Clinical trial NCT01884285: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2013-06-24
Enrollment: 147
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Safety and tolerability
timeFrame: Routine safety assessments, throughout the period that patients receive AZD8186 up to 30 days following discont of last dose of study treatment.
Secondary outcomes:
measure: Part A: The number of evaluable patients with dose limiting toxicities (DLTs).
timeFrame: DLTs assessed during the first 21 days of multiple dosing.
measure: Part A, B, C + D: Antitumor activity of AZD8186 monotherapy or in combination
timeFrame: Every 12 weeks (non prostate patients) or every 6 weeks (prostate patients) from baseline up to disease progression or withdrawal of consent
measure: Part A, B, C and D: Anti-tumour activity of AZD8186 monotherapy or in combination
timeFrame: 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).
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)
timeFrame: Prior to first dose and during first 28 days of treatment
measure: Part A + B: 4 beta-hydroxy cholesterol concentration in blood samples.
timeFrame: 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.
measure: Part B: Obtaining a preliminary assessment of the antitumour activity of AZD8186 as monotherapy
timeFrame: 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)
measure: Part B: Obtaining a preliminary assessment of AZD8186 drug effect in the tumour
timeFrame: 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)
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)
timeFrame: 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)
measure: Part C: safety and tolerability assessed by dose limiting toxicity of AZD8186 with abiraterone acetate (and prednisone)
timeFrame: DLTs assessed during the first 21 days of multiple dosing
measure: Part C: pharmacokinetics of and exposure to AZD8186, its major metabolite M1, and abiraterone
timeFrame: 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.
measure: Part C: steady state exposure to abiraterone
timeFrame: 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.
measure: Part C: steady state exposure of AZD8186 in combination with abiraterone acetate
timeFrame: 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.
measure: Part D: Measure the dose limiting toxicity of AZD8186 in combination with AZD2014.
timeFrame: DLTs assessed during the first 21 days of multiple dosing
measure: Part D: Single dose and multiple dose pharmacokinetics of and assess exposure to AZD8186, its major metabolite M1, and AZD2014 when co-administered
timeFrame: 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)
measure: Part D: Measure the exposure to AZD2014 following the last weekly dose of AZD2014 in the absence and presence of multiple dose AZD8186.
timeFrame: 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)
measure: Part D: Measure the exposure on the 4th administred dose of AZD8186 in the absence and presence of multiple dose AZD2014
timeFrame: 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)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: New York
country: United States
facility: Research Site
state: New York
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Madison
country: United States
facility: Research Site
state: Wisconsin
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Pozuelo de Alarcon
country: Spain
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Michele Mochetta, MD
role: STUDY_DIRECTOR
affiliation: Princess Margaret Hospital, Canada
name: Lillian Siu, MD
role: PRINCIPAL_INVESTIGATOR
References: