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

Launched by ASTRAZENECA · Oct 6, 2014

Keywords

ClinConnect Summary

AZD8835 is a novel small molecule that inhibits cancer progression by blocking PI3 kinase pathway components p110α and p110δ.

In this first-time-in-patient study, AZD8835 will initially be administered as a single agent to patients with advanced solid malignancies. Patients will be treated at a starting dose of 20 mg twice daily (BID), administered weekly on Days 1 and 4 and will be escalated to reach a maximum-tolerated dose (MTD) in patients as defined by dose-limiting toxicities (DLTs). A BID intermittent dosing schedule administered weekly on Days 1 and 4 of an oral formulation of AZD8...

Gender

ALL

Eligibility 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