Randomized, Double-Blind, Placebo-Controlled Phase II Study of AMG 386 Combined With Weekly Paclitaxel in Patients With Recurrent Ovarian Cancer

• Published in: Journal of clinical oncology Vol. 30; no. 4; pp. 362 - 371
• Main Authors: KARLAN, Beth Y, OZA, Amit M, COVENS, Allan, NAGARKAR, Raj V, DAVY, Margaret, LEATH, Charles A, NGUYEN, Hoa, STEPAN, Daniel E, WEINREICH, David M, TASSOUDJI, Marjan, SUN, Yu-Nien, VERGOTE, Ignace B, RICHARDSON, Gary E, PROVENCHER, Diane M, HANSEN, Vincent L, BUCK, Martin, CHAMBERS, Setsuko K, GHATAGE, Prafull, PIPPITT, Charles H, BROWN, John V
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 01.02.2012
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Disease-Free Survival; Double-Blind Method; Fallopian Tube Neoplasms - drug therapy; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - pathology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Paclitaxel - administration & dosage; Paclitaxel - adverse effects; Peritoneal Neoplasms - drug therapy; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - adverse effects; Survival Analysis; Tumors; Antineoplastic agent; Human; Relapse; Ovary cancer; Administration schedule; Malignant tumor; Female genital diseases; Ovarian diseases; Randomization; Cancerology; Treatment; Taxane derivatives; Phase II trial; Paclitaxel; Placebo; Antimitotic; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2010.34.3178

To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m(2) once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarone's test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.