A phase II trial of trebananib (AMG 386; IND#111071), a selective angiopoietin 1/2 neutralizing peptibody, in patients with persistent/recurrent carcinoma of the endometrium: An NRG/Gynecologic Oncology Group trial

Abstract

Objectives Ang1&2 (angiopoietin-1; -2) interact with Tie2 receptors on endothelial cells to mediate vascular remodeling in an angiogenesis signaling pathway distinct from the VEGF axis. Trebaninib is a peptide Fc fusion protein that binds Ang1 and 2 and prevents interaction with Tie2. The efficacy of trebananib in recurrent/persistent endometrial cancer (EC) was studied. Methods The primary objective was to determine the frequency of patients with objective tumor responses (ORR) and event-free survival for ≥6 months (6-month EFS) and determine toxicity of trebananib at a dose and schedule of 15mg/kg, IV QW. Recurrent/persistent EC, measurable disease, and ≤2 prior chemotherapy lines were required. Results Thirty-two patients were eligible and treated. The most common histologies were G1/2 endometrioid (31%), G3 endometrioid (28%) and serous (31.3%). 78% of patients had 1 prior regimen. Patients received 1-9+ cycles of trebananib; 24 patients (75%) received ≤2 cycles. One patient had a partial response (3.1%); 8 patients had stable disease (25%) and 5 patients (15.6%) had 6 month EFS. Median progression-free survival and overall-survival were 1.97 months (90% CI 1.77-2.1) and 6.6 months (90% CI 4.01-14.75), respectively. Most common adverse events (AE) were fatigue, anemia, and GI issues. Grade 3 and 4 AEs were: GI 31 and 0%; Vascular 22 and 0%; Metabolism/nutrition 19 and 3%; General (including edema) 16 and 0%. Conclusions Trebananib has insufficient single agent activity in recurrent EC to warrant further investigation at this dose/schedule.

Phase 2 and biomarker study of trebananib, an angiopoietin‐blocking peptibody, with and without bevacizumab for patients with recurrent glioblastoma

“…The disappointing efficacy results from our study are consistent with a lack of meaningful antitumor benefit observed with trebananib across several cancer types to date. Trebananib was ineffective when administered as a single agent for endometrial cancer and angiosarcoma, and it also did not improve outcome when combined with chemotherapy for metastatic colorectal carcinoma or metastatic esophageal cancer or when combined with sorafenib for patients with metastatic clear cell kidney cancer . Among patients with metastatic ovarian cancer, a large, placebo‐controlled, double‐blind phase 3 study demonstrated that the addition of trebananib to paclitaxel improved PFS but not OS …”

Pharmacological Treatment of Advanced, Persistent or Metastatic Endometrial Cancer: State of the Art and Perspectives of Clinical Research for the Special Issue “Diagnosis and Management of Endometrial Cancer”

“…The treatment of EC patients with multitarget tyrosine kinase inhibitors sorafenib, sunitinib, nintedanib and lenvatinib achieved disappointing results [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ] ( Table 5 ).…”

Paclitaxel, Carboplatin, and Bevacizumab in Advanced and Recurrent Endometrial Carcinoma

“…18 Unfortunately, trebananib (AMG 386), a selective angiopoietin 1/2 neutralizing peptibody, showed minimal activity, with a 3.1% response rate with 15.6% PFS at 6 months. 19 Mutations resulting in loss of function of PTEN, a tumor suppressor gene, appear to be important in the pathogenesis of endometrial carcinomas. 21 Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling, which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression.…”