AG-636 for the Treatment of Adults with Advanced Lymphoma: Initiation of a Phase 1 Clinical Study

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.1286-1286
• Main Authors: Huntington, Scott F., Kallam, Avyakta, Basile, Frank G., Ulanet, Danielle, Xu, Huansheng, Yin, Feng, Mobilia, Michelle, Cooper, Michael, Shah, Bijal, Leonard, John P., von Keudell, Gottfried R., Gopal, Ajay K.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-123420

Background: Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme involved in the de novo synthesis of pyrimidines, key building blocks for RNA and DNA biosynthesis. Inhibitors of DHODH are currently in clinical use for the treatment of rheumatoid arthritis (leflunomide) and multiple sclerosis (teriflunomide). Brequinar, a more specific and potent DHODH inhibitor, was evaluated in several phase 1 trials in patients with advanced solid tumors in the 1990s and demonstrated little evidence of antitumor activity; however, patients with hematologic malignancies were not evaluated in those studies. More recent preclinical studies show that cell lines and in vivo models derived from hematologic malignancies are highly sensitive to inhibition of DHODH. AG-636, a novel small molecule DHODH inhibitor, demonstrated strong in vitro and in vivo anti-tumor activity across diverse models of lymphoma and acute leukemia, supporting the evaluation of AG-636 as a treatment for patients with lymphoma and other hematologic malignancies. A phase 1, multicenter, open-label study investigating AG-636 for the treatment of patients with advanced lymphoma began enrollment on May 24, 2019 (NCT03834584). Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of AG-636 and to characterize its dose-limiting toxicities (DLTs) when given to patients with advanced lymphoma. The study includes a dose escalation phase followed by an expansion phase. Approximately 54 adults (42 in the dose escalation phase and 12 in the expansion phase) with advanced lymphoma refractory to standard treatment, will be enrolled at up to 6 centers in the United States. Broad inclusion criteria enable patients with Hodgkin, Diffuse Large B-Cell (DLBCL), Follicular, Peripheral T-Cell, Cutaneous T-Cell, Mantle Cell, and less common subtypes of lymphoma as defined in 2017 by the World Health Organization to enroll. There are no limits on the number of prior lines of therapy and patients may have received prior stem cell transplant or chimeric antigen receptor T-cell therapy. Patients with active central nervous system disease are excluded. Patients must have an Eastern Cooperative Oncology Group performance status ≤2, an absolute neutrophil count ≥1.0×109/L, a platelet count ≥75×109/L, a serum total bilirubin level ≤1.5×upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase levels ≤3.0×ULN, and a creatinine clearance ≥30 mL/min (Cockcroft-