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

NCT03414658

Last updated date
Study Location
Georgetown University Medical Center
Washington, District of Columbia, 20007, United States
Contact
617-632-5313

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Breast Cancer
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- 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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 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.

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Advanced Information
Descriptive Information
Brief Title  ICMJE The AVIATOR Study: Trastuzumab and Vinorelbine With Avelumab OR Avelumab & Utomilumab in Advanced HER2+ Breast Cancer
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Trastuzumab + Vinorelbine
    • Trastuzumab is administered intravenously twice per cycle
    • Vinorelbine is administered intravenously 3 times per cycle
    Interventions:
    • Drug: Vinorelbine
    • Drug: Trastuzumab
  • 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
    Interventions:
    • Drug: Vinorelbine
    • Drug: Trastuzumab
    • Drug: Avelumab
  • 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
    Interventions:
    • Drug: Vinorelbine
    • Drug: Trastuzumab
    • Drug: Avelumab
    • Drug: Utomilumab
  • 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
    Interventions:
    • Drug: Trastuzumab
    • Drug: Avelumab
    • Drug: Utomilumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 26, 2018)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 31, 2025
Estimated Primary Completion Date May 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Project Manager617-632-5313[email protected]
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03414658
Other Study ID Numbers  ICMJE 17-455
TBCRC045 ( Other Identifier: TBCRC )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party Ian E. Krop, MD, PhD, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Ian E. Krop, MD, PhD
Collaborators  ICMJE
  • Pfizer
  • Breast Cancer Research Foundation
  • Johns Hopkins University
Investigators  ICMJE
Principal Investigator:Ian Krop, MD, PhDDana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP