Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies. Issue 1 (18th April 2017)

• Record Type: Journal Article
• Authors: Reilley, Matthew J.; Bailey, Ann; Subbiah, Vivek; Janku, Filip; Naing, Aung; Falchook, Gerald; Karp, Daniel; Piha-Paul, Sarina; Tsimberidou, Apostolia; Fu, Siqing; Lim, JoAnn; Bean, Stacie; Bass, Allison; Montez, Sandra; Vence, Luis; Sharma, Padmanee; Allison, James; Meric-Bernstam, Funda; Hong, David S.
• Is Part Of: Journal for immunotherapy of cancer. Volume 5:Issue 1(2017)
• Publication Date: 2017-04-18
• Subjects: Melanoma -- Imatinib -- Maximum Toxic Dose -- Dasatinib -- Ipilimumab; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1186/s40425-017-0238-1
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : 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.