PMID- 28428884 OWN - NLM STAT- MEDLINE DCOM- 20180608 LR - 20210102 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 5 DP - 2017 TI - Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies. PG - 35 LID - 10.1186/s40425-017-0238-1 [doi] LID - 35 AB - BACKGROUND: Imatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer. METHODS: Primary objective of the dose-escalation study (3 + 3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives included evaluation of antitumor activity of the combination based on KIT mutation status and the capacity of tumor-associated immune biomarkers to predict response. RESULTS: The primary objective to establish the maximum tolerated dose (MTD) was achieved, and the recommended phase II doses are ipilimumab at 3 mg/kg every 3 weeks and imatinib 400 mg twice daily. Of the 35 patients treated in the escalation and GIST expansion, none experienced dose-limiting toxicities. The most common grade 1/2-related adverse events (AEs) were fatigue (66%), nausea (57%), anorexia, vomiting (each 31%), edema (29%), and anemia, diarrhea, and rash (each 23%). Grade 3 AEs occurred in 6 patients (17%) and included fatigue, anemia, fever, rash, and vomiting. There were no grade 4 AEs. In general, the combination was well tolerated. Among all patients, 2 responses were seen: 1 partial response (GIST) and 1 partial response (melanoma). Stable disease was seen in 6 patients lasting an average of 6 months. The melanoma responder was KIT mutated and the GIST responder was wild-type. CONCLUSIONS: Our findings suggest that this combination of a targeted agent with checkpoint blockade is safe across multiple tumor types. Low activity with no clear signal for synergy was observed in escalation or GIST expansion cohorts. Assessment of antitumor activity of this combination in the KIT-mutant melanoma population is being evaluated. TRIAL REGISTRATION: Clinicaltrials.gov NCT01738139, registered 28 November 2012. FAU - Reilley, Matthew J AU - Reilley MJ AD - Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Bailey, Ann AU - Bailey A AD - Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Subbiah, Vivek AU - Subbiah V AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Janku, Filip AU - Janku F AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Naing, Aung AU - Naing A AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Falchook, Gerald AU - Falchook G AD - Sarah Cannon Research Institute at HealthOne, 1800 Williams Street, Suite 300, Denver, CO 80218 USA. FAU - Karp, Daniel AU - Karp D AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Piha-Paul, Sarina AU - Piha-Paul S AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Tsimberidou, Apostolia AU - Tsimberidou A AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Fu, Siqing AU - Fu S AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Lim, JoAnn AU - Lim J AD - Pharamacy Clinical Programs, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Bean, Stacie AU - Bean S AD - Pharamacy Clinical Programs, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Bass, Allison AU - Bass A AD - Pharamacy Clinical Programs, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Montez, Sandra AU - Montez S AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Vence, Luis AU - Vence L AD - Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Sharma, Padmanee AU - Sharma P AD - Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Allison, James AU - Allison J AD - Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Meric-Bernstam, Funda AU - Meric-Bernstam F AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. FAU - Hong, David S AU - Hong DS AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA. AD - Department of Cancer Medicine, John Mendelsohn Faculty Center (FC8.3050), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0455, Houston, TX 77030 USA. LA - eng SI - ClinicalTrials.gov/NCT01738139 PT - Clinical Trial, Phase I PT - Journal Article DEP - 20170418 PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Ipilimumab) RN - 8A1O1M485B (Imatinib Mesylate) SB - IM MH - Adult MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/pharmacology/*therapeutic use MH - Female MH - Humans MH - Imatinib Mesylate/administration & dosage/pharmacology/*therapeutic use MH - Ipilimumab/administration & dosage/pharmacology/*therapeutic use MH - Male MH - Middle Aged MH - Neoplasms/*drug therapy/pathology MH - Young Adult PMC - PMC5394629 EDAT- 2017/04/22 06:00 MHDA- 2018/06/09 06:00 PMCR- 2017/04/18 CRDT- 2017/04/22 06:00 PHST- 2016/11/18 00:00 [received] PHST- 2017/03/29 00:00 [accepted] PHST- 2017/04/22 06:00 [entrez] PHST- 2017/04/22 06:00 [pubmed] PHST- 2018/06/09 06:00 [medline] PHST- 2017/04/18 00:00 [pmc-release] AID - 238 [pii] AID - 10.1186/s40425-017-0238-1 [doi] PST - epublish SO - J Immunother Cancer. 2017 Apr 18;5:35. doi: 10.1186/s40425-017-0238-1. eCollection 2017.