Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218. Issue 3 (4th November 2018)

• Record Type: Journal Article
• Authors: Deyell, Rebecca J.; Wu, Bing; Rassekh, S. Rod; Tu, Dongsheng; Samson, Yvan; Fleming, Adam; Bouffet, Eric; Sun, Xiaoqun; Powers, Jean; Seymour, Lesley; Baruchel, Sylvain; Morgenstern, Daniel A.
• Is Part Of: Pediatric blood & cancer. Volume 66:Issue 3(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-11-04
• Subjects: antiangiogenesis‐angiogenesis -- mTOR -- phase I -- sirolimus -- temsirolimus -- vinblastine; Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.27540
• Languages: English
• ISSNs: 1545-5009

Abstract

Abstract: Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children. Procedure: Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m 2 ) and temsirolimus (15 mg/m 2 ) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected. Results: Seven patients with median age 12 years (range, 8–18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose‐limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level −2 (temsirolimus 10 mg/m 2, vinblastine 4 mg/m 2 ) with no protocol‐related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred—an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)—unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1–8.3 months). Conclusion: The combination of weekly temsirolimus (15 mg/m 2 ) and vinblastine (4 mg/m 2 ) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.