Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy

• Published in: Breast cancer research and treatment Vol. 183; no. 3; pp. 617 - 627
• Main Authors: Dudek, Arkadiusz Z., Liu, Li C., Fischer, James H., Wiley, Elizabeth L., Sachdev, Jasgit C., Bleeker, Jonathan, Hurley, Randolph W., Tonetti, Debra A., Thatcher, Gregory R. J., Venuti, Robert P., O’Regan, Ruth M.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.10.2020; Springer; Springer Nature B.V
• Subjects: Antitumor activity; Aspartate; Aspartate transaminase; Breast cancer; Cancer; Cancer patients; Cancer research; Clinical Trial; Cyclin-dependent kinase 4; Diarrhea; Drug therapy; Embolism; Estrogen; Estrogen receptors; Medicine; Medicine & Public Health; Metastases; Metastasis; Myalgia; NCT; NCT03201913; Oncology; Oncology, Experimental; Patients; Pharmacokinetics; Protein kinase C; Pulmonary embolism; Stroma; Toxicity; Transaminase; Tumors; Estrogen receptor; TTC-352; Phase 1 study; Refractory breast cancer
• ISSN: 0167-6806; 1573-7217; 1573-7217
• DOI: 10.1007/s10549-020-05787-z

Purpose TTC-352 is a selective human estrogen receptor (ER) partial agonist developed for treatment of hormone-refractory ER + breast cancer. Methods This was an accelerated dose escalation study with the primary endpoint of maximum tolerated dose that evaluated five dose levels of TTC-352 in breast cancer progressing after at least two lines of hormonal therapy including one in combination with a CDK4/6 inhibitor. The secondary objectives were to determine treatment tolerability, pharmacokinetics of TTC-352, best response, progression-free survival (PFS), and PKCα expression in tumors. Results The study enrolled 15 patients. No dose-limiting toxicity was observed. Patients experienced the following grade 3 toxicities: asymptomatic pulmonary embolism, diarrhea, aspartate transaminase elevation, and myalgia, and one grade 4 toxicity of gamma glutamyltransferase elevation. Pharmacokinetic half-life was 7.6–14.3 h. The intra- and inter-individual variability for AUC 0 -∞ hampered assessment of the relationship between dose and AUC 0 -∞. Median PFS was 58 days (95% CI = 28,112). Higher PKCα expression in tumor stroma was associated with a trend toward longer PFS. Conclusions TTC-352 demonstrates safety and early clinical evidence of antitumor activity against heavily pretreated hormone-refractory breast cancer. Based upon TTC-352 plasma concentrations and tolerability, the 180 mg twice a day is recommended for further testing. (ClinicalTrials.gov Identifier: NCT03201913)