Study of AZD2014 and Palbociclib in Patients With Estrogen Receptor Positive (ER+) Metastatic Breast Cancer

NCT02599714 | Completed Phase 1 DMC FDA Drug

• 3 other identifiers: D2270C000202644772015-003320-30
• Study Type: interventional
• Target: 54
• Locations: 2 countries
• Sites: 7

Brief Summary

This dose finding/extension study was designed originally to consist of three parts: Part A was intended to identify the MTD of the AZD2014/ palbociclib combination on a background of fulvestrant (referred to as the triplet) in postmenopausal women with locally advanced/ metastatic estrogen receptor positive (ER+) breast cancer. Part B was to further characterize safety, tolerability, PK, and preliminary efficacy in single-arm dose expansion groups. Part C was to be a Phase 2, randomized, double-blind, extension comparing the triplet and doublet combinations. Part C was deleted from the protocol and was not performed.

Conditions

Advanced and Metastatic Breast Cancer

Keywords

AZD2014; Palbociclib; Fulvestrant; Hormonal Therapy; Estrogen Receptor Positive; Breast Cancer

Outcome Measures

Primary Outcomes (1)

• Parts A and B: Number of adverse events experienced by patients

  Safety and tolerability assessed through the incidence of adverse events.

  Approximately 16 months

Secondary Outcomes (15)

• Part B: Progression Free Survival (PFS)

  Assessed every 8 weeks for approximately 16 months

• Parts A and B: Best Objective Response (BOR)

  Assessed every 8 weeks for approximately 16 months

• Parts A and B: Objective Response Rate (ORR)

  Assessed every 8 weeks for approximately 16 months

• Part B: Duration of Response (DoR)

  Assessed every 8 weeks for approximately 16 months

• Part B: Overall Survival (OS)

  Approximately 24 months

Study Arms (2)

Triplet Combination (Dose Finding)

EXPERIMENTAL

Phase 1 triplet dose finding phase in 3-6 patients per cohort - approximately 30 patients depending on emerging data to determine the maximum tolerated dose (MTD) of the triplet.

Drug: AZD2014; Drug: Palbociclib; Drug: Fulvestrant

Triplet Combination (Dose Expansion)

EXPERIMENTAL

Additional patients will be enrolled at the dose determined in Part A.

Drug: AZD2014; Drug: Palbociclib; Drug: Fulvestrant

Interventions

AZD2014 DRUG

The triplet combination will be comprised of AZD2014 + palbociclib + fulvestrant.

Also known as: vistusertib

Triplet Combination (Dose Expansion); Triplet Combination (Dose Finding)

Palbociclib DRUG

cyclin dependent kinase inhibitor

Also known as: Ibrance, PD-0332991

Triplet Combination (Dose Expansion); Triplet Combination (Dose Finding)

Fulvestrant DRUG

Fulvestrant hormonal therapy as background

Also known as: Faslodex

Triplet Combination (Dose Expansion); Triplet Combination (Dose Finding)

Eligibility Criteria

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

You may qualify if:

• Signed and dated written informed consent prior to any mandatory study specific procedures, sampling and analyses.
• Signed and dated written informed consent for tumour biopsies. If the tumour is found not to be safely accessible the biopsy will not be taken. Accessible lesions are defined as those which are biopsiable and amenable to repeat biopsy, unless clinically contraindicated. In this case the patient will remain in the study and there will be no penalty or loss of benefit to the patient and they will not be excluded from other aspects of the study.
• Postmenopausal women aged ≥ 18 years
• Negative pregnancy test prior to dosing and willing to use a highly effective method of contraception for the duration of the study and for 90 days after the last dose of IP if they are under 50 unless they have medically confirmed irreversible premature ovarian failure, bilateral oophorectomy, bilateral salpinectomy, or complete or partial hysterectomy.
• Highly effective methods of contraception are:
• Use of oral, injected or implanted hormonal methods of contraception which inhibit ovulation, either estrogen and progestogen containing intravaginal, transdermal) or only progesterone containing (oral, injectable, implantable)
• Placement of an intrauterine device (IUD or intrauterine system (IUS)
• True abstinence
• Bilateral tubal ligation
• Vasectomised partner
• World Health Organisation/Eastern Cooperative Oncology Group (ECOG) performance status of patient is 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.
• Histologically or cytologically proven diagnosis of breast cancer with evidence of locally advanced or metastatic disease, not amenable to resection or radiation therapy with curative intent.
• Documentation of estrogen receptor positive (ER+) breast cancer based on most recent tumour biopsy (unless bone-only disease).
• Documented human epidermal growth factor receptor 2 negative (HER2-) tumor on most recent tumor biopsy.
• Where regionally permitted, all patients must agree to provide if available a formalin-fixed paraffin embedded (FFPE) tissue biopsy sample taken at the time of presentation with recurrent or metastatic disease.

You may not qualify if:

• Prior chemotherapy, biological therapy, radiation therapy, or immunotherapy, androgens, thalidomide, other anticancer agents, investigational drug or corticosteroids within 14 days. Patients who received prior radiotherapy to \>= 25% of bone marrow are not eligible independent of when it was received. Patients is not eligible if there are unresolved toxicities from prior therapy \> CTCAE grade 1 at the start of study treatment with the exception of alopecia.
• Exposure to potent or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) or BCRP within stated washout periods.
• Exposure to sensitive or narrow therapeutic range substrates of drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K within wash-out period (5 x elimination half-life).
• Exposure to proton pump inhibitors within wash-out period (5 x elimination half-life).
• \. Previous AZD2014, AZD8055 or other dual mTORC1/2 inhibitor
• In Part B only: Prior treatment with CDK4/6, or everolimus or any PI3K-mTOR pathway
• \. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease. Patients with a history of CNS metastases or cord compression are eligible if definitively treated and clinically stable and off anticonvulsants and steroids for at least 4 weeks. Patients are not eligible if there is spinal cord compression and/or brain metastases, unless asymptomatic or treated and stable and off steroids for at least 4 weeks.
• \. Evidence of severe or uncontrolled systemic diseases such as:
• Severe hepatic impairment
• Interstitial lung disease (bilateral, diffuse, parenchymal lung disease)
• Current unstable or uncompensated respiratory or cardiac conditions
• Uncontrolled hypertension
• Active bleeding diatheses
• Any active infection
• \. Other malignancy within 3 years, except adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (7)

Research Site

Encinitas, California, 92024, United States

Location

Research Site

Sarasota, Florida, 34232, United States

Location

Research Site

Detroit, Michigan, 48201, United States

Location

Research Site

Nashville, Tennessee, 37203, United States

Location

Research Site

Milwaukee, Wisconsin, 53226, United States

Location

Research Site

Liverpool, L7 8XP, United Kingdom

Location

Research Site

London, W1G 6AD, United Kingdom

Location

Related Links

• Redacted CSR synopsis

MeSH Terms

Conditions

Breast Neoplasms

Interventions

vistusertib; palbociclib; 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

• Anja Wiliams

  Sarah Cannon Research Institute UK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: Study was originally designed as randomized and double blinded. Currently (CSP v.8.0 of 14-Dec-2021) no masking and no randomization is planned.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 5, 2015
• First Posted: November 9, 2015
• Study Start: December 7, 2015
• Primary Completion: March 30, 2018
• Study Completion: November 23, 2023
• Last Updated: June 6, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

GB (2); US (5)