A. Dimitrios Colevas

A Randomized Phase II Study of Cilengitide (EMD 121974) in Patients with Metastatic Melanoma

Cilengitide (EMD 121974) is a selective inhibitor of integrins &agr;v&bgr;3 and &agr;v&bgr;5. The &agr;v&bgr;3 promotes the proliferation of tumor-associated endothelial cells and potentially the survival of melanoma cells. We conducted a randomized phase II trial in patients with metastatic melanoma to evaluate the clinical efficacy of cilengitide. Patients with stage IV or unresectable stage III melanoma who were either chemonaive or who had previously received one systemic therapy were enrolled. Patients were randomly assigned to either 500 or 2000 mg of cilengitide administered intravenously twice weekly. The primary aim of this study was to determine the progression-free survival rate at 8 weeks. Tumor samples and blood samples were collected for pharmacodynamic and pharmacokinetic studies. Twenty-nine patients were enrolled, of whom 26 were treated (14 at 500 mg and 12 at 2000 mg). Among those treated, only three were progression free at 8 weeks: two in the 500 mg arm and one in the 2000 mg arm. One patient in the 2000 mg arm showed a prolonged partial response after an initial 28% enlargement of her target lesions. The treatment was well tolerated without clinically significant adverse events. The sole responder and one of two patients with stable disease had no &agr;v&bgr;3 expression at baseline. Overall, &agr;v&bgr;3 expression was decreased by day 8 of the treatment (P=0.05). Cilengitide was well tolerated by patients in both the treatment arms but had minimal clinical efficacy as a single-agent therapy for metastatic melanoma, and the efficacy was not related to baseline &agr;v&bgr;3 expression.

A Phase II Study of Ixabepilone (BMS-247550) in Metastatic Renal-Cell Carcinoma

Introduction Ixabepilone (BMS-247550) is a semi-synthetic analog of epothilone B that has been characterized as a microtubule stabilizing agent with a mechanism of action distinct from taxanes. Suggestion of activity in renal cell carcinoma (RCC) has been seen in early clinical studies. Methods Eligible patients had metastatic RCC as well as ECOG performance status 0-2 and normal organ function. Patients received ixabepilone at a dose of 40 mg/m2 intravenously over 3 hours every 21 days. There was no restriction on RCC histology or prior treatment type, but prior treatment with tubule inhibitors was not allowed. The primary endpoint was RECIST defined response and radiographic evaluations were performed every 3 cycles. Toxicity evaluations utilized CTCAE v3.0 and were performed every cycle. Using a Simon two-stage optimal design with α=0.1, β=0.1, a null hypothesized response rate of 0.05 and an alternative response rate of 0.2, an initial 12 patients were to be accrued with full accrual of 37 patients if at least one response were observed. Results A median of 5 cycles were administered. No objective responses were observed in the first 12 evaluable patients, and six patients showed stable disease for more than 18 weeks on therapy. Median time to progression among those with objective progression was 9 weeks. One patient experienced grade 4 anemia and lymphopenia. Grade 3 adverse events included lymphopenia, neutropenia, leukopenia, diarrhea, and infection. Common grade 2 toxicities included alopecia, fatigue, and anemia. Conclusion Ixabepilone administered at a dose of 40 mg/m2 every 21 days should not be advanced for further study in metastatic RCC. Given previous results, however, other dosing schedules may be worthy of further investigation.

In vitro and In vivo Clinical Pharmacology of Dimethyl Benzoylphenylurea, a Novel Oral Tubulin-Interactive Agent

Dimethyl benzoylphenylurea (BPU) is a novel tubulin-interactive agent with poor and highly variable oral bioavailability. In a phase I clinical trial of BPU, higher plasma exposure to BPU and metabolites was observed in patients who experienced dose-limiting toxicity. The elucidation of the clinical pharmacology of BPU was sought. BPU, monomethylBPU, and aminoBPU were metabolized by human liver microsomes. Studies with cDNA-expressed human cytochrome P450 enzymes revealed that BPU was metabolized predominantly by CYP3A4 and CYP1A1 but was also a substrate for CYP2C8, CYP2D6, CYP3A5, and CYP3A7. BPU was not a substrate for the efflux transporter ABCG2. Using simultaneous high-performance liquid chromatography/diode array and tandem mass spectrometry detection, we identified six metabolites in human liver microsomes, plasma, or urine: monomethylBPU, aminoBPU, G280, G308, G322, and G373. In patient urine, aminoBPU, G280, G308, and G322 collectively represented <2% of the given BPU dose. G280, G308, G322, and G373 showed minimal cytotoxicity. When BPU was given p.o. to mice in the presence and absence of the CYP3A and ABCG2 inhibitor, ritonavir, there was an increase in BPU plasma exposure and decrease in metabolite exposure but no overall change in cumulative exposure to BPU and the cytotoxic metabolites. Thus, we conclude that (a) CYP3A4 and CYP1A1 are the predominant cytochrome P450 enzymes that catalyze BPU metabolism, (b) BPU is metabolized to two cytotoxic and four noncytotoxic metabolites, and (c) ritonavir inhibits BPU metabolism to improve the systemic exposure to BPU without altering cumulative exposure to BPU and the cytotoxic metabolites.

Cervical Lymph Nodes and Unknown Primary Tumors of the Head and Neck

Risk Assessment Models The AJCC recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use. Although this is a monumental step toward the goal of precision medicine, this work was published only very recently. Therefore, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine Core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.