Steven Zhang

Phase I Dose-Escalation Study of the Novel Antiandrogen BMS-641988 in Patients with Castration-Resistant Prostate Cancer

Purpose: BMS-641988 is an androgen receptor antagonist with increased potency relative to bicalutamide in both in vitro and in vivo prostate cancer models. A first-in-man phase I study was conducted to define the safety and tolerability of oral BMS-641988 in patients with castration-resistant prostate cancer (CRPC). Experimental Design: Doses were escalated from 5 to 150 mg based on discrete pharmacokinetic parameters in cohorts of three to six subjects. After establishing safety with 20 mg of BMS-641988 in the United States, a companion study was opened in Japan to assess differences in drug metabolism between populations. Results: Sixty-one men with CRPC were treated with daily BMS-641988. The pharmacokinetics (PK) of BMS-641988 and its active metabolites were proportional to dose. One patient experienced an epileptic seizure at a dose of 60 mg administered twice. Despite achieving target drug exposures, antitumor activity was limited to one partial response. Seventeen of 23 evaluable patients (74%) exhibited stable disease on imaging (median 15 weeks; range 8–32), and 10 of 61 patients (16%) achieved a ≥30% decline in levels of prostate-specific antigen (PSA). Partial agonism was seen within the context of this study upon removal of the drug as evidenced by a decrease in PSA. Conclusions: Although the clinical outcomes of predominantly stable disease and partial agonism were similar to what was observed in the preclinical evaluation of the compound, the limited antitumor activity of BMS-641988 at therapeutic dose levels coupled with an episode of seizure activity led to study closure. Clin Cancer Res; 17(4); 880–7. ©2010 AACR.

Metabolism and Disposition of [14C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non–small-cell lung cancer and metastatic breast cancer. The disposition of [14C]BMS-690514 was investigated in nine healthy male subjects (group 1, n = 6; group 2, n = 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose. In group 2 subjects, bile was collected from 3 to 8 h postdose. Across groups, approximately 50 and 34% of administered radioactivity was recovered in the feces and urine, respectively. An additional 16% was recovered in the bile of group 2 subjects. Less than 28% of the dose was recovered as parent drug in the combined excreta, suggesting that BMS-690514 was highly metabolized. BMS-690514 was rapidly absorbed (median time of maximum observed concentration 0.5 h) with the absorbed fraction estimated to be approximately 50 to 68%. BMS-690514 represented ≤7.9% of the area under the concentration-time curve from time 0 extrapolated to infinite time of plasma radioactivity, indicating that the majority of the circulating radioactivity was from metabolites. BMS-690514 was metabolized via multiple oxidation reactions and direct glucuronidation. Circulating metabolites included a hydroxylated rearrangement product (M1), a direct ether glucuronide (M6), and multiple secondary glucuronide conjugates. None of these metabolites is expected to contribute to the pharmacology of BMS-690514. In summary, BMS-690514 was well absorbed and extensively metabolized via multiple metabolic pathways in humans, with excretion of drug-related radioactivity in both bile and urine.

Phase I–IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours

PURPOSE BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514. PATIENTS AND METHODS In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD. RESULTS In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (≥4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways. CONCLUSION This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.

Food Increased the Bioavailability of BMS‐690514, an Orally Active EGFR/HER2/VEGF Receptor Kinase Inhibitor, in Healthy Subjects

We studied the effect of food on pharmacokinetics, safety, and tolerability of BMS‐690514. Two open‐label, randomized, single‐dose, 2‐treatment, 2‐period crossover studies were performed in healthy subjects. In study 1 (N = 26), a single oral dose of BMS‐690514, 200 mg, was administered while fasting or after a high‐fat meal, and in study 2 (N = 17), a single oral dose of BMS‐690514, 200 mg, was administered while fasting or after a light meal. Compared with fasting, the adjusted geometric mean maximum observed plasma concentration (Cmax), area under the plasma concentration‐time curve from time zero to time of last quantifiable concentration (AUC0‐T), area under the plasma concentration‐time curve from time zero extrapolated to infinite time (AUCINF) of BMS‐690514 increased by 55%, 33%, and 34%, respectively, following a high‐fat meal (951 kcal, 52% fat) and by 41%, 20%, and 20%, respectively, following a light meal (336 kcal, 75% carbohydrate). BMS‐690514 was well tolerated in both studies. Most frequently occurring adverse events were diarrhea and acne in study 1 and rash, dry skin, and diarrhea in study 2. Systemic exposure of highly soluble BMS‐690514 was increased when given along with a meal, probably through inhibition of intestinal first‐pass metabolism and/or efflux transporters by food. These studies also demonstrated a tolerable safety profile of BMS‐690514 in the absence and presence of food.