AZD8186 First Time In Patient Ascending Dose Study

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2015 by AstraZeneca
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01884285
First received: June 17, 2013
Last updated: August 21, 2015
Last verified: August 2015
  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/mutated or PIK3CB mutated/amplified advanced solid malignancies.


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 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

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 96
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)
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 be modified in response to safety, tolerability, pharmacokinetic and preclinical data.

Detailed Description:

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).

  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
  • Tumours that are known to have genomic alterations in PTEN or PIK3CB by local test results may also be eligible

Exclusion Criteria:

  • Treatment before study with (a) Nitrosourea or mitomycin C within 6 weeks; (b) Investigational agents from a previous clinical study within 4 weeks; (c) Chemotherapy, immunotherapy or anticancer agents within 4 weeks; (d) hormonal therapy (e.g., steroids for prostate cancer)
  • Treatment before study with (a) Strong inhibitors and strong or moderate inducers of CYP3A4 (b) Radiotherapy with a wide field of radiation within 4 weeks
  • 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 Center 1-877-240-9479 information.center@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
Spain
Research Site Not yet recruiting
Barcelona, Spain
United Kingdom
Research Site Not yet recruiting
Manchester, United Kingdom
Research Site Recruiting
Sutton, United Kingdom
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: David Brooks AstraZeneca
Principal Investigator: Lillian Siu, 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: August 21, 2015
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/mutated Advanced Solid Malignancies
PIK3CB mutated/amplified advanced solid malignancies

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

ClinicalTrials.gov processed this record on September 02, 2015