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AZD8186 First Time In Patient Ascending Dose Study

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2017 by AstraZeneca
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01884285
First received: June 17, 2013
Last updated: April 27, 2017
Last verified: April 2017

June 17, 2013
April 27, 2017
July 9, 2013
September 30, 2019   (Final data collection date for primary outcome measure)
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. ]
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. ]
Complete list of historical versions of study NCT01884285 on ClinicalTrials.gov Archive Site
  • 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. ]
  • 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 ]
  • 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 ]
  • 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 ]
    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. ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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 ]
  • 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. ]
  • 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. ]
  • 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. ]
  • 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 ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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: DLTs assessed during the first 21 days of multiple dosing. ]
  • 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 ]
    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 ]
  • 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) ]
    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. ]
  • 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) ]
  • 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) ]
  • 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 ]
    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 ]
    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) ]
Not Provided
Not Provided
 
AZD8186 First Time In Patient Ascending Dose Study
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
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.

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, monotherapy dose escalation, Part B, monotherapy expansion cohort(s) in PTEN deficient patients at the monotherapy intended therapeutic dose(s) and schedule(s), Part C, AZD8186 added to abiraterone accetate (with prednisone) treatment - dose/ schedule finding followed by expansion phase in PTEN-deficient/mutated or PIK3CB mutated 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/mutated or PIK3CB mutated TNBC.

Interventional
Phase 1
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
  • Advanced Castrate-resistant Prostate Cancer CRPC
  • Squamous Non-Small Cell Lung Cancer sqNSCLC
  • Triple Negative Breast Cancer TNBC
  • Drug: Part A: 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.
  • Drug: Part B: AZD8186 monotherapy
    Part B will be at a dose(s) and schedule(s) at or below from Part A
  • Drug: Part C1: Abiraterone acetate combination with AZD8186
    Dose and schedule finding of AZD8186 added to approved labelled dose of abiraterone acetate (with prednisone).
  • Drug: Part D1: AZD2014 combination with AZD8186
    Dose & schedule finding of AZD8186 in combination with AZD2014
  • Drug: Part D2 AZD2014 combination with AZD8186
    Combination AZD8186/ AZD2014 dose expansion at dose determined in Part D1
  • Drug: Part C2: Abiraterone acetate combination with AZD8186
    Dose expansion of AZD8186 at dose determined in Part C1 added to approved dose of abiraterone acetate (with prednisone)
  • 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.
    Intervention: Drug: Part A: AZD8186 monotherapy
  • Experimental: Part C2: AZD8186/abiraterone
    Part C2: AZD8186 & Abiraterone (prednisone) dose expansion
    Intervention: Drug: Part C2: Abiraterone acetate combination with AZD8186
  • Experimental: Part D1: AZD8186 and AZD2014
    Part D1: AZD2014 and AZD8186 dosing finding
    Intervention: Drug: Part D1: AZD2014 combination with AZD8186
  • Experimental: Part B: AZD8186 monotherapy
    Part B - multiple dosing of intermittent dose schedule
    Intervention: Drug: Part B: AZD8186 monotherapy
  • Experimental: Part D2: AZD8186/ AZD2014
    Part D2: AZD8186/ AZD2014 dose expansion
    Intervention: Drug: Part D2 AZD2014 combination with AZD8186
  • Experimental: Part C1: AZD8186 & abiraterone
    Part C1: AZ8186 & abiraterone (prednisone) dose finding
    Intervention: Drug: Part C1: Abiraterone acetate combination with AZD8186
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
180
September 30, 2019
September 30, 2019   (Final data collection date for primary outcome measure)

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 (all patients):

  • May have received treatment with abiraterone acetate, enzalutamide and/or one prior chemotherapy (docetaxel)
  • Serum testosterone concentration ≤50 ng/dL sustained by medical or surgical castration.
  • 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
  • Serum potassium > 3.5 mmol/L

Parts C2 and D2

- Prospectively determined eligible PTEN alteration determined by next generation sequencing, protein deficient determined by IHC or PIK3CB mutation/amplification.

Part D2

- Measurable disease (at least 1 lesion ≥10 mm longest diameter or for lymph nodes short axis ≥15 mm) by CT/MRI

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 crtieria Part C

  • Pre-existing Grade 2 or higher chronic diarrhoea
  • Major bowel surgery which in the opinion of the Investigator should exclude the patient
  • Use of antibiotics to treat chronic infections within 28 days prior to first dose
  • Sensitive or narrow therapeutic range substrates of CYP2D6
  • Severe or moderate hepatic impairment
  • Persistent uncontrolled hypertension (systolic >160 mmHg/ diastolic >100 mmHg

Exclusion Criteria 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
  • 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
Sexes Eligible for Study: All
18 Years to 130 Years   (Adult, Senior)
No
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
United States,   Canada,   Spain,   United Kingdom
 
 
NCT01884285
D4620C00001
No
Not Provided
Not Provided
Not Provided
AstraZeneca
AstraZeneca
Not Provided
Study Director: Wolfram Brugger AstraZeneca
Principal Investigator: Lillian Siu, MD Princess Margaret Hospital, Canada
AstraZeneca
April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP