756P - First-in-human phase I study of a novel claudin 6 (CLDN6) targeted antibody drug conjugate (ADC) TORL-1-23

Background

CLDN6 is expressed at high levels in multiple cancers with little to no expression in normal tissues and has been implicated in the initiation, progression, and metastasis of some cancers. CLDN6 is an ideal target for development of new therapeutics. TORL-1-23 is first-in-class ADC targeting the tumor-specific antigen CLDN6.

Methods

This ongoing first in human study (TORL123-001, NCT05103683) characterizes the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of TORL-1-23 in participants with advanced solid tumors. Pharmacokinetics (PK), immunogenicity and clinical efficacy are also assessed. TORL-1-23 is administered IV every 3 weeks. In Dose Escalation, cohorts up to 6 participants are evaluated at each dose level according to an accelerated titration design. In Dose Expansion, patients with CLDN6-expressing cancers will be evaluated to confirm the RP2D in ovarian cancer, NSCLC, and other CLDN6+ cancers using an IHC companion diagnostic. Doses above the historic MTD for MMAE containing ADCs are being evaluated given the favorable safety/tolerability at doses <2.4 mg/kg.

Results

30 patients with ovarian (n=22), testicular (n=5), and endometrial (n=3) cancers were enrolled across 9 dose levels ranging from 0.2 to 3 mg/kg IV every 3 weeks (as of 01MAY2023). 93% of pts had received ≥ 3 prior lines of treatment in the metastatic setting. The most common treatment-related adverse events were Gr1/2 fatigue (n=6), anemia (n=5), and peripheral neuropathy (n=4). No DLTs were observed at doses ≤2.4 mg/kg. Sustained PK exposure of TORL-1-23 over the dosing interval and low levels of circulating MMAE are noted. Partial responses (PR) were observed in 7/22 (32%) efficacy evaluable participants with CLDN6+ disease (6 ovarian, 1 testicular) across dose levels. 3/3 (100%) participants with CLDN6+ ovarian cancer responded at the 2.4 mg/kg dose level. Data from 3 mg/kg are pending.

Conclusions

In participants with heavily-pretreated CLDN6-expressing ovarian cancer, the novel TORL-1-23 ADC has a favorable safety/tolerability profile and encouraging antitumor activity in a phase 1 dose finding study. Further evaluation in ovarian cancer and other CLDN6+ cancers is warranted.

Clinical trial identification

NCT05103683.

Editorial acknowledgement

None.

Legal entity responsible for the study

TORL Biotherapeutics.

Funding

TORL Biotherapeutics.

Disclosure

A. Machado, S. Davenport, S. Bilic, L. Miller, A. Chung: Financial Interests, Institutional, Other, Fee for Service: TORL Biotherapeutics. M.F. Press: Financial Interests, Personal, Advisory Board: Biocartis, Cepheid, Lilly USA, LLC; Financial Interests, Personal, Other, Consultant: Zymeworks, Inc., Eli Lilly & Company, AstraZeneca, Merck, Novartis; Financial Interests, Personal, Ownership Interest: TORL Biotherapeutics LLC; Financial Interests, Institutional, Other, Fee-for-Service Agreements: Zymeworks, Inc., TRIO-US, TRIO; Financial Interests, Institutional, Other, Fee-For-Service Agreements: TORL Biotherapeutics LLC; Financial Interests, Institutional, Other, Fee-for-Service Agreement: Ambrx, 1200 Pharma. S. Letrent: Financial Interests, Personal, Full or part-time Employment: TORL Biotherapeutics. D. Slamon: Financial Interests, Personal and Institutional, Leadership Role: TORL Biotherapeutics; Financial Interests, Personal and Institutional, Ownership Interest: TORL Biotherapeutics. All other authors have declared no conflicts of interest.