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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.

Journal Article


Abstract


  • Background

    AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD).

    Methods

    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.

    Results

    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.

    Conclusion

    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.

Publication Date


  • 2015

Citation


  • Omlin, A., Jones, R. J., van der Noll, R., Satoh, T., Niwakawa, M., Smith, S. A., . . . Elliott, T. (2015). 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.. Investigational new drugs, 33(3), 679-690. doi:10.1007/s10637-015-0235-5

Web Of Science Accession Number


Start Page


  • 679

End Page


  • 690

Volume


  • 33

Issue


  • 3

Abstract


  • Background

    AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD).

    Methods

    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.

    Results

    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.

    Conclusion

    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.

Publication Date


  • 2015

Citation


  • Omlin, A., Jones, R. J., van der Noll, R., Satoh, T., Niwakawa, M., Smith, S. A., . . . Elliott, T. (2015). 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.. Investigational new drugs, 33(3), 679-690. doi:10.1007/s10637-015-0235-5

Web Of Science Accession Number


Start Page


  • 679

End Page


  • 690

Volume


  • 33

Issue


  • 3