Phase I Trial of IV Fenretinide (4-HPR) Plus IV Safingol for Patients With Relapsed Malignancies
Status:
Unknown status
Trial end date:
2020-12-01
Target enrollment:
Participant gender:
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.