AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

• DOI: 10.1007/s10637-015-0235-5
• Publication Date: 2015-04-28T23:45:32Z
• Authors: A. Omlin; R. J. Jones; R. van der Noll; T. Satoh; M. Niwakawa; S. A. Smith; J. Graham; M. Ong; R. D. Finkelman; J. H. M. Schellens; A. Zivi; M. Crespo; R. Riisnaes; D. Nava-Rodrigues; M. D. Malone; C. Dive; R. Sloane; D. Moore; J. J. Alumkal; A. Dymond; P. A. Dickinson; M. Ranson; G. Clack; J. de Bono; T. Elliott
• Keywords: Male; Selective androgen receptor down-regulator; Administration, Oral; Down-Regulation; Antineoplastic Agents; 03 medical and health sciences; Phase I; 0302 clinical medicine; SDG 3 - Good Health and Well-being; Taverne; Humans; Pharmacology (medical); Aged; Pharmacology; Aged, 80 and over; Dose-Response Relationship, Drug; Middle Aged; Prostate-Specific Antigen; Neoplastic Cells, Circulating; ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre; 3. Good health; Pyridazines; Radiography; Prostatic Neoplasms, Castration-Resistant; Oncology; (5) Castration-resistant prostate cancer; Receptors, Androgen; First-in-human; AZD3514

AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD).In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule.In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1.AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.