We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies. Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg−1 every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment. Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.

PURPOSEExpression of the Bcl-2 protein confers resistance to various apoptotic signals. G3139 [oblimersen sodium (Genasense)] is a phosphorothioate antisense oligodeoxynucleotide that targets Bcl-2 mRNA, downregulates Bcl-2 protein translation, and enhances the antitumor effects of subtherapeutic doses of docetaxel (Taxotere).PATIENTS AND METHODSWe performed a phase I trial to determine the maximum tolerated dose (MTD) and safety profile of combined therapy with G3139 and weekly docetaxel in patients with advanced Bcl-2-positive solid tumors. Cohorts of three to six patients were enrolled to escalating doses of G3139 and a fixed dose of weekly docetaxel using either of two schedules. In part I, G3139 was administered by continuous infusion for 21 days (D1-22), and docetaxel (35 mg/m2) was given weekly on days 8, 15 and 22. In part II, G3139 was given by continuous infusion for 5 days before the first weekly dose of docetaxel, and for 48 h before the second and third weekly docetaxel doses. For both schedules, cycles were repeated every 4 weeks.RESULTSTwenty-two patients were enrolled. Thirteen patients were treated on the part I schedule with doses of G3139 escalated from 1 to 4 mg/kg/day. Nine patients were on the part II schedule of shorter G3139 infusion at G3139 doses of 5-9 mg/kg/day. Hematologic toxicities were mild, except for one case of persistent grade 3 thrombocytopenia in part I. The most common adverse events were cumulative fatigue and transaminase elevation, which prevented further dose escalation beyond 4 mg/kg/day for 21 days with the part I schedule. In part II of the study, using the abbreviated G3139 schedule, even the highest daily doses were tolerated without dose-limiting toxicity or the need for dose modification. Objective tumor response was observed in two patients with breast cancer, including one whose cancer previously progressed on trastuzumab plus paclitaxel. Four patients had stable disease. Pharmacokinetic results for G3139 were similar to those of other trials.CONCLUSIONSG3139 in combination with standard-dose weekly docetaxel was well tolerated. The shortened and intermittent G3139 infusion had less cumulative toxicities and still allowed similar total G3139 delivery as the longer infusion. Further studies should examine the molecular effect of the regimen, as well as clinical activities in malignancies for which taxanes are indicated.