Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children’s Oncology Group phase 1 consortium study (ADVL1212)

Emily Greengard, Yael P. Mosse, Xiaowei Liu, Charles G. Minard, Joel M. Reid, Stephan Voss, Keith Wilner, Elizabeth Fox, Frank Balis, Susan M. Blaney, Peter C. Adamson, Brenda J. Weigel

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: This phase 1 study aimed to determine the safety, tolerability and recommended phase 2 dose (RP2D) of crizotinib in combination with cytotoxic chemotherapy for children with refractory solid tumors and ALCL. Methods: Pediatric patients with treatment refractory solid tumors or ALCL were eligible. Using a 3 + 3 design, crizotinib was escalated in three dose levels: 165, 215, or 280 mg/m2/dose BID. In Part A, patients received crizotinib oral solution (OS) in combination with topotecan and cyclophosphamide (topo/cyclo); in Part B, crizotinib OS was administered with vincristine and doxorubicin (vcr/dox). In Parts C and D, patients received topo/cyclo in combination with either crizotinib-formulated capsules (FC) or microspheres (cMS), respectively. Crizotinib pharmacokinetic evaluation was required. Results: Forty-four eligible patients were enrolled, 39 were evaluable for toxicity. Parts A and B were terminated due to concerns regarding palatability and tolerability of the OS. In Part C, crizotinib, FC 215 mg/m2/dose BID, in combination with topo/cyclo was tolerated. In Part D, the maximum tolerated dose (MTD) was exceeded at 165 mg/m2/dose of crizotinib cMS. Pharmacokinetics of crizotinib in combination with chemotherapy was similar to single-agent crizotinib and exposures were not formulation dependent. Conclusions: The RP2D of crizotinib FCs in combination with cyclophosphamide and topotecan was 215 mg/m2/dose BID. The oral solution of crizotinib was not palatable in this patient population. Crizotinib cMS was palatable; however, patients experienced increased toxicity that was not explained by the relative bioavailability or exposure and warrants further investigation. Clinical trial registry: The trial is registered as NCT01606878 at Clinicaltrials.gov.

Original languageEnglish (US)
Pages (from-to)829-840
Number of pages12
JournalCancer chemotherapy and pharmacology
Volume86
Issue number6
DOIs
StatePublished - Dec 1 2020

Keywords

  • Chemotherapy combinations
  • Crizotinib
  • Oncology
  • Pediatric
  • Phase 1

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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