Clinical Trials /

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

NCT03414658

Description:

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)

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 17-455
  • SECONDARY ID: TBCRC045
  • NCT ID: NCT03414658

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
VinorelbineTrastuzumab + Vinorelbine
TrastuzumabTrastuzumab + Vinorelbine
AvelumabTrastuzumab + Vinorelbine + Avelumab
UtomilumabTrastuzumab + Vinorelbine + Avelumab + Utomilumab

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Trastuzumab + VinorelbineExperimentalTrastuzumab is administered intravenously twice per cycle Vinorelbine is administered intravenously 3 times per cycle
  • Vinorelbine
  • Trastuzumab
Trastuzumab + Vinorelbine + AvelumabExperimentalTrastuzumab 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
  • Vinorelbine
  • Trastuzumab
  • Avelumab
Trastuzumab + Vinorelbine + Avelumab + UtomilumabExperimentalTrastuzumab 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
  • Vinorelbine
  • Trastuzumab
  • Avelumab
  • Utomilumab
Trastuzumab + Avelumab + UtomilumabExperimentalThis 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
  • Trastuzumab
  • Avelumab
  • Utomilumab

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival
Time Frame:2 years
Safety Issue:
Description: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

Measure:Objective Response Rate
Time Frame:2 years
Safety Issue:
Description:Objective Response Rate is determined by Complete Response or Partial Response by RECIST 1.1
Measure:Duration of Response
Time Frame:2 years
Safety Issue:
Description: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
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:Overall survival is defined as the time from randomization to death from any cause, or is censored at date last known alive.
Measure:Safety and Tolerability
Time Frame:2 years
Safety Issue:
Description:Safety and TOlerability will be assessed by the number of participants with adverse events. Adverse events are assessed using NCI-CTCAE version 4.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Ian E. Krop, MD, PhD

Trial Keywords

  • Breast Cancer

Last Updated

January 26, 2018