Abstract PR03: A phase 1 trial of AG-270 in patients with advanced solid tumors or lymphoma with homozygous MTAP deletion
Authors: Heist Rebecca S , Gounder Mrinal M , Postel-Vinay Sophie , Wilson Frederick , Garralda Elena , Do Khanh , Shapiro Geoffrey I , Martin-Romano Patricia , Wulf Gerburg , Cooper Michael , Almon Caroline , Nabhan Salah , Iyer Varsha , Zhang Yanwei , Marks Kevin , Aguado-Fraile Elia , Basile Frank , Flaherty Keith , Burris Howard A 
Published: March 2020

Abstract
Background: Homozygous deletion of MTAP, the gene encoding the metabolic enzyme methylthioadenosine phosphorylase, occurs in ~15% of human malignancies. Tumor cells with this deletion are selectively vulnerable to decreases in the methyl donor S-adenosylmethionine (SAM). AG-270 is a first-in-class, oral, potent, reversible inhibitor of methionine adenosyltransferase 2A (MAT2A), the key enzyme responsible for SAM synthesis. We report preliminary results from an ongoing, first-in-human, phase 1 trial of AG-270 (ClinicalTrials.gov Identifier: NCT03435250). Aims: The primary objective of this study is to determine the maximum tolerated dose (MTD) of AG-270. Secondary objectives include safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Methods: Eligibility requires homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) in the patient’s tumor (as MTAP is usually co-deleted with CDKN2A), or loss of MTAP by IHC. Patients receive AG-270 daily in 28-day cycles, with intensive PK/PD sampling after the first dose and after 2 weeks of treatment. Paired tumor biopsies are collected at baseline and at the end of cycle 1. Disease evaluation is performed every 2 cycles. Results: As of 20 May 2019, 39 patients had been treated with AG-270: 50 mg once daily (QD; n=3), 100 mg QD (n=7), 150 mg QD (n=6), 200 mg QD (n=11), 400 mg QD (n=6), or 200 mg twice daily (BID; n=6). AG-270 was well absorbed. Plasma concentrations increased in a dose-proportional manner except at 400 mg QD, where exposure was lower than anticipated. The geometric mean area under the curve from 0-24 h at steady state (AUC0-24,ss) in the QD cohorts ranged from 33200 to 199085 ng*h/mL, and the geometric mean AUC0-24,ss in the 200 mg BID cohort was 254616 ng*h/mL. The median half-life of AG-270 ranged from 16.1 to 38.4 h. Decreases in plasma [SAM] were exposure-dependent. After 2 weeks of dosing, maximal reductions in plasma [SAM] ranged from 51% to 71% across the tested cohorts. Analysis of 9 paired tumor biopsies by IHC showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues, consistent with MAT2A inhibition; the average H-score reduction compared to baseline was 36.4% [-98.8%, +21.4%]. Asymptomatic, exposure-dependent increases in unconjugated bilirubin were observed starting at 100 mg QD, consistent with the known potential of AG-270 to inhibit UGT1A1. Three patients (at 100 mg QD, 150 mg QD, and 200 mg BID) developed grade 2 and 3 diffuse erythematous rashes during the second week of dosing that resolved within 1 week of stopping treatment. Exposure-dependent, reversible decreases in platelet counts were first observed at 200 mg QD and were grade 3 and 4 in severity at 200 mg BID. Two patients treated at 200 mg BID developed reversible but dose-limiting grade 3 and 4 increases in liver enzymes. The MTD of AG-270 is 200 mg QD. An unconfirmed partial response has been observed in a patient with a high-grade neuroendocrine carcinoma of the lung. Seven patients have achieved radiographically confirmed stable disease of 2.0 to 9.9 months’ duration. Conclusions: AG-270 causes reductions in plasma [SAM] and in tumor SDMA levels at well-tolerated doses. This trial will next evaluate the combination of AG-270 with taxane-based chemotherapy, given preclinical data demonstrating enhanced antitumor activity with AG-270 and taxanes in MTAP-deleted cancer models.
Citation Format: Rebecca S Heist, Mrinal M Gounder, Sophie Postel-Vinay, Frederick Wilson, Elena Garralda, Khanh Do, Geoffrey I Shapiro, Patricia Martin-Romano, Gerburg Wulf, Michael Cooper, Caroline Almon, Salah Nabhan, Varsha Iyer, Yanwei Zhang, Kevin Marks, Elia Aguado-Fraile, Frank Basile, Keith Flaherty, Howard A Burris. A phase 1 trial of AG-270 in patients with advanced solid tumors or lymphoma with homozygous MTAP deletion [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR03. doi:10.1158/1535-7163.TARG-19-PR03