Abstract
Background
The checkpoint kinase 1 (CHK1) inhibitor prexasertib exhibited modest monotherapy antitumor activity in prior trials, suggesting that combination with chemotherapy or other targeted agents may be needed to maximize efficacy.
Objectives
The aim of this study was to determine the recommended phase II dose and schedule of prexasertib in combination with either cisplatin, cetuximab, pemetrexed, or 5-fluorouracil in patients with advanced and/or metastatic cancer, and to summarize preliminary antitumor activity of these combinations.
Patients and Methods
This phase Ib, nonrandomized, open-label study comprised dose-escalation phase(s) with multiple sub-arms evaluating different prexasertib–drug combinations: Part A, prexasertib + cisplatin (n = 63); Part B, prexasertib + cetuximab (n = 41); Part C, prexasertib + pemetrexed (n = 3); Part D, prexasertib + 5-fluorouracil (n =8). Alternate dose schedules/regimens intended to mitigate toxicity and maximize dose exposure and efficacy were also explored in sub-parts.
Results
In Part A, the maximum tolerated dose (MTD) of prexasertib in combination with cisplatin (75 mg/m2) was declared at 80 mg/m2, with cisplatin administered on Day 1 and prexasertib on Day 2 of a 21-day cycle. The overall objective response rate (ORR) in Part A was 12.7%, and 28 of 55 evaluable patients (50.9%) had a decrease in target lesions from baseline. The most frequent treatment-related adverse events (AEs) in Part A were hematologic, with the most common being white blood cell count decreased/neutrophil count decreased, experienced by 73.0% (any grade) and 66.7% (grade 3 or higher) of patients. In Part B, an MTD of 70 mg/m2 was established for prexasertib administered in combination with cetuximab (500 mg /m2), both administered on Day 1 of a 14-day cycle. The overall ORR in Part B was 4.9%, and 7 of 31 evaluable patients (22.6%) had decreased target lesions compared with baseline. White blood cell count decreased/neutrophil count decreased was also the most common treatment-related AE (56.1% any grade; 53.7% grade 3 or higher). In Parts A and B, hematologic toxicities, even with the addition of prophylactic granulocyte colony-stimulating factor, resulted in frequent dose adjustments (> 60% of patients). In Part C, evaluation of prexasertib + pemetrexed was halted due to dose-limiting toxicities in two of the first three patients; MTD was not established. In Part D, the MTD of prexasertib in combination with 5-fluorouracil (label dose) was declared at 40 mg /m2, both administered on Day 1 of a 14-day cycle. In Part D, overall ORR was 12.5%.
Conclusions
This study demonstrated the proof-of-concept that prexasertib can be combined with cisplatin, cetuximab, and 5-fluorouracil. Schedule was a key determinant of the tolerability and feasibility of combining prexasertib with these standard-of-care agents. Reversible hematologic toxicity was the most frequent AE and was dose-limiting. Insights gleaned from this study will inform future combination strategies for the development of prexasertib and next-generation CHK1 inhibitors.
ClinicalTrials.gov Identifier
NCT02124148 (date of registration 28 April 2014).
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Acknowledgments
We thank our patients and their caregivers for their participation in this study, the study investigators and their staff, and the Study JTJF clinical trial team. We wish to thank Abby Jeske and Nicholas Pulliam of Eli Lilly and Company for providing project management support, Michele Niland and Aaron Fink for their significant contributions as clinical trial managers, Wei Zhang for statistical contributions, and Suzanne Young for medical support and insights. Antonia Baldo of Syneos Health provided editorial support, funded by Eli Lilly and Company.
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This study was funded by Eli Lilly and Company.
Conflict of interest
Kathleen N. Moore reports personal fees (advisory board) from Astra Zeneca, Aravive, Abbvie, Eisai, GSK/Tesaro, Genentech/Roche, Immunogen, Myriad, Mersana, Merck, Tarveda, VBL Therapeutics, Sorrento, and Vavotar, outside the submitted work. David S. Hong reports research/grant funding from AbbVie, Adaptimmune, Adlai Nortye, Amgen, Astra-Zeneca, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, EMD Serono, Erasca, Fate Therapeutics, Genentech, Genmab, GlaxoSmithKline, Ignyta, Infinity, Kite, Kyowa, LOXO, Merck, MedImmune, Millenium, Mirati, miRNA, Molecular Templates, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics, Verstatem, and VM Oncology; consulting fees or advisory role for Alpha Insights, Acuta, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Boxer Capital, COG, Ecor1, Genentech, GLG, Group H, Guidepoint, HCW Precision, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, and WebMD; travel support from AACR, Amgen, ASCO, Astra Zeneca, Bayer, Celgene, Eli Lilly, Genentech, Genmab, GlaxoSmithKline, Janssen, LOXO, miRNA, Pfizer, Philips, SITC, and Takeda; and other ownership interests from Molecular Match (Advisor), OncoResponse (Founder), Presagia Inc. (Advisor). Manish R. Patel reports research funding (paid to institution) from Genentech, Vedanta Biosciences, Relay Therapeutics, Synthorx, Ribon Therapeutics, Clovis Pharma, Xencor, Black Diamond Therapeutics, Vigeo Therapeutics, Qilu Puget Sound Biotherapeutics, Daiichi Sankyo Pharma, Cyteir Therapeutics, Bicycle Therapeutics, Kymab, Prelude Therapeutics, ADC Therapeutics, Revolution Medicines, Klus Pharma, Janssen R&D, Birdie Biopharmaceuticals, Merck, Jacobio Pharmaceuticals, MacroGenics, TopAlliance Biosciences, Moderna, Agenus, Boehringer lngelheim, Eli Lilly, Tesaro, GlaxoSmithKline, Stemline Therapeutics, BioNTech, Hutchinson MediPharma, Evelo Biosciences, lgnyta, EMO Sereno, Novartis Pharmaceuticals, Loxo Oncology, Acerta Pharma, Portola Pharmaceuticals, Celgene Corporation, Taiho Oncology, LSK BioPartners, Olema Pharmaceuticals, Phoenix Molecular Designs, H3 Biomedicine, and Syndax; and personal fees (speakers bureau) from AstraZeneca, outside the submitted work. Shubham Pant reports research funding (paid to institution) from Mirati Therapeutics, Inc., Eli Lilly, Red Hill Biopharma Ltd, Xencor, Five Prime Therapeutics, Novartis, Rgenix, Sanofi-Aventis, Arqule, Bristol-Myers Squibb, Onco Response, Sanofi US Services Inc., and GlaxoSmith Kline; and honoraria from 4D, Tyme, Xencor, Zymeworks, and Ipsen. Susanna V. Ulahannan reports research funding (paid to institution) from Abbvie, Arqule, AstraZeneca, Boeringer lngelheim, BMS, Celgene, Ciclomed, Evelo Biosciences, GI therapeutics, GSK, lsofol, Klus Pharma, Macrogenics, Merck, Mersana, Oncomed pharma, Pfizer, Regeneron, Revolution Medicines, Takeda, Tarveda Therapeutics, Tesaro, Tempest, lncyte, and Vigeo Therapeutics; and personal fees (advisory board) from Array, Bayer, Exelxis, Syros and lncyte, outside the submitted work. Suzanne Jones reports grants from Eli Lilly, during the conduct of the study; and stock ownership from HCA Healthcare, outside the submitted work. Funda Meric-Bernstam reports receiving consulting fees from AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, and Zymeworks; Advisory Committee fees from Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis; sponsored research paid to the institution from Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd, Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical (formerly Millennium Pharmaceutical), Novartis, Puma Biotechnology Inc., and Taiho Pharmaceutical Co.; and honoraria from Chugai Biopharmaceuticals for a speaking engagement. Judy S. Wang reports research funding (paid to institution) from Genentech, Vedanta Biosciences, Relay Therapeutics, Synthorx, Ribon Therapeutics, Clovis Pharma, Xencor, Black Diamond Therapeutics, Vigeo Therapeutics, Qilu Puget Sound Biotherapeutics, Daiichi Sankyo Pharma, Cyteir Therapeutics, Bicycle Therapeutics, Kymab, Prelude Therapeutics, ADC Therapeutics, Revolution Medicines, Klus Pharma, Janssen R&D, Birdie Biopharmaceuticals, Merck, Jacobio Pharmaceuticals, MacroGenics, TopAlliance Biosciences, Moderna, Agenus, Boehringer lngelheim, Eli Lilly, Tesaro, GlaxoSmithKline, Stemline Therapeutics, BioNTech, Hutchinson MediPharma, Evelo Biosciences, lgnyta, EMO Serono, Novartis Pharmaceuticals, Loxo Oncology, Acerta Pharma, Portola Pharmaceuticals, Celgene Corporation, Taiho Oncology, LSK BioPartners, Olema Pharmaceuticals, Phoenix Molecular Designs, H3 Biomedicine, and Syndax; and personal fees (speakers bureau) from AstraZeneca and Eisai, outside the submitted work. Raid Aljumaily has no discloses to declare. Erika P. Hamilton reports research funding (paid to institution) from OncoMed, Genentech/Roche, Zymeworks, Rgenix, ArQule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer lngelheim, lmmunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, Medlmmune, SeaGen, Puma Biotechnology, Compugen, Taplmmune, Lilly, Pfizer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, lnventisBio, Lycera, Mersana, Radius Health, Abbvie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMO Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Polyphor, lmmunogen, Plexxicon, Amgen, Akesobio Australia, and Shattuck Labs; and consulting/advisory role (paid to institution only) for Genentech/Roche, Boehringer lngelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, and Seagen. Erika S. Wittchen is an employee of Syneos Health who contracts with Eli Lilly and Company. Medical writing support was funded by Eli Lilly and Company. Xuejing Wang is an employee of Eli Lilly and Company and reports stock ownership from Eli Lilly. Aimee Bence Lin is an employee of Eli Lilly and Company and reports stock ownership from Eli Lilly, outside the submitted work. Johanna C. Bendell reports grants and other/consulting fees (paid to institution) from Gilead, Genentech/Roche, BMS, Five Prime, Eli Lilly, Merck , Medlmmune, Celgene, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, Bl, Daiichi Sankyo, Bayer, lncyte, Apexigen, Array, Sanofi, Agios, ARMO, Ipsen, Merrimack, Oncogenex, Evelo, FORMA, Innate, Arch Oncology, Prelude Therapeutics, Amgen, Pfizer, Seattle Genetics, Bicycle Therapeutics, and Relay Therapeutics; other/consulting fees (paid to institution) from Phoenix Bio, Cyteir, Molecular Partners, Torque, Tizona, Janssen, Tolero, TD2 (Translational Drug Development), Moderna Therapeutics, Tanabe Research Laboratories, Beigene, Continuum Clinical, Amgen, Piper Biotech, and Samsung Bioepios; grants (paid to institution) from EMO Serano, Koltan, SynDevRex, Forty Seven, Abbvie, Onyx, Takeda, Eisai, Celldex, Cytomx, Nektar, Boston Biomedical, Tarveda, Tyrogenex, Marshall Edwards, Pieris, Mersana, Calithera, Blueprint, Merus, Jacobio, Effector, Novocare, Arrys, Tracon, Sierra, Unum Therapeutics, Vyriad, Harpoon, ADC, Millennium, lmclome, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Tempest Tx, Shattuck Labs, Synthorx, Inc., Revolution Medicines Inc., Zymeworks, AtlasMedx, Scholar Rock, and NGM Biopharma, outside the submitted work.
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All procedures involving human participants were performed in accordance with consensus ethics principles derived from international ethics guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, International Conference on Harmonisation Good Clinical Practice (ICH GCP) Guideline [E6], and all applicable laws and regulations.
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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, and read and approved the final manuscript.
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Moore, K.N., Hong, D.S., Patel, M.R. et al. A Phase 1b Trial of Prexasertib in Combination with Standard-of-Care Agents in Advanced or Metastatic Cancer. Targ Oncol 16, 569–589 (2021). https://doi.org/10.1007/s11523-021-00835-0
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DOI: https://doi.org/10.1007/s11523-021-00835-0