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

doi:10.1007/s00280-020-04171-4

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

Oncology

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	829-840
Number of pages	12
Journal	Cancer chemotherapy and pharmacology
Volume	86
Issue number	6
DOIs	https://doi.org/10.1007/s00280-020-04171-4
State	Published - 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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Greengard, E., Mosse, Y. P., Liu, X., Minard, C. G., Reid, J. M., Voss, S., Wilner, K., Fox, E., Balis, F., Blaney, S. M., Adamson, P. C., & Weigel, B. J. (2020). 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). Cancer chemotherapy and pharmacology, 86(6), 829-840. https://doi.org/10.1007/s00280-020-04171-4

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). / Greengard, Emily; Mosse, Yael P.; Liu, Xiaowei et al.
In: Cancer chemotherapy and pharmacology, Vol. 86, No. 6, 01.12.2020, p. 829-840.

Research output: Contribution to journal › Article › peer-review

Greengard, E, Mosse, YP, Liu, X, Minard, CG, Reid, JM, Voss, S, Wilner, K, Fox, E, Balis, F, Blaney, SM, Adamson, PC & Weigel, BJ 2020, '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)', Cancer chemotherapy and pharmacology, vol. 86, no. 6, pp. 829-840. https://doi.org/10.1007/s00280-020-04171-4

Greengard E, Mosse YP, Liu X, Minard CG, Reid JM, Voss S et al. 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). Cancer chemotherapy and pharmacology. 2020 Dec 1;86(6):829-840. doi: 10.1007/s00280-020-04171-4

Greengard, Emily ; Mosse, Yael P. ; Liu, Xiaowei et al. / 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). In: Cancer chemotherapy and pharmacology. 2020 ; Vol. 86, No. 6. pp. 829-840.

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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.",

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T2 - a Children’s Oncology Group phase 1 consortium study (ADVL1212)

AU - Greengard, Emily

AU - Mosse, Yael P.

AU - Liu, Xiaowei

AU - Minard, Charles G.

AU - Reid, Joel M.

AU - Voss, Stephan

AU - Wilner, Keith

AU - Fox, Elizabeth

AU - Balis, Frank

AU - Blaney, Susan M.

AU - Adamson, Peter C.

AU - Weigel, Brenda J.

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N2 - 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.

AB - 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.

KW - Chemotherapy combinations

KW - Crizotinib

KW - Oncology

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KW - Phase 1

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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)

Abstract

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