PubMed | Eli Lilly and Company, Arizona Cancer Center, Northwestern University, Progenics Pharmaceuticals and 6 more.
Type: Clinical Trial, Phase II | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016
This phase II trial evaluated the efficacy and safety of cixutumumab, a human anti-insulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor-positive breast cancer.Patients with hormone receptor-positive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored.Ninety-three patients were randomized (arm A, n = 62; arm B, n = 31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)].Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1R-targeted therapies requires further validation.
PubMed | Tennessee; Tennessee Oncology PLLC
Type: Clinical Trial, Phase I | Journal: Cancer | Year: 2015
The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors.Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle.A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 g/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*g/mL. One patient with small cell lung cancer achieved a partial response for 52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [ 40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [ 31 weeks]).The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy.