Clinical-stage biopharmaceutical company Mersana Therapeutics has confirmed that a first patient has been dosed in a Phase I dose-escalation study evaluating XMT-1592.

XMT-1592 is the Mersana’s first clinical candidate created using Mersana’s customizable and homogenous Dolasynthen ADC technology platform. The investigational agent is designed to target NaPi2b-expressing tumors, using the company’s proprietary NaPi2b antibody and auristatin DolaLock payload.

Technology platform
Mersana’s Dolasynthen technology platform is a synthetic scaffold for precise control of drug-to-antibody ratio (DAR; from 2 to 24) and site-specific antibody bioconjugation.

MabPlex
 

The platform is also able to homogeneously generate ADCs with precisely defined DARs for consistent drug delivery to cancer cells. The Dolasynthen scaffold has been precisely balanced to provide optimal water solubility, charge balance, linker stability, and DAR.

In preclinical studies, Dolasynthen has shown four times greater efficacy in a patient-derived lung tumor model in comparison to Dolaflexin, a platform that has already shown success when targeted to NaPi2b.

During the 2019 annual meeting of the American Association for Cancer Research (AACR) Mersana presented preclinical data demonstrating how the optimized Dolasynthen ADC technology platform exhibits a broad therapeutic index as a cancer therapy. These data further demonstrated the ability of the Dolasynthen platform to generate and identify the optimal ADC for a given target and antibody, and the significant potential for clinical application.

Investigational drug
“XMT-1592 has shown a differentiated preclinical profile, particularly in NSCLC where we saw a four-fold increase in efficacy over XMT-1536, consistent with increased exposure to the DolaLock payload in the tumor, and we look forward to working to validate the clinical differentiation of this candidate,” said Anna Protopapas, President and Chief Executive Officer of Mersana Therapeutics.

“XMT-1592 also has the potential to further extend our leadership position in NaPi2b-expressing malignancies, and we are very pleased to have reached this important 2020 goal of advancing this promising ADC candidate into the clinic.”

Study design
In this Phase I, open-label, multi-center, dose-escalation part of the trial, XMT-1592 will be administered as an intravenous infusion once every 3 weeks (Q3W). The dose-escalation part of the study will establish the expansion dose and is intended to establish the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D) for the investigational drug in patients with high grade serous ovarian cancer (HGSOC) or non-small cell lung cancer (NSCLC), adenocarcinoma subtype.

The expansion dose of the study will consist of 2 parallel cohorts of patients (HGSOC and NSCLC) to confirm the MTD or RP2D and estimate the objective response rate (ORR) in each selected patient population.

In the dose-escalation part of the study, the observation period for dose-limiting toxicities is 21 days, between Day 1 through the end of Cycle 1 which includes the pre-dose assessments before receiving the Cycle 2 dose. All adverse events (AEs) will be graded according to NCI, CTCAE v5.0). In general, AEs ≥Grade 3 are dose-limiting toxicities (DLT) with some modifications.

Clinical trials
First-in-Human Study of XMT-1592 in Patients With Ovarian Cancer and NSCLC Likely to Express NaPi2b – NCT04396340

Reference
Susan M. Clardy, Alex Yurkovetskiy, Mao Yin, Dmitry Gumerov, Ling Xu, Elena Ter-Ovanesyan, Charlie Bu, Alex Johnson, Marina Protopopova, Qingxiu Zhang, Natalya Bodyak, Marc Damelin, David H. Lee, Donald Bergstrom, Timothy B. Lowinger. Unique pharmacologic properties of Dolaflexin-based ADCs—a controlled bystander effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl): Abstract nr 754.