A Phase 3 Open-Label, Randomized, Multicenter Study of Imprime Pgg in Combination with Cetuximab in Patients with Kras Wild Type Metastatic Colorectal Cancer

Abstract

ABSTRACT Background: For patients (pts) with epidermal growth factor receptor (EGFR) expressing, KRAS wild-type (WT) metastatic colorectal cancer (mCRC) who failed oxaliplatin- and irinotecan-based therapy or who are intolerant to irinotecan, single-agent cetuximab has been shown to improve objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). The mechanism of action of cetuximab is thought to rely on competitive blockade of endogenous ligand binding and downstream signaling, internalization and downregulation of EGFR, as well as antibody-dependent cellular cytotoxicity (ADCC) (Erbitux SmPC). Imprime PGG (Imprime) is a novel immune modulator (complex carbohydrate biologic), which harnesses innate immune cells to enhance killing of antibody-targeted tumor cells. In a phase 2 single-arm clinical trial in mCRC, the combination of Imprime with cetuximab resulted in 24% ORR, 62% disease control rate (DCR), and median time to progression (TTP) of 12 wks (Tamayo ME, Ann Onc 2010), representing approximate 100% increases vs historical control (Cunningham, NEJM 2004). ORR was 45%, DCR 82% and TTP 24 wks in pts with KRAS WT tumors (post hoc analysis). The current trial, sponsored by Biothera and registered with ClinicalTrials.gov NCT01309126, EudraCT 2010-023562-51, is to confirm these findings in phase 3. Trial design: Approximately 795 pts with previously treated, KRAS WT mCRC will be randomized 2:1 to weekly open-label Imprime plus cetuximab or cetuximab alone, until disease progression. Randomization will be stratified by geographic region, prior chemotherapy and site. The primary endpoint of the study is OS. Secondary endpoints are PFS, ORR (based on RECIST 1.1), quality of life, safety and pharmacokinetics. Exploratory endpoints include biomarker analyses. The primary analysis will occur when ∼709 deaths have occurred. Eligible pts have measurable disease, an ECOG performance status of 0 or 1 and have received prior oxaliplatin- and irinotecan-based therapy or are intolerant to irinotecan. Pts with known hypersensitivity to cetuximab or yeast are excluded. Pt screening and enrollment is underway in Europe and the United States. Disclosure: M.L. Patchen, M. Gargano, M. Grady, J. Lowe, R.D. Huhn and A. Braun: Author is a Biothera employee and has stock options and/or grants.