Clinical Trials /

AZD8186 First Time In Patient Ascending Dose Study

NCT01884285

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 as monotherapy and in combination with abiraterone acetate or AZD2014.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
  • Prostate Carcinoma
  • Squamous Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: AZD8186 First Time In Patient Ascending Dose Study
  • 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

Clinical Trial IDs

  • ORG STUDY ID: D4620C00001
  • NCT ID: NCT01884285

Conditions

  • Advanced Castrate-resistant Prostate Cancer CRPC
  • Squamous Non-Small Cell Lung Cancer sqNSCLC
  • Triple Negative Breast Cancer TNBC

Interventions

DrugSynonymsArms
Part A: AZD8186 monotherapyPart A: AZD8186 monotherapy
Part B: AZD8186 monotherapyPart B: AZD8186 monotherapy
Part C1: Abiraterone acetate combination with AZD8186Part C1: AZD8186 & abiraterone
Part D1: AZD2014 combination with AZD8186Part D1: AZD8186 and AZD2014
Part D2 AZD2014 combination with AZD8186Part D2: AZD8186/ AZD2014
Part C2: Abiraterone acetate combination with AZD8186Part C2: AZD8186/abiraterone

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.

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, 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.
    

Trial Arms

NameTypeDescriptionInterventions
Part A: AZD8186 monotherapyExperimentalPatients will receive a single dose on Day 1 followed by ongoing multiple dosing. The initial schedule will use intermittent dosing of AZD8186.
  • Part A: AZD8186 monotherapy
Part C2: AZD8186/abirateroneExperimentalPart C2: AZD8186 & Abiraterone (prednisone) dose expansion
  • Part C2: Abiraterone acetate combination with AZD8186
Part D1: AZD8186 and AZD2014ExperimentalPart D1: AZD2014 and AZD8186 dosing finding
  • Part D1: AZD2014 combination with AZD8186
Part B: AZD8186 monotherapyExperimentalPart B - multiple dosing of intermittent dose schedule
  • Part B: AZD8186 monotherapy
Part D2: AZD8186/ AZD2014ExperimentalPart D2: AZD8186/ AZD2014 dose expansion
  • Part D2 AZD2014 combination with AZD8186
Part C1: AZD8186 & abirateroneExperimentalPart C1: AZ8186 & abiraterone (prednisone) dose finding
  • Part C1: Abiraterone acetate combination with AZD8186

Eligibility 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 (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
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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.
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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.
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:Blood samples will be collected at multiple timepoints on 2 intense PK collection days, with sparse sampling on additional days.
Measure: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.
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • 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

Last Updated

August 16, 2017