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Purpose: This phase I study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor effects of sunitinib combined with modified FOLFOX6 (mFOLFOX6)., Methods: Patients with advanced solid malignancies received mFOLFOX6 in 2-week cycles with escalating sunitinib doses (25, 37.5, and 50 mg/day) on three schedules: 2 weeks on, 2 weeks off (2/2); 4 weeks on, 2 weeks off (4/2); or continuous daily dosing (CDD). Patients received up to 8 treatment cycles (Schedule 2/2 and CDD schedule) or 6 cycles (Schedule 4/2). An expansion cohort enrolled patients with metastatic colorectal cancer at the Schedule 2/2 MTD., Results: Overall, 53 patients were enrolled, with 43 evaluable for dose-limiting toxicity (DLT). On Schedule 2/2 (n = 18), DLTs occurred in three patients at 50 mg/day (grade 4 neutropenia [n = 1]; grades 3 and 4 thrombocytopenia [n = 2]) and two patients achieved partial responses (PRs). On Schedule 4/2 (n = 13), 37.5 mg/day exceeded the MTD with two DLTs (febrile neutropenia and grade 4 hypokalemia, respectively). On the CDD schedule (n = 12), the MTD was 25 mg/day; one DLT (grade 3 stomatitis) was reported and two patients achieved PRs. The most common adverse events were neutropenia, fatigue, and thrombocytopenia. No clinically significant drug-drug interactions were apparent between sunitinib, its metabolite SU12662, and mFOLFOX6., Conclusions: Sunitinib combined with mFOLFOX6 had acceptable tolerability. The MTDs were sunitinib 50 mg/day on Schedule 2/2 and 25 mg/day on the CDD schedule. A MTD for Schedule 4/2 was not established.

Purpose: The primary objective of this phase I dose-escalation study was to identify the maximum tolerated dose (MTD) of sunitinib plus pemetrexed in patients with advanced cancer., Methods: Using a 3 + 3 dose-escalation design, patients received oral sunitinib qd by continuous daily dosing (CDD schedule; 37.5 or 50 mg) or 2 weeks on/1 week off treatment schedule (Schedule 2/1; 50 mg). Pemetrexed (300-500 mg/m(2) IV) was administered q3w. At the proposed recommended phase 2 dose (RP2D), additional patients with non-small cell lung cancer (NSCLC) were enrolled., Results: Thirty-five patients were enrolled on the CDD schedule and seven on Schedule 2/1. MTDs were sunitinib 37.5 mg/day (CDD/RP2D) or 50 mg/day (Schedule 2/1) with pemetrexed 500 mg/m(2). Dose-limiting toxicities included grade (G) 5 cerebral hemorrhage, G3 febrile neutropenia, and G3 anorexia. Common G3/4 drug-related non-hematologic adverse events (AEs) at the CDD MTD included fatigue, anorexia, and hand-foot syndrome. G3/4 hematologic AEs included lymphopenia, neutropenia, and thrombocytopenia. No significant drug-drug interactions were identified. Five (24%) NSCLC patients had partial responses., Conclusions: In patients with advanced solid malignancies, the MTD of sunitinib plus 500 mg/m(2) pemetrexed was 37.5 mg/day (CDD schedule) or 50 mg/day (Schedule 2/1). The CDD schedule MTD was tolerable and demonstrated promising clinical benefit in NSCLC.

There are potential advantages to detecting pharmacodynamic (PD) and pharmacokinetic (PK) endpoints in a tissue-based compartment such as the skin during the development of molecularly targeted drugs. We explored regional differences between inner arm, inner thigh, lower back and buttocks in 12 healthy male Caucasian volunteers in the tolerability of skin biopsy procedures; the Ki67 proliferation index; the frequency of detecting hair follicles and sweat glands; and the percentage of melanocytes. We also explored the amounts of tissue and protein obtained, and two separate methods of splitting biopsies for processing in mutually exclusive media. Biopsies from all body sites were well tolerated. The subjective ranking order was inner arm > buttocks = back > thigh. There were no statistically significant differences in the Ki67 labelling index (P > 0.05). The frequency of detecting sweat glands was the same in all body sites, but the frequency of detecting hair follicles was higher in back and buttock, compared to arm and thigh. The percentage of melanocytes was significantly lower in the buttocks compared to the back and thigh (P < 0.05), but not compared to the arm (P = 0.07). A 4-mm punch biopsy yielded a mean of 16.8 mg of tissue (range: 9-28 mg) and 160 microg of protein (range: 80-270 microg). In vivo sample splitting, by following a 2-mm punch with a 4-mm overpunch, had a shorter time from devascularisation to immersion into processing medium than ex vivo dissection of a 4-mm sample, which may be of importance to the assessment of labile endpoints. We conclude that multiple punch biopsies of the skin are feasible, with the buttocks representing the studied body site with the optimal balance between tolerability, hair follicle density and melanocyte density for obtaining tissue in which to assess PD and PK endpoints during drug development studies.