Phase I Study of Fenretinide Delivered Intravenously in Patients with Relapsed or Refractory Hematologic Malignancies: A California Cancer Consortium Trial

Abstract

Purpose: A phase I study was conducted to determine the MTD, dose-limiting toxicities (DLT), and pharmacokinetics of fenretinide delivered as an intravenous emulsion in relapsed/refractory hematologic malignancies.Experimental Design: Fenretinide (80-1,810 mg/m2/day) was administered by continuous infusion on days 1 to 5, in 21-day cycles, using an accelerated titration design.Results: Twenty-nine patients, treated with a median of three prior regimens (range, 1-7), were enrolled and received the test drug. Ninety-seven courses were completed. An MTD was reached at 1,280 mg/m2/day for 5 days. Course 1 DLTs included 6 patients with hypertriglyceridemia, 4 of whom were asymptomatic; 2 patients experienced DLT thrombocytopenia (asymptomatic). Of 11 patients with response-evaluable peripheral T-cell lymphomas, two had complete responses [CR, progression-free survival (PFS) 68+ months; unconfirmed CR, PFS 14+ months], two had unconfirmed partial responses (unconfirmed PR, PFS 5 months; unconfirmed PR, PFS 6 months), and five had stable disease (2-12 cycles). One patient with mature B-cell lymphoma had an unconfirmed PR sustained for two cycles. Steady-state plasma levels were approximately 10 mcg/mL (mid-20s μmol/L) at 640 mg/m2/day, approximately 14 mcg/mL (mid-30s μmol/L) at 905 mg/m2/day, and approximately 22 mcg/mL (mid-50s μmol/L) at 1,280 mg/m2/day.Conclusions: Intravenous fenretinide obtained significantly higher plasma levels than a previous capsule formulation, had acceptable toxicities, and evidenced antitumor activity in peripheral T-cell lymphomas. A recommended phase II dosing is 600 mg/m2 on day 1, followed by 1,200 mg/m2 on days 2 to 5, every 21 days. A registration-enabling phase II study in relapsed/refractory PTCL (ClinicalTrials.gov identifier: NCT02495415) is ongoing. Clin Cancer Res; 23(16); 4550-5. ©2017 AACR.

©2017 American Association for Cancer Research.

Figures

Figure 1

(A) End-infusion fenretinide plasma levels for dosing cohorts (+120 hours). Closed circles represent patients completing infusion course. Open circles represent last plasma sample of patients with infusions stopped due to hypertriglyceridemia. Bar represents reported achievable plasma levels using oral capsule dosed on seven-day schedule. (B) Progression Free Survival (PFS) of evaluable patients by tumor type; peripheral T-Cell (n=14), median 5.7 months (95% CI, 2.1 to 14.6); mature B-Cell lymphoma or leukemia (n=10), median 0.8 months (95% CI, 0.5 to 1.3) months; Other hematologic malignancy (n=5), median 1.2 months (95% CI, 0.6 to not available); difference in PFS between T-cell and B-cell, P