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First-in-human study of AMG 655, a pro-apoptotic TRAIL receptor-2 agonist, in adult patients with advanced solid tumors

2007; Lippincott Williams & Wilkins; Volume: 25; Issue: 18_suppl Linguagem: Inglês

10.1200/jco.2007.25.18_suppl.3534

1527-7755

Patricia LoRusso, David S. Hong, Elisabeth I. Heath, Razelle Kurzrock, D. Wang, M. Hsu, Lovely Goyal, Jeffrey S. Wiezorek, Chris Storgard, Roy S. Herbst,

Cancer Research and Treatments

3534 Introduction: AMG 655 is a fully human monoclonal agonist antibody that binds human TRAIL receptor 2 (TR-2/DR5), activates caspases, and induces apoptosis in sensitive tumor cells. The primary objectives of this ongoing first-in-human study were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 655 in patients (pts) with advanced solid tumors. Methods: Three to 9 pts were enrolled into 1 of 5 sequential dose cohorts (0.3, 1, 3, 10, or 20 mg/kg) of AMG 655 administered intravenously Q2W. No AMG 655 was administered on day 43 to allow assessment of terminal PK parameters. RECIST and FDG-PET were analyzed by central radiology. Pts remained on study until tumor progression or unacceptable toxicities occurred. Results: As of October 19, 2006, 16 pts (4 in the 10 mg/kg cohort; 3 in each of the other cohorts) had received = 1 dose of AMG 655; 12 pts were men, mean (SD) age was 53 (±8.9) years. No DLTs or AMG 655-related serious AEs were reported. The MTD was not reached. Nine pts reported AMG 655-related AEs. Treatment-related AEs in 3 or more pts were: pyrexia (4 pts), fatigue (3 pts), and hypomagnesaemia (3 pts). Fatigue and elevated serum lipase were the only grade 3 or higher AMG 655-related AEs and both occurred in the same pt (0.3-mg/kg cohort). No anti-AMG 655 antibodies were detected. PK data were available from dose cohorts 1 to 3 (0.3, 1, and 3 mg/kg); AMG 655 demonstrated dose-linear kinetics with a half-life of ∼10 days. Tumor- response data were available for 13 pts. Partial response was observed in 1 pt with non-small cell lung cancer (NSCLC) who experienced a 46% reduction in tumor volume by RECIST and remains on study after 48 weeks. Stable disease was reported in 4 pts (range 6 to 35 weeks), and progressive disease in 8 pts. One pt with colorectal cancer and stable disease demonstrated a metabolic partial response with a 34% reduction in maximum standardized uptake value (SUV max ). Conclusions: AMG 655 administered up to 20 mg/kg Q2W appeared to be well tolerated in these pts. The anti-tumor activity of AMG 655 was confirmed with observation of a partial response in NSCLC and a metabolic partial response in colorectal cancer. Further studies evaluating AMG 655 in combination with chemotherapy and targeted agents are warranted. No significant financial relationships to disclose.