Phase 1 Evaluation Of The Androgen Receptor Modulator Cr1447 In Patients With Advanced Breast Cancer (Sakk 21/12)

Background: CR1447 (4-OH-testosterone, 4-OHT), a steroidal small molecule, strongly binds to the androgen receptor (AR) and has aromatase inhibiting activity. Pre-clinical studies show that CR1447 given as an ointment is efficiently absorbed and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells. Methods: CR1447 was administered topically on a daily basis to patients with ER-positive/HER2-negative or ER-negative/PR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. One cycle was defined as 21 days of treatment. Disease evaluation was performed at 3 and 6 months in order to determine tumor response (i.e. complete/partial remission and stable disease) in 3 cohorts of 3 evaluable patients each plus 3 confirmatory patients (dose escalation 100, 200, 400 mg). Results: 14 patients have been treated for a total of 38 cycles. Two patients are still on treatment at the time of analysis. Two patients, one in cohort 1 and one in cohort 2, showed early tumor progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447, resulting in sufficient plasma concentrations of 4-OHT. 4-OH-androstenedione, a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Conclusions: CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative and ER-negative/PR-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day. Citation Format: Schoenfeld W, Zweifel M, Thuerlimann B, Riniker S, Weder P, von Moos R, Pagani O, Bigler M, Rothgiesser KM, Pilop C, Brauchli P, Tapia C, Sessa C. Phase 1 evaluation of the androgen receptor modulator CR1447 in patients with advanced breast cancer (SAKK 21/12). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-05.