Abstract CT011: First-in-human Phase I study of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase-1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid malignancies
Authors: Papadopoulos Kyriakos , Eder Paul , Piha-Paul Sarina A. , Gimmi Claude , Hussey Elizabeth , Zhang Sen , Li Lu , Habermehl Christina , Naing Aung 
Published: August 2019

Abstract
BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) and the related enzyme tryptophan 2,3-dioxygenase 2 (TDO2) are enzymes that mediate the rate limiting step in the metabolism of tryptophan (Trp) into the immunosuppressive metabolite kynurenine (Kyn). The accumulation of Kyn suppresses effector T and activates suppressor T regs generating an immune suppressive environment and escape mechanism for anti-PD-L1/anti-PD-1 agents. While both enzymes are upregulated in various tumors, the expression of IDO1 and TDO2 in human cancers is distinct and not overlapping, suggesting that the use of dual inhibitor should provide an enhanced anti-tumor effect. This is a first in human Phase I study investigating the safety, PK, pharmacodynamic effect and preliminary clinical activity of M4112, a highly selective dual IDO1/TDO2 inhibitor.
PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with M4112 (100, 200, 400, 600, or 800mg twice daily [BID] oral). The dose-escalation evaluated patients in 28-day cycles. Treatment was continued until disease progression, or unacceptable toxicity.
RESULTS: 15 patients were enrolled. One dose-limiting toxicity (DLT) occurred at 800 mg BID (grade 3, rash, with fever and hypotension). The adverse events regardless of causality in &gt;20% of patients were fatigue, nausea, rash, cough, CK increase, vomiting, diarrhea and decreased appetite. Exposure for 100mg and 200mg doses were proportional, with greater than proportional increase in exposure observed at 400mg and 600mg but less than proportional increase at 800mg. The observed Cmin (C1D15) at doses ≥ 400mg BID was above the IC50 based on animal studies. M4112 treatment resulted in dose-dependent IDO1 inhibition in ex vivo stimulated blood with approximately &gt;90% IDO1 activity inhibited throughout the dosing period at 800mg BID. In contrast, M4112 did not show sustained reduction of plasma Kyn levels up to 800mg BID: 12-35% decrease in plasma Kyn levels were observed on C1D1 up to 6h post dosing, that returned to or exceeded baseline values on C1D15. Consistent with preclinical findings, the plasma Trp increased during C1D1 at dose levels ≥200mg, suggesting liver TDO2 inhibition responsible for this increase. There were no objective responses, however in 7 of 15 cancer patients time until documented progressive disease was ≥16 weeks. These are preliminary data.
CONCLUSIONS: M4112 was generally well tolerated, with stable disease as best response. M4112 achieved &gt;90% IDO1 inhibition in ex vivo stimulated blood assay. Unlike IDO1 specific inhibitors, ex vivo IDO1 inhibition did not translate into plasma Kyn reduction following M4112 treatment. This is the first report of a dual inhibition of IDO1 and TDO2 showing acceptable safety profile and prolonged time to progression in cancer patients. Further investigation is warranted.
Citation Format: Kyriakos Papadopoulos, Paul Eder, Sarina A. Piha-Paul, Claude Gimmi, Elizabeth Hussey, Sen Zhang, Lu Li, Christina Habermehl, Aung Naing. First-in-human Phase I study of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase-1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT011.