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 maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of fenretinide delivered as an intravenous emulsion in relapsed/refractory hematologic malignancies. <br /><br />Experimental Design: Fenretinide (80 - 1810 mg/m²/day) was administered by continuous infusion on Days 1 - 5, in 21-day cycles, using an accelerated titration design. <br /><br />Results: Twenty-nine patients, treated with a median of three prior regimens (range, 1 to 7), were enrolled and received test drug. 97 courses were completed. An MTD was reached at 1280 mg/m²/day x 5 days. Course 1 DLTs included six patients with hypertriglyceridemia, four of which were asymptomatic; two patients experienced DLT thrombocytopenia (asymptomatic). Of eleven response-evaluable peripheral T-cell lymphomas, two had complete responses (CR, 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 mature B-cell lymphoma had an unconfirmed PR sustained for two cycles. Steady-state plasma levels were ~10 mcg/mL (mid-20's μmol/L) at 640 mg/m²/day; ~14 mcg/mL (mid-30's μmol/L) at 905 mg/m²/day; and ~22 mcg/mL (mid-50's μmol/L) at 1280 mg/m²/day. <br /><br />Conclusions: Intravenous fenretinide obtained significantly higher plasma levels than a previous capsule formulation, had acceptable toxicities, and evidenced anti-tumor activity in peripheral T-cell lymphomas. A recommended phase II dosing is 600 mg/m² on Day 1, followed by 1200 mg/m² on Days 2 - 5, every 21 days. A registration-enabling phase II study in relapsed/refractory PTCL (ClinicalTrials.gov identifier: NCT02495415) is ongoing.

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