AZD8186 First Time In Patient Ascending Dose Study

NCT ID: NCT01884285

Last Updated: 2020-05-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 147 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-07-09
• Study Completion Date: 2020-02-07

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.

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Part A: AZD8186 monotherapy

Intervention Type: DRUG

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 C2: AZD8186/abiraterone

Patients will receive a week of abiraterone acetate with prednisone followed by combination dosing with AZD8186.

Group Type: EXPERIMENTAL

Part C2: Abiraterone acetate combination with AZD8186

Intervention Type: DRUG

Dose expansion of AZD8186 at dose determined in Part C1 added to approved dose of abiraterone acetate (with prednisone)

Part D1: AZD8186 and AZD2014

Combination dosing with AZD8186 and AZD2014 both given on an intermittent schedule at escalating dose levels of each IMP for combination dose finding

Group Type: EXPERIMENTAL

Part D1: AZD2014 combination with AZD8186

Intervention Type: DRUG

Dose \& schedule finding of AZD8186 in combination with AZD2014

Part B: AZD8186 monotherapy

Part B - multiple dosing of intermittent dose schedule

Group Type: EXPERIMENTAL

Part B: AZD8186 monotherapy

Intervention Type: DRUG

Part B will be at a dose(s) and schedule(s) at or below from Part A

Part D2: AZD8186/ AZD2014

Expanded cohort of patients will be treated at a tolerated combination dose level established in Part D1

Group Type: EXPERIMENTAL

Part D2 AZD2014 combination with AZD8186

Intervention Type: DRUG

Combination AZD8186/ AZD2014 dose expansion at dose determined in Part D1

Part C1: AZD8186 & abiraterone

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

Group Type: EXPERIMENTAL

Part C1: Abiraterone acetate combination with AZD8186

Intervention Type: DRUG

Dose and schedule finding of AZD8186 added to approved labelled dose of abiraterone acetate (with prednisone).

Interventions

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.

Intervention Type: DRUG

Part B: AZD8186 monotherapy

Part B will be at a dose(s) and schedule(s) at or below from Part A

Intervention Type: DRUG

Part C1: Abiraterone acetate combination with AZD8186

Dose and schedule finding of AZD8186 added to approved labelled dose of abiraterone acetate (with prednisone).

Intervention Type: DRUG

Part D1: AZD2014 combination with AZD8186

Dose \& schedule finding of AZD8186 in combination with AZD2014

Intervention Type: DRUG

Part D2 AZD2014 combination with AZD8186

Combination AZD8186/ AZD2014 dose expansion at dose determined in Part D1

Intervention Type: 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)

Intervention Type: DRUG

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

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 130 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michele Mochetta, MD

Role: STUDY_DIRECTOR

AstraZeneca

Lillian Siu, MD

Role: PRINCIPAL_INVESTIGATOR

Princess Margaret Hospital, Canada

Locations

Research Site

Boston, Massachusetts, United States

Research Site

Detroit, Michigan, United States

Research Site

New York, New York, United States

Research Site

Seattle, Washington, United States

Research Site

Madison, Wisconsin, United States

Research Site

Toronto, Ontario, Canada

Research Site

Barcelona, , Spain

Research Site

Barcelona, , Spain

Research Site

Pozuelo de Alarcón, , Spain

Research Site

Cambridge, , United Kingdom

Research Site

London, , United Kingdom

Research Site

Manchester, , United Kingdom

Research Site

Sutton, , United Kingdom

Countries

United States; Canada; Spain; United Kingdom

Other Identifiers

D4620C00001

Identifier Type: -

Identifier Source: org_study_id