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
Overview
- Phase
- Phase 2
- Intervention
- Vinorelbine
- Conditions
- Breast Cancer
- Sponsor
- Adrienne G. Waks
- Enrollment
- 100
- Locations
- 17
- Primary Endpoint
- Progression Free Survival
- Status
- Active, not recruiting
- Last Updated
- 10 months ago
Overview
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.
Investigators
Adrienne G. Waks
Principal Investigator
Dana-Farber Cancer Institute
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
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.
Arms & Interventions
NH: Trastuzumab + Vinorelbine
* Trastuzumab is administered intravenously twice per cycle * Vinorelbine is administered intravenously 3 times per cycle
Intervention: Vinorelbine
NH: Trastuzumab + Vinorelbine
* Trastuzumab is administered intravenously twice per cycle * Vinorelbine is administered intravenously 3 times per cycle
Intervention: Trastuzumab
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
Intervention: Vinorelbine
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
Intervention: Trastuzumab
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
Intervention: Avelumab
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
Intervention: Vinorelbine
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
Intervention: Trastuzumab
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
Intervention: Avelumab
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
Intervention: Utomilumab
Outcomes
Primary Outcomes
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 Outcomes
- Overall Survival(5 years)
- Duration of Response(3 years)
- Objective Response Rate(2 years)