TY - JOUR T1 - Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1186/s40425-017-0238-1 VL - 5 IS - 1 SP - 35 AU - Matthew J. Reilley AU - Ann Bailey AU - Vivek Subbiah AU - Filip Janku AU - Aung Naing AU - Gerald Falchook AU - Daniel Karp AU - Sarina Piha-Paul AU - Apostolia Tsimberidou AU - Siqing Fu AU - JoAnn Lim AU - Stacie Bean AU - Allison Bass AU - Sandra Montez AU - Luis Vence AU - Padmanee Sharma AU - James Allison AU - Funda Meric-Bernstam AU - David S. Hong Y1 - 2017/12/01 UR - http://jitc.bmj.com/content/5/1/35.abstract N2 - 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.Abbreviations:AEAdverse eventALCAbsolute lymphocyte countAMCAbsolute monocyte countANCAbsolute neutrophil countCLIAClinical laboratory improvement amendmentCTCAECommon terminology criteria for adverse eventsCTLA-4Cytotoxic T-lymphocyte antigen 4DLTDose-limiting toxicityECOGEastern cooperative oncology groupGISTGastrointestinal stromal tumorHIVHuman immunodeficiency virusirRCImmune-related response criteriaMTDMaximum tolerated dosePBMCPeripheral blood mononuclear cellsPCRPolymerase chain reactionRECISTResponse criteria in solid tumors ER -