Phase I Open-Label, Dose-Escalation Study Of Ana773 Tosylate, An Oral Prodrug Of A Toll-Like Receptor-7 Agonist, In Patients With Advanced Solid Tumors.

2524 Background: ANA773 is an oral prodrug of a small molecule, TLR7-selective agonist which has demonstrated pharmacological activity in preclinical studies. In a study in healthy volunteers, dose-related increases in markers of interferon-alpha dependent responses (e.g. oligoadenylate synthetase (OAS), neopterin, and OAS1 and other Interferon Stimulated Gene mRNAs) were observed after administration of ANA773 with little or no increase in circulating IFN-alpha. This study aimed to determine the MTD, pharmacodynamics (PD), pharmacokinetics (PK), and anti-tumor activity in pts with advanced cancer. Methods: Phase I dose escalation in pts with advanced solid tumors. Pts were treated with ANA773 dosed orally every other day for 14 days followed by a 14 day rest period, on continuous 28-day cycles. A minimum of 3 pts were enrolled at each dose level. Endpoints included safety, PK, biomarkers of immune activation and tumor response by RECIST. Results: 20 pts have been treated at 5 dose levels (50, 100, 200, 400, and 800mg QOD). ANA773 was well tolerated; the MTD was not reached in this trial. CTC grade 1-2 AEs considered possibly treatment related included fatigue, nausea, diarrhea, headaches, vomiting and weight loss. One pt had gr 3 fatigue. One pt had DLT; a pt with malignant melanoma experienced grade 3 neutropenia at 800mg QOD and was dose reduced to 600mg QOD starting in cycle 2. This pt achieved a PR and continued treatment for 19 cycles. 4 pts had stable disease (SD): adenocystic carcinoma (13 cycles), prostatic carcinoma (6 cycles), uveal melanoma (7 cycles) and uveal melanoma (11 cycles). PK analysis indicates that exposure to the active TLR7 agonist is dose proportional. At 400 and 800 mg QOD an increased expression for interferon-responsive genes (OAS1, ISG15, IFIT1 and IFI27) was demonstrated in PBMCs. Consistent with ongoing TLR7 activation, substantial induction of all four genes occurred on D13. Conclusions: ANA773 was well tolerated in pts with advanced solid tumors. Continued clinical development is supported by the early evidence for its activity, including evidence of TLR7 agonist-mediated pharmacology and responses observed in pts with melanoma.