation. Both trials were permanently closed. The most common grade 3–4 adverse events were ALT elevation (two [67%] of three) and rash (two [67%] of three) for patients with mantle cell lymphoma and neutropenia (five [63%] of eight) and rash (four [50%] of eight) for patients with follicular lymphoma. The primary endpoint of safety and tolerability was not met. Interpretation. The combination of idelalisib, lenalidomide, and rituximab in these trials is excessively toxic, and these trials serve as cautionary notes as new combinations are proposed. Off-target effects, drug–drug interactions, and emerging toxicities should be carefully assessed when investigating biological agents in combination and should never be done outside of a clinical trial setting.

Reference:
  1. Smith S.M. et al. Safety and tolerability of idelalisib, lenalidomide, and rituximab in relapsed and refractory lymphoma: the Alliance for Clinical Trials in Oncology A051201 and A051202 phase 1 trials. The Lancet Haematology. 2017 Mar 14; 4(4): e176–82. DOI: 10.1016/S2352-3026(17)30028-5. Epub 2017 Mar 15.