Phase Ia study of CBP-1008, a bi-specific ligand drug conjugate targeting FRα and TRPV6, in patients with advanced solid tumors.
Jifang Gong, Xichun Hu, Jian Zhang, Yiqun Du, Robert Huang, Yan Teng, Wei Phin Tan, Lin Shen
Abstract
3077 Background: CBP-1008 is a first-in-class bi-specific ligand drug conjugate targeting folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) with a high potency tublin inhibitor payload, monomethyl auristatin E (MMAE). A first-in-human, multicenter, phase I study of CBP-1008 (NCT 04740398) is ongoing, and we herein report the preliminary result of part A which is to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of CBP-1008 in solid tumors. Methods: Dose escalation commenced in single-patient cohorts for the first 2 planned dose levels and then followed by a standard 3 + 3 scheme. CBP-1008 was administered as intravenous infusion at escalating doses (0.015, 0.03, 0.12, 0.15, and 0.18 mg/kg). The primary endpoints were to determine the safety and maximum tolerated dose (MTD). Adverse events (AEs) and dose-limiting toxicities (DLTs) were evaluated. Results: Eighteen patients with advanced solid tumors who had failed multiple systemic treatment regimens were enrolled. The diseases include colorectal cancer (n = 7), breast cancer (n = 5), non-small cell lung cancer (n = 2), ovarian cancer (n = 2), adrenocortical carcinoma (n = 1), and follicular dendritic cell sarcoma (n = 1). The DLTs observed included grade 4 hypophosphatemia (0.15 mg/kg), grade 4 neutropenia (0.12, 0.15, and 0.18 mg/kg), grade 4 febrile neutropenia (FN) (0.18 mg/kg), grade 3 hyperglycemia (0.15 mg/kg), and grade 3 alanine aminotransferase (ALT) elevation (0.18 mg/kg). The most common all grade AEs suspected to be drug-related were fever (83.3%, totally limited to grade 1-2), aspartate aminotransferase (AST) elevation (72.2%, 5.6% evaluated as grade 3-4), leukopenia (66.7%, 27.8% as grade 3-4), neutropenia (66.7%, 38.9% as grade 3-4) and hypohemoglobinemia (55.6%, 5.6% as grade 3-4), with no drug-related deaths. MTD is estimated between 0.15 mg/kg and 0.18 mg/kg Q2W. Best overall response was partial response (PR) in 1 patient at 0.18 mg/kg and 4 patients (22.2%) achieved stable disease (SD). Responses occurred in patients with FRα and/or TRPV6 -positive expression advanced solid tumors. Conclusions: CBP-1008 has demonstrated acceptable safety profile. Tumor response correlating with dosing and FRα/TRPV6 receptor expression levels has been well observed. Clinical trial information: 04740398.