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)

• Published in: Cancer chemotherapy and pharmacology Vol. 86; no. 6; pp. 829 - 840
• Main Authors: Greengard, Emily, Mosse, Yael P., Liu, Xiaowei, Minard, Charles G., Reid, Joel M., Voss, Stephan, Wilner, Keith, Fox, Elizabeth, Balis, Frank, Blaney, Susan M., Adamson, Peter C., Weigel, Brenda J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2020; Springer Nature B.V
• Subjects: Anaplastic large-cell lymphoma; Bioavailability; Cancer Research; Chemotherapy; Children; Clinical Trial Report; Consortia; Cyclophosphamide; Cytotoxicity; Doxorubicin; Exposure; Lymphoma; Medicine; Medicine & Public Health; Microspheres; Oncology; Palatability; Patients; Pediatrics; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Solid tumors; Targeted cancer therapy; Topotecan; Toxicity; Tumors; Vincristine; Crizotinib; Oncology; Phase 1; Pediatric; Chemotherapy combinations
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-020-04171-4

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/m 2 /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/m 2 /dose BID, in combination with topo/cyclo was tolerated. In Part D, the maximum tolerated dose (MTD) was exceeded at 165 mg/m 2 /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/m 2 /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.