Phase I study of fenretinide delivered intravenously in patients with relapsed or refractory hematologic malignancies: A California cancer consortium trial

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 mmol/L) at 640 mg/m²/day, approximately 14 mcg/mL (mid-30s mmol/L) at 905 mg/m²/day, and approximately 22 mcg/mL (mid-50s mmol/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.