AZD8186 First Time In Patient Ascending Dose Study

Completed · Phase 1

Conditions studied: Advanced Castrate-resistant Prostate Cancer CRPC, Squamous Non-Small Cell Lung Cancer sqNSCLC, Triple Negative Breast Cancer TNBC

In brief

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.

Key facts

Study ID

NCT01884285

Run by

AstraZeneca

People needed

147

Starts

2013-07-09

Expected to finish

2020-02-07

Last updated by the study team

2020-05-29

Who can join

Age: 18 and older, up to 130. Sex: any. Healthy volunteers: not accepted.

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):
• 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

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).
• 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

Where it is running

• 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

Full record on ClinicalTrials.gov

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