Breast Cancer
Conditions
Keywords
Breast Cancer
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.
Interventions
DRUGVinorelbine
work by interfering with cell division, which leaves the tumor unable to grow and spread
DRUGTrastuzumab
trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2.
DRUGAvelumab
monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein
DRUGUtomilumab
Utomilumab is an antibody designed to stimulate the body's immune system to fight cancer cells
Sponsors
Pfizer
Breast Cancer Research Foundation
Johns Hopkins University
Adrienne G. Waks
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 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
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 2 years | Objective Response Rate is determined by Complete Response or Partial Response by RECIST 1.1. Per RECIST 1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Duration of Response | 3 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. Per RECIST 1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. |
| Overall Survival | 5 years | Overall survival is defined as the time from randomization to death from any cause, or is censored at date last known alive. |
Countries
United States
Participant flow
Recruitment details
AVIATOR enrolled 100 patients in 16 centers in the US between June 21, 2018 and March 1, 2023.
Participants by arm
| Arm | Count |
|---|---|
| NH: Trastuzumab + Vinorelbine * Trastuzumab is administered intravenously twice per cycle
* Vinorelbine is administered intravenously 3 times per cycle
Vinorelbine: work by interfering with cell division, which leaves the tumor unable to grow and spread
Trastuzumab: trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2. | 18 |
| 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
Vinorelbine: work by interfering with cell division, which leaves the tumor unable to grow and spread
Trastuzumab: trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2.
Avelumab: monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein | 45 |
| 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
Vinorelbine: work by interfering with cell division, which leaves the tumor unable to grow and spread
Trastuzumab: trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2.
Avelumab: monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein
Utomilumab: Utomilumab is an antibody designed to stimulate the body's immune system to fight cancer cells | 34 |
| Total | 97 |
Baseline characteristics
| Characteristic | Total | NHAU: Trastuzumab + Vinorelbine + Avelumab + Utomilumab | NHA: Trastuzumab + Vinorelbine + Avelumab | NH: Trastuzumab + Vinorelbine |
|---|---|---|---|---|
| Age, Continuous | 54 years | 57 years | 53 years | 54 years |
| BMI | 25.2 kg/m^2 | 26.4 kg/m^2 | 24.9 kg/m^2 | 23.8 kg/m^2 |
| ECOG PS 0 | 58 Participants | 23 Participants | 24 Participants | 11 Participants |
| ECOG PS 1 | 39 Participants | 11 Participants | 21 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 1 Participants | 6 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 87 Participants | 31 Participants | 38 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 4 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 2 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 68 Participants | 26 Participants | 31 Participants | 11 Participants |
| Region of Enrollment United States | 97 participants | 34 participants | 45 participants | 18 participants |
| Sex: Female, Male Female | 96 Participants | 33 Participants | 45 Participants | 18 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 18 | 23 / 45 | 20 / 34 |
| other Total, other adverse events | 18 / 18 | 45 / 45 | 34 / 34 |
| serious Total, serious adverse events | 5 / 18 | 9 / 45 | 9 / 34 |
Outcome results
Primary
Progression Free Survival
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.
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NH: Trastuzumab + Vinorelbine | Progression Free Survival | 2 months |
| NHA: Trastuzumab + Vinorelbine + Avelumab | Progression Free Survival | 3.8 months |
| NHAU: Trastuzumab + Vinorelbine + Avelumab + Utomilumab | Progression Free Survival | 4.9 months |
p-value: 0.02580% CI: [0.35, 0.81]Log Rank
p-value: 0.3280% CI: [0.8, 1.64]Log Rank
Secondary
Duration of Response
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. Per RECIST 1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions.
Time frame: 3 years
Population: Participants who had response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NH: Trastuzumab + Vinorelbine | Duration of Response | NA months |
| NHA: Trastuzumab + Vinorelbine + Avelumab | Duration of Response | 15.8 months |
| NHAU: Trastuzumab + Vinorelbine + Avelumab + Utomilumab | Duration of Response | 4.2 months |
Secondary
Objective Response Rate
Objective Response Rate is determined by Complete Response or Partial Response by RECIST 1.1. Per RECIST 1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NH: Trastuzumab + Vinorelbine | Objective Response Rate | 11.1 percent of participants |
| NHA: Trastuzumab + Vinorelbine + Avelumab | Objective Response Rate | 20 percent of participants |
| NHAU: Trastuzumab + Vinorelbine + Avelumab + Utomilumab | Objective Response Rate | 11.8 percent of participants |
Secondary
Overall Survival
Overall survival is defined as the time from randomization to death from any cause, or is censored at date last known alive.
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NH: Trastuzumab + Vinorelbine | Overall Survival | 22.8 months |
| NHA: Trastuzumab + Vinorelbine + Avelumab | Overall Survival | 26.3 months |
| NHAU: Trastuzumab + Vinorelbine + Avelumab + Utomilumab | Overall Survival | 27 months |