Advanced Castrate-resistant Prostate Cancer CRPCPhase 1NCT01884285
AZD8186 First Time In Patient Ascending Dose Study
A Phase 1 study testing Part A: AZD8186 monotherapy, Part B: AZD8186 monotherapy and Part C1: Abiraterone acetate combination with AZD8186 in people with Advanced Castrate-resistant Prostate Cancer CRPC and Squamous Non-Small Cell Lung Cancer sqNSCLC, run by AstraZeneca at 13 sites in 4 countries.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 130 years
- Conditions the study is for
- Advanced Castrate-resistant Prostate Cancer CRPC, Squamous Non-Small Cell Lung Cancer sqNSCLC, Triple Negative Breast Cancer TNBC
- What is being tested?
- Part A: AZD8186 monotherapy, Part B: AZD8186 monotherapy and Part C1: Abiraterone acetate combination with AZD8186
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 147 participants
- Where
- 13 sitesin 4 countries
- Study dates
- 9 Jul 2013to 7 Feb 2020
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 130 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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
Who cannot join
- Treatment before study with
- Nitrosourea or mitomycin C within 6 weeks
- Investigational agents from previous clinical study within 4 weeks
- Chemotherapy, immunotherapy or anticancer agents within 4 weeks
- hormonal therapy
- Treatment before study with
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- Strong inhibitors and strong or moderate inducers of CYP3A4
- 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).
- 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
- 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
Trial locations and contacts
13 sites in 4 countries.
13 sites in 4 countries
United States5 sites
Research Site
Boston, Massachusetts, 02215
Research Site
Detroit, Michigan, 48201
Research Site
Madison, Wisconsin, 53792-5666
Research Site
New York, New York, 10065
Research Site
Seattle, Washington, 98109
United Kingdom4 sites
Research Site
Cambridge, CB2 0QQ
Research Site
London, WC1E 6BT
Research Site
Manchester, M20 4BX
Research Site
Sutton, SM1 2DL
Spain3 sites
Research Site
Barcelona, 08035
Research Site
Barcelona, 8036
Research Site
Pozuelo de Alarcón, 28223
About this 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
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.
Read the 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.
- Conditions
- Advanced Castrate-resistant Prostate Cancer CRPC, Squamous Non-Small Cell Lung Cancer sqNSCLC, Triple Negative Breast Cancer TNBC
- Being tested
- Part A: AZD8186 monotherapy, Part B: AZD8186 monotherapy, Part C1: Abiraterone acetate combination with AZD8186, Part D1: AZD2014 combination with AZD8186, Part D2 AZD2014 combination with AZD8186
- 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
- Medical subject headings
- Triple Negative Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Part A: AZD8186 monotherapyDrug
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.
Part B: AZD8186 monotherapyDrug
Part B will be at a dose(s) and schedule(s) at or below from Part A
Part C1: Abiraterone acetate combination with AZD8186Drug
Dose and schedule finding of AZD8186 added to approved labelled dose of abiraterone acetate (with prednisone).
Part D1: AZD2014 combination with AZD8186Drug
Dose \& schedule finding of AZD8186 in combination with AZD2014
Part D2 AZD2014 combination with AZD8186Drug
Combination AZD8186/ AZD2014 dose expansion at dose determined in Part D1
Part C2: Abiraterone acetate combination with AZD8186Drug
Dose expansion of AZD8186 at dose determined in Part C1 added to approved dose of abiraterone acetate (with prednisone)
| Study group | Role | What they receive |
|---|---|---|
| Part A: AZD8186 monotherapy | Experimental | Patients will receive a single dose on Day 1 followed by ongoing multiple dosing. The initial schedule will use intermittent dosing of AZD8186. Receives: Drug: Part A: AZD8186 monotherapy |
| Part C2: AZD8186/abiraterone | Experimental | Patients will receive a week of abiraterone acetate with prednisone followed by combination dosing with AZD8186. Receives: Drug: Part C2: Abiraterone acetate combination with AZD8186 |
| Part D1: AZD8186 and AZD2014 | Experimental | Combination dosing with AZD8186 and AZD2014 both given on an intermittent schedule at escalating dose levels of each IMP for combination dose finding Receives: Drug: Part D1: AZD2014 combination with AZD8186 |
| Part B: AZD8186 monotherapy | Experimental | Part B - multiple dosing of intermittent dose schedule Receives: Drug: Part B: AZD8186 monotherapy |
| Part D2: AZD8186/ AZD2014 | Experimental | Expanded cohort of patients will be treated at a tolerated combination dose level established in Part D1 Receives: Drug: Part D2 AZD2014 combination with AZD8186 |
| Part C1: AZD8186 & abiraterone | Experimental | Patients will receive a week of abiraterone acetate with prednisone followed by combination dosing with AZD8186 at escalating doses of AZD8186 for the purpose of dose finding Receives: Drug: Part C1: Abiraterone acetate combination with AZD8186 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety and tolerability
Assess safety and tolerability of AZD8186 when given as monotherapy or in combination with abiraterone acetate (with prednisone) or with AZD2014 by measuring AEs, SAE (incl death), safety measures incl ECG, physical exam, pulse, blood pressure, weight, lab variables
Measured: Routine safety assessments, throughout the period that patients receive AZD8186 up to 30 days following discont of last dose of study treatment.
Secondary outcomes (16)
Part A: The number of evaluable patients with dose limiting toxicities (DLTs).
Measure the number of evaluable patients with reported dose limiting toxicities (DLTs) at escalating dose levels and different intermittent and continuous dose schedules of AZD8186 monotherapy
Measured: DLTs assessed during the first 21 days of multiple dosing.
Part A, B, C + D: Antitumor activity of AZD8186 monotherapy or in combination
Evaluation of tumour response using RECIST 1.1 or Prostate Cancer Clinical Trials Working Group (PCWG2) criteria for those patients with prostate cancer
Measured: 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
Measurement of changes in circulating prostate-specific antigen (PSA) and circulating tumour cells (CTC) enumeration in pts with prostate cancer.
Measured: PSA at Screening, Days 1, 8 & 15 then every 28 days, discontinuation of treatment (on average after 4 months), 30-day follow-up: CTC enumeration Days 1, 56 & 84, then every 12 weeks, at discontinuation (on average after 4 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)
Blood samples will be collected at multiple timepoints on 2 intense PK collection days, with sparse sampling on additional days.
Measured: Prior to first dose and during first 28 days of treatment
Part A + B: 4 beta-hydroxy cholesterol concentration in blood samples.
Understanding of the CYP3A4 induction potential of AZD8186
Measured: 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 a preliminary assessment of the antitumour activity of AZD8186 as monotherapy
Evaluation of proof of mechanism biomarkers in PTEN-deficient TNBC or mCRPC tumour tissue
Measured: Paired tumour biopsies will be collected; one prior to treatment and the other during treatment (after at least 3 consecutive days of dosing 2-4 hours post-dose during 2nd week of trreatment)
Part B: Obtaining a preliminary assessment of AZD8186 drug effect in the tumour
Evaluation of pharmacodynamics biomarker changes in tumour tissue
Measured: Paired tumour biopsies will be collected; one prior to treatment and the other during treatment (after at leat 3 consecutive days of dosing 2-4 hours post-dose in the second week of treatment)
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)
Evaluation of the pharmacokinetics of AZD8186
Measured: Urine samples will collected at multiple time points: Day 1 (predose, 15min post dose, 30min post dose); Last dosing day during week 3 (predose and 15min post dose)
Part C: safety and tolerability assessed by dose limiting toxicity of AZD8186 with abiraterone acetate (and prednisone)
Dose limiting toxicity of AZD8186 when given at different doses and schedules in combination with abiraterone (with prednisone)
Measured: DLTs assessed during the first 21 days of multiple dosing
Part C: pharmacokinetics of and exposure to AZD8186, its major metabolite M1, and abiraterone
Assess the impact of co-administration on pharmacokinetics of and exposure to AZD8186, its major metabolite M1, and abiraterone
Measured: Blood samples will be collected at multiple timepoints on 2 intense PK collection days between screening and the end of the first 28 days of combination treatment.
Part C: steady state exposure to abiraterone
Measure the steady state exposure to abiraterone in the absence and presence of steady state AZD8186
Measured: Blood samples will be collected at multiple timepoints on 2 intense PK collection days between screening and the end of the first 28 days of combination treatment.
Part C: steady state exposure of AZD8186 in combination with abiraterone acetate
Measure the steady state exposure of AZD8186 in combination with abiraterone acetate and compare to previous steady state exposures when administered as a monotherapy
Measured: Blood samples will be collected at multiple timepoints on 2 intense PK collection days between screening and the end of the first 28 days of combination treatment.
Part D: Measure the dose limiting toxicity of AZD8186 in combination with AZD2014.
Safety and tolerability of the combination of AZD8186 and AZD2014
Measured: DLTs assessed during the first 21 days of multiple dosing
Part D: Single dose and multiple dose pharmacokinetics of and assess exposure to AZD8186, its major metabolite M1, and AZD2014 when co-administered
Measure the pharmacokinetics of and exposure to AZD8186, its major metabolite M1, and AZD2014 when co-administered
Measured: Blood samples will be collected at multiple timepoints on intense PK collection days for AZD8186 and AZD2014 monotherapy run-in, cycle 0 (single dose), 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.
Assessment of exposure to AZD2014 in absence and presence of multiple dose AZD8186
Measured: Blood samples will be collected at multiple timepoints on intense PK collection days for AZD8186 and AZD2014 monotherapy run-in, cycle 0 (single dose), Day 9 of treatment (multiple dose)
Part D: Measure the exposure on the 4th administred dose of AZD8186 in the absence and presence of multiple dose AZD2014
Assessment of exposure of AZD8186 in absence and presence of multiple dose AZD2014
Measured: Blood samples will be collected at multiple timepoints on intense PK collection days for AZD8186 and AZD2014 monotherapy run-in, cycle 0 (single dose), day 9 (multiple dose)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jun 2013 (estimated)
- Study start9 Jul 2013
- Primary completion31 Mar 2019
- Study completion7 Feb 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced Castrate-resistant Prostate Cancer CRPCStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 147 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Michele Mochetta, MD, Study director, AstraZenecaLillian Siu, MD, Principal investigator, Princess Margaret Hospital, Canada
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01884285
- Sponsor's protocol ID
- D4620C00001
- Status last verified
- May 2020
- First submitted
- 17 Jun 2013
- Last updated
- 29 May 2020
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
Study at a glance
From the registry record, last updated by the sponsor on 29 May 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01884285
- Acronym / sponsor ID
- D4620C00001
- Conditions
- Advanced Castrate-resistant Prostate Cancer CRPC, Squamous Non-Small Cell Lung Cancer sqNSCLC, Triple Negative Breast Cancer TNBC
- 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
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 147 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Study start
- 9 Jul 2013 (actual)
- Primary completion
- 31 Mar 2019 (actual)
- Study completion
- 7 Feb 2020 (actual)
- First posted
- 24 Jun 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Part A: AZD8186 monotherapy | Experimental | Drug: Part A: AZD8186 monotherapyPatients will receive a single dose on Day 1 followed by ongoing multiple dosing. The initial schedule will use intermittent dosing of AZD8186. |
| Part C2: AZD8186/abiraterone | Experimental | Drug: Part C2: Abiraterone acetate combination with AZD8186Patients will receive a week of abiraterone acetate with prednisone followed by combination dosing with AZD8186. |
| Part D1: AZD8186 and AZD2014 | Experimental | Drug: Part D1: AZD2014 combination with AZD8186Combination dosing with AZD8186 and AZD2014 both given on an intermittent schedule at escalating dose levels of each IMP for combination dose finding |
| Part B: AZD8186 monotherapy | Experimental | Drug: Part B: AZD8186 monotherapyPart B - multiple dosing of intermittent dose schedule |
| Part D2: AZD8186/ AZD2014 | Experimental | Drug: Part D2 AZD2014 combination with AZD8186Expanded cohort of patients will be treated at a tolerated combination dose level established in Part D1 |
| Part C1: AZD8186 & abiraterone | Experimental | Drug: Part C1: Abiraterone acetate combination with AZD8186Patients will receive a week of abiraterone acetate with prednisone followed by combination dosing with AZD8186 at escalating doses of AZD8186 for the purpose of dose finding |
Who may qualify
- Ages
- 18 to 130 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- 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
Key exclusion criteria (23 listed)
- Treatment before study with
- Treatment before study with
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Part A: AZD8186 monotherapyThe 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 A: AZD8186 monotherapy |
| Part B: AZD8186 monotherapyPart B will be at a dose(s) and schedule(s) at or below from Part A | Drug | Part B: AZD8186 monotherapy |
| Part C1: Abiraterone acetate combination with AZD8186Dose and schedule finding of AZD8186 added to approved labelled dose of abiraterone acetate (with prednisone). | Drug | Part C1: AZD8186 & abiraterone |
| Part D1: AZD2014 combination with AZD8186Dose \& schedule finding of AZD8186 in combination with AZD2014 | Drug | Part D1: AZD8186 and AZD2014 |
| Part D2 AZD2014 combination with AZD8186Combination AZD8186/ AZD2014 dose expansion at dose determined in Part D1 | Drug | Part D2: AZD8186/ AZD2014 |
| Part C2: Abiraterone acetate combination with AZD8186Dose expansion of AZD8186 at dose determined in Part C1 added to approved dose of abiraterone acetate (with prednisone) | Drug | Part C2: AZD8186/abiraterone |
Primary outcome
Safety and tolerability
Time frame: Routine safety assessments, throughout the period that patients receive AZD8186 up to 30 days following discont of last dose of study treatment.
Assess safety and tolerability of AZD8186 when given as monotherapy or in combination with abiraterone acetate (with prednisone) or with AZD2014 by measuring AEs, SAE (incl death), safety measures incl ECG, physical exam, pulse, blood pressure, weight, lab variables
16 secondary outcomes
Part A: 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
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
Time frame: PSA at Screening, Days 1, 8 & 15 then every 28 days, discontinuation of treatment (on average after 4 months), 30-day follow-up: CTC enumeration Days 1, 56 & 84, then every 12 weeks, at discontinuation (on average after 4 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: Prior to first dose and during first 28 days of treatment
Part A + B: 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 a preliminary assessment of the antitumour activity of AZD8186 as monotherapy
Time frame: Paired tumour biopsies will be collected; one prior to treatment and the other during treatment (after at least 3 consecutive days of dosing 2-4 hours post-dose during 2nd week of trreatment)
Part B: Obtaining a preliminary assessment of AZD8186 drug effect in the tumour
Time frame: Paired tumour biopsies will be collected; one prior to treatment and the other during treatment (after at leat 3 consecutive days of dosing 2-4 hours post-dose in the second week of treatment)
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 week 3 (predose and 15min post dose)
Part C: safety and tolerability assessed by dose limiting toxicity of AZD8186 with abiraterone acetate (and prednisone)
Time frame: DLTs assessed during the first 21 days of multiple dosing
Part C: pharmacokinetics of and exposure to AZD8186, its major metabolite M1, and abiraterone
Time frame: Blood samples will be collected at multiple timepoints on 2 intense PK collection days between screening and the end of the first 28 days of combination treatment.
Part C: steady state exposure to abiraterone
Time frame: Blood samples will be collected at multiple timepoints on 2 intense PK collection days between screening and the end of the first 28 days of combination treatment.
Part C: steady state exposure of AZD8186 in combination with abiraterone acetate
Time frame: Blood samples will be collected at multiple timepoints on 2 intense PK collection days between screening and the end of the first 28 days of combination 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: 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), 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), Day 9 of treatment (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), day 9 (multiple dose)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 May 2020.
- Individual participant dataSharing planned: Yes. Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michele Mochetta, MD study director
AstraZeneca
Lillian Siu, MD principal investigator
Princess Margaret Hospital, Canada
13 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Part A: AZD8186 monotherapy, Part B: AZD8186 monotherapy and Part C1: Abiraterone acetate combination with AZD8186 in people with Advanced Castrate-resistant Prostate Cancer CRPC and Squamous Non-Small Cell Lung Cancer sqNSCLC, run by AstraZeneca at 13 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 May 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in United States, United Kingdom, Spain, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety and tolerability (time frame: Routine safety assessments, throughout the period that patients receive AZD8186 up to 30 days following discont of last dose of study treatment.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2020.