A Phase i Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

Florence Atrafi; Oliver Boix; Vivek Subbiah; Jennifer R. Diamond; Sant P. Chawla; Anthony W. Tolcher; Patricia M. Lorusso; Joseph P. Eder; Martin Gutierrez; Kumar Sankhala; Prabhu Rajagopalan; Isabelle Genvresse; Simon Langer; Ron H.J. Mathijssen; Jaap Verweij; Ingmar Bruns; Martijn P. Lolkema

doi:10.1158/1078-0432.CCR-20-4185

A Phase i Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

Florence Atrafi, Oliver Boix, Vivek Subbiah, Jennifer R. Diamond, Sant P. Chawla, Anthony W. Tolcher, Patricia M. Lorusso, Joseph P. Eder, Martin Gutierrez, Kumar Sankhala, Prabhu Rajagopalan, Isabelle Genvresse, Simon Langer, Ron H.J. Mathijssen, Jaap Verweij, Ingmar Bruns, Martijn P. Lolkema^*

^*Corresponding author for this work

Medical Oncology

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

25 Citations (Scopus)

Abstract

Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: Patients with solid tumors were randomized to receive oralBAY(twice daily 2-days-on/5-days-off) withweekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. Results: In total, 75 patients were enrolled. The main doselimiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0-12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure-toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities. _2021 American Association for Cancer Research.

Original language	English
Pages (from-to)	6366-6375
Number of pages	10
Journal	Clinical Cancer Research
Volume	27
Issue number	23
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-4185
Publication status	Published - 1 Dec 2021

Bibliographical note

Funding Information:
This study was sponsored by Bayer Pharmaceuticals. Assistance for pharmacokinetic calculations was provided by Michaela Damaske of Bayer Pharma AG. We also thank Ray Valencia and Fabricio Souza for implementation of this clinical study and Lucia Giannini for assistance with Supplementary Fig. S3.

Funding Information:
F. Atrafi reports grants from Bayer during the conduct of the study. O. Boix reports other support from Bayer AG during the conduct of the study, as well as other support from Bayer AG outside the submitted work. V. Subbiah reports grants from Bayer and a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study. V. Subbiah also reports research grants from Roche/ Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, UT MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, Pharmamar, and Medimmune; advisory board/ consultant positions with Helsinn, Incyte, QED Pharma, Daiichi Sankyo, Signant Health, Novartis, Relay therapeutics, Roche, and Medimmune; travel funds from Pharmamar, Incyte, ASCO, and ESMO; and other support from Medscape outside the submitted work. J.R. Diamond reports grants from Bayer during the conduct of the study, as well as other support from Gilead outside the submitted work. S.P. Chawla reports other support from Amgen, Roche, TRACON Pharma, Karyopharm, Advenchen Laboratories, NKBioTech, InhibRx, and Epizyme outside the submitted work. A.W. Tolcher reports personal fees and other support from AbbVie Inc., ABL Bio Inc., Adagene Inc., ADC Therapeutics SA, Agenus Inc., Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Apros Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC, Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd., BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., Codiak BioSciences, Inc., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, eFFECTOR Therapeutics, Inc., Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., GlaxoSmithKline Research & Development Limited, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc., Kiromic Biopharma, Inc., Mabspace Biosciences (Suzhou) Co., Ltd., Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Mersana Therapeutics, Inc., Mirati Therapeutics, Inc., NatureWise Biotech & Medicals Corporation, Navire Pharma Inc., NBE-Therapeutics AG, NextCure, Inc., Nitto BioPharma, Inc., Odonate Therapeutics, Inc., ORIC Pharmaceuticals, Pelican Therapeutics, Inc., Petra Pharma, Pfizer, Inc., Pieris Pharmaceuticals, Inc., PMV Pharmaceuticals, Inc., Qilu Puget Sound Biotherapeutics Corporation, Samumed, LLC, Seattle Genetics, Inc., Spring Bank Pharmaceuticals, Inc., Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., Symphogen A/S, Syndax Pharmaceuticals Inc., Synthorx, Inc., Takeda, Tizona Therapeutics, and Zymeworks Inc. during the conduct of the study, as well as personal fees and other support from AbbVie Inc., Agenus, Inc., Asana Biosciences, Ascentage, AxImmune, Bayer, Gilde Heathcare Partners, HBM Partners, Immunomet Therapeutics, Inc., Karma Oncology, Mekanistic Therapeutics, Menarini Ricerche, Mersana, Nanobiotix, Partner Therapeutics, Pfizer Inc., Pierre Fabre, RYVU Therapeutics, Seattle Genetics, SOTIO Biotechnology Inc., Spirea Limited Inc., Transcenta Therapeutics Inc., Trillium Therapeutics Inc., Adagene, Inc., ARO Biotherapeutics, Bioinvent,

Publisher Copyright:
© 2021 American Association for Cancer Research Inc.. All rights reserved.

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10.1158/1078-0432.CCR-20-4185

Cite this

Atrafi, F., Boix, O., Subbiah, V., Diamond, J. R., Chawla, S. P., Tolcher, A. W., Lorusso, P. M., Eder, J. P., Gutierrez, M., Sankhala, K., Rajagopalan, P., Genvresse, I., Langer, S., Mathijssen, R. H. J., Verweij, J., Bruns, I., & Lolkema, M. P. (2021). A Phase i Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation. Clinical Cancer Research, 27(23), 6366-6375. https://doi.org/10.1158/1078-0432.CCR-20-4185

@article{4a36eb39c81d47bfbfc985bcc05895f7,

title = "A Phase i Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation",

abstract = "Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: Patients with solid tumors were randomized to receive oralBAY(twice daily 2-days-on/5-days-off) withweekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. Results: In total, 75 patients were enrolled. The main doselimiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0-12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure-toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities. _2021 American Association for Cancer Research.",

author = "Florence Atrafi and Oliver Boix and Vivek Subbiah and Diamond, {Jennifer R.} and Chawla, {Sant P.} and Tolcher, {Anthony W.} and Lorusso, {Patricia M.} and Eder, {Joseph P.} and Martin Gutierrez and Kumar Sankhala and Prabhu Rajagopalan and Isabelle Genvresse and Simon Langer and Mathijssen, {Ron H.J.} and Jaap Verweij and Ingmar Bruns and Lolkema, {Martijn P.}",

note = "Funding Information: This study was sponsored by Bayer Pharmaceuticals. Assistance for pharmacokinetic calculations was provided by Michaela Damaske of Bayer Pharma AG. We also thank Ray Valencia and Fabricio Souza for implementation of this clinical study and Lucia Giannini for assistance with Supplementary Fig. S3. Funding Information: F. Atrafi reports grants from Bayer during the conduct of the study. O. Boix reports other support from Bayer AG during the conduct of the study, as well as other support from Bayer AG outside the submitted work. V. Subbiah reports grants from Bayer and a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study. V. Subbiah also reports research grants from Roche/ Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, UT MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, Pharmamar, and Medimmune; advisory board/ consultant positions with Helsinn, Incyte, QED Pharma, Daiichi Sankyo, Signant Health, Novartis, Relay therapeutics, Roche, and Medimmune; travel funds from Pharmamar, Incyte, ASCO, and ESMO; and other support from Medscape outside the submitted work. J.R. Diamond reports grants from Bayer during the conduct of the study, as well as other support from Gilead outside the submitted work. S.P. Chawla reports other support from Amgen, Roche, TRACON Pharma, Karyopharm, Advenchen Laboratories, NKBioTech, InhibRx, and Epizyme outside the submitted work. A.W. Tolcher reports personal fees and other support from AbbVie Inc., ABL Bio Inc., Adagene Inc., ADC Therapeutics SA, Agenus Inc., Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Apros Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC, Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd., BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., Codiak BioSciences, Inc., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, eFFECTOR Therapeutics, Inc., Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., GlaxoSmithKline Research & Development Limited, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc., Kiromic Biopharma, Inc., Mabspace Biosciences (Suzhou) Co., Ltd., Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Mersana Therapeutics, Inc., Mirati Therapeutics, Inc., NatureWise Biotech & Medicals Corporation, Navire Pharma Inc., NBE-Therapeutics AG, NextCure, Inc., Nitto BioPharma, Inc., Odonate Therapeutics, Inc., ORIC Pharmaceuticals, Pelican Therapeutics, Inc., Petra Pharma, Pfizer, Inc., Pieris Pharmaceuticals, Inc., PMV Pharmaceuticals, Inc., Qilu Puget Sound Biotherapeutics Corporation, Samumed, LLC, Seattle Genetics, Inc., Spring Bank Pharmaceuticals, Inc., Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., Symphogen A/S, Syndax Pharmaceuticals Inc., Synthorx, Inc., Takeda, Tizona Therapeutics, and Zymeworks Inc. during the conduct of the study, as well as personal fees and other support from AbbVie Inc., Agenus, Inc., Asana Biosciences, Ascentage, AxImmune, Bayer, Gilde Heathcare Partners, HBM Partners, Immunomet Therapeutics, Inc., Karma Oncology, Mekanistic Therapeutics, Menarini Ricerche, Mersana, Nanobiotix, Partner Therapeutics, Pfizer Inc., Pierre Fabre, RYVU Therapeutics, Seattle Genetics, SOTIO Biotechnology Inc., Spirea Limited Inc., Transcenta Therapeutics Inc., Trillium Therapeutics Inc., Adagene, Inc., ARO Biotherapeutics, Bioinvent, Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research Inc.. All rights reserved.",

year = "2021",

month = dec,

day = "1",

doi = "10.1158/1078-0432.CCR-20-4185",

language = "English",

volume = "27",

pages = "6366--6375",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "23",

}

Atrafi, F, Boix, O, Subbiah, V, Diamond, JR, Chawla, SP, Tolcher, AW, Lorusso, PM, Eder, JP, Gutierrez, M, Sankhala, K, Rajagopalan, P, Genvresse, I, Langer, S, Mathijssen, RHJ, Verweij, J, Bruns, I & Lolkema, MP 2021, 'A Phase i Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation', Clinical Cancer Research, vol. 27, no. 23, pp. 6366-6375. https://doi.org/10.1158/1078-0432.CCR-20-4185

TY - JOUR

T1 - A Phase i Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

AU - Atrafi, Florence

AU - Boix, Oliver

AU - Subbiah, Vivek

AU - Diamond, Jennifer R.

AU - Chawla, Sant P.

AU - Tolcher, Anthony W.

AU - Lorusso, Patricia M.

AU - Eder, Joseph P.

AU - Gutierrez, Martin

AU - Sankhala, Kumar

AU - Rajagopalan, Prabhu

AU - Genvresse, Isabelle

AU - Langer, Simon

AU - Mathijssen, Ron H.J.

AU - Verweij, Jaap

AU - Bruns, Ingmar

AU - Lolkema, Martijn P.

N1 - Funding Information: This study was sponsored by Bayer Pharmaceuticals. Assistance for pharmacokinetic calculations was provided by Michaela Damaske of Bayer Pharma AG. We also thank Ray Valencia and Fabricio Souza for implementation of this clinical study and Lucia Giannini for assistance with Supplementary Fig. S3. Funding Information: F. Atrafi reports grants from Bayer during the conduct of the study. O. Boix reports other support from Bayer AG during the conduct of the study, as well as other support from Bayer AG outside the submitted work. V. Subbiah reports grants from Bayer and a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study. V. Subbiah also reports research grants from Roche/ Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, UT MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, Pharmamar, and Medimmune; advisory board/ consultant positions with Helsinn, Incyte, QED Pharma, Daiichi Sankyo, Signant Health, Novartis, Relay therapeutics, Roche, and Medimmune; travel funds from Pharmamar, Incyte, ASCO, and ESMO; and other support from Medscape outside the submitted work. J.R. Diamond reports grants from Bayer during the conduct of the study, as well as other support from Gilead outside the submitted work. S.P. Chawla reports other support from Amgen, Roche, TRACON Pharma, Karyopharm, Advenchen Laboratories, NKBioTech, InhibRx, and Epizyme outside the submitted work. A.W. Tolcher reports personal fees and other support from AbbVie Inc., ABL Bio Inc., Adagene Inc., ADC Therapeutics SA, Agenus Inc., Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Apros Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC, Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd., BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., Codiak BioSciences, Inc., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, eFFECTOR Therapeutics, Inc., Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., GlaxoSmithKline Research & Development Limited, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc., Kiromic Biopharma, Inc., Mabspace Biosciences (Suzhou) Co., Ltd., Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Mersana Therapeutics, Inc., Mirati Therapeutics, Inc., NatureWise Biotech & Medicals Corporation, Navire Pharma Inc., NBE-Therapeutics AG, NextCure, Inc., Nitto BioPharma, Inc., Odonate Therapeutics, Inc., ORIC Pharmaceuticals, Pelican Therapeutics, Inc., Petra Pharma, Pfizer, Inc., Pieris Pharmaceuticals, Inc., PMV Pharmaceuticals, Inc., Qilu Puget Sound Biotherapeutics Corporation, Samumed, LLC, Seattle Genetics, Inc., Spring Bank Pharmaceuticals, Inc., Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., Symphogen A/S, Syndax Pharmaceuticals Inc., Synthorx, Inc., Takeda, Tizona Therapeutics, and Zymeworks Inc. during the conduct of the study, as well as personal fees and other support from AbbVie Inc., Agenus, Inc., Asana Biosciences, Ascentage, AxImmune, Bayer, Gilde Heathcare Partners, HBM Partners, Immunomet Therapeutics, Inc., Karma Oncology, Mekanistic Therapeutics, Menarini Ricerche, Mersana, Nanobiotix, Partner Therapeutics, Pfizer Inc., Pierre Fabre, RYVU Therapeutics, Seattle Genetics, SOTIO Biotechnology Inc., Spirea Limited Inc., Transcenta Therapeutics Inc., Trillium Therapeutics Inc., Adagene, Inc., ARO Biotherapeutics, Bioinvent, Publisher Copyright: © 2021 American Association for Cancer Research Inc.. All rights reserved.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: Patients with solid tumors were randomized to receive oralBAY(twice daily 2-days-on/5-days-off) withweekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. Results: In total, 75 patients were enrolled. The main doselimiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0-12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure-toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities. _2021 American Association for Cancer Research.

AB - Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: Patients with solid tumors were randomized to receive oralBAY(twice daily 2-days-on/5-days-off) withweekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. Results: In total, 75 patients were enrolled. The main doselimiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0-12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure-toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities. _2021 American Association for Cancer Research.

UR - http://www.scopus.com/inward/record.url?scp=85120466568&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-20-4185

DO - 10.1158/1078-0432.CCR-20-4185

M3 - Article

C2 - 34518310

AN - SCOPUS:85120466568

SN - 1078-0432

VL - 27

SP - 6366

EP - 6375

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 23

ER -

A Phase i Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

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