AZD8186 First Time In Patient Ascending Dose Study

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by AstraZeneca
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01884285
First received: June 17, 2013
Last updated: July 15, 2014
Last verified: July 2014
  Purpose

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 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) at the intended therapeutic dose(s).


Condition Intervention Phase
Advanced Castrate-resistant Prostate Cancer (CRPC);
Squamous Non-Small Cell Lung Cancer (sqNSCLC);
Triple Negative Breast Cancer (TNBC)
Drug: AZD8186
Phase 1

Study Type: Interventional
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 Castrate-resistant Prostate Cancer (CRPC), Squamous Non-Small Cell Lung Cancer (sqNSCLC), Triple Negative Breast Cancer (TNBC) and Patients With Known PTEN-deficient Advanced Solid Malignancies, With Expansion to Assess the Pharmacodynamic Activity of AZD8186 Within Prospectively-validated PTEN Deficient Tumours

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Parts A and B: Safety and tolerability 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 ]

Secondary Outcome Measures:
  • Part A: Definition of either the maximum tolerated dose (MTD), if possible, or maximum feasible dose (MFD) by measuring the number of evaluable patients with dose limiting toxicities (DLT's). [ Time Frame: DLT's assessed during the first 21 days of multiple dosing. ] [ Designated as safety issue: No ]
  • Part A+ B: Antitumor activity by evaluation of tumour response assessments using Response Evaluation Criteria in Solid Tumours (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 constent, assessed up to 19 months ] [ Designated as safety issue: No ]
    For non Prostate patients tumour response assessments will be will be every 12 weeks from baseline up to disease progression or withdrawal of constent. For Prostate patients tumour response assessments will be will be every 6 weeks from baseline up to disease progression or withdrawal of constent.

  • Part A + B: Anti-tumour activity by measurement of changes in circulating prostate-specific antigen (PSA) [ Time Frame: PSA will be measured at mutiple timepoints: at screening; predose on first day of dosing Day1, cycle 1 day 8, cycle 1 day 15; every 28 days Cycle 2 and beyond; at study discontinuation, assessed up to 19 months ] [ 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: PartA/Day1(predose,0.25,0.5,1,1.5,2,3,4,6,8,10,12,24h);PartA/last day of dosing/Cycle1/week3(predose,0.25,0.5,1,1.5,2,3,4,6,8,10,12,24h);PartB/Cycle1/Day1(predose,0.25,0.5,1,1.5,2,3,4,6,8,10,12h);PartB/Cycle1/Day2(predose,0.25,0.5,1,1.5,2,3,4,6,8,10,12h) ] [ Designated as safety issue: No ]
    Blood samples will be collected at multiple timepoints following dosing: Part A Day 1 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours) ; Part A last day of dosing during Cycle 1 week 3 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours): Part B Cycle 1 Day 1 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours); Part B Cycle 1 Day 2 (pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours)

  • 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 ]
  • Obtaining of 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 ]
  • Investigation of predictive markers and acquired resistance to AZD8186 that may be observed in tumour from patients treated with AZD8186. [ Time Frame: At baseline,predose first day of dosing,last day of dosing during cycle 1 week 2,cycle 4 day 1 then every 6 weeks thereafter (for Prostate patients) or 12 weeks (for non Prostate patients),and at the time of discontinuation, assessed up to 19 months ] [ Designated as safety issue: No ]
    For Prostate patients blood samples will be taken to provide one sample of plasma and one sample of serum per each of the following timepoints: at screening, predose first day of dosing, last day of dosing during cycle 1 week 2, cycle 4 day 1 then every 6 weeks thereafter (if continuing on treatment), and at the time of discontinuation. For non Prostate patients blood samples will be taken to provide one sample of plasma and one sample of serum per each of the following timepoints: at screening, predose first day of dosing, last day of dosing during cycle 1 week 2, cycle 4 day 1 then every 12 weeks thereafter (if continuing on treatment), and at the time of discontinuation.

  • Investigation of predictive markers and acquired resistance to AZD8186 that may be observed in plasma circulating free DNA from patients treated with AZD8186. [ Time Frame: At baseline,predose first day of dosing,last day of dosing during cycle 1 week 2,cycle 4 day 1 then every 6 weeks thereafter (for Prostate patients) or 12 weeks (for non Prostate patients),and at the time of discontinuation, assessed up to 19 months ] [ Designated as safety issue: No ]
    For Prostate patients blood samples will be taken to provide one sample of plasma and one sample of serum per each of the following timepoints: at screening, predose first day of dosing, last day of dosing during cycle 1 week 2, cycle 4 day 1 then every 6 weeks thereafter (if continuing on treatment), and at the time of discontinuation. For non Prostate patients blood samples will be taken to provide one sample of plasma and one sample of serum per each of the following timepoints: at screening, predose first day of dosing, last day of dosing during cycle 1 week 2, cycle 4 day 1 then every 12 weeks thereafter (if continuing on treatment), and at the time of discontinuation.

  • Part A: Urine concentrations of AZD8186 and pharmacokinetic parameters (Cmax, tmax, AUC, terminal rate constant, clearance, half life, volume of distribution and mean resistance 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 ]

Estimated Enrollment: 96
Study Start Date: July 2013
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AZD8186
Patients will receive a single dose on Day 1 folowed by ongoing multiple dosing. The initial schedule will use intermittent dosing of AZD8186.
Drug: AZD8186
The initial schedule will use intermittent dosing of AZD8186. Dose, frequency and schedule in subsequent cohorts may increase or decrease in response to safety, tolerability, pharmacokinetic and preclinical data.

Detailed Description:

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 Castrate-resistant Prostate Cancer (CRPC), Squamous Non-Small Cell Lung Cancer (sqNSCLC), Triple Negative Breast Cancer (TNBC) and patients with known PTEN-deficient Advanced Solid Malignancies, with Expansion to Assess the Pharmacodynamic Activity of AZD8186 within Prospectively-validated PTEN deficient Tumours

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provision of signed and dated, written informed consent prior to any study specific procedures
  • Male or female, aged 18 years and older
  • Histologically or cytologically proven diagnosis of prostate cancer, squamous non small cell lung cancer (sqNSCLC), triple negative breast cancer (TNBC), or a known PTEN-deficient solid malignancy, that is refractory to standard therapies
  • Females should be using adequate contraceptive measures (see Section 4.3), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential
  • World Health Organisation (WHO)/ECOG performance status 0 to 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks

Exclusion Criteria:

  • Treatment before study with (a) Nitrosourea or mitomycin C; (b) Investigational agents from a previous clinical study; (c) Chemotherapy, immunotherapy or anticancer agents; (d) hormonal therapy (e.g., steroids)
  • Treatment before study with (a) Strong inhibitors and strong or moderate inducers of CYP3A4 (b) Radiotherapy with a wide field of radiation
  • With the exception of alopecia or toxicities related to the use of gonadotropin-releasing hormone agonists any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events grade 1 at the time of study treatment
  • Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids
  • Any evidence of severe or uncontrolled systemic diseases including active liver disease (other than malignancy), active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01884285

Contacts
Contact: AstraZeneca Clinical Study Information 800-236-9933 ClinicalTrialTransparency@astrazeneca.com
Contact: AstraZeneca Cancer Study Locator Service www.emergingmed.com/networks/AstraZeneca 1-877-400-4656 astrazeneca@emergingmed.com

Locations
United States, Massachusetts
Research Site Recruiting
Boston, Massachusetts, United States
United States, Washington
Research Site Recruiting
Seattle, Washington, United States
United States, Wisconsin
Research Site Recruiting
Madison, Wisconsin, United States
Canada, Ontario
Research Site Recruiting
Toronto, Ontario, Canada
United Kingdom
Research Site Recruiting
Sutton, United Kingdom
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Glen Clack AstraZeneca
Principal Investigator: Lillian Sui, MD Princess Margaret Hospital, Canada
  More Information

No publications provided

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01884285     History of Changes
Other Study ID Numbers: D4620C00001
Study First Received: June 17, 2013
Last Updated: July 15, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by AstraZeneca:
Advanced Castrate-resistant Prostate Cancer(CRPC)
Squamous Non-Small Cell Lung Cancer(sqNSCLC)
Triple Negative Breast Cancer(TNBC)
PTEN-deficient Advanced Solid Malignancies

Additional relevant MeSH terms:
Breast Neoplasms
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Prostatic Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Genital Neoplasms, Male
Urogenital Neoplasms
Genital Diseases, Male
Prostatic Diseases

ClinicalTrials.gov processed this record on August 19, 2014