Abstract 2549
Background
The androgen receptor (AR) is expressed in ∼ 90% of ER+ BC. Androgen-based therapies have had response rates up to 20-25%, but are not in common use due to poor tissue selectivity, potential aromatization to estrogen, and emergence of ER-targeted agents. RAD140 is an oral nonsteroidal selective AR modulator (SARM) with tissue-selective AR agonist activity in BC cells but attenuated activity in other androgen-responsive tissues. RAD140 inhibited the growth of multiple in vitro and in vivo AR+/ER+ BC models.
Methods
This is a phase 1 study of RAD140 with a 3 + 3 design. The primary objective is safety and to determine the maximum tolerated dose (MTD); secondary objectives are pharmacokinetics and antitumor activity. Key eligibility criteria are: ER+/HER2- and inoperable/metastatic BC (mBC), post-menopausal, and ineligible for standard therapy. AR status is by immunohistochemistry (IHC). Sex hormone-binding globulin (SHBG) and serum prostate specific antigen (PSA) are used to assess AR-engagement.
Results
Dose escalation (n = 16 patients, pts) has been completed. Median age = 58 years, 88% visceral disease, and 94% AR+ by IHC. Median number of prior lines of therapy for mBC = 5; prior fulvestrant 88%, aromatase inhibitor (i) 100%, CDK4/6i 94%, mTORi/PI3Ki 50%, chemotherapy 94%. Dose levels were 50 mg (n = 6), 100 mg (n = 7), and 150 mg (n = 3) QD. Median time on treatment = 8 (range <1-25) wk. The most frequent (>30%) adverse events were elevated ALT/AST, decreased weight/appetite, and constipation. Dose-limiting toxicities (all grade 3 and reversible) were hypophosphatemia (n = 2; 150 mg) and elevated ALT/AST (n = 2; 50 and 100 mg). No drug-related deaths occurred. There was 1 partial response (PR, 100 mg) and 2 pts with stable disease ≥12 wk. The time to PR was 15.9 wk and the duration was 8.6+ wk. SHBG decreased in 12/12 pts and PSA increased in 10/14 pts, most notably in the pt with PR who remains on treatment at 7 mo.
Conclusions
The provisional MTD for RAD140 is 100 mg QD. RAD140 is a novel oral AR-targeted agent for treatment of ER+ mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity. NCT03088527.
Clinical trial identification
NCT03088527.
Editorial acknowledgement
Legal entity responsible for the study
Radius Health, Inc.
Funding
Radius Health, Inc.
Disclosure
E. Hamilton: Advisory / Consultancy: Flatiron Health; Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Clovis Oncology; Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech/Roche; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Helsinn Therapeutics; Travel / Accommodation / Expenses: HERON; Travel / Accommodation / Expenses: Lexicon; Research grant / Funding (institution), Travel / Accommodation / Expenses: Medivation; Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Sysmex; Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro. N. Vidula: Research grant / Funding (institution): Radius Health; Research grant / Funding (institution): Daewha; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Pfizer. C. Ma: Research grant / Funding (self): Eisai; Research grant / Funding (self): Puma; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy: Syndex; Advisory / Consultancy: Seattle Genetics. R.G. Bagley: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. Z. Yu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. M. Annett: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. A. Weitzman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. M.G. Conlan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Radius Health. A. Weise: Speaker Bureau / Expert testimony: Array BioPharma. All other authors have declared no conflicts of interest.
Resources from the same session
4413 - Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF trial
Presenter: Ghassan Abou-Alfa
Session: Poster Display session 2
Resources:
Abstract
4710 - Phase 3 (COSMIC-312) study of cabozantinib (C) in combination with atezolizumab (A) vs sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy
Presenter: Lorenza Rimassa
Session: Poster Display session 2
Resources:
Abstract
5509 - A Randomized Controlled, Open label, Adaptive Phase-3 Trial to Evaluate Safety and Efficacy of EndoTAG-1 Plus Gemcitabine versus Gemcitabine alone in Patients with Measurable Locally Advanced and/or Metastatic Adenocarcinoma of the Pancreas Failed on FOLFIRINOX Treatment (NCT03126435)
Presenter: Li-Tzong Chen
Session: Poster Display session 2
Resources:
Abstract
1463 - Modified FOLFOX versus modified FOLFOX plus nivolumab and ipilimumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction – Moonlight, a randomized phase 2 trial of the German Gastric Group of the AIO.
Presenter: Sylvie Lorenzen
Session: Poster Display session 2
Resources:
Abstract
2392 - GLOW: Randomized Phase 3 Study of Zolbetuximab + CAPOX Compared With Placebo + CAPOX as First-line Treatment of Patients With CLD18.2⁺/HER2⁻ Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
Presenter: Manish Shah
Session: Poster Display session 2
Resources:
Abstract
5217 - PRODIGE67_UCGI33 ARION: Association of Radiochemotherapy and Immunotherapy for the treatment of unresectable Oesophageal caNcer: a comparative randomized phase II trial
Presenter: Rosine Guimbaud
Session: Poster Display session 2
Resources:
Abstract
1726 - Randomized phase II trial of weekly paclitaxel + ramucirumab versus weekly nab-paclitaxel + ramucirumab for unresectable advanced or recurrent gastric cancer with peritoneal dissemination refractory to first-line therapy: WJOG10617G/P-SELECT
Presenter: Kenro Hirata
Session: Poster Display session 2
Resources:
Abstract
2279 - FRONTiER: A Feasibility Trial of Nivolumab With Neoadjuvant CF or DCF Therapy for Locally Advanced Esophageal Carcinoma
Presenter: Shun Yamamoto
Session: Poster Display session 2
Resources:
Abstract
4912 - A phase Ib/II study of AK104, a PD-1/CTLA-4 Bispecific Antibody, Combined With mXELOX as First-line Therapy for Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
Presenter: Jiafu Ji
Session: Poster Display session 2
Resources:
Abstract
3780 - Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK.
Presenter: Salah-Eddin Al-Batran
Session: Poster Display session 2
Resources:
Abstract