Investigating Safety, Tolerability and Efficacy of AZD5363 in Prostate Cancer. (PYRUS)

A Phase Ib Multicentre Study of AZD5363 Monotherapy to Assess Anti-Tumour Activity,Safety,Tolerability,and Pharmacokinetics in Patients With Metastatic Castrate-Resistant Prostate Cancer (mCRPC)(PYRUS)

To investigate the safety, tolerability and anti-tumour activity of AZD5363, as monotherapy, in patients with metastatic Castrate-Resistant Prostate Cancer. AZD5363 will be investigated in patients who have progressed after chemotherapy (Part A) and in patients who have progressed before receiving chemotherapy (Part B).

Recruitment into Part A, Group 1 has been suspended. A new design for this group is currently being evaluated. Part A, group 2 patients (progressed after 1 or more 2nd generational anti-hormonal therapies) will receive AZD5363 480mg bid intermittently (4 days on/3days off).

Part B will only start if there is evidence of anti-tumour activity along with AZD5363 having an acceptable safety profile in Part A. Part B will be conducted in pre-chemotherapy patients on a dose and schedule selected from Part A.

Study Overview

• Status: Completed
• Conditions: Metastatic Castrate-Resistant Prostate Cancer (mCRPC),; Efficacy,; Safety and Tolerability,; Pharmacokinetics,; Pharmacodynamics,; Tumour Response.
• Intervention / Treatment: Drug: Intermittent dosing of AZD5363; Drug: Intermittent dosing of AZD5363; Drug: Intermittent dosing of AZD5363

Detailed Description

A Phase Ib Multicentre Study of AZD5363 Monotherapy to Assess Anti-Tumour Activity, Safety, Tolerability, and Pharmacokinetics in Patients With Metastatic Castrate-Resistant Prostate Cancer (mCRPC) (PYRUS)

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Cardiff, Wales, United Kingdom
    • Research Site
  • London, United Kingdom
    • Research Site
  • Southampton, United Kingdom
    • Research Site
• United States
  • Florida
    • Sarasota, Florida, United States
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States
      • Research Site
  • New Jersey
    • Hackensack, New Jersey, United States
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Provision of informed consent
• Males aged 18 years and older
• Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features for which no standard therapy is currently considered appropriate
• Documented evidence of Metastatic Castrate-Resistant Prostate Cancer (mCRPC)
• Part A: Patients must have received prior docetaxel-based chemotherapy for mCRPC and have a Circulating Tumour Cell score of 5;
• Part B: Patients must have progressed before receiving any chemotherapy for mCRPC;

Exclusion Criteria:

• Any prior exposure to agents which inhibit AKT as the primary pharmacological activity
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C, and human immunodeficiency virus
• Spinal cord compression or brain metastases unless asymptomatic, treated, and stable and not requiring steroids
• Clinically significant abnormalities of glucose metabolism
• Major surgery within the previous 4 weeks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A Group 1 Intermittent; Recruitment suspended and will not be re-opened. See intervention description below.	Drug: Intermittent dosing of AZD5363; Intermittent dosing of AZD5363: oral solid formulation, twice daily (480 mg bid 4 days on and 3 days off). Recruitment suspended and will not be re-opened.; Drug: Intermittent dosing of AZD5363; Intermittent dosing of AZD5363: oral solid formulation, twice daily (480 mg bid 4 days on and 3 days off). Treatment to begin on Day 1 and to continue to study withdrawal. Recruitment complete.; Drug: Intermittent dosing of AZD5363; Intermittent dosing of AZD5363: oral solid formulation, twice daily (480 mg bid 4 days on and 3 days off). Treatment to begin on Day 1 and to continue until study drug withdrawal. This part of the study will not be conducted.
Experimental: Part A Group 2 Intermittent; Recruitment complete. See intervention description below.	Drug: Intermittent dosing of AZD5363; Intermittent dosing of AZD5363: oral solid formulation, twice daily (480 mg bid 4 days on and 3 days off). Recruitment suspended and will not be re-opened.; Drug: Intermittent dosing of AZD5363; Intermittent dosing of AZD5363: oral solid formulation, twice daily (480 mg bid 4 days on and 3 days off). Treatment to begin on Day 1 and to continue to study withdrawal. Recruitment complete.; Drug: Intermittent dosing of AZD5363; Intermittent dosing of AZD5363: oral solid formulation, twice daily (480 mg bid 4 days on and 3 days off). Treatment to begin on Day 1 and to continue until study drug withdrawal. This part of the study will not be conducted.
Experimental: Part B; This part of the study will not be conducted following a review of data from Part A. See intervention description below.	Drug: Intermittent dosing of AZD5363; Intermittent dosing of AZD5363: oral solid formulation, twice daily (480 mg bid 4 days on and 3 days off). Recruitment suspended and will not be re-opened.; Drug: Intermittent dosing of AZD5363; Intermittent dosing of AZD5363: oral solid formulation, twice daily (480 mg bid 4 days on and 3 days off). Treatment to begin on Day 1 and to continue to study withdrawal. Recruitment complete.; Drug: Intermittent dosing of AZD5363; Intermittent dosing of AZD5363: oral solid formulation, twice daily (480 mg bid 4 days on and 3 days off). Treatment to begin on Day 1 and to continue until study drug withdrawal. This part of the study will not be conducted.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Parts A and B: Anti-tumour activity by measurement of changes in circulating prostate-specific antigen (PSA)	PSA measured from baseline for every 4 weeks. Primary assessment is at 12 weeks
Parts A and B: Anti-tumour activity by measurement of changes in circulating tumour cells (CTC)	CTC measured from baseline for every 4 weeks to week 12 (primary assessment) then measured every 12 weeks
Parts A and B: Anti-tumour activity by measurement of malignant soft tissue response rate	Tumour assessments by RECIST v1.1 every 12 weeks from baseline up to disease progression or withdrawal of consent
Parts A and B: Anti-tumour activity by measurement of metastatic bone disease status	Bone lesion assessments by bone scan (PCWG2) criteria every 12 weeks from baseline up to disease progression or withdrawal of consent.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parts A and B: Safety and tolerability of AZD5363 in terms of adverse events, serious adverse events (including death) and safety measures: ECG, ECHO/MUGA, physical examination, pulse, blood pressure, weight and laboratory variables		Routine safety assessments, throughout the period that patients receive AZD5363 up to 28 days following discontinuation of study treatment.
Parts A and B: AZD5363 PK: time to maximum plasma concentration, terminal rate constant,terminal half life, area under plasma concentration time curve, plasma clearance & volume of distribution		Multiple AZD5363 PK blood sample assessments.AZD5363 plasma concentration blood samples will be taken on Day 1(pre-dose,2,4,8 hours post-dose);D2(pre-dose);D8(continous) or D11(intermittent) (pre-dose and at 2,4,and 8 hours post-dose);D15,Cyc
Parts A and B: Plasma concentrations of pharmacodynamic (PD) biomarker		Multiple PD blood sample assessments.PD blood samples will be taken on the same schedule as PK sample and then Day 1 of every 12 weeks thereafter, and at the discontinuation visit
Parts A and B: Progression-free survival (PFS)		Tumour assessments by RECIST v1.1 every 12 weeks from baseline up to disease progression or withdrawal of consent.
Parts A and B: Quality of life (QoL)	EORTC QLQ-C15-PAL, EORTC QLQ-PR25, and EORTC QLQ-BM22 Questionnaires	QOL will be documented from date of randomization and for 12 weeks.

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Paul Stockman, MBChB, PhD, AstraZeneca

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: September 19, 2012
• First Submitted That Met QC Criteria: September 21, 2012
• First Posted (Estimate): September 25, 2012

Study Record Updates

• Last Update Posted (Estimate): June 19, 2014
• Last Update Submitted That Met QC Criteria: June 18, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: prostate cancer,; Metastatic Castrate-Resistant Prostate Cancer (mCRPC),; adenocarcinoma of the prostate,; progressive disease,; advanced disease.
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms
• Other Study ID Numbers: D3610C00003; GU86