Premium
Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218
Author(s) -
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.
Publication year - 2019
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.27540
Subject(s) - temsirolimus , medicine , mucositis , neutropenia , vinblastine , febrile neutropenia , toxicity , refractory (planetary science) , adverse effect , gastroenterology , phases of clinical research , pharmacology , chemotherapy , surgery , pi3k/akt/mtor pathway , apoptosis , biochemistry , chemistry , physics , astrobiology , discovery and development of mtor inhibitors
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.