TTC-352 is a selective human estrogen receptor (ER) partial agonist developed for treatment of hormone-refractory ER + breast cancer.
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.
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 AUC0-∞ hampered assessment of the relationship between dose and AUC0-∞. Median PFS was 58 days (95% CI = 28,112). Higher PKCα expression in tumor stroma was associated with a trend toward longer PFS.
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)
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For the data supporting the presented results please contact the corresponding author. Supplementary information is available at the British Journal of Cancer’s website.
Conjugated equine estrogens
- Cmax :
Maximum plasma concentration
Cancer Institute Common Terminology Criteria for Adverse Events
Eastern Cooperative Oncology Group
- ER + :
Estrogen receptor positive
Human epidermal growth factor receptor 2 negative
Maximum tolerated dose
Protein kinase C alpha SEMs
Selective estrogen mimics
Selective human ER partial agonist
Selective estrogen receptor downregulator
- t1/2-λz :
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We are thankful to James P. Zacny, PhD for his editorial support with the clinical protocol and manuscript.
We acknowledge funding from TTC Oncology, LLC, and the Engdahl Family Foundation.
Conflicts of interest
AZD serves as Chief Medical Officer and obtained honoraria from TTC Oncology and Vanquish Oncology. AZD has received honoraria for consulting work from EMD Serono. AZD has equity in TTC Oncology, IGF Oncology, Squarex, and Martell Diagnostic Laboratories. AZD reports research funding to institutions from Merck, and Eli Lilly. DAT and GRJT have equity in TTC Oncology. RPV has received honoraria from TTC Oncology. RMO serves as an advisor for Lilly, PUMA, Novartis, Genomic Health and Biotheranostics and receives grant support from PUMA, Novartis, Seattle Genetics, and Eisai. All other authors declare no competing interests.
This clinical trial was approved by the Institutional Review Board at the participating institutions. It was conducted in accordance with the Declaration of Helsinki.
All participants provided written informed consent.
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Dudek, A.Z., Liu, L.C., Fischer, J.H. et al. Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy. Breast Cancer Res Treat 183, 617–627 (2020). https://doi.org/10.1007/s10549-020-05787-z
- Estrogen receptor
- Phase 1 study
- Refractory breast cancer