Phase I study of AMG 211/MEDI-565 administered as continuous intravenous infusion (cIV) for relapsed/refractory gastrointestinal (GI) adenocarcinoma

Abstract

Background: AMG 211 is a bispecific CEA-directed CD3 T-cell engager (BiTE(R)) that inhibits growth of CEA-expressing cancer cells in various cancer models. It was explored as intermittent 3-hour infusion for 5 subsequent days in a Ph 1 study (Pishvaian et al, 2016). The present study used cIV administration suggesting an improved therapeutic index versus an intermittent infusion by reduction of adverse events attributable to high Cmax and steady state exposure levels maintained above a threshold required for anti-tumor activity. Methods: To evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy, patients (pts) with relapsed/refractory GI adenocarcinomas were treated with cIV AMG 211 for 7, 14 or 28 days at 0.2-12.8 mg/day in repeated cycles until confirmed disease progression, occurrence of a dose-limiting toxicity (DLT) or discontinuation for other reasons. A Bayesian logistic regression model was intended to guide dose escalation after a first DLT. Results: 44 pts (median age 64.5 (range 57, 70), Karnofsky > 70%) were dosed in up to 7 cycles (median 2) in 8 dose cohorts without observing a DLT. The majority (N = 32) were pts with CRC, 6 had pancreatic cancer, 4 cholangiocarcinoma and one each esophageal and appendix adenocarcinoma. AMG 211 was discontinued due to disease progression in 33 pts (73%), adverse event in 7 pts (16%), pts request and due to other reason in 2 pts (4%) each. Adverse events reported in > 20% of pts were fatigue (54%), nausea, abdominal pain, pyrexia (39% each) and diarrhea (32%). PK steady-state concentrations of AMG 211 were reached within 2 days of dosing and maintained throughout the treatment. In general, exposure, assessed by Cmax, Css, and AUC, was increasing with dose. Initial changes in inflammatory and tumor markers were seen. The study was discontinued after observation of anti-AMG 211 antibodies in all pts treated at high doses of > 3.2 mg and drop in exposure with high titers. Conclusions: PD markers confirmed BiTE® mechanism of action. However, despite an acceptable safety profile immunogenicity leading to insufficient exposure for objective responses precluded the definition of a therapeutic window for AMG 211. Clinical trial identification: NCT02291614. Legal entity responsible for the study: Amgen. Funding: Amgen. Disclosure: W.M. Fiedler: Participation in advisary boards: Amgen, Pfizer, Novartis, Jazz Pharmaceuticals, Ariad/Incyte; Royalties: Amgen; Research funding: Amgen, Pfizer; Support for meeting attendance: Teva, Amgen, GSO Global, Jazz Pharmaceuticals, Daiichi Sanko Oncology; Support in medical writing: Amgen, Pfizer, Abbvie. H.M. Verheul: Research funding: Amgen, Vitromics, Immunovo, Novartis, Roche; Consulting fees: Boehringer Ingelheim, Pfizer, Roche; Other: Glycostsem advisory board. V. Heinemann: Research grant: Merck KgaA, Pfizer, Amgen, Roche, Boehringer Ingelheim, Celgene, Shire, Bayer, Celgene; Consulting fees: Merck KgaA, Roche AG, Amgen, Sanofi, Lilly, Sirtex, Boehringer Ingelheim, Baxalta, Taiho, Merrimack, Servier; Speakers bureau: Merck KgaA, Roche AG, Amgen, Sanofi, Sirtex, Baxalta, Servier; Travel expenses: Merck KgaA, Roche AG, Amgen, Sanofi, Sirtex, Baxalta, Servier. T.J. Ettrich: Research grant: Baxalta/Shire; Consulting fees: Merck-Serono, Sanofi, Sirtex, Medical, Novartis, Bayer, Bristol-Myers Squibb, Pfizer. E. Rasmussen: Stock: Amgen; Employment: Amgen. P. Bogner: Stocks: LTI-participation according to end-year review (compliant). Employment: Amgen. S. Stienen: Stock options or bond holdings in a for-profit corporation or self-directed pension plan. Employment: Amgen, include ownership of Amgen stock above if applicable. E.G.E. de Vries: Research grant: Amgen, Genentech, Roche, Chugai, Synthon, CytomX, Nordic Nanovector, Regeneron, G1 Therapeutics, AstraZeneca, Radius Health; all payments to the institution. Consulting fees: Pfizer, Sanofi; all payments to the institution. All other authors have declared no conflicts of interest.