Phase I, Dose Study to Look at the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours

Plain-language summary

This study evaluates the safety and how the body processes (pharmacokinetics) the drug AZD8835, alone and in combination with fulvestrant, in patients with advanced solid tumors. Adults with advanced solid tumors (including ER-positive, HER2-negative breast cancer, some with a PIK3CA gene mutation) and good general condition (ECOG 0-1) were able to take part. The study was carried out in Phase 1 and has been completed.

The summary above is a plain-language rendering of the official record. The original English title is shown for reference.

Trial details

Phase

Phase 1

Status

Completed

Sponsor

AstraZeneca

Intervention

AZD8835, AZD8835, AZD8835 in combination with fulvestrant, AZD8835 in combination with fulvestrant

Start date

11/1/2014

Estimated completion

7/1/2016

Countries

United States, United Kingdom

Related genes

Locations

• Denver, United States
• Greenville, United States
• Nashville, United States
• Houston, United States
• Milwaukee, United States
• Cambridge, United Kingdom
• London, United Kingdom
• London, United Kingdom
• Manchester, United Kingdom

Eligibility criteria

Criteria are reproduced from the ClinicalTrials.gov record in the original English. Only the trial team can determine eligibility.

Inclusion Criteria:

1. Part A: Histological or cytological confirmation of a solid tumor and disease progression. Part B: Histological or cytological confirmation of ER positive, HER2 negative breast cancer and disease progression or any other solid tumor with a PIK3CA gene mutation. Part C: Histological or cytological confirmation of ER positive, HER2 negative postmenopausal breast cancer with locally advanced or metastatic disease that is eligible for fulvestrant treatment. Part D: Histological or cytological confirmation of ER positive, HER2 negative postmenopausal breast cancer with locally advanced or metastatic disease that is eligible for fulvestrant treatment. Patients must also present with a tumor related mutation of the PIK3CA gene.
2. Availability of archival tumour tissue sample. If archival sample is not available, a fresh tumour biopsy must be provided.
3. At least one measurable lesion per RECIST v1.1. However, breast cancer patients with only bone disease are also eligible.
4. ECOG Performance Status 0-1.
5. Adequate organ function at baseline:

   1. Serum total bilirubin ≤ 1.5 x ULN and AST/SGOT and ALT/SGPT ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present.
   2. Creatinine ≤ 1.5 x ULN, or calculated or measured creatinine clearance ≥ 50 mL/min, or 24-hour measured urine creatinine clearance ≥ 50 mL/min.
   3. Platelets ≥ 100 x 10\^9, Hb ≥ 90 g/L, ANC ≥ 1.5 x 10\^9/L.
   4. aPTT ≤ 1.5 x ULN
   5. Fasting glucose \< 140 mg/dL (7.8 mmol/L).
   6. Glycated haemoglobin (HbA1c) \< 8%
6. Female patients and male patients with female partners of child bearing potential must be using adequate contraception.

Exclusion Criteria:

1. Recent chemotherapy, radiotherapy, hormonal therapy, immunotherapy or investigational drugs within 21 days or 5 half-days from enrolment.
2. Received palliative/focal radiotherapy within 2 weeks of first dose of study treatment.
3. Major surgery ≤ 21 days from beginning of study drug
4. Any of the following cardiac criteria: CHF \> Class II, cardiac ventricular arrhythmia requiring therapy, unstable angina or new-onset angina, QTcF interval \>470ms, abnormal ECHO or MUGA at baseline (LVEF \<50%).
5. Leptomeningeal disease
6. Part A: Intolerable AEs due to other PI3K inhibitors, dual PI3K and mTOR inhibitors or AKT inhibitors. Parts B, C, and D: Prior exposure to any of the following: pharmacological inhibitors of AKT, PI3K, or dual PI3K and mTOR kinase activity
7. Strong inhibitors and potent inducers of CYP3A4
8. Peripheral neuropathy CTCAE v4.03 Grade ≥ 3
9. Diarrhoea CTCAE v4.03 Grade ≥ 2
10. Acute or chronic pancreatitis
11. Clinically manifest diabetes mellitus, history of gestational diabetes mellitus and/or known glucose intolerance.
12. Patients currently receiving any medication that has the potential to prolong the QT interval or induce Torsades de Pointes
13. Spinal cord compression or brain metastases unless asymptomatic and not requiring steroids for at least 4 weeks
14. Patients in the combination arms - known hypersensitivity to fulvestrant
15. Therapeutic treatment with Coumadin or any other coumarin-derivative anticoagulant
16. Impaired GI function or GI disease that may interfere with absorption of AZD8835 or patients unable to take oral medication
17. As judged by the investigator any evidence of severe or uncontrolled systemic disease
18. Patients treated with hematopoietic colony-stimulating growth factors e.g., G-CSF, GM-CSF, M-CSF) ≤ 2 weeks prior to start. Erythropoietin or darbepoetin is allowed if it was initiated at least 2 weeks prior to entry