Abstract P5-11-06: Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine therapy
Authors: O'Regan Ruth , Hurley Randolph , Sachdev Jasgit , Bleeker Jonathan , Tonetti Debra , Thatcher Gregory , Venuti Robert , Dudek Arkadiusz 
Published: March 2020

Abstract
Background: TTC-352 is a selective human ER partial agonist (ShERPA) developed for treatment of ER+ breast cancer (BC). ShERPAs mimic the effects of estradiol (E2) in hormone-independent, endocrine-resistant BC cells, but since it has only partial agonist activity in ER+ cells, it could have an improved side effect profile. Thus, TTC-352 could be a promising option for endocrine-resistant BC.
Methods: This is an open-label, accelerated dose escalation study with primary endpoint of maximum tolerated dose (MTD) that is evaluating up to five dose levels of TTC-352 in patients with ER+ endocrine-resistant metastatic BC (NCT03201913). The MTD of TTC-352 is determined using initial single-patient cohort escalations until grade 2 toxicity, then expansion to a modified-Fibonacci dose-escalation 3+3 design. The secondary objectives are: best response (BR), progression-free survival, overall survival, treatment tolerability, and pharmacokinetics (PK) of TTC-352. Patient population: patients with metastatic ER+ BC who received and progressed on at least two lines of endocrine therapy, with one that included a CDK4/CDK6 inhibitor, and with adequate hepatic, renal, and bone marrow function at screening.
Results: This study completed enrollment of a total of 15 patients on June 5, 2019.
Dose LevelTTC-352 Dose Level (mg)Number of SubjectsTwice-Daily (BID) DoseTotal Daily Dose115302230601360120141202401518036010
No dose limiting toxicity has been seen to date with any of the tested dose levels.
There was one treatment-related grade 3 event of asymptomatic pulmonary embolism (30mg BID). The number and percentage (n, %) of patients with treatment-related grade 1 and grade 2 adverse events reported in two or more patients across all dose levels were diarrhea (9, 60), hot flush (4, 26), headache (3, 20), nausea (3, 20), abdominal pain (3, 20), rash (3, 20), blurred vision (2, 13) vomiting (2, 13), dizziness (2, 13), peripheral neuropathy (2, 13), breast pain (2, 13), uterine/vaginal hemorrhage (2, 13) and vaginal discharge (2, 13).
BR in the 7 evaluable patients (patients with at least two 28-day cycles of treatment) showed that 3 patients had stable disease (SD) for 4, and 10 months, respectively; 1 patient continues study treatment with SD after 9 months; and 4 patients had progressive disease (PD) after completing two cycles of treatment. All 5 non-evaluable patients had PD prior to completing two cycles of treatment. PK: The intra- and inter-individual variability for AUC0-∞ hampered assessment of the relationship between dose and AUC0-∞., Half-life was 7.6-14.3 hrs. Trough TTC-352 plasma concentrations at steady-state (SS) remained well above the plasma concentrations associated with efficacy in animal models. PKC alpha expression in tumor tissue did not correlate with length of disease control with TTC-352 therapy, though the numbers are small and not all of the available specimens were metastatic.
Conclusions: TTC 352 demonstrates manageable safety and early clinical evidence of antitumor activity in patients with BC progressing on endocrine therapy. Based upon SS TTC-352 plasma concentrations and tolerability, the 180mg BID dose is recommended for further testing.
Citation Format: Ruth O'Regan, Randolph Hurley, Jasgit Sachdev, Jonathan Bleeker, Debra Tonetti, Gregory Thatcher, Robert Venuti, Arkadiusz Dudek. Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-06.