AZD8186 First Time In Patient Ascending Dose Study

Study identifier:D4620C00001

ClinicalTrials.gov identifier:NCT01884285

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

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

Medical condition

Advanced Castrate-resistant Prostate Cancer CRPC

Phase

Phase 1

Healthy volunteers

Study drug

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, Part C2: Abiraterone acetate combination with AZD8186

Sex

All

Actual Enrollment

147

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 09 Jul 2013

Primary Completion Date: 29 Mar 2019

Study Completion Date: 07 Feb 2020

Study design

Allocation: Non-randomized
Endpoint Classification: Safety
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Mar 2021 by AstraZeneca

Collaborators

Inclusion and exclusion 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
(a) Nitrosourea or mitomycin C within 6 weeks
(b)Investigational agents from previous clinical study within 4 weeks
(c) Chemotherapy, immunotherapy or anticancer agents within 4 weeks
(d) hormonal therapy
- Treatment before study with
(a)Strong inhibitors and strong or moderate inducers of CYP3A4
(b)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

No locations available

Arms	Assigned Interventions
Experimental: 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.	Drug: 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. Other Name: None
Experimental: Part C2: AZD8186/abiraterone Patients will receive a week of abiraterone acetate with prednisone followed by combination dosing with AZD8186.	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) Other Name: None
Experimental: 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	Drug: Part D1: AZD2014 combination with AZD8186 Dose & schedule finding of AZD8186 in combination with AZD2014 Other Name: None
Experimental: Part B: AZD8186 monotherapy Part B - multiple dosing of intermittent dose schedule	Drug: Part B: AZD8186 monotherapy Part B will be at a dose(s) and schedule(s) at or below from Part A Other Name: None
Experimental: Part D2: AZD8186/ AZD2014 Expanded cohort of patients will be treated at a tolerated combination dose level established in Part D1	Drug: Part D2 AZD2014 combination with AZD8186 Combination AZD8186/ AZD2014 dose expansion at dose determined in Part D1 Other Name: None
Experimental: 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	Drug: Part C1: Abiraterone acetate combination with AZD8186 Dose and schedule finding of AZD8186 added to approved labelled dose of abiraterone acetate (with prednisone). Other Name: None

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]

Contact Backup

AstraZeneca Cancer Study Locator Service www.emergingmed.com/networks/AstraZeneca

1-877-400-4656