Efficacy, maximal tolerated dose, and toxicokinetics of TTC-352 in rats and dogs, a partial ER agonist for metastatic ER+ breast cancer.

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e14090 Background: The high prevalence of treatment resistance for estrogen receptor positive (ER+) breast cancer cause more deaths than all other breast cancers, despite the availability of endocrine therapeutics including selective ER downregulators (SERDs). Before tamoxifen, high dose estradiol (E2) delivered clinical efficacy slightly superior to tamoxifen. While recent clinical trials have shown efficacy of low dose E2, unacceptable side effects including vaginal bleeding, endometrial hypertrophy, and the negative perceptions of both patients and physicians limit acceptance. In preclinical models, tamoxifen resistant (TR) breast cancer is sensitive to treatment by E2. TTC-352 is an orally bioavailable selective human ERα partial agonist (ShERPA) designed to mimic E2 in causing tumor regression of TR breast cancer xenografts without uterine proliferation caused by E2 and tamoxifen. Methods: The published preclinical efficacy studies were extended to multiple TR ER+ cell lines in 3D spheroid cell cultures comparing to E2 and the SERD GDC0810. The maximum tolerated dose (MTD) was determined in Sprague-Dawley rats at: 200, 300, 600, 1000 and 2000 mg/kg by oral gavage (N = 3). Animals were observed for 7 days prior to necropsy. A single MTD range finding study was performed in dogs at: 50, 100, and 200 mg/kg TTC-352, administered orally in gelatin capsules. Based on these results, a 7-day repeated dose studies were completed at 30, 100, 300 and 1000 mg/kg/day in rats (3/sex/dose) and 15, 75, and 150 mg/kg (2/sex/dose) in dogs. Results: Growth of three TR ER+ breast cancer cell cultures in 3D was inhibited by TTC-352, which mimicked E2 and was equivalent to GDC0810. In female rats MTD was 1000 mg/kg and TTC-352 was well tolerated following a single oral dose of 200, 300, 600 mg/kg. The oral administration of TTC-352 at doses of 30, 100, and 300 mg/kg/day in rats (both sexes) and 15, 75 or 150 mg/kg/day in dogs (both sexes) for seven days was generally well tolerated. Conclusions: TTC-352 has demonstrated efficacy in preclinical models of TR breast cancer. Completed rat and dog studies indicated favorable tolerability and rapid absorption up to 300 mg/kg/day in rats and 150 mg/kg/day in dogs.