Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced/metastatic cholangiocarcinoma: A Phase 1b/2 study

Mitesh J. Borad; Li Yuan Bai; Donald Richards; Kabir Mody; Joleen Hubbard; Sun Young Rha; John Soong; Daniel McCormick; Emmett Tse; Daniel O'Brien; Ahmad Bayat; Daniel Ahn; S. Lindsey Davis; Joon Oh Park; Do Youn Oh

doi:10.1002/hep.32804

Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced/metastatic cholangiocarcinoma: A Phase 1b/2 study

Mitesh J. Borad, Li Yuan Bai, Donald Richards, Kabir Mody, Joleen Hubbard, Sun Young Rha, John Soong, Daniel McCormick, Emmett Tse, Daniel O'Brien, Ahmad Bayat, Daniel Ahn, S. Lindsey Davis, Joon Oh Park, Do Youn Oh

Department of Internal Medicine

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

1 Citation (Scopus)

Abstract

Background and Aims: This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma. Approach and Results: This work is a Phase 1b/2 study (S4-13-001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21-day cycle. Primary efficacy endpoint was progression-free survival (PFS) in the modified intent-to-treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) (p = 0.0496); 10-month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study. Conclusions: Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first-line treatment of patients with locally advanced/metastatic cholangiocarcinoma.

Original language	English
Pages (from-to)	760-773
Number of pages	14
Journal	Hepatology
Volume	77
Issue number	3
DOIs	https://doi.org/10.1002/hep.32804
Publication status	Published - 2023 Mar

Bibliographical note

Funding Information:
Mitesh J. Borad consults for ADC Therapeutics, Exelixis, G1 Therapeutics, HUYA, Genentech, Immunovative, Inspyr, Lynx Group, Merck, OncBioMune, and Western Oncolytics. He received grants from Adaptimmune, Agios, ARIAD, Astra Zeneca, Basilea, Bioline, Boston Biomed, Celgene, Dicerna, EMD Serono, Halozyme, Incyte, Isis Pharmaceuticals, Medimmune, Mirna, Novartis, PUMA, Sun Biopharmacueticals, Senhwa Pharmaceuticals, QED, Redhill, Sillajen, Taiho, and Toray. Kabir Mody owns stock in and is employed by IMV, Inc. He owns stock in and advises CytoDyn, Inc. He consults for AstraZeneca, Ipsen, Genentech, BTG, Boston Scientific, Incyte, QED, and Taiho. Joleen Hubbard advises and received grants from Bayer, Merck, and Incyte. She advises BeiGene. She received grants from Boston Biomedical, Senhwa Pharmaceuticals, TriOncology, Seattle Genetics, Hutchison MediPharma, Pionyr Immunotherapeutics, Trovogene, G1 Therapeutics, Roche, and Treos Bio. John Soong owns stock in and is employed by Senhwa Biosciences. Daniel McCormick is employed by Senhwa Biosciences. Emmett Tse is employed by Senhwa Biosciences. Ahmad Bayat is employed by and has other interests in Amarex Clinical Research. Daniel Ahn owns stock in Natera. He consults for Eisai, Genentech, Exelixis, Novartis, and Advanced Accelerator Applications. S. Lindsey Davis advises Genentech. Joon Oh Park consults for and received grants from BMS and Servier. He advises and received grants from MedPacto. He consults for AstraZeneca. He advises MediRama. He received grants from ABL Bio. Do‐Youn Oh advises and received grants from AstraZeneca and Novartis. She received grants from Genentech/Roche, Merck, Serono, Bayer, Taiho, and ASLAN. She received grants from Array, Eli Lilly, Servier, BeiGene, MSD, and Handa.

Funding Information:
We thank all the patients who participated in this study, the patients’ families, Dr Carlos Becerra, the clinical investigators, clinical research nurses, clinical research monitors, data management team, and all other members of the S4‐13‐001 clinical study team. We also thank Lee Miller and Kevin De‐Voy from Miller Medical Communications for their medical editing/writing assistance, which was funded by Senhwa Biosciences Corporation.

Funding Information:
Supported by Senhwa Biosciences.

Publisher Copyright:
© 2023 John Wiley and Sons Inc.. All rights reserved.

All Science Journal Classification (ASJC) codes

Hepatology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/hep.32804

Cite this

Borad, M. J., Bai, L. Y., Richards, D., Mody, K., Hubbard, J., Rha, S. Y., Soong, J., McCormick, D., Tse, E., O'Brien, D., Bayat, A., Ahn, D., Davis, S. L., Park, J. O., & Oh, D. Y. (2023). Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced/metastatic cholangiocarcinoma: A Phase 1b/2 study. Hepatology, 77(3), 760-773. https://doi.org/10.1002/hep.32804

@article{6ec3c7c746c648419bb6e187ded936c9,

title = "Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced/metastatic cholangiocarcinoma: A Phase 1b/2 study",

abstract = "Background and Aims: This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma. Approach and Results: This work is a Phase 1b/2 study (S4-13-001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21-day cycle. Primary efficacy endpoint was progression-free survival (PFS) in the modified intent-to-treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) (p = 0.0496); 10-month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study. Conclusions: Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first-line treatment of patients with locally advanced/metastatic cholangiocarcinoma.",

author = "Borad, {Mitesh J.} and Bai, {Li Yuan} and Donald Richards and Kabir Mody and Joleen Hubbard and Rha, {Sun Young} and John Soong and Daniel McCormick and Emmett Tse and Daniel O'Brien and Ahmad Bayat and Daniel Ahn and Davis, {S. Lindsey} and Park, {Joon Oh} and Oh, {Do Youn}",

note = "Funding Information: Mitesh J. Borad consults for ADC Therapeutics, Exelixis, G1 Therapeutics, HUYA, Genentech, Immunovative, Inspyr, Lynx Group, Merck, OncBioMune, and Western Oncolytics. He received grants from Adaptimmune, Agios, ARIAD, Astra Zeneca, Basilea, Bioline, Boston Biomed, Celgene, Dicerna, EMD Serono, Halozyme, Incyte, Isis Pharmaceuticals, Medimmune, Mirna, Novartis, PUMA, Sun Biopharmacueticals, Senhwa Pharmaceuticals, QED, Redhill, Sillajen, Taiho, and Toray. Kabir Mody owns stock in and is employed by IMV, Inc. He owns stock in and advises CytoDyn, Inc. He consults for AstraZeneca, Ipsen, Genentech, BTG, Boston Scientific, Incyte, QED, and Taiho. Joleen Hubbard advises and received grants from Bayer, Merck, and Incyte. She advises BeiGene. She received grants from Boston Biomedical, Senhwa Pharmaceuticals, TriOncology, Seattle Genetics, Hutchison MediPharma, Pionyr Immunotherapeutics, Trovogene, G1 Therapeutics, Roche, and Treos Bio. John Soong owns stock in and is employed by Senhwa Biosciences. Daniel McCormick is employed by Senhwa Biosciences. Emmett Tse is employed by Senhwa Biosciences. Ahmad Bayat is employed by and has other interests in Amarex Clinical Research. Daniel Ahn owns stock in Natera. He consults for Eisai, Genentech, Exelixis, Novartis, and Advanced Accelerator Applications. S. Lindsey Davis advises Genentech. Joon Oh Park consults for and received grants from BMS and Servier. He advises and received grants from MedPacto. He consults for AstraZeneca. He advises MediRama. He received grants from ABL Bio. Do‐Youn Oh advises and received grants from AstraZeneca and Novartis. She received grants from Genentech/Roche, Merck, Serono, Bayer, Taiho, and ASLAN. She received grants from Array, Eli Lilly, Servier, BeiGene, MSD, and Handa. Funding Information: We thank all the patients who participated in this study, the patients{\textquoteright} families, Dr Carlos Becerra, the clinical investigators, clinical research nurses, clinical research monitors, data management team, and all other members of the S4‐13‐001 clinical study team. We also thank Lee Miller and Kevin De‐Voy from Miller Medical Communications for their medical editing/writing assistance, which was funded by Senhwa Biosciences Corporation. Funding Information: Supported by Senhwa Biosciences. Publisher Copyright: {\textcopyright} 2023 John Wiley and Sons Inc.. All rights reserved.",

year = "2023",

month = mar,

doi = "10.1002/hep.32804",

language = "English",

volume = "77",

pages = "760--773",

journal = "Hepatology",

issn = "0270-9139",

publisher = "John Wiley and Sons Ltd",

number = "3",

}

Borad, MJ, Bai, LY, Richards, D, Mody, K, Hubbard, J, Rha, SY, Soong, J, McCormick, D, Tse, E, O'Brien, D, Bayat, A, Ahn, D, Davis, SL, Park, JO & Oh, DY 2023, 'Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced/metastatic cholangiocarcinoma: A Phase 1b/2 study', Hepatology, vol. 77, no. 3, pp. 760-773. https://doi.org/10.1002/hep.32804

TY - JOUR

T1 - Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced/metastatic cholangiocarcinoma

T2 - A Phase 1b/2 study

AU - Borad, Mitesh J.

AU - Bai, Li Yuan

AU - Richards, Donald

AU - Mody, Kabir

AU - Hubbard, Joleen

AU - Rha, Sun Young

AU - Soong, John

AU - McCormick, Daniel

AU - Tse, Emmett

AU - O'Brien, Daniel

AU - Bayat, Ahmad

AU - Ahn, Daniel

AU - Davis, S. Lindsey

AU - Park, Joon Oh

AU - Oh, Do Youn

N1 - Funding Information: Mitesh J. Borad consults for ADC Therapeutics, Exelixis, G1 Therapeutics, HUYA, Genentech, Immunovative, Inspyr, Lynx Group, Merck, OncBioMune, and Western Oncolytics. He received grants from Adaptimmune, Agios, ARIAD, Astra Zeneca, Basilea, Bioline, Boston Biomed, Celgene, Dicerna, EMD Serono, Halozyme, Incyte, Isis Pharmaceuticals, Medimmune, Mirna, Novartis, PUMA, Sun Biopharmacueticals, Senhwa Pharmaceuticals, QED, Redhill, Sillajen, Taiho, and Toray. Kabir Mody owns stock in and is employed by IMV, Inc. He owns stock in and advises CytoDyn, Inc. He consults for AstraZeneca, Ipsen, Genentech, BTG, Boston Scientific, Incyte, QED, and Taiho. Joleen Hubbard advises and received grants from Bayer, Merck, and Incyte. She advises BeiGene. She received grants from Boston Biomedical, Senhwa Pharmaceuticals, TriOncology, Seattle Genetics, Hutchison MediPharma, Pionyr Immunotherapeutics, Trovogene, G1 Therapeutics, Roche, and Treos Bio. John Soong owns stock in and is employed by Senhwa Biosciences. Daniel McCormick is employed by Senhwa Biosciences. Emmett Tse is employed by Senhwa Biosciences. Ahmad Bayat is employed by and has other interests in Amarex Clinical Research. Daniel Ahn owns stock in Natera. He consults for Eisai, Genentech, Exelixis, Novartis, and Advanced Accelerator Applications. S. Lindsey Davis advises Genentech. Joon Oh Park consults for and received grants from BMS and Servier. He advises and received grants from MedPacto. He consults for AstraZeneca. He advises MediRama. He received grants from ABL Bio. Do‐Youn Oh advises and received grants from AstraZeneca and Novartis. She received grants from Genentech/Roche, Merck, Serono, Bayer, Taiho, and ASLAN. She received grants from Array, Eli Lilly, Servier, BeiGene, MSD, and Handa. Funding Information: We thank all the patients who participated in this study, the patients’ families, Dr Carlos Becerra, the clinical investigators, clinical research nurses, clinical research monitors, data management team, and all other members of the S4‐13‐001 clinical study team. We also thank Lee Miller and Kevin De‐Voy from Miller Medical Communications for their medical editing/writing assistance, which was funded by Senhwa Biosciences Corporation. Funding Information: Supported by Senhwa Biosciences. Publisher Copyright: © 2023 John Wiley and Sons Inc.. All rights reserved.

PY - 2023/3

Y1 - 2023/3

N2 - Background and Aims: This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma. Approach and Results: This work is a Phase 1b/2 study (S4-13-001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21-day cycle. Primary efficacy endpoint was progression-free survival (PFS) in the modified intent-to-treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) (p = 0.0496); 10-month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study. Conclusions: Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first-line treatment of patients with locally advanced/metastatic cholangiocarcinoma.

AB - Background and Aims: This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma. Approach and Results: This work is a Phase 1b/2 study (S4-13-001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21-day cycle. Primary efficacy endpoint was progression-free survival (PFS) in the modified intent-to-treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) (p = 0.0496); 10-month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study. Conclusions: Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first-line treatment of patients with locally advanced/metastatic cholangiocarcinoma.

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Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced/metastatic cholangiocarcinoma: A Phase 1b/2 study

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UN SDGs

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