Phase I Trial of IV Fenretinide (4-HPR) Plus IV Safingol for Patients With Relapsed Malignancies
Recruitment status was Not yet recruiting
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.
Drug: Fenretinide (4-HPR) plus Intravenous Safingol
|Study Design:||Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Trial of Intravenous Fenretinide (4-HPR) Plus Intravenous Safingol for Patients With Relapsed Malignancies|
- Determine the maximum tolerated dose of an intravenous safingol in combination with fenretinide [ Time Frame: approximately six months ] [ Designated as safety issue: Yes ]The primary outcome mesure of this study is to determine the maximum tolerated dose (MTD) of an intravenous (emulsion) safingol when administered as a continuous intravenous (c.i.v.) infusion for two days, once every 3 weeks, in combination with fenretinide (4-HPR) intravenous emulsion administered as a continuous intravenous infusion for five days, once every 3 weeks.
|Study Start Date:||March 2012|
|Estimated Primary Completion Date:||March 2014 (Final data collection date for primary outcome measure)|
Fenretinide (4-HPR) plus Intravenous Safingol
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01553071
|Contact: Ying Dongemail@example.com|
|United States, Texas|
|University of Texas Southwestern|
|Dalls, Texas, United States, 75390|