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
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- AstraZeneca
- Enrollment
- 147
- Locations
- 1
- Primary Endpoint
- Safety and tolerability
Overview
Brief 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 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
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 130 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
Exclusion Criteria
- Not provided
Arms & Interventions
Part D2: AZD8186/ AZD2014
Expanded cohort of patients will be treated at a tolerated combination dose level established in Part D1
Intervention: Part D2 AZD2014 combination with AZD8186 (Drug)
Outcomes
Primary Outcomes
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
Secondary Outcomes
- Part A, B, C + D: Antitumor activity of AZD8186 monotherapy or in combination(Every 12 weeks (non prostate patients) or every 6 weeks (prostate patients) from baseline up to disease progression or withdrawal of consent)
- 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)(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 A: The number of evaluable patients with dose limiting toxicities (DLTs).(DLTs assessed during the first 21 days of multiple dosing.)
- Part A + B: 4 beta-hydroxy cholesterol concentration in blood samples.(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 C: safety and tolerability assessed by dose limiting toxicity of AZD8186 with abiraterone acetate (and prednisone)(DLTs assessed during the first 21 days of multiple dosing)
- Part C: pharmacokinetics of and exposure to AZD8186, its major metabolite M1, and abiraterone(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 B: Obtaining a preliminary assessment of the antitumour activity of AZD8186 as monotherapy(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 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)(Prior to first dose and during first 28 days of treatment)
- Part A, B, C and D: Anti-tumour activity of AZD8186 monotherapy or in combination(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 B: Obtaining a preliminary assessment of AZD8186 drug effect in the tumour(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 C: steady state exposure of AZD8186 in combination with abiraterone acetate(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.(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(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 on the 4th administred dose of AZD8186 in the absence and presence of multiple dose AZD2014(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 C: steady state exposure to abiraterone(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 exposure to AZD2014 following the last weekly dose of AZD2014 in the absence and presence of multiple dose AZD8186.(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))