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)
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)
Brief Title
The AVIATOR Study: Trastuzumab and Vinorelbine With Avelumab OR Avelumab & Utomilumab in Advanced HER2+ Breast Cancer
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.
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.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Breast Cancer
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.
* 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.
Inclusion 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.
* 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.
Gender
All
Gender Based
false
Keywords
Breast Cancer
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT03414658
Org Class
Other
Org Full Name
Dana-Farber Cancer Institute
Org Study Id
17-455
Overall Status
Active, not recruiting
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome 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.
Outcome Measure
Progression Free Survival
Outcome Time Frame
2 years
Secondary Ids
Secondary Id
TBCRC045
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
2 years
Outcome Measure
Objective Response Rate
Outcome 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. 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.
Outcome Time Frame
3 years
Outcome Measure
Duration of Response
Outcome Description
Overall survival is defined as the time from randomization to death from any cause, or is censored at date last known alive.
Outcome Time Frame
5 years
Outcome Measure
Overall Survival
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Sun Young Oh
Investigator Email
suyoung@montefiore.org
Investigator Phone
918-405-8404