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

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ClinicalTrials.gov Identifier: NCT03414658
Recruitment Status : Recruiting
First Posted : January 30, 2018
Last Update Posted : January 15, 2019
Sponsor:
Collaborators:
Pfizer
Breast Cancer Research Foundation
Johns Hopkins University
Information provided by (Responsible Party):
Ian E. Krop, MD, PhD, Dana-Farber Cancer Institute

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)

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Vinorelbine Drug: Trastuzumab Drug: Avelumab Drug: Utomilumab Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Phase II Study Comparing Trastuzumab and Vinorelbine in Combination With Avelumab or Avelumab and Utomilumab (41BB/CD137 Agonist), in Patients With HER2-positive Metastatic Breast Cancer Who Have Progressed on Prior Trastuzumab and Pertuzumab
Actual Study Start Date : June 21, 2018
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : May 31, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Trastuzumab + Vinorelbine
  • Trastuzumab is administered intravenously twice per cycle
  • Vinorelbine is administered intravenously 3 times per cycle
Drug: Vinorelbine
work by interfering with cell division, which leaves the tumor unable to grow and spread

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

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

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

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

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

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

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

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

Experimental: Trastuzumab + Avelumab + Utomilumab

This is a crossover arm

  • 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
  • Trastuzumab is administered intravenously twice per cycle
Drug: Trastuzumab
trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2.

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

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




Primary Outcome Measures :
  1. Progression Free Survival [ Time Frame: 2 years ]
    Progression Free Survival is defined from the time from randomization to the first occurrence of disease progression as determined by the investigator using RECIST 1.1 or death from any cause, whichever occurs first.


Secondary Outcome Measures :
  1. Objective Response Rate [ Time Frame: 2 years ]
    Objective Response Rate is determined by Complete Response or Partial Response by RECIST 1.1

  2. Duration of Response [ Time Frame: 2 years ]
    Duration of Response is measured from the time criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented

  3. Overall Survival [ Time Frame: 2 years ]
    Overall survival is defined as the time from randomization to death from any cause, or is censored at date last known alive.

  4. Safety and Tolerability [ Time Frame: 2 years ]
    Safety and TOlerability will be assessed by the number of participants with adverse events. Adverse events are assessed using NCI-CTCAE version 4.0.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03414658


Contacts
Contact: Project Manager 617-632-5313 ctopm@dfci.harvard.edu
Contact: Jesse Logan 617-632-6452 Jesse_Logan@DFCI.HARVARD.EDU

Locations
United States, Illinois
University of Chicago Medical Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Rita Nanda, MD       rnanda@medicine.bsd.uchicago.edu   
Principal Investigator: Rita Nanda, MD         
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Contact: Roisin Connolly, MD       Rconnol2@jhmi.edu   
Principal Investigator: Roisin Connolly, MD         
United States, Massachusetts
Beth Israel Deaconess Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Nadine Tung, MD       ntung@bidmc.harvard.edu   
Principal Investigator: Nadine Tung, MD         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Jesse Logan    617-632-6452    Jesse_Logan@DFCI.HARVARD.EDU   
Principal Investigator: Ian Krop, MD         
United States, New York
Montefiore Medical Center Recruiting
Bronx, New York, United States, 10467
Contact: Sun Y. Oh, MD       Suyoung@montefiore.org   
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Vandana G. Abramson, MD       Vandana.abramson@vanderbilt.edu   
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Rashmi Murthy, MD       RMurthy1@mdanderson.org   
Sub-Investigator: Rashmi Murthy, MD         
Sponsors and Collaborators
Ian E. Krop, MD, PhD
Pfizer
Breast Cancer Research Foundation
Johns Hopkins University
Investigators
Principal Investigator: Ian Krop, MD, PhD Dana-Farber Cancer Institute

Responsible Party: Ian E. Krop, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT03414658     History of Changes
Other Study ID Numbers: 17-455
TBCRC045 ( Other Identifier: TBCRC )
First Posted: January 30, 2018    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ian E. Krop, MD, PhD, Dana-Farber Cancer Institute:
Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Vinorelbine
Trastuzumab
Vinblastine
Antibodies, Monoclonal
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs