687TiP - A phase I, first in human study of TORL-4-500 in patients with advanced cancer

Background

Delta-like 1 homolog protein (DLK1), also known as preadipocyte factor 1 (PREF-1) and fetal antigen 1 (FA1), is a transmembrane protein and an inhibitor of NOTCH1 signaling. It modulates a wide range of developmental processes where NOTCH signaling is critical including cellular proliferation, cell fate, and terminal differentiation. As a result of its role in developmental signaling, expression of DLK1 decreases as development proceeds, with limited expression in adult tissues, with the exception of adrenal and pituitary glands, and ovaries. DLK1 is highly expressed in several cancers, including adrenocortical, uterine, and testicular cancers as well as a subset of pancreatic, sarcoma, liver, and lung cancers. Taken together, this expression profile makes DLK1 an attractive candidate for targeted therapeutic approaches. TORL-4-500 is an antibody-drug conjugate (ADC) with a fully humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) selective for DLK1 linked to monomethyl auristatin E (MMAE), an anti-mitotic agent via a cathepsin hydrolysable dipeptide valine-citrulline (vc) linker.

Trial design

TORL-4-500-001 is a two-part first in human study to characterize the safety, tolerability, and dose-limiting toxicities (DLT) and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of TORL-4-500 administered as monotherapy intravenously Q3W in patients with advanced cancer. Serum PK, immunogenicity, and antitumor activity will also be evaluated. Endpoints include frequency and severity of adverse events and objective response rate (ORR) based on RECIST v1.1 criteria. Correlative biomarker studies will evaluate the relationship of clinical benefit with blood and tissue biomarkers. This study is currently open with patients enrolling in dose escalation. Once the RP2D is established, dose expansion in DLK1+ indication-specific cohorts will commence.

Clinical trial identification

NCT06005740.

Editorial acknowledgement

Legal entity responsible for the study

TORL Biotherapeutics.

Funding

TORL Biotherapeutics.

Disclosure

J.W. Goldman: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Genentech, Eli Lilly, Janssen, AbbVie, Gritstone; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Eli Lilly; Financial Interests, Institutional, Local PI: Genentech, Janssen, BMS, AbbVie. L.S. Rosen: Financial Interests, Institutional, Funding, PI at UCLA Health Hem/Onc for Inspirna trial, Institution receives research funding: Inspirna. A. Kung, A. Romero, I. Qazi, H. Dokainish, S. Letrent: Financial Interests, Personal, Stocks/Shares: TORL Bio. D. Slamon: Financial Interests, Personal and Institutional, Member of Board of Directors: TORL Bio.