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- Title
A Phase I Study of a Combination of Liposomal Irinotecan and Veliparib in Solid Tumors.
- Authors
LaRose, Meredith; Connolly, Roisin M; O'Sullivan, Ciara C; Velcheti, Vamsidhar; Vilimas, Rasa; Gano, Katherine; Bates, Susan E; Pommier, Yves; Thomas, Anish
- Abstract
Background Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors, but such combinations have proven too toxic in clinical trials. Liposomal irinotecan (nal-IRI) achieved similar intratumoral exposure with better antitumor activity than the conventional TOP1 inhibitor irinotecan in preclinical models. Tumor targeted delivery of TOP1 inhibitor using nal-IRI and an intermittent schedule of administration of PARP inhibitor may provide a tolerable combination. Methods A phase I study was performed to evaluate the safety and tolerability of escalating doses of nal-IRI and the PARP inhibitor veliparib in patients with solid tumors resistant to standard treatments. Nal-IRI was administered on days 1 and 15 and veliparib on days 5-12 and 19-25 in 28-day cycles. Results Eighteen patients were enrolled across 3 dose levels. Five patients encountered dose–limiting toxicities, including grade 3 diarrhea lasting more than 72 h in 3 patients and 1 patient each with grade 4 diarrhea and grade 3 hyponatremia. The most common grade 3 or 4 toxicities included diarrhea (50% of patients), nausea (16.6%), anorexia, and vomiting (11.1% each) (Table 1). There was no difference in frequencies of adverse events based on UGT1A1*28 status or prior opioid use (Table 1). Conclusion The clinical trial was terminated due to high frequency of unacceptable gastrointestinal toxicities, which precluded dose escalation of veliparib in combination with nal-IRI (ClinicalTrials.gov Identifier: NCT02631733).
- Subjects
THERAPEUTIC use of antineoplastic agents; DRUG efficacy; DRUG tolerance; CLINICAL trials; DIARRHEA; NAUSEA; IRINOTECAN; ANTINEOPLASTIC agents; HYPONATREMIA; VOMITING; TUMORS; ANOREXIA nervosa; ENZYME inhibitors; PATIENT safety; DRUG toxicity
- Publication
Oncologist, 2023, Vol 28, Issue 5, p460
- ISSN
1083-7159
- Publication type
Article
- DOI
10.1093/oncolo/oyad023