PT  - JOURNAL ARTICLE
AU  - Aung Naing
AU  - Joseph P Eder
AU  - Sarina A Piha-Paul
AU  - Claude Gimmi
AU  - Elizabeth Hussey
AU  - Sen Zhang
AU  - Vera Hildebrand
AU  - Vinayak Hosagrahara
AU  - Christina Habermehl
AU  - Jacques Moisan
AU  - Kyriakos P Papadopoulos
TI  - Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors
AID  - 10.1136/jitc-2020-000870
DP  - 2020 Aug 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e000870
VI  - 8
IP  - 2
4099  - http://jitc.bmj.com/content/8/2/e000870.short
4100  - http://jitc.bmj.com/content/8/2/e000870.full
SO  - J Immunother Cancer2020 Aug 01; 8
AB  - Background M4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors.Methods In preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects.Results In mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%).Conclusions There were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure. Trial registration number NCT03306420.