Abstract CT051: Phase I study of TTC-352 in patients with estrogen receptor-positive metastatic breast cancer

Background: TTC-352 is a selective human estrogen receptor (ER) partial agonist (ShERPA). ShERPAs mimic the effects of estradiol in endocrine-resistant breast cancer (ERBC) cells, but has only partial agonist activity, and as such should have an improved side effect profile and be a promising option for ERBC. Methods: This is an open-label, accelerated dose escalation study with primary endpoint of maximum tolerated dose (MTD) that is evaluating up to 5 dose levels of TTC-352 in patients with ER+ metastatic ERBC (ERMBC). The MTD 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 of TTC-352. Patients with ER+ MBC who have experienced disease progression on at least 2 lines of endocrine therapy (ET), with one that included a CDK4/CDK6 inhibitor, and with adequate organ function are eligible. This study is currently enrolling patients (NCT03201913). Results: A total of 9 patients have been enrolled to date. Dose LevelTTC-352 Dose Level (mg)Number of SubjectsTwice-Daily (BID) DoseTotal Daily Dose11530223060136012014120240151803604 No dose limiting toxicity has been seen to date. There was 1 treatment-related grade 3 adverse event (AE) of asymptomatic pulmonary embolism (30mg BID), and single patient grade 2 AEs of anemia (180mg BID), diarrhea (180mg BID), fatigue (180mg BID), hypophosphatemia (180mg BID), peripheral neuropathy (15mg BID), rash (180mg BID), somnolence (60mg BID), and uterine bleeding (60mg BID). Grade 1 AEs included (n, %) diarrhea (6, 67), hot flashes (3, 33), abdominal pain (3, 33), nausea (2, 22), vomiting (2, 22), headache (2, 22) and myalgia/muscle spasms (2, 22%). BR in the 5 evaluable patients (at least 2 cycles of treatment) showed that 3 patients had stable disease (SD) and 2 patients had progressive disease (PD). The large 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 plasma concentrations at steady-state (SS) remained well above the plasma concentrations associated with efficacy in animal models. Conclusions: TTC 352 has manageable safety and early clinical evidence of activity in patients with MBC progressing on ET. Its PK is characterized by high intra- and inter-individual variability. Based up