AMG 386 in combination with sorafenib in patients with metastatic clear cell carcinoma of the kidney

Abstract

BACKGROUND This study evaluated the tolerability and antitumor activity of AMG 386, a peptibody (a peptide Fc fusion) that neutralizes the interaction of angiopoietin-1 and angiopoietin-2 with Tie2 (tyrosine kinase with immunoglobulin-like and EGF-like domains 2), plus sorafenib in patients with clear cell metastatic renal cell carcinoma (mRCC) in a randomized controlled study. METHODS Previously untreated patients with mRCC were randomized 1:1:1 to receive sorafenib 400 mg orally twice daily plus intravenous AMG 386 at 10 mg/kg (arm A) or 3 mg/kg (arm B) or placebo (arm C) once weekly (qw). Patients in arm C could receive open-label AMG 386 at 10 mg/kg qw plus sorafenib following disease progression. The primary endpoint was progression-free survival (PFS). RESULTS A total of 152 patients were randomized. Median PFS was 9.0, 8.5, and 9.0 months in arms A, B, and C, respectively (hazard ratio for arms A and B vs arm C, 0.88; 95% confidence interval [CI], 0.60–1.30; P = .523). The objective response rate (95% CI) for arms A, B, and C, respectively, was 38% (25%–53%), 37% (24%–52%), and 25% (14%–40%). Among 30 patients in arm C who had disease progression and subsequently received open-label AMG 386 at 10 mg/kg qw, the objective response rate was 3% (95% CI, 0%–17%). Frequently occurring adverse events (AEs) included diarrhea (arms A/B/C, 70%/67%/56%), palmar-plantar erythrodysesthesia syndrome (52%/47%/54%), alopecia (50%/45%/50%), and hypertension (42%/49%/46%). Fifteen patients had grade 4 AEs (arms A/B/C, n = 3/7/5); 4 had fatal AEs (n = 2/1/1), with 1 (abdominal pain, arm B) considered possibly related to AMG 386. CONCLUSIONS In patients with mRCC, AMG 386 plus sorafenib was tolerable but did not significantly improve PFS compared with placebo plus sorafenib.

A phase 1b study of trebananib in combination with pegylated liposomal doxorubicin or topotecan in women with recurrent platinum-resistant or partially platinum-sensitive ovarian cancer

“…In this study, toxicities were generally consistent with those that have been associated with monotherapy of trebananib, PLD, or topotecan [16,32,33]. Peripheral edema has been previously identified as a risk associated with trebananib treatment and generally manageable across studies [16,17,34,35]. Other AEs that have been associated with trebananib in combination with chemotherapy are ascites and pleural effusion [35].…”

Pharmacokinetic drug-drug interaction study of the angiopoietin-1/angiopoietin-2-inhibiting peptibody trebananib (AMG 386) and paclitaxel in patients with advanced solid tumors

“…The incidence and severity of edema (local and peripheral) observed in the present study (approximately half of patients and mostly mild) are commensurate with previous reports. Other adverse events associated with trebananib treatment are hypokalemia and pleural effusion [16,15,3], both of which also occurred in the present study, and ascites and proteinuria [15,19,16] which were not observed here.…”

A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors

“…Inhibition of the angiopoietin pathway has been shown to result in tumor growth inhibition in preclinical models, with simultaneous inhibition of Ang1 and Ang2 resulting in greater tumor growth suppression compared with targeting either ligand in isolation (16,17). In early-phase clinical studies, treatment with trebananib (AMG 386), a peptibody that inhibits the interaction between Ang1 and Ang2 and the Tie2 receptor (18), showed anticancer activity, reducing tumor size and inducing objective responses in some patients (19)(20)(21)(22)(23). In a randomized, double-blind, phase III clinical study, trebananib plus weekly paclitaxel prolonged progression-free survival of patients with recurrent ovarian cancer compared with placebo plus paclitaxel [7.2 months vs. 5.4 months; HR, 0.66; 95% confidence interval (CI), 0.57-0.77; P < 0.0001; ref .…”