AZD8186 First Time In Patient Ascending Dose Study

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2016 by AstraZeneca
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01884285
First received: June 17, 2013
Last updated: July 18, 2016
Last verified: July 2016
  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 as monotherapy and in combination with abiraterone acetate or AZD2014.

Condition Intervention Phase
Advanced Castrate-resistant Prostate Cancer (CRPC);
Squamous Non-Small Cell Lung Cancer (sqNSCLC);
Triple Negative Breast Cancer (TNBC)
Drug: AZD8186 monotherapy
Drug: Part B: AZD8186 monotherapy
Drug: Part C: Abiraterone acetate in combination with AZD8186
Drug: Part D1: AZD2014 combination with AZD8186
Drug: Part D2 AZD2014 combination with 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, Pharmacodynamics and Preliminary Anti-tumour Activity 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/ Amplified Advanced Solid Malignancies as Monotherapy and in Combination With Abiraterone Acetate or AZD2014

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Safety and tolerability of AZD8186 monotherapy or in combination with Abiraterone acetate (with prednisone) or AZD2014 in terms of AEs, SAEs (incl death), safety measures: ECG, physical exam, pulse, blood pressure, weight, lab variables. [ Time Frame: Routine safety assessments, throughout the period that patients receive AZD8186 up to 30 days following discont of last dose of study treatment. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Part A: Definition of the recommended Ph II dose(s) and schedule(s) of AZD8186 monotherapy 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, B, C + D: Antitumor activity of AZD8186 monotherapy or in combination 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, C and D: Anti-tumour activity of AZD8186 monotherapy or in combination by measurement of changes in circulating prostate-specific antigen (PSA) in pts with prostate cancer [ 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 ]
  • Part C: Dose limiting toxicity of AZD8186 with abiraterone acetate (and prednisone) at different doses and schedules will be measured [ Time Frame: DLTs assessed during the first 21 days of multiple dosing ] [ Designated as safety issue: Yes ]
  • Part C: Measure the pharmacokinetics of and assess exposure to AZD8186, its major metabolite M1, and abiraterone when co-administered [ Time Frame: Blood samples will be collected at multiple timepoints on 2 intense PK collection days between screening and the end of the first full cycle of treatment. ] [ Designated as safety issue: No ]
  • Part C: Measure the steady state exposure to abiraterone in the absence and presence of steady state AZD8186. [ Time Frame: Blood samples will be collected at multiple timepoints on 2 intense PK collection days between screening and the end of the first full cycle of treatment. ] [ Designated as safety issue: No ]
  • Part C: Measure the steady state exposure of AZD8186 in combination with abiraterone acetate and compare to previous steady state exposures when administered as a monotherapy [ Time Frame: Blood samples will be collected at multiple timepoints on 2 intense PK collection days between screening and the end of the first full cycle of treatment. ] [ Designated as safety issue: No ]
  • Part D: Measure the dose limiting toxicity of AZD8186 in combination with AZD2014. [ Time Frame: DLTs assessed during the first 21 days of multiple dosing ] [ Designated as safety issue: Yes ]
  • Part D: Measure the single dose and multiple dose pharmacokinetics of and assess exposure to AZD8186, its major metabolite M1, and AZD2014 when co-administered [ Time Frame: Blood samples will be collected at multiple timepoints on intense PK collection days for AZD8186 and AZD2014 monotherapy run-in, cycle 0 (single dose), cycle 1 week 2 day 9 (multiple dose) ] [ Designated as safety issue: No ]
  • Part D: Measure the exposure to AZD2014 following the last weekly dose of AZD2014 in the absence and presence of multiple dose AZD8186. [ Time Frame: Blood samples will be collected at multiple timepoints on intense PK collection days for AZD8186 and AZD2014 monotherapy run-in, cycle 0 (single dose), cycle 1 week 2 day 9 (multiple dose) ] [ Designated as safety issue: No ]
  • Part D: Measure the exposure on the 4th administred dose of AZD8186 in the absence and presence of multiple dose AZD2014 [ Time Frame: Blood samples will be collected at multiple timepoints on intense PK collection days for AZD8186 and AZD2014 monotherapy run-in, cycle 0 (single dose), cycle 1 week 2 day 9 (multiple dose) ] [ Designated as safety issue: No ]

Estimated Enrollment: 180
Study Start Date: July 2013
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A: AZD8186 monotherapy
Patients will receive a single dose on Day 1 followed by ongoing multiple dosing. The initial schedule will use intermittent dosing of AZD8186.
Drug: AZD8186 monotherapy
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.
Experimental: Part C AZD8186 & abiraterone/ prednisone
Part C AZD8186 & Abiraterone/ prednisone
Drug: Part C: Abiraterone acetate in combination with AZD8186
AZD8186 dose from Part A with Abiraterone acetate (with prednisone) with approved labelled dose.
Experimental: Part D1: AZD8186 and AZD2014
Part D1: AZD2014 and AZD8186 dosing finding
Drug: Part D1: AZD2014 combination with AZD8186
Part D1 dose & schedule finding
Experimental: Part B: AZD8186 monotherapy
Part B - multiple dosing of intermittent dose schedule
Drug: Part B: AZD8186 monotherapy
Part B will be at a dose(s) and schedule(s) at or below from Part A
Experimental: Part D2: AZD8186/ AZD2014 dose expansion
Part D2: AZD8186/ AZD2014 dose expansion
Drug: Part D2 AZD2014 combination with AZD8186
Combination AZD8186/ AZD2014 dose expansion

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 4 parts to this study: Part A, dose escalation, Part B, expansion cohort(s) in PTEN deficient patients at the intended therapeutic dose(s) and schedule(s), Part C, AZD8186 in combination with abiraterone accetate (with prednisone) - dose/ schedule confirmation followed by expansion phase in PTEN-deficient mCRPC) and Part D, AZD8186 in combination with AZD2014 (a novel dual mTORC1/2 inibitor) dose/schedule finding followed by expansion phase in PTEN deficient TNBC.

  Eligibility

Ages Eligible for Study:   18 Years to 130 Years   (Adult, Senior)
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, sqNSCLC, TNBC, or known PTEN-deficient solid malignancy, and is refractory to standard therapies.
  • Females should be using adequate contraceptive measures, not be breast feeding and must have negative pregnancy test prior to start of dosing if of child-bearing potential
  • WHO/ECOG performance status 0 to 1 with no deterioration over the previous 2 weeks and min 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.

Part B

- Tumour amenable to taking of paired biopsies in opinion of the investigator.Patients with TNBC or mCRPC: PTEN-deficient tumours

Parts A,B or D1(mCRPC)

  • PSA at screening must be ≥2 µg/L.
  • Preceding line of treatment included response to anti-androgen, progression documented after withdrawal of the anti-androgen.
  • Serum testosterone concentration ≤50 ng/dL sustained by medical or surgical castration

Parts A,B or D (TNBC) - Oestrogen receptor, progesterone receptor and HER2 negative advanced adenocarcinoma of breast.

Parts A, B or D1 (solid malignancies)

- Consented provision of formalin fixed paraffin embedded blocks/ slides from most recent tissue sample.

Part C:

  • Serum testosterone concentration ≤50 ng/dL sustained by medical or surgical castration.
  • Receiving abiraterone acetate (with prednisone) with early or confirmed evidence of progressive disease.
  • Last PSA value should have increase of ≥ 25% of the first PSA value and an absolute increase of ≥2 ng/mL over the first PSA value
  • No narcotics for pain
  • Serum potassium > 3.5 mmol/L

Exclusion Criteria

  • Treatment before study with

    1. Nitrosourea or mitomycin C within 6 weeks
    2. Investigational agents from previous clinical study within 4 weeks
    3. Chemotherapy, immunotherapy or anticancer agents within 4 weeks
    4. hormonal therapy
  • Treatment before study with

    1. Strong inhibitors and strong or moderate inducers of CYP3A4
    2. 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 CTCAE grade 1 at time of study treatment
  • Spinal cord compression or brain metastases unless asymptomatic treated and stable and not requiring steroids
  • 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).

Exclusion Criterion Specific to Part D

  • Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 and CYP2C8 if taken within the stated washout periods before the first dose of study treatment
  • Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19 or the drug transporters Pgp, BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 within the appropriate wash-out period before the first dose of study treatment.
  • Haemopoietic growth factors within 2 weeks prior to receiving study drug.
  • Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months: coronary artery bypass graft, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association Grade ≥2, supraventricular arrhythmias including atrial fibrillation, which are uncontrolled, haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding.
  • Abnormal ECHO or MUGA at baseline <55%.
  • Patients with Diabetes Type I or uncontrolled Type II as judged by the Investigator
  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, Michigan
Research Site Recruiting
Detroit, Michigan, 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 Recruiting
Barcelona, Spain
United Kingdom
Research Site Recruiting
Manchester, United Kingdom
Research Site Recruiting
Sutton, United Kingdom
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Glen Clack AstraZeneca
Principal Investigator: Lillian Siu, MD Princess Margaret Hospital, Canada
  More Information

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01884285     History of Changes
Other Study ID Numbers: D4620C00001 
Study First Received: June 17, 2013
Last Updated: July 18, 2016
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration
Canada: Health Canada
Spain: Agencia Espanola de Medicamentos y Productos Sanitarios

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
Lung Neoplasms
Prostatic Neoplasms
Carcinoma, Non-Small-Cell Lung
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Genital Neoplasms, Male
Urogenital Neoplasms
Genital Diseases, Male
Prostatic Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Prednisone
Abiraterone Acetate
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 24, 2016