BackgroundImatinib 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.MethodsPrimary 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.ResultsThe 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.ConclusionsOur 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 registrationClinicaltrials.gov NCT01738139, registered 28 November 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-017-0238-1) contains supplementary material, which is available to authorized users.

Background Both MET and c-SRC are important mediators of cancer progression and there is cross talk between the two molecules. Preclinical studies have demonstrated combination of MET and c-SRC inhibitors is effective in multiple cancer types. Methods We analyzed the safety and efficacy of administering a c-SRC inhibitor (dasatinib) in combination with a MET inhibitor (crizotinib) in a two-arm concurrent phase I study. Arm A consisted of crizotinib fixed at 250 mg twice per day with escalation of dasatinib. Arm B consisted of dasatinib fixed at 140 mg daily with escalation of crizotinib. Endpoints included dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), and response (RECIST 1.1). Results We enrolled 61 patients (arm A: 31, arm B: 30). The most common cancers were sarcoma (21%) and prostate cancer (16%). In Arm A, at dose level 2 (DL2), 40% (2/5) experienced DLTs. In the expanded DL1, 21% (4/19) experienced DLTs (all grade 3). In Arm B, at DL2, 50% (2/4) experienced DLTs. In the expanded DL1, 22% (4/18) experienced DLTs (all grade 3). RP2D was determined to be arm A, DL1 (250 mg crizotinib orally twice per day plus 50 mg dasatinib orally daily). Partial response (N = 1) and stable disease for ≥6 months (N = 3) were seen. Conclusions The combination of crizotinib and dasatinib is safe to administer but tolerability is limited given the high rate of adverse events. Responses and durable stable disease were limited. Further precision therapy approach using this specific combination may be difficult given the toxicity.

The combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. Based on this study, the recommended phase 2 dose is gemcitabine 1000 mg/m, nab-paclitaxel 125 mg/m, and bevacizumab 15 mg/kg. VEGF polymorphism data should be evaluated in future bevacizumab-based trials.

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.

Background Infusion reactions (IRs) to anti-neoplastic agents require prompt recognition and immediate treatment to avert significant complications. Methods We conducted a retrospective review of the medical records of consecutive patients who received anti-neoplastic therapy in the outpatient treatment center of the Department of Investigational Cancer Therapeutics from January 1, 2013 to November 30, 2013. Results Of the 597 patients who received treatment, 9 (1.5%) had IRs (all ≤ grade 2). The most common IRs observed on first occurrence were chills (n=5), itching, rash, and facial flushing (n=3 each). There were no IR-related deaths. All the IRs were reversible with appropriate symptomatic treatment and the therapy was completed after temporary cessation of infusion in 7 of the 9 patients. The infusion was stopped in 2 patients due to symptoms suggestive of IgE-mediated allergic reaction and cytokine storm. Five of the 8 patients who were re-challenged with the same therapy developed a similar reaction. However, the infusion was completed in 4 of the 5 patients after administration of intravenous diphenhydramine and/or hydrocortisone, or slowing the rate of infusion and subsequently cycles with the same agents were uneventful. Conclusion IRs to anti-neoplastic agents are rare. Though the clinical presentations are overlapping, most IRs are not IgE-mediated allergic reactions. Appropriate premedication and slow rate of infusion facilitates uneventful administration of the anti-neoplastic agents in subsequent cycles. Further study in a larger cohort of patients to identify biomarkers of hypersensitivity is warranted.