AZD8186 First Time In Patient Ascending Dose Study

NCT01884285 | Completed Phase 1

• 1 other identifier: D4620C00001
• Study Type: interventional
• Target: 147
• Locations: 4 countries
• Sites: 13

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.

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

Outcome Measures

Primary Outcomes (1)

• 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

  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).

  DLTs assessed during the first 21 days of multiple dosing.

• 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, 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 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: 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.

Study Arms (6)

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.

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.

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

Drug: Part D1: AZD2014 combination with AZD8186

Part B: AZD8186 monotherapy

EXPERIMENTAL

Part B - multiple dosing of intermittent dose schedule

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

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

Drug: Part C1: Abiraterone acetate combination with AZD8186

Interventions

Part A: AZD8186 monotherapy 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 A: AZD8186 monotherapy

Part B: AZD8186 monotherapy DRUG

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

Part B: AZD8186 monotherapy

Part C1: Abiraterone acetate combination with AZD8186 DRUG

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

Part C1: AZD8186 & abiraterone

Part D1: AZD2014 combination with AZD8186 DRUG

Dose \& schedule finding of AZD8186 in combination with AZD2014

Part D1: AZD8186 and AZD2014

Part D2 AZD2014 combination with AZD8186 DRUG

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

Part D2: AZD8186/ AZD2014

Part C2: Abiraterone acetate combination with AZD8186 DRUG

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

Part C2: AZD8186/abiraterone

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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):

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (13)

Research Site

Boston, Massachusetts, 02215, United States

Location

Research Site

Detroit, Michigan, 48201, United States

Location

Research Site

New York, New York, 10065, United States

Location

Research Site

Seattle, Washington, 98109, United States

Location

Research Site

Madison, Wisconsin, 53792-5666, United States

Location

Research Site

Toronto, Ontario, M5G 2M9, Canada

Location

Research Site

Barcelona, 08035, Spain

Location

Research Site

Barcelona, 8036, Spain

Location

Research Site

Pozuelo de Alarcón, 28223, Spain

Location

Research Site

Cambridge, CB2 0QQ, United Kingdom

Location

Research Site

London, WC1E 6BT, United Kingdom

Location

Research Site

Manchester, M20 4BX, United Kingdom

Location

Research Site

Sutton, SM1 2DL, United Kingdom

Location

MeSH Terms

Conditions

Triple Negative Breast Neoplasms

Interventions

AZD8186

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Michele Mochetta, MD

  AstraZeneca

  STUDY DIRECTOR

• Lillian Siu, MD

  Princess Margaret Hospital, Canada

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 17, 2013
• First Posted: June 24, 2013
• Study Start: July 9, 2013
• Primary Completion: March 31, 2019
• Study Completion: February 7, 2020
• Last Updated: May 29, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Locations

US (5); CA (1); GB (4); ES (3)