Phase I trial of intravenous fenretinide (4-HPR) plus safingol in advanced malignancies.

Autor: Boulter AC; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.; Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA., Maurer BJ; Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA., Pogue M; Division of Hematology-Oncology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA., Kang MH; Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA., Cho H; Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.; Jeonbuk National University, Jeonju, South Korea., Knight A; South Plains Oncology Consortium, Lubbock, TX, USA., Reynolds CP; Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.; South Plains Oncology Consortium, Lubbock, TX, USA., Quick D; Joe Arrington Cancer Center, Lubbock, TX, USA., Awasthi S; Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.; Doctors Hospital Cayman, George Town, Cayman Islands., Gerber DE; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA. david.gerber@utsouthwestern.edu.; Division of Hematology-Oncology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA. david.gerber@utsouthwestern.edu.; Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA. david.gerber@utsouthwestern.edu.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2023 Aug; Vol. 92 (2), pp. 97-105. Date of Electronic Publication: 2023 May 18.
DOI: 10.1007/s00280-023-04543-6
Abstrakt: Purpose: Fenretinide (4-HPR) is a synthetic retinoid that induces cytotoxicity through dihydroceramide production. Safingol, a stereochemical-variant dihydroceramide precursor, exhibits synergistic effects when administered with fenretinide in preclinical studies. We conducted a phase 1 dose-escalation clinical trial of this combination.
Methods: Fenretinide was administered as a 600 mg/m 2 24-h infusion on Day 1 of a 21-day cycle followed by 900 mg/m 2 /day on Days 2 and 3. Safingol was concurrently administered as a 48-h infusion on Day 1 and 2 using 3 + 3 dose escalation. Primary endpoints were safety and maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetics and efficacy.
Results: A total of 16 patients were enrolled (mean age 63 years, 50% female, median three prior lines of therapy), including 15 patients with refractory solid tumors and one with non-Hodgkin lymphoma. The median number of treatment cycles received was 2 (range 2-6). The most common adverse event (AE) was hypertriglyceridemia (88%; 38% ≥ Grade 3), attributed to the fenretinide intralipid infusion vehicle. Other treatment-related AEs occurring in ≥ 20% of patients included anemia, hypocalcemia, hypoalbuminemia, and hyponatremia. At safingol dose 420 mg/m 2 , one patient had a dose-limiting toxicity of grade 3 troponinemia and grade 4 myocarditis. Due to limited safingol supply, enrollment was halted at this dose level. Fenretinide and safingol pharmacokinetic profiles resembled those observed in monotherapy trials. Best radiographic response was stable disease (n = 2).
Conclusion: Combination fenretinide plus safingol commonly causes hypertriglyceridemia and may be associated with cardiac events at higher safingol levels. Minimal activity in refractory solid tumors was observed.
Trial Registration Number: NCT01553071 (3.13.2012).
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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