1033P - First-in-human study of MALT1 inhibitor MPT-0118: Results from monotherapy dose escalation in advanced or metastatic refractory solid tumors

Background

MALT1 protease inhibition reprograms tumor-resident regulatory T cells (Treg), inducing interferon-gamma (IFN) expression and loss of immunosuppressive function. MPT-0118 is an orally bioavailable MALT1 inhibitor undergoing phase 1 clinical evaluation.

Methods

Part A enrolled eligible patients (pts) into escalating dose cohorts of MPT-0118. Primary study objectives were safety, tolerability, and assessment of the recommended phase 2 dose (RP2D). Other objectives were the assessment of pharmacokinetics (PK), biomarkers, and objective response rate (ORR) per RECIST v1.1 and iRECIST. Paired biopsies were obtained during screening and after 8 days of treatment.

Results

17 pts were treated (median age 54 years (32-77), 59% male, median 4 prior lines of therapy, 35% prior immunotherapy). No dose-limiting toxicities (DLT) were observed, and all treatment-related adverse events (TRAE) were reversible. Table: 1033P

*Dizziness (5), vision blurred (4), fatigue (4), dry mouth (3), tremor (3), representing all observed AEs with frequency ≥ 3 Note: AEs were graded according to the NCI-CTCAE version 5.0.

The RP2D was at 200 mg/day based on PK and clinical observations. Among 13 response-evaluable pts, 5 had stable disease (SD) (38%) after ≥2 treatment cycles, of which 3 had tumor shrinkage, including chordoma, gastric and breast cancers. In an immunotherapy naïve MSS gastric cancer pt, tumor size decreased by 20% with a concurrent improvement of ascites and doubling of tumor-infiltrating CD8+ T cells. MPT-0118 ex vivo incubation of gastric cancer ascites collected outside the study resulted in Treg reprogramming. In the other SD pts, median CD8 T-cells, IFN, or PD-L1 markers increased. PK data showed a dose-proportional increase in plasma drug concentrations.

Conclusions

In this first human trial of a MALT1 inhibitor in solid tumor pts, MPT-0118 demonstrated good tolerability with no immune-related toxicities and single-agent activity in cold tumors with poor response to checkpoint inhibitors. The biomarker data are consistent with the purported mechanism. The results warrant advancing to study Part B in combination with pembrolizumab.

Clinical trial identification

NCT04859777.

Editorial acknowledgement

Legal entity responsible for the study

Monopteros Therapeutics Inc.

Funding

Monopteros Therapeutics Inc.

Disclosure

P. Pearson: Financial Interests, Personal, Research Funding: Monopteros Therapeutics. J. Lufkin: Financial Interests, Personal, Sponsor/Funding: Monopteros Therapeutics. P. Keller: Financial Interests, Personal, Member of Board of Directors: Monopteros Therapeutics. H. Youssoufian: Financial Interests, Research Funding: Monopteros. A. DeCillis: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. I. Mazo: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. All other authors have declared no conflicts of interest.