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

NCT ID: NCT02260661

Last Updated: 2016-10-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-11-30
• Study Completion Date: 2016-07-31

Brief 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.

Detailed Description

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 AZD8835 will be used, as deemed optimal and effective in non-clinical studies, primarily to determine the safety and tolerability of AZD8835. The pharmacokinetics (PK) of AZD8835 and potential biological activity will also be investigated. In Part A of this study, AZD8835 will be administered as a single agent in a multiple ascending dose escalation phase to investigate the appropriate monotherapy dose level for clinical use. Additional dosing schedules may be studies, including dosing on Days 1 and 2 of each week, rather than Days 1 and 4.

Backfilled pharmacodynamic (PDc) cohorts in selected patients with tumours that have documented mutations in the phosphatidylinositol-4,5- bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene will allow further preliminary assessment of the biological effect of AZD8835 in these patients.

Following the single-agent dose-escalation phase of the study, additional patients with tumours that have documented mutations in the PIK3CA gene will be enrolled to a single-agent dose-expansion phase at the MTD or recommended Phase II dose (RP2D) at the selected dose schedule (as appropriate) to explore further the safety, tolerability, PK, and biological activity at the selected dose (Part B).

In addition, a further dose-escalation phase will be initiated following the observation of specific pre-determined criteria in the single-agent dose escalation, in which postmenopausal patients with oestrogen receptor positive (ER+), HER2 negative breast cancer will receive AZD8835 in combination with fulvestrant (Part C). The combination dose-escalation phase will investigate the appropriate combination dose level for clinical use.

Following the combination dose-escalation phase of the study, additional postmenopausal patients with ER+ breast cancer and tumours with documented mutations of the PIK3CA gene will be enrolled to a AZD8835 and fulvestrant combination dose-expansion phase at the MTD or RP2D (as appropriate) to explore further the safety, tolerability, PK, and biological activity at the selected dose (Part D).

Conditions

Advanced Solid Malignancies; Breast Cancer - ER+, HER2 -; Breast Cancer - ER+, HER2-, PIK3CA Gene Mutation

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part A

AZD8835 single agent dose escalation

Group Type: EXPERIMENTAL

AZD8835

Intervention Type: DRUG

AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components

Part B

Following the single agent dose escalation (Part A), additional patients with mutations in the PIK3CA gene will be enrolled to a single agent dose expansion phase at the MTD or recommended phase II dose (RP2D) at the selected dose schedule (as appropriate) to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected dose (Part B). Part B will include patients with ER+/HER2 negative breast cancer whose tumours have a mutation of the PIK3CA gene and patients with any solid tumours which have a mutation of the PIK3CA gene.

Group Type: EXPERIMENTAL

AZD8835

Intervention Type: DRUG

AZD 8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components

Part C

AZD8835 in combination with fulvestrant dose escalation

Group Type: EXPERIMENTAL

AZD8835 in combination with fulvestrant

Intervention Type: DRUG

AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy.

Part D

Following the combination dose escalation segment of the study (Part C), additional postmenopausal patients with ER+/HER negative breast cancer and mutations of the PIK3CA gene will be enrolled to a AZD8835 and fulvestrant combination dose expansion phase at the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) (as appropriate) to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected dose (Part D).

Group Type: EXPERIMENTAL

AZD8835 in combination with fulvestrant

Intervention Type: DRUG

AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy

Interventions

AZD8835

AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components

Intervention Type: DRUG

AZD8835

AZD 8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components

Intervention Type: DRUG

AZD8835 in combination with fulvestrant

AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy.

Intervention Type: DRUG

AZD8835 in combination with fulvestrant

AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy

Intervention Type: DRUG

Other Intervention Names

Faslodex; Faslodex

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 130 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hendrik-Tobias Arkenau, FRCP, PhD

Role: PRINCIPAL_INVESTIGATOR

Sarah Cannon Research Institute, United Kingdom

Locations

Research Site

Denver, Colorado, United States

Research Site

Greenville, South Carolina, United States

Research Site

Nashville, Tennessee, United States

Research Site

Houston, Texas, United States

Research Site

Milwaukee, Wisconsin, United States

Research Site

Cambridge, , United Kingdom

Sarah Cannon Research Institute, United Kingdom

London, , United Kingdom

Research Site

London, , United Kingdom

Research Site

Manchester, , United Kingdom

Countries

United States; United Kingdom

Other Identifiers

D6140C00001

Identifier Type: -

Identifier Source: org_study_id