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A phase 1 dose-escalation study of checkpoint kinase 1 (CHK1) inhibitor prexasertib in combination with p38 mitogen-activated protein kinase (p38 MAPK) inhibitor ralimetinib in patients with advanced or metastatic cancer

  • Johanna C. BendellEmail author
  • Helge G. Bischoff
  • Jimmy Hwang
  • Hans Christian Reinhardt
  • Thomas Zander
  • Xuejing Wang
  • Scott Hynes
  • Celine Pitou
  • Robert Campbell
  • Philip Iversen
  • Daphne L. Farrington
  • Katherine Bell-McGuinn
  • Michael Thomas
PHASE I STUDIES

Summary

Purpose The primary objective was to determine the recommended Phase 2 dose (RP2D) of checkpoint kinase 1 inhibitor, prexasertib, in combination with the p38 mitogen-activated protein kinase inhibitor, ralimetinib, which may be safely administered to patients with advanced cancer. Methods This Phase 1, nonrandomized, open-label, dose-escalation study of prexasertib+ralimetinib included patients with advanced and/or metastatic cancer, followed by a planned cohort expansion in patients with colorectal or non-small-cell lung cancer with KRAS and/or BRAF mutations. Intravenous prexasertib was administered at 60 mg/m2 (days 1 and 15 of a 28-day cycle), together with oral ralimetinib every 12 h (days 1 to 14 at 100 mg [Cohort 1, n = 3] or 200 mg [Cohort 2, n = 6]). Dose escalations for each agent were planned using a model-based 3 + 3 escalation paradigm. Safety was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0X. Tumor response was determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results Nine patients were treated; 3 experienced dose-limiting toxicities, all in Cohort 2, prohibiting further dose escalation. The most common ≥Grade 3 adverse event was neutrophil count decreased; other reported ≥Grade 3 hematological toxicities included febrile neutropenia and anemia. The pharmacokinetics of prexasertib+ralimetinib was comparable to the monotherapy population profile for each agent. One patient achieved a best overall response of stable disease (for 2 cycles); there were no complete/partial responses. Conclusions This study did not achieve its primary objective of establishing an RP2D of combination prexasertib + ralimetinib that could be safely administered to patients with advanced cancer.

Keywords

LY2606368 Prexasertib Ralimetinib CHK1 p38 MAPK 

Notes

Acknowledgments

The authors would like to thank all the patients who participated in this study and their families, the study investigators, and study staff. This study was funded by Eli Lilly and Company. Erika S. Wittchen PhD, of Syneos Health, provided medical writing support.

Author contributions

All authors contributed to at least one of the following: study conception, design, data acquisition, analysis, and/or interpretation. All authors contributed to drafting of the manuscript and/or critical revision of the work for important intellectual content. All authors read and approved the final manuscript.

Funding

This study was funded by Eli Lilly and Company.

Compliance with ethical standards

Conflict of interest

Dr. Bendell reports the following: grants (payment to institution for conduct of clinical trials for which Dr. Bendell served as PI) from EMD Serono, Koltan, SynDevRex, Forty Seven, Abbvie, Onyx, Takeda, Eisai, CellDex, Cytomx, Nektar, Boston Biomedical, Tarveda, Tyrogenex, Marshall Edwards, Pieris, Pfizer, Mersana, Calithera, Blueprint, Evelo, Merus, Jacobio, Effector, Novocare, Arrys, tracon, Sierra, Unum Therapeutics, Vyriad, Harpoon, Acerta Pharma, Rgenix, Millennium, ImClone, ADC, and Bellicum; grants and consulting services (payment to institution for conduct of clinical trials for which Dr. Bendell served as PI, and payment to institution for consulting services by Dr. Bendell) from Gilead, Genentech/Roche, Bristol Myers Squibb, Five prime, Eli Lilly, Merck, MedImmune, Celgene, Taiho, Marcogenics, GSK, Novartis, OncMed, LEAP, TG Therapeutics, Astra Zeneca, BI, Bayer, Apexgen, Array, Prelude Oncology, Sanofi, Agios, ARMO, Ispen, Merrimack, Oncogenex, FORMA, Innate, Arch Oncology, and Amgen; consulting services (payment to institution for consulting services by Dr. Bendell) from Phoenix Bio, Cyteir, Molecular Partners, Torque, Tizona, Translational Drug Development, Seattle Genetics, Moderna Therapeutics, Tanabe Research Laboratories, Beigene, and Continuum Clinical.

Dr. Bischoff has nothing to disclose.

Dr. Hwang has nothing to disclose.

Dr. Reinhardt has nothing to disclose.

Dr. Zander reports serving on advisory boards from Roche, BMS, MSD, Novartis, Pfizer, and Eli Lilly.

Dr. Bell-McGuinn, Dr. Campbell, and Dr. Wang are employees and shareholders of Eli Lilly.

Dr. Hynes, Dr. Iversen, Dr. Pitou are employees of Eli Lilly.

D. Farrington is an employee and shareholder of Verastem Oncology, and reports personal fees and is a shareholder of Eli Lilly, and is a shareholder of Sesen Bio Inc.

Dr. Thomas reports personal fees from AbbVie, grants, personal fees and non-financial support from Bristol-Myers Squibb, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Lilly, personal fees and non-financial support from MSD, personal fees and non-financial support from Novartis, grants and personal fees from Roche, and grants from AstraZeneca, during the conduct of the study.

Ethical approval

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 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was registered at ClinicalTrials.gov as NCT02860780. Informed consent was obtained from all individual participants included in the study.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10637_2019_873_MOESM1_ESM.pdf (202 kb)
ESM 1 (PDF 202 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Johanna C. Bendell
    • 1
    Email author
  • Helge G. Bischoff
    • 2
  • Jimmy Hwang
    • 3
  • Hans Christian Reinhardt
    • 4
    • 5
  • Thomas Zander
    • 6
  • Xuejing Wang
    • 7
  • Scott Hynes
    • 7
  • Celine Pitou
    • 7
  • Robert Campbell
    • 7
  • Philip Iversen
    • 7
  • Daphne L. Farrington
    • 7
    • 8
  • Katherine Bell-McGuinn
    • 7
  • Michael Thomas
    • 2
  1. 1.Sarah Cannon Research InstituteTennessee Oncology PLLCNashvilleUSA
  2. 2.Department of Thoracic Oncology, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL)Heidelberg University HospitalHeidelbergGermany
  3. 3.Levine Cancer InstituteAtrium HealthCharlotteUSA
  4. 4.University of Cologne, University Hospital Cologne, Clinic I for Internal MedicineCologneGermany
  5. 5.University of Cologne, Center for Molecular Medicine CologneCologneGermany
  6. 6.Clinic I of Internal Medicine, University Hospital of CologneCologneGermany
  7. 7.Eli Lilly and CompanyIndianapolisUSA
  8. 8.Verastem OncologyNeedhamUSA

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