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



Status:Active, not recruiting
Conditions:Breast Cancer, Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - 127
Updated:6/30/2016
Start Date:November 2014
End Date:May 2017

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

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.

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).

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
We found this trial at
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Cambridge,
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Denver, CO
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Greenville, South Carolina 29605
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