Study details:

Background:. Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancers and is defined by the absence of immunostaining for estrogen receptor (ER), progesterone receptor (PR), and non-amplified HER2 expression. Patients with metastatic TNBC exhibit a particularly poor clinical outcome, generally with rapid progression and a median overall survival (OS) rate of approximately 16 months.

The current standard of care in the treatment of TNBC is cytotoxic chemotherapy and immunotherapy and the development of well-tolerated, effective, and targeted regimens that delay the need for cytotoxic chemotherapy and its side effects is an unmet need. Understanding breast cancer heterogeneity has enabled investigators to identify novel targets for the development of new therapeutic interventions. The androgen receptor (AR) is one such target.

AR is expressed in 70-90% of all invasive breast cancers. Emerging data suggest that the AR-signalling pathway may play a critical role in breast cancer pathogenesis. Seviteronel is an orally bioavailable, selective cytochrome P450c17a (CYP17) lyase (lyase) and AR inhibitor.

It is approximately 10-fold more selective for CYP17 lyase versus CYP17 17-α hydroxylase (hydroxylase) inhibition. Seviteronel inhibits the AR through competitive antagonism of both wild-type and mutated forms of the receptor. Through this unique, dual mechanism of action, it inhibits androgen production, thus reducing downstream estrogen aromatization from androgens, while also inhibiting AR binding and activation.

In our own unpublished work, the investigators have shown that AR expression is often present in the cytoplasm of TNBC cells. When scoring patient samples for cytoplasmic AR, the investigators observed that \~cytoplasmic AR was present in 20% of TNBC patient tumours. This suggests that AR-targeted therapies may be beneficial for a far greater number of TNBC patients than is represented by the traditionally defined triple negative breast cancer AR subtype alone.

Seviteronel has been shown to inhibit the growth in multiple breast cancer models, both in vitro and in vivo. Three early-phase prospective clinical studies investigating anti-androgen therapy have demonstrated clinical benefit of single-agent AR-targeted agents in women with metastatic AR positive TNBC. In our preliminary laboratory data (unpublished) demonstrates an increase in survival and suppression of metastatic TNBC when seviteronel is used in combination with docetaxel.

Aim:. To determine the feasibility, safety and efficacy of seviteronel and dexamethasone (SEVI-D) in combination with chemotherapy for the treatment of metastatic breast cancer. This study is conducted in two parts: part 1: dose exploration, and part 2: dose expansion.

Objectives:. To evaluate the safety and tolerability of SEVI-D and chemotherapy (docetaxel) in patients with metastatic breast cancer and determine the recommended phase II dose (RP2D) for SEVI-D/docetaxel combination therapy. Part 1: Metastatic breast cancer.

• To assess the pharmacokinetic and pharmacodynamic profiles of SEVI-D and chemotherapy (docetaxel) in metastatic breast cancer. Part 2: Androgen receptor-positive metastatic triple-negative breast cancer. * To assess the pharmacokinetic and pharmacodynamic profiles of SEVI-D and chemotherapy (docetaxel).

* To evaluate the clinical activity SEVI-D and chemotherapy (docetaxel) in participants with cytoplasmic androgen receptor-positive metastatic triple negative breast cancer. Design and sample size:. Part 1: Dose exploration - 6- 18 patients based on a rolling 6 design Part 2: Dose expansion - 35-45 patients in a single arm two-stage investigation.

Study population:. Part 1: Patients with metastatic breast cancer. Part 2: Patients with cytoplasmic AR-positive metastatic triple-negative breast cancer confirmed by immunohistochemistry.

Study treatment:. Part 1: Seviteronel will be administered orally beginning with 450 mg (3 x 150 mg tablets) once daily along with 0. 5 mg dexamethasone, continuously in 28-day cycles with docetaxel 75mg/m2 administered intravenously 3 weekly.

Part 2: The recommended phase 2 dose for seviteronel (established in Part 1) once daily along with 0. 5 mg dexamethasone, continuously in 21-day cycles with docetaxel 75mg/m2 administered intravenously 3 weekly. Screening for participation includes review of patient history, current health status, availability of a biospecimen for AR screening and patient willingness to be in a trial if eligible.

Clinical and safety assessments are scheduled prior to registration and every 8 weeks until death. Imaging and other response assessments are required at baseline and every 2 cycles from cycle 1 day 1 until progression. Blood collection for translational studies will occur at: baseline (collected within 21 days prior to registration) or within 28 days of C1D1 treatment, every 2nd cycle and at the end of treatment.

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