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

NCT02260661 | Completed Phase 1

• 1 other identifier: D6140C00001
• Study Type: interventional
• Target: 20
• Locations: 2 countries
• Sites: 9

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.

Conditions

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

Keywords

AZD8835; Fulvestrant; Breast Cancer; PIK3CA Gene Mutation

Outcome Measures

Primary Outcomes (2)

• Determine the maximum tolerated dose (MTD) or recommended Phase II dose of oral AZD8835 as a single agent and in combination with fulvestrant

  MTD - A dose will be considered non-tolerated and dose escalation will stop if 2 or more of up to 6 evaluable patients experience a dose limiting toxicity at a dose level. Once the non-tolerated dose is defined, the MTD will be confirmed at the previous dose level below the non-tolerated dose or a dose between the non-tolerated dose and the last tolerated dose my be investigated. A minimum of 6 evaluable patients are required to determine the MTD. Recommended Phase II dose - A minimum of 6 evaluable patients is necessary to determine the recommended dose. A dose will be considered non-tolerated and dose escalation will stop if 2 or more patients experience a dose dose limiting toxicity at a dose level.

  At the end of one cycle of treatment

• Establish the preliminary safety and tolerability profile of oral AZD8835 as a single agent and in combination with fulvestrant

  Assessed in terms of adverse events and laboratory data that is collected on all patients

  Up to a projected 36 months

Secondary Outcomes (3)

• To establish the pharmacokinetic profile of oral AZD8835 as a single agent and in combination with fulvestrant

  Venous blood samples will be collected pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 96 hours post dose - exact schedule varies according to Part A, B, C, or D

• To evaluate the preliminary efficacy and anti-tumor activity of oral AZD8835 as a single agent or in combination with fulvestrant

  Tumour response will be assessed at the completion of Cycle 2 (Week 8) and patients will be restaged after every 8 weeks for up to 1 year and every 12 weeks thereafter; assessments should be performed until disease progression.

• To evaluate the pharmacodynamic (PDc) effect of oral AZD8835 as a single agent and in combination with fulvestrant

  Tumour biopsies will be collected: (1) at pretreatment, (2) at one on-treatment time point (preferably Cycle 2 Day 1), and (3) at end of study treatment (preferably at disease progression)

Study Arms (4)

Part A

EXPERIMENTAL

AZD8835 single agent dose escalation

Drug: AZD8835

Part B

EXPERIMENTAL

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

Part C

EXPERIMENTAL

AZD8835 in combination with fulvestrant dose escalation

Drug: AZD8835 in combination with fulvestrant

Part D

EXPERIMENTAL

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

Interventions

AZD8835 DRUG

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

Part A

AZD8835 in combination with fulvestrant 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.

Also known as: Faslodex

Part C

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Availability of archival tumour tissue sample. If archival sample is not available, a fresh tumour biopsy must be provided.
• At least one measurable lesion per RECIST v1.1. However, breast cancer patients with only bone disease are also eligible.
• ECOG Performance Status 0-1.
• Adequate organ function at baseline:
• 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.
• Creatinine ≤ 1.5 x ULN, or calculated or measured creatinine clearance ≥ 50 mL/min, or 24-hour measured urine creatinine clearance ≥ 50 mL/min.
• Platelets ≥ 100 x 10\^9, Hb ≥ 90 g/L, ANC ≥ 1.5 x 10\^9/L.
• aPTT ≤ 1.5 x ULN
• Fasting glucose \< 140 mg/dL (7.8 mmol/L).
• Glycated haemoglobin (HbA1c) \< 8%
• Female patients and male patients with female partners of child bearing potential must be using adequate contraception.

You may not qualify if:

• Recent chemotherapy, radiotherapy, hormonal therapy, immunotherapy or investigational drugs within 21 days or 5 half-days from enrolment.
• Received palliative/focal radiotherapy within 2 weeks of first dose of study treatment.
• Major surgery ≤ 21 days from beginning of study drug
• 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%).
• Leptomeningeal disease
• 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
• Strong inhibitors and potent inducers of CYP3A4
• Peripheral neuropathy CTCAE v4.03 Grade ≥ 3
• Diarrhoea CTCAE v4.03 Grade ≥ 2
• Acute or chronic pancreatitis
• Clinically manifest diabetes mellitus, history of gestational diabetes mellitus and/or known glucose intolerance.
• Patients currently receiving any medication that has the potential to prolong the QT interval or induce Torsades de Pointes
• Spinal cord compression or brain metastases unless asymptomatic and not requiring steroids for at least 4 weeks
• Patients in the combination arms - known hypersensitivity to fulvestrant
• Therapeutic treatment with Coumadin or any other coumarin-derivative anticoagulant

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (9)

Research Site

Denver, Colorado, United States

Location

Research Site

Greenville, South Carolina, United States

Location

Research Site

Nashville, Tennessee, United States

Location

Research Site

Houston, Texas, United States

Location

Research Site

Milwaukee, Wisconsin, United States

Location

Research Site

Cambridge, United Kingdom

Location

Sarah Cannon Research Institute, United Kingdom

London, W1G 6AD, United Kingdom

Location

Research Site

London, United Kingdom

Location

Research Site

Manchester, United Kingdom

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

AZD8835; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Hendrik-Tobias Arkenau, FRCP, PhD

  Sarah Cannon Research Institute, United Kingdom

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 6, 2014
• First Posted: October 9, 2014
• Study Start: November 1, 2014
• Primary Completion: July 1, 2016
• Study Completion: July 1, 2016
• Last Updated: October 10, 2016

Record last verified: 2016-10

Locations

US (5); GB (4)