The AVIATOR Study: Trastuzumab and Vinorelbine With Avelumab OR Avelumab & Utomilumab in Advanced HER2+ Breast Cancer

NCT ID: NCT03414658

Last Updated: 2025-07-02

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-21
• Study Completion Date: 2026-05-31

Brief Summary

This research study is studying a combination of drugs as a possible treatment for breast cancer.

The drugs involved in this study are:

• Group A: Trastuzumab (Herceptin) + Vinorelbine (Navelbine)
• Group B: Trastuzumab + Vinorelbine + Avelumab
• Group C: Trastuzumab + Vinorelbine + Avelumab + Utomilumab (PF-05082566)

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the drug combination works in treating a specific disease. "Investigational" means that drug combination is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved Utomilumab as a treatment for any disease.

The FDA (the U.S. Food and Drug Administration) has approved Avelumab as a treatment for other diseases.

The FDA (the U.S. Food and Drug Administration) has approved trastuzumab as a treatment option for this disease.

The FDA (the U.S. Food and Drug Administration) has approved vinorelbine as a treatment for other diseases and is commonly used as a treatment option for this disease.

The immune system is the body's natural defense against disease. The immune system sends a type of cells called T cells throughout the body to detect and fight infections and diseases-including cancers. One way the immune system controls the activity of T cells is through the PD-1 (programmed cell death protein-1) pathway. However, some cancer cells hide from T-cell attack by taking control of the PD-1 pathway and this stops T cells from attacking cancer cells. Avelumab is a type of drug, known as an antibody which is designed to block the PD-1 pathway and helps the immune system in detecting and fighting cancer cells. An antibody is a protein produced by the body's immune system when it detects harmful substances. Previous studies show that the administration of antibodies which block the PD-1 pathway can lead to tumor destruction.

Utomilumab is an antibody designed to stimulate the body's immune system to fight cancer cells. Previous studies have shown that the administration of this type of antibody may help to prevent tumors from growing.

In the laboratory, adding avelumab and Utomilumab to trastuzumab appears to improve effectiveness. It is not known whether this is true in humans.

In this research study, the investigators are evaluating the activity of 3 different combinations: (a)trastuzumab and vinorelbine combined, (b) trastuzumab, vinorelbine and avelumab combined, and (c) trastuzumab, vinorelbine, avelumab and utomilumab combined in participants with metastatic HER2- positive breast cancer.

Conditions

Breast Cancer

Study Design

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

Study Groups

NH: Trastuzumab + Vinorelbine

• Trastuzumab is administered intravenously twice per cycle
• Vinorelbine is administered intravenously 3 times per cycle

Group Type: EXPERIMENTAL

Vinorelbine

Intervention Type: DRUG

work by interfering with cell division, which leaves the tumor unable to grow and spread

Trastuzumab

Intervention Type: DRUG

trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2.

NHA: Trastuzumab + Vinorelbine + Avelumab

• Trastuzumab is administered intravenously twice per cycle
• Vinorelbine is administered intravenously 3 times per cycle
• Avelumab is administered intravenously twice per cycle
• Antihistamine and with acetaminophen is mandatory 30 to 60 minutes prior to each dose of avelumab

Group Type: EXPERIMENTAL

Vinorelbine

Intervention Type: DRUG

work by interfering with cell division, which leaves the tumor unable to grow and spread

Trastuzumab

Intervention Type: DRUG

trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2.

Avelumab

Intervention Type: DRUG

monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein

NHAU: Trastuzumab + Vinorelbine + Avelumab + Utomilumab

• Trastuzumab is administered intravenously twice per cycle
• Vinorelbine is administered intravenously 3 times per cycle
• Avelumab is administered intravenously twice per cycle
• Antihistamine and with acetaminophen is mandatory 30 to 60 minutes prior to each dose of avelumab
• Utomilumab is administered intravenously once per cycle

Group Type: EXPERIMENTAL

Vinorelbine

Intervention Type: DRUG

work by interfering with cell division, which leaves the tumor unable to grow and spread

Trastuzumab

Intervention Type: DRUG

trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2.

Avelumab

Intervention Type: DRUG

monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein

Utomilumab

Intervention Type: DRUG

Utomilumab is an antibody designed to stimulate the body's immune system to fight cancer cells

Interventions

Vinorelbine

work by interfering with cell division, which leaves the tumor unable to grow and spread

Intervention Type: DRUG

Trastuzumab

trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2.

Intervention Type: DRUG

Avelumab

monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein

Intervention Type: DRUG

Utomilumab

Utomilumab is an antibody designed to stimulate the body's immune system to fight cancer cells

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age ≥18 years or older
• Histologically confirmed breast adenocarcinoma that is unresectable loco-regionally advanced or metastatic
• HER2-positive (immunohistochemistry score 3+) or ERBB2- amplification (Ratio ERBB2/centromeres ≥ 2.0 or mean gene copy number ≥ 6) on primary tumor or of metastatic or unresectable loco-regional biopsy.
• Measurable disease per RECIST v1.1 (see Section 11)
• Patients must have previous treatment with ado-trastuzumab emtansine (Kadcyla, T-DM1) in any setting. Patients must have previously received trastuzumab and pertuzumab in the metastatic setting or within 12 months of neoadjuvant/adjuvant treatment.
• Patient must have progressed on their most recent line of therapy. Progression must have been demonstrated by radiological or clinical assessment.
• Left ventricular ejection fraction (LVEF) ≥ 50%
• Willingness and availability to submit FFPE tissue for central confirmation of HER2 positivity and central assessment of PD-L1 status. This can be from archival tissue from unresectable loco-regional or metastatic disease obtained ≤ 1 year prior to enrollment or new tissue material from a recently obtained surgical or diagnostic biopsy. Tissue obtained for the biopsy must not have been previously irradiated. If a patient does not have any available archival tissue ≤ 1 year old and the treating investigator does not feel that it would be safe to perform a fresh biopsy, the requirement for a fresh biopsy may be waived after discussion with the Principal Investigator.
• Written informed consent for screening and trial participation procedures including biological material transfer and handling.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Hematopoietic status:

• Absolute neutrophil count ≥ 1.0 × 109/L,
• Platelet count ≥ 100 × 109/L,
• Hemoglobin ≥ 9 g/dL
• Hepatic status:

• Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (< 2 × ULN) is allowed.
• AST and ALT ≤ 2.5 × ULN; if the patient has liver metastases, ALT and AST must be ≤ 5 × ULN.
• Renal status:

• Creatinine ≤ 1.5 ×ULN or creatinine clearance > 60 ml/min
• Proteinuria < 1 g/day
• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulant.
• If female of childbearing potential, must have a negative pregnancy test within 7 days of initiating treatment. Childbearing potential is defined by: those who have not been surgically sterilized and/or have had a menstrual period in the past year.
• Participants of childbearing potential (as defined above) must be willing to use effective contraception during treatment and up to 7 months after stop of trial treatment. Acceptable methods of contraception are intrauterine devices, bilateral tubal occlusion, vasectomized, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed.
• Must not be breastfeeding/lactating.

Exclusion Criteria

• Prior therapy with any anti-PD-1, anti-PD-L1, L2, anti-4-1BB (CD137), or anti-CTLA4 therapy
• Known Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
• Positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]).
• History of interstitial lung disease
• Active central nervous system metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth (patients with history of CNS metastases or spinal cord compression are eligible if they are clinically stable for at least 4 weeks before first dose of investigational product and do not require high-dose steroid treatment).
• History of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association functional classification ≥3), angina, myocardial infarction or ventricular arrhythmia.
• Previous severe hypersensitivity reaction to treatment with another monoclonal antibody.
• Active infection requiring systemic therapy.
• Chronic systemic therapy with immunosuppressive agents including corticosteroids.
• Active autoimmune disease or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the trial. Patients with hypothyroidism stable on hormone replacement or Sjögren's syndrome will not be excluded from the trial.
• Concurrent disease or condition that would make the patient inappropriate for trial participation or any serious medical disorder that would interfere with the patient's safety.
• No uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen.
• Chemotherapy, radiotherapy, and/or biological cancer therapy within 3 weeks prior to the first trial dose or has not recovered to CTCAE v.4 grade 1 or better from adverse events (except alopecia).
• Unresolved or unstable, serious adverse events from prior administration of another investigational drug.
• Live vaccines within 30 days prior to the first dose of trial therapy and during trial treatment.

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

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

Breast Cancer Research Foundation

OTHER

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: collaborator

Adrienne G. Waks

OTHER

Sponsor Role: lead

Responsible Party

Adrienne G. Waks

Principal Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Adrienne Waks, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber Cancer Institute

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

University of California San Francisco

San Francisco, California, United States

Georgetown University Medical Center

Washington D.C., District of Columbia, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Indiana University Health Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States

Johns Hopkins University

Baltimore, Maryland, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Montefiore Medical Center

The Bronx, New York, United States

University of Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Baylor College of Medicine

Houston, Texas, United States

MD Anderson Cancer Center

Houston, Texas, United States

University of Washington Fred Hutchinson Cancer Care

Seattle, Washington, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

TBCRC045

Identifier Type: OTHER

Identifier Source: secondary_id

17-455

Identifier Type: -

Identifier Source: org_study_id