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

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, Joshi Alumkal, A. DymondP. A. Dickinson, M. Ranson, G. Clack, J. De Bono, T. Elliott

    Research output: Contribution to journalArticle

    25 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)679-690
    Number of pages12
    JournalInvestigational New Drugs
    Volume33
    Issue number3
    DOIs
    StatePublished - Apr 30 2015

    Fingerprint

    Castration
    Androgen Receptors
    Prostatic Neoplasms
    Appointments and Schedules
    Nausea
    Vomiting
    AZD3514
    Drug-Related Side Effects and Adverse Reactions
    Androgens
    Tablets
    Capsules
    Neoplasms
    Pharmacokinetics

    Keywords

    • (5) Castration-resistant prostate cancer
    • AZD3514
    • First-in-human
    • Phase I
    • Selective androgen receptor down-regulator

    ASJC Scopus subject areas

    • Pharmacology
    • Pharmacology (medical)
    • Oncology

    Cite this

    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. / Omlin, A.; Jones, R. J.; Van Der Noll, R.; Satoh, T.; Niwakawa, M.; Smith, S. A.; Graham, J.; Ong, M.; Finkelman, R. D.; Schellens, J. H M; Zivi, A.; Crespo, M.; Riisnaes, R.; Nava-Rodrigues, D.; Malone, M. D.; Dive, C.; Sloane, R.; Moore, D.; Alumkal, Joshi; Dymond, A.; Dickinson, P. A.; Ranson, M.; Clack, G.; De Bono, J.; Elliott, T.

    In: Investigational New Drugs, Vol. 33, No. 3, 30.04.2015, p. 679-690.

    Research output: Contribution to journalArticle

    Omlin, A, Jones, RJ, Van Der Noll, R, Satoh, T, Niwakawa, M, Smith, SA, Graham, J, Ong, M, Finkelman, RD, Schellens, JHM, Zivi, A, Crespo, M, Riisnaes, R, Nava-Rodrigues, D, Malone, MD, Dive, C, Sloane, R, Moore, D, Alumkal, J, Dymond, A, Dickinson, PA, Ranson, M, Clack, G, De Bono, J & 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, vol. 33, no. 3, pp. 679-690. https://doi.org/10.1007/s10637-015-0235-5
    Omlin, A. ; Jones, R. J. ; Van Der Noll, R. ; Satoh, T. ; Niwakawa, M. ; Smith, S. A. ; Graham, J. ; Ong, M. ; Finkelman, R. D. ; Schellens, J. H M ; Zivi, A. ; Crespo, M. ; Riisnaes, R. ; Nava-Rodrigues, D. ; Malone, M. D. ; Dive, C. ; Sloane, R. ; Moore, D. ; Alumkal, Joshi ; Dymond, A. ; Dickinson, P. A. ; Ranson, M. ; Clack, G. ; De Bono, J. ; Elliott, T. / 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. In: Investigational New Drugs. 2015 ; Vol. 33, No. 3. pp. 679-690.
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    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.",
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    T1 - 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

    AU - Omlin, A.

    AU - Jones, R. J.

    AU - Van Der Noll, R.

    AU - Satoh, T.

    AU - Niwakawa, M.

    AU - Smith, S. A.

    AU - Graham, J.

    AU - Ong, M.

    AU - Finkelman, R. D.

    AU - Schellens, J. H M

    AU - Zivi, A.

    AU - Crespo, M.

    AU - Riisnaes, R.

    AU - Nava-Rodrigues, D.

    AU - Malone, M. D.

    AU - Dive, C.

    AU - Sloane, R.

    AU - Moore, D.

    AU - Alumkal, Joshi

    AU - Dymond, A.

    AU - Dickinson, P. A.

    AU - Ranson, M.

    AU - Clack, G.

    AU - De Bono, J.

    AU - Elliott, T.

    PY - 2015/4/30

    Y1 - 2015/4/30

    N2 - 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.

    AB - 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.

    KW - (5) Castration-resistant prostate cancer

    KW - AZD3514

    KW - First-in-human

    KW - Phase I

    KW - Selective androgen receptor down-regulator

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