AZD8186 First Time In Patient Ascending Dose Study
Advanced Castrate-resistant Prostate Cancer (CRPC);
Squamous Non-Small Cell Lung Cancer (sqNSCLC);
Triple Negative Breast Cancer (TNBC)
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Ascending Doses of AZD8186 in Patients With Advanced Castration-resistant Prostate Cancer (CRPC), Squamous Non-Small Cell Lung Cancer (sqNSCLC), Triple Negative Breast Cancer (TNBC) and Patients With Known PTEN-deficient/Mutated or PIK3CB Mutated Advanced Solid Malignancies, With Expansion to Assess the Pharmacodynamic Activity of AZD8186|
- Safety and tolerability of AZD8186 monotherapy in terms of adverse events, serious adverse events (including death) and safety measures: ECG, physical examination, pulse, blood pressure, weight and laboratory variables [ Time Frame: Routine safety assessments, throughout the period that patients receive AZD8186 up to 30 days following discontinuation of last dose of study treatment. ] [ Designated as safety issue: Yes ]
- Part A: Definition of either the maximum tolerated dose (MTD) of AZD8186 monotherapy, if possible, or maximum feasible dose (MFD) by measuring the number of evaluable patients with dose limiting toxicities (DLTs). [ Time Frame: DLTs assessed during the first 21 days of multiple dosing. ] [ Designated as safety issue: Yes ]Part A of the study is AZD8186 monotherapy dose escalation to define the recommended phase 2 dose and schedule Part B of the study is AZD8186 monotherapy expansion cohort(s) with paired tumour biopsies for proof of mechanism
- Part A + B: Antitumor activity of AZD8186 monotherapy by evaluation of tumour response assessments using RECIST 1.1 or Prostate Cancer Clinical Trials Working Group (PCWG2) criteria in the case of patients with Prostate Cancer. [ Time Frame: Every 12 weeks (non prostate patients) or every 6 weeks (prostate patients) from baseline up to disease progression or withdrawal of consent ] [ Designated as safety issue: No ]
- Part A + B: Anti-tumour activity of AZD8186 monotherapy by measurement of changes in circulating prostate-specific antigen (PSA) [ Time Frame: PSA will be measured at Screening, Pre-dose first day of dosing, Cycle 1 Day 8, Cycle 1 Day 15, Day 1 of subsequent cycles, Study discontinuation and 30-day follow up after discontinuation ] [ Designated as safety issue: No ]
- Part A + B: Plasma concentrations of AZD8186 and pharmacokinetic parameters (Cmax, tmax, AUC, terminal rate constant, clearance, half life, volume of distribution and mean resistance time) [ Time Frame: Cycle 1 + pre-dose ] [ Designated as safety issue: No ]Blood samples will be collected at multiple timepoints on 2 intense PK collection days, with sparse sampling on additional days.
- Part A + B: Understanding of the CYP3A4 induction potential of AZD8186 by measuring 4 beta-hydroxy cholesterol concentration in blood samples. [ Time Frame: Blood samples will be collected from all patients for 4 beta-hydroxy cholesterol concentration measurements pre-dose day 1 and pre-morning dose day 22 in both Part A and B. ] [ Designated as safety issue: No ]
- Part B: Obtaining of a preliminary assessment of the antitumour activity of AZD8186 as monotherapy by evaluation of proof of mechanism biomarkers in PTEN-deficient tumour tissue [ Time Frame: Paired tumour biopsies will be collected; one prior to treatment and the other during treatment (last day of dosing in the second week of cycle 1) ] [ Designated as safety issue: No ]
- Part B: Obtaining a preliminary assessment of AZD8186 drug effect in the tumour by evaluation of pharmacodynamic biomarker changes [ Time Frame: Paired tumour biopsies will be collected; one prior to treatment and the other during treatment (last day of dosing in the second week of cycle 1) ] [ Designated as safety issue: No ]
- Part A: Urine concentrations of AZD8186 and pharmacokinetic parameters (Cmax, tmax, AUC, terminal rate constant, clearance, half life, volume of distribution and mean residence time) [ Time Frame: Urine samples will collected at multiple time points: Day 1 (predose, 15min post dose, 30min post dose); Last dosing day during Cycle 1 week 3 (predose and 15min post dose) ] [ Designated as safety issue: No ]
|Study Start Date:||July 2013|
|Estimated Study Completion Date:||November 2017|
|Estimated Primary Completion Date:||March 2017 (Final data collection date for primary outcome measure)|
Patients will receive a single dose on Day 1 folowed by ongoing multiple dosing. The initial schedule will use intermittent dosing of AZD8186.
The initial schedule will use intermittent dosing of AZD8186. Dose, frequency and schedule in subsequent cohorts may be modified in response to safety, tolerability, pharmacokinetic and preclinical data.
This is a phase I, open-label, multicentre study of AZD8186 administered orally in patients with advanced castrate-resistant prostate cancer (CRPC), squamous non-small cell lung cancer (sqNSCLC), triple negative breast cancer (TNBC) and known PTEN-deficient/mutated or PIK3CB mutated/amplified advanced solid malignancies. The study design allows an escalation of dose with intensive safety monitoring to ensure the safety of the patients.
There are two parts to this study: Part A, dose escalation, and Part B, expansion cohort(s) in PTEN deficient patients at the intended therapeutic dose(s) and schedule(s).
Please refer to this study by its ClinicalTrials.gov identifier: NCT01884285
|Contact: AstraZeneca Clinical Study Information Centeremail@example.com|
|Contact: AstraZeneca Cancer Study Locator Service www.emergingmed.com/networks/AstraZenecafirstname.lastname@example.org|
|United States, Massachusetts|
|Boston, Massachusetts, United States|
|United States, Washington|
|Seattle, Washington, United States|
|United States, Wisconsin|
|Madison, Wisconsin, United States|
|Toronto, Ontario, Canada|
|Research Site||Not yet recruiting|
|Manchester, United Kingdom|
|Sutton, United Kingdom|
|Study Director:||David Brooks||AstraZeneca|
|Principal Investigator:||Lillian Siu, MD||Princess Margaret Hospital, Canada|