AMG 386 in combination with sorafenib in patients with metastatic clear cell carcinoma of the kidney: a randomized, double-blind, placebo-controlled, phase 2 study.

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.

• Authors: Brian Rini, Cezary Szczylik, Nizar M Tannir, Piotr Koralewski, Piotr Tomczak, Andrzej Deptala, Luc Y Dirix, Mayer Fishman, Rodryg Ramlau, Alain Ravaud, Wojciech Rogowski, Karolyn Kracht, Yu-Nien Sun, Michael B Bass, Markus Puhlmann, Bernard Escudier
• Journal: Cancer (Cancer) Vol. 118 Issue 24 Pg. 6152-61 (Dec 15 2012) ISSN: 1097-0142 [Electronic] United States
• PMID: 22692704 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Cancer Society.

Chemical References

• Antineoplastic Agents
• Benzenesulfonates
• Biomarkers, Tumor
• Phenylurea Compounds
• Pyridines
• Recombinant Fusion Proteins
• Niacinamide
• Sorafenib
• trebananib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Benzenesulfonates (therapeutic use)
• Biomarkers, Tumor (metabolism)
• Carcinoma, Renal Cell (drug therapy, mortality, secondary)
• Double-Blind Method
• Enzyme-Linked Immunosorbent Assay
• Female
• Follow-Up Studies
• Humans
• Kidney Neoplasms (drug therapy, mortality, pathology)
• Male
• Middle Aged
• Neoplasm Staging
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Prognosis
• Pyridines (therapeutic use)
• Recombinant Fusion Proteins (therapeutic use)
• Sorafenib
• Survival Rate