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Research Article

Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer

Jeffrey W Clark

,

D Ross Camidge

,

Eunice L Kwak

,

Robert G Maki

,

Geoffrey I Shapiro

,

Isan Chen^‡

,

Weiwei Tan

,

Sophia Randolph^‡

,

James G Christensen^‡

,

Mark Ozeck

,

Yiyun Tang

,

Keith D Wilner

&

Ravi Salgia

Jeffrey W Clark

*Author for correspondence: Tel.: +1 617-643-3415; Fax: +1 617-724-1136;

E-mail Address: clark.jeffrey@mgh.harvard.edu

Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA

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,

Division of Medical Oncology, University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA

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,

Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA

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,

Don Monti Division of Medical Oncology & Hematology, Northwell Cancer Institute & Cold Spring Harbor Laboratory, Lake Success, NY 11724, USA

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,

Geoffrey I Shapiro

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA

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,

Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA

‡These authors were employees of Pfizer at the time this work was conducted

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,

Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA

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,

Sophia Randolph^‡

Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA

‡These authors were employees of Pfizer at the time this work was conducted

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,

James G Christensen^‡

Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA

‡These authors were employees of Pfizer at the time this work was conducted

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,

Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA

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,

Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA

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,

Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA

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&

Department of Medical Oncology & Therapeutics Research, The City of Hope, Duarte, CA 91010, USA

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Published Online:28 Nov 2019https://doi.org/10.2217/fon-2019-0653

Abstract

Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily–300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced ≥1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195

Keywords:

Papers of special note have been highlighted as: • of interest

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Vol. 16, No. 1

Supplemental Materials

Metrics

Downloaded 504 times

History

Received 16 October 2019

Accepted 12 November 2019

Published online 28 November 2019

Published in print January 2020

Information

© 2019 Future Medicine Ltd

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: http://www.futuremedicine.com/doi/suppl/10.2217/fon-2019-0653

Author contributions

All authors contributed to the concept and design of the study, to conducting the analysis, interpretation of the results, writing and revisions of the manuscript and approval of the final version submitted for publication.

Acknowledgments

The authors thank K Letrent (formerly of Pfizer Inc.) for providing review comments on this article during the draft stage. The authors wish to thank J Prokop, K Turnball and G Emory (formerly of Pfizer Inc.) for their assistance with the study. The authors especially thank all of the patients, their families, nurses and research personnel that made this study possible.

Financial & competing interests disclosure

DR Camidge was supported in part by the University of Colorado Lung Cancer Specialized Program of Research Excellence (NCI-P50 CA058187). JW Clark was supported in part by the DFHCC P30CA06516 NCI-ASCO Clinical Investigator Team Leadership Supplemental Award. RG Maki reports grants from Pfizer for institutional research support during the conduct of the study. EL Kwak is a current employee of Novartis. W Tan, KD Wilner and M Ozeck are employees of Pfizer. I Chen, JG Christensen and S Randolph were employees of Pfizer at the time this work was conducted. This study was supported by Pfizer Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing support was funded by Pfizer Inc. and was provided by M Quinn of ACUMED® (Tytherington, UK) and J Drummond, S Lancaster and K Williams of inScience Communications, Springer Healthcare (Chester, UK).

Prior presentation

Crizotinib pharmacokinetic data and midazolam data appeared in a poster presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting, June 4–8, 2010, Chicago, IL, USA: Tan W, Wilner KD, Bang Y et al. Pharmacokinetics (PK) of PF-02341066, a dual ALK/MET inhibitor, after multiple oral doses to advanced cancer patients [abstract]. J. Clin. Oncol. 28(Suppl. 15), 2596 (2010).

Ethical conduct of research

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Data sharing statement

The authors certify that this manuscript reports original clinical trial data: NCT00585195. Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.