Phase I, Dose Study to look at the Safety and Pharmacokinetics of AZD8835 in Patients with Advanced Solid Tumours - None

Study identifier:D6140C00001

ClinicalTrials.gov identifier:NCT02260661

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase I, Open-Label, Multicentre, Dose-Escalation Study to Investigate the Safety and Pharmacokinetics of AZD8835 in Patients with Advanced Solid Tumours

Medical condition

Advanced solid malignancies

Phase

Phase 1

Healthy volunteers

Study drug

AZD8835, AZD8835 in combination with fulvestrant

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 06 Nov 2014

Primary Completion Date: 11 Jul 2016

Study Completion Date: 11 Jul 2016

Study design

Allocation: Non-randomized
Endpoint Classification: Safety
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Apr 2018 by AstraZeneca

Collaborators

Inclusion and exclusion 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:
a) 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.
b) Creatinine ≤ 1.5 x ULN, or calculated or measured creatinine clearance ≥ 50 mL/min, or 24-hour measured urine creatinine clearance ≥ 50 mL/min.
c) Platelets ≥ 100 x 10^9, Hb ≥ 90 g/L, ANC ≥ 1.5 x 10^9/L.
d) aPTT ≤ 1.5 x ULN
e) Fasting glucose < 140 mg/dL (7.8 mmol/L).
f) 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

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).

No locations available

Arms	Assigned Interventions
Experimental: Part A AZD8835 single agent dose escalation	Drug: AZD8835 AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components Other Name: N/A
Experimental: 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.	Drug: AZD8835 AZD 8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components Other Name: N/A
Experimental: Part C AZD8835 in combination with fulvestrant dose escalation	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. Other Name: Faslodex
Experimental: 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).	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 Other Name: Faslodex

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]

Investigators

Principal Investigator

Hendrik-Tobias Arkenau

Sarah Cannon Research Institute, United Kingdom