Clinical Trial: Phase I Open Label Dose Escalation Study to Investigate the Safety & Pharmacokinetics of AZD5312 in Patients With Androgen Receptor Tumors

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase I, Open-Label, Multicentre Dose-Escalation Study to Investigate the Safety and Pharmacokinetics of AZD5312 in Patients With Advanced Solid Tumours Where the Androgen Rece

Brief Summary:

This is a first time in man (FTIM), Phase I study to determine the Maximum Tolerated Dose, Recommended Phase 2 Dose, safety, tolerability and Pharmacokinetics of AZD5312. This is a multicentre study with sites in the United States and United Kingdom. Approximately 90 patients are expected to be enrolled in this study.

The study involves two parts, Part A, Dose Escalation and Part B, Dose Expansion.


Detailed Summary:

This is a first time in man (FTIM), Phase I study to determine the Maxiimum Tolerated Dose, Recommended Phase 2 Dose, safety, tolerability and Pharmacokinetics of AZD5312. This is a multicentre study with sites in the United States and United Kingdom. Approximately 90 patients are expected to be enrolled in this study.The study involves two parts, Part A, Dose Escalation and Part B, Dose Expansion.

AZD5312 will be given intravenously (IV) as an infusion, over one hour. For the purpose of planning, each 4 week period (28 days) will be called a Cycle. AZD5312 will initially be administered 4 times within the first 11 days, (on Days [1, 4, 8 and 11]± 2), with no dosing on sequential days. Patients will receive weekly treatments on Days 15 and 22 to complete Cycle.

1. During the subsequent cycles, patients will receive weekly treatment on Days 1, 8, 15 and 22 (±2). The AZD5312 dose will not change unless dose reductions are required due to treatment-related toxicity. Patients will continue to receive AZD5312 until disease progression, intolerable toxicity, or discontinuation criteria have been met. Toxicity, Pharmacokinetics and biomarker data will be assessed throughout the study. Alternative infusion durations and/or treatment schedules may be explored if preliminary data suggest these would be more appropriate.


Sponsor: AstraZeneca

Current Primary Outcome:

  • Maximum Tolerated Dose of AZD5312 in pts with advanced solid tumours where androgen receptor pathway is a potential factor. [ Time Frame: 13 months ]
    The patient population used for determination of the MTD will consist of patients who have met the minimum safety evaluation requirements of the study, and/or who have experienced a DLT. Minimum safety requirements will be met if, during Cycle 1 of treatment, the patient receives all doses of AZD5312, completes all required safety evaluations, and is observed for at least 28 days following the first dose of AZD5312.
  • Safety and tolerability of AZD5312 in patients assessed in terms of AEs, labs, vitals, ECGs and conc. med use. [ Time Frame: 13 months ]
  • Recommended Phase 2 Dose of AZD5312 in patients with advanced solid tumours where androgen receptor pathway is a potential factor. [ Time Frame: 13 Months ]
    •3 evaluable patients (pts) will be enrolled at each dose level (3+3 design) •Evaluated for 28 days before escalation to next dose level. •If more than 1 experiences Dose Limiting Toxicity (DLT), additional 3 patients treated with the same dose. •Maximum of 6 pts enrolled per dose level. •100% increase in dosing until 2 pts (out of 3) at dose level experience toxicity of ≥ Grade 2, or 1 pt. experiences DLT. •Accelerated titration stopped, and subsequent dose escalation will be ≤ 50%. •Evaluation of a cohort of at least 3 patients completing 1 cycle of treatment (28 days) required prior to next dose level. •Dose escalation decisions take into account safety profile of prior dose groups, and available PK data. •Additional patients may be enrolled at lower doses for

    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • Preliminary anti-tumour activity of AZD5312 in patients with advanced solid tumours. [ Time Frame: 25 months ]
      •Proportion of mCRPC patients with a Prostate-specific antigen (PSA) response: Effect of AZD5312 on the PSA levels will be done by looking at PSA by waterfall plots according to the PCWG2 guidelines which measures (1) the percent difference from baseline at 12 weeks treatment points and (2) maximum decline in PSA at any point. •CTC conversions: For prostate cancer patients only, CTC conversions will be asessed which is defined as a significant change in CTC count from the baseline assessment. (Assess absolute reduction in CTC counts). •Metastatic bone disease status of mCRPC patients (PCWG2 criteria, (Scher et al, 2008). •Malignant soft tissue response rate will be assessed byResponse Evaluation Criteria in Solid Tumors (RECIST v1.1) (Eisenhauer et al. 2009) for all patients with measurable disease whenever possible.
    • Pharmacokinetics of AZD5312 determined by Cmax [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by tmax [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by λz [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by t½λz [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by (AUC(0-24) [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by AUC(0-t) [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by AUC [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by CL [ Time Frame: 25 months ]
    • PK of AZD5312 determined Vz [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by MRT [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by CLR [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by Ae;%dose [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by Css max [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by tss max [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by Css min [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined byAUCss [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by CLss [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by RAC [ Time Frame: 25 Months ]


    Original Secondary Outcome:

    • Prelimiinary anti-tumour activity of AZD5312 in patients with advanced solid tumours. [ Time Frame: 25 months ]
      •Proportion of mCRPC patients with a Prostate-specific antigen (PSA) response: Effect of AZD5312 on the PSA levels will be done by looking at PSA by waterfall plots according to the PCWG2 guidelines which measures (1) the percent difference from baseline at 12 weeks treatment points and (2) maximum decline in PSA at any point. •CTC conversions: For prostate cancer patients only, CTC conversions will be asessed which is defined as a significant change in CTC count from the baseline assessment. (Assess absolute reduction in CTC counts). •Metastatic bone disease status of mCRPC patients (PCWG2 criteria, (Scher et al, 2008). •Malignant soft tissue response rate will be assessed byResponse Evaluation Criteria in Solid Tumors (RECIST v1.1) (Eisenhauer et al. 2009) for all patients with measurable disease whenever possible.
    • Pharmacokinetics of AZD5312 determined by Cmax [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by tmax [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by λz [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by t½λz [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by (AUC(0-24) [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by AUC(0-t) [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by AUC [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by CL [ Time Frame: 25 months ]
    • PK of AZD5312 determined Vz [ Time Frame: 25 months ]
    • Pharmacokinetics of AZD5312 determined by MRT [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by CLR [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by Ae;%dose [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by Css max [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by tss max [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by Css min [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined byAUCss [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by CLss [ Time Frame: 25 Months ]
    • Pharmacokinetics of AZD5312 determined by RAC [ Time Frame: 25 Months ]


    Information By: AstraZeneca

    Dates:
    Date Received: April 29, 2014
    Date Started: May 2014
    Date Completion:
    Last Updated: July 13, 2016
    Last Verified: July 2016