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.
- Provision of signed and dated, written informed consent prior to any study specific
- 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
- 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
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
- Serum testosterone concentration ≤50 ng/dL sustained by medical or surgical
- 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.
- Measurable disease (at least 1 lesion ≥10 mm longest diameter or for lymph nodes short
axis ≥15 mm) by CT/MRI
- 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
- 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
- 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