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

• Status: Completed
• Trial end date: 2016-07-01
• Target enrollment: 0
• Participant gender: All

Summary

First time in patients study of AZD8835. The study has four parts. Part A AZD8835 is administered as a single agent in a multiple ascending dose escalation phase to investigate dose level for monotherapy. Part B follows the multiple ascending dose phase, additional patients with tumors with documented PIK3CA gene mutation will be enrolled to a single dose expansion phase. Part C is a second dose escalation phase in which post-menopausal patients with estrogen receptor positive (ER+), HER2 negative breast cancer will receive AZD8835 in combination with fulvestrant. Part D follows the combination dose escalation phase of the study, additional postmenopausal patients with ER+/HER2 negative breast cancer with documented PIK3CA gene mutation will be enrolled to a AZD8835 and fulvestrant combination dose-expansion phase at maximum tolerated dose or recommended phase II dose.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: AstraZeneca
• Treatments: Estradiol; Fulvestrant; Polystyrene sulfonic acid

Criteria

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