Abstract P047: A phase 1/2 trial of CBX-12, an alphalexTM peptide drug conjugate, in patients with advanced or metastatic refractory solid tumors
Authors: Tolcher Anthony , Eder Joseph Paul , Sommerhalder David , Gayle Sophia , Pearson Paul , Chapman Deb , DeCillis Arthur P. , Thomas Anish , Meric-Bernstam Funda 
Published: December 2021

Abstract
Background Tumor-targeted drug delivery technologies are urgently needed to overcome the lack of tumor selectivity, a major drawback of conventional chemotherapy. In addition, the acidic intercellular microenvironment in solid tumors traps weak acid/base chemotherapy agents, preventing necessary intracellular concentrations in tumour cells. An alphalex conjugate, which contains a low-pH insertion peptide, a linker, and a payload, is designed to overcome these limitations. Unlike antibody drug conjugates, these peptide drug conjugates target tumors in an antigen-agnostic manner. At pH ≥7.0, the peptide is unstructured. In the low-pH tumor microenvironment, the peptide forms an alpha helix, inserts directionally in the cell membrane delivering the linker and payload intracellularly where the linker is cleaved. CBX-12 consists of the pH-sensitive peptide, a self-immolating linker, and the topoisomerase 1 (TOP1) inhibitor exatecan. Methods CBX-12-101 is a first-in-human, open-label, dose-escalation, safety, pharmacokinetics (PK), and biomarker study of CBX-12 in patients with advanced or metastatic refractory solid tumors. CBX-12 is administered as a 1-hour intravenous infusion. Two dosing schedules, daily x 5 every 3 weeks (Part A) and daily x 3 every 3 weeks (Part B), are being evaluated. The starting dose in Part A is 0.25 mg/kg. Single-patient cohorts will be enrolled initially, with dose-escalations up to 100% of the prior dose, until a patient has a ≥ Grade 2 adverse event (AE) considered possibly related to CBX-12 during Cycle 1 (the DLT period), at which time 2 additional patients will be enrolled in that cohort, and a 3 + 3 design will subsequently be utilized. Further dose escalations may be no more than 50% of the prior dose. After at least 2 cohorts have been evaluated in Part A, Part B will open for accrual. Maximum tolerated doses and recommended phase 2 doses will be determined for each dosing schedule. The PK of the CBX-12 conjugate and free exatecan will be determined. The stability of the conjugate in circulation will be evaluated by the ratio of CBX-12 to free exatecan. Pre- and on-treatment tumor biopsies are required. Biomarker and pharmacodynamic evaluations including measuring intratumor exatecan levels, TOP1, gamma H2AX and schlafen-11 are planned. Antitumor activity will be assessed per RECIST v 1.1. Phase 2 expansion cohorts are planned in patients with platinum-resistant ovarian and small cell lung cancer. As of July 2021, patients are enrolling in Part A Cohort 2 at a dose of 0.50 mg/kg.
Citation Format: Anthony Tolcher, Joseph Paul Eder, David Sommerhalder, Sophia Gayle, Paul Pearson, Deb Chapman, Arthur P. DeCillis, Anish Thomas, Funda Meric-Bernstam. A phase 1/2 trial of CBX-12, an alphalexTM peptide drug conjugate, in patients with advanced or metastatic refractory solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P047.