First-in-human phase 1 trial of ELI-002 immunotherapy as treatment for subjects with Kirsten rat sarcoma (KRAS)-mutated pancreatic ductal adenocarcinoma and other solid tumors.

TPS2701 Background: Mutations in KRAS and NRAS occur in one quarter of human solid tumors. The G12D allele is the most commonly occurring variant in pancreatic, colorectal, non-small cell lung, ovarian, biliary and gallbladder cancers. ELI-002 2P is an immunotherapeutic comprised of a lymph-node targeted amphiphile (AMP)-modified G12D and G12R mutant KRAS peptides together with an AMP-modified CpG oligonucleotide adjuvant. In preclinical models, ELI-002 demonstrated increased cytotoxic KRAS-specific T cells compared to non-lymph node targeted controls using the same peptide and adjuvant. Clinical evaluation of adoptively transferred KRAS-specific T cells demonstrated objective antitumor activity (Tran 2016). Circulating tumor (ctDNA) methodology permits identification of patients with minimal residual disease (MRD) following locoregional treatment. In MRD setting, immunotherapy is anticipated to succeed as the ratio of effector T cells to target tumor cells is maximized prior to bulk visible disease. The AMPLIFY-201 study (NCT04853017) is evaluating ELI-002 in patients with KRAS mutated solid tumors with MRD. Methods: AMPLIFY-201 is an open-label, dose-escalation and expansion phase I, first in human, trial evaluating ELI-002 2P in patients with KRAS mutated tumors with MRD following standard of care therapy. The initial phase I cohort enrolls patients with colorectal and pancreatic cancer to receive multiple doses of AMP-peptides 70mcg each (1.4 mg total) admixed with AMP-CpG 0.1 mg, administered once every two weeks. Subsequent phase I cohorts will enroll patients with RAS-mutated pancreatic, colorectal, non-small cell lung, ovarian, bile duct or gallbladder cancer, who will receive a fixed dose of AMP-peptides 70 mcg each, together with escalating doses of AMP-CpG. Safety and efficacy will be summarized with descriptive statistics. The maximum tolerated dose (if any) and the recommended phase II dose (RP2D) will be determined with the dose-response activity of ELI-002 2P in eliciting functional KRAS-specific T cells. Preliminary antitumor activity will be characterized using changes from baseline in ctDNA, serum biomarkers appropriate for tumor type, and progression free survival time. Eligibility includes patients who have received standard of care locoregional treatment according to NCCN guidelines and whom have MRD persistence or relapse (ctDNA positive). Patients with colon and pancreas cancer with Stage IV oligometastatic disease (< 3 lesions in one organ) rendered surgically free of disease and with MRD, are also eligible. The dose escalation portion of the study is currently enrolling. Clinical trial information: NCT04853017.