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Cancer Therapy: Clinical

Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab

Sandra P. D'Angelo, Alexander N. Shoushtari, Mary Louise Keohan, Mark A. Dickson, Mrinal M. Gounder, Ping Chi, Jennifer K. Loo, Leigh Gaffney, Lee Schneider, Zarine Patel, Joseph Patrick Erinjeri, Mark J. Bluth, Ana Sjoberg, Howard Streicher, Naoko Takebe, Li-Xuan Qin, Cristina Antonescu, Ronald P. DeMatteo, Richard D. Carvajal and William D. Tap
Sandra P. D'Angelo
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.Weill Cornell Medical College, New York, New York.
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  • For correspondence: dangelos@mskcc.org
Alexander N. Shoushtari
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.Weill Cornell Medical College, New York, New York.
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Mary Louise Keohan
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.Weill Cornell Medical College, New York, New York.
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Mark A. Dickson
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.Weill Cornell Medical College, New York, New York.
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Mrinal M. Gounder
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.Weill Cornell Medical College, New York, New York.
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Ping Chi
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.Weill Cornell Medical College, New York, New York.
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Jennifer K. Loo
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Leigh Gaffney
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Lee Schneider
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Zarine Patel
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Joseph Patrick Erinjeri
Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Mark J. Bluth
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Ana Sjoberg
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Howard Streicher
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
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Naoko Takebe
Investigational Drug Branch, Cancer Therapy Evaluation Program, Rockville, Maryland.
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Li-Xuan Qin
Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Cristina Antonescu
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Ronald P. DeMatteo
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Richard D. Carvajal
Columbia University Medical Center, New York, New York.
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William D. Tap
Department of Medicine, Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.Weill Cornell Medical College, New York, New York.
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DOI: 10.1158/1078-0432.CCR-16-2349
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    • Supplemental Figure 1 - Synergy of dasatinib and anti-CTLA-4. Using murine GIST mouse, it was observed that treatment with the KIT-targeted dasatinib for 7 days alone or with chronic anti-CTLA-4 alone decreased tumor volume initially; however tumors rapidly re-grew. Mice treated with KIT-targeted TKI for 7 days and chronic anti-CTLA-4 blockade showed augmentation and durability of the initial response. KITV5880+ mice received dasatinib 15mg/kg i.p. bid (Bristol Myers Squibb) on days 1 through 7, with or without anti-CTLA-5 (BioXcell.) Mice were imaged at baseline and serially during therapy using MRI and volumetric analysis was done using Image K software. Anti-CTLA-4 dosing regimen 200 microgram of clone 9H10 i.p. on day 3, then 100 microgram on day 6, 9 and 12, followed by clone 9D (100 micrograms i.p. every 3 days thereafter.)
    • Supplemental Table 1 - Table of adverse events grade 1-4, at least possibly related to treatment. All G1-G4 at least possible related toxicity.
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Published OnlineFirst March 20, 2017
doi: 10.1158/1078-0432.CCR-16-2349

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Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab
Sandra P. D'Angelo, Alexander N. Shoushtari, Mary Louise Keohan, Mark A. Dickson, Mrinal M. Gounder, Ping Chi, Jennifer K. Loo, Leigh Gaffney, Lee Schneider, Zarine Patel, Joseph Patrick Erinjeri, Mark J. Bluth, Ana Sjoberg, Howard Streicher, Naoko Takebe, Li-Xuan Qin, Cristina Antonescu, Ronald P. DeMatteo, Richard D. Carvajal and William D. Tap
Clin Cancer Res March 20 2017 DOI: 10.1158/1078-0432.CCR-16-2349

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Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab
Sandra P. D'Angelo, Alexander N. Shoushtari, Mary Louise Keohan, Mark A. Dickson, Mrinal M. Gounder, Ping Chi, Jennifer K. Loo, Leigh Gaffney, Lee Schneider, Zarine Patel, Joseph Patrick Erinjeri, Mark J. Bluth, Ana Sjoberg, Howard Streicher, Naoko Takebe, Li-Xuan Qin, Cristina Antonescu, Ronald P. DeMatteo, Richard D. Carvajal and William D. Tap
Clin Cancer Res March 20 2017 DOI: 10.1158/1078-0432.CCR-16-2349
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Clinical Cancer Research
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