Phase I Trial of IV Fenretinide (4-HPR) Plus IV Safingol for Patients With Relapsed Malignancies

Summary

In preclinical studies, the anti-cancer efficacy of fenretinide, a synthetic retinoid that causes cytotoxicity by mechanisms which include increased intracellular dihydroceramides, has been shown to be enhanced by safingol, a stereochemical-variant dihydroceramide precursor. This phase I study represents the first clinical trial employing this promising combination. The drug administration schedule (fenretinide given on Days 1-5, safingol given on Days 1-2 of each 21-day cycle) reflects the in vitro observation that tumor cell exposure to safingol increased fenretinide efficacy both during and after safingol administration. The total dose of fenretinide, 4600 mg/m2 over 5 days, represents a 30% total dose reduction from the single agent MTD dose of 1280 mg/m2/day x 5 days determined on the PhI-42 study. This fenretinide dose is expected to produce plasma levels in the 30?s ?M. This dose reduction has been employed to reduce the potential for overlapping hepatic toxicities between these two agents.

The administration of a reduced fenretinide dose on Day 1 (600 mg/m2 on Day 1, escalated to 1000 mg/m2/day on Days 2-5) has been selected due to earlier observations that initial exposure to the soy bean oil vehicle in the fenretinide emulsion may induce endogenous lipases, thereby permitting tolerance of higher total doses fenretinide emulsion subsequently administered. The starting dose of safingol in this study, 210 mg/m2/day x 2 days (420 mg/m2 total), corresponds to 50% of the recommended Phase II safingol dose (bolus) determined in the Schwartz, et al, Phase I study of safingol plus cisplatin 60 mg/m2 (the MTD of single-agent, intravenous (emulsion) safingol was not reached in the Phase I safingol run-in monotherapy portion of this study), and was selected to provide an adequate safety margin against the potential for overlapping toxicities (such as hepatic transaminitis).

The study has been designed to optimize the safety of this novel combination. Treatment will be administered in the inpatient setting. Central venous access will be mandated to avoid the potential for hemolysis and thrombophlebitis associated with the preclinical peripheral administration of a previous safingol formulation in rats. To reduce the incidence of hypertriglyceridemia, a revised fenretinide delivery schedule will be employed. Patients will also be encouraged to maintain a low-fat diet during fenretinide administration. Serum triglycerides will be monitored every 12 hours. To monitor for cardiac toxicity, which was noted in canine studies at the highest dose of safingol plus fenretinide tested, serum troponin T levels will be monitored daily. To limit the potential for hepatotoxicity resulting from a possible drug interaction observed between intravenous fenretinide, ceftriaxone and acetaminophen in a pediatric patient, the concurrent administration of ceftriaxone, or acetaminophen, with the fenretinide emulsion infusion will be prohibited.

Conditions

• Solid Tumor

Interventions

DRUG

Fenretinide (4-HPR) plus Intravenous Safingol

A course for this study is defined as the 5 days of treatment with Fenretinide (4-HPR) plus Safingol followed by 16 days of rest. A course is repeated every 21 days if there is no clinical evidence of disease progression for a maximum of six 5-day infusions. Days 1-5 of every cycle: Day 1 Fenretinide (4-HPR) intravenous emulsion: 600 mg/m2 for 24 hours Given concurrently (at the same time) with: Safingol intravenous 210 mg/m2 for 24 hours Day 2 Fenretinide (4-HPR) intravenous emulsion: 1000 mg/m2 for 24 hours Given concurrently (at the same time) with: Safingol intravenous 210 mg/m2 for 24 hours Days 3-5 Fenretinide (4-HPR) intravenous emulsion: 1000 mg/m2 continuously for 3 days Days 8 and 15 : Weekly blood draw to monitor side effects requires a clinic visit for approximately 1 hour Days 6,7,9-14, 16-21 Rest and monitor side effects.

Sponsors & Collaborators

• South Plains Oncology Consortium

  lead NETWORK

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2016-11-30

Primary Completion

2020-12-31

Completion

2020-12-31

Countries

• United States

Study Locations