Trastuzumab, Vinorelbine Tartrate, and Avelumab with or without Utomilumab in Treating Patients with HER2-Positive Metastatic Breast Cancer
- Histologically confirmed breast cancer that is metastatic or unresectable loco-regionally advanced.
- Histologically confirmed HER-2 positive breast cancer by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) 2013 guidelines. NOTE: Central confirmation of HER-2 status is not required: * IHC 3+ based on circumferential membrane staining that is complete, intense -AND/OR- * Fluorescence in situ hybridization (FISH) positive based on one of the three following criteria: ** Single-probe average HER2 copy number >= 6.0 signals/cell; OR ** Dual-probe HER2/CEP17 ratio >= 2.0 OR ** Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell.
- Measurable disease per RECIST version (v)1.1.
- Participants must have previous treatment with ado-trastuzumab emtansine (Kadcyla, T-DM1) in any setting.
- Participants must have previously received trastuzumab and pertuzumab in the metastatic setting or recurred =< 12 months after a neoadjuvant/adjuvant regimen containing trastuzumab and pertuzumab. It is not mandatory to have a trastuzumab and/or pertuzumab containing regimen as the most recent treatment.
- Participants 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%, as determined by multigated acquisition (MUGA) or echocardiogram.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Absolute neutrophil count >= 1250/uL.
- Platelet count >= 100,000/uL.
- Hemoglobin >= 9 g/dL.
- Serum total bilirubin =< 1.5 x institutional upper limit of normal (ULN). In the case of known Gilbert’s syndrome, a higher serum total bilirubin (< 2 x ULN) is allowed.
- Aspartate aminotransferase (AST) =< 2.5 x ULN or =< 5 x ULN if patient has liver metastases.
- Alanine aminotransferase (ALT) =< 2.5 x ULN or =< 5 x ULN if patient has liver metastases.
- Creatinine =< 1.5 x institutional ULN or creatinine clearance >= 60 mL/min/1.73 m^2.
- Urinary protein: creatinine (UPC) ratio < 1.0.
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulant.
- Willingness and availability to submit formalin-fixed paraffin-embedded (FFPE) tissue for research purposes. 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 protocol chair.
- If female of childbearing potential, must have a negative pregnancy test within 7 days of registration. Childbearing potential is defined as: those who have not been surgically sterilized and/or have had a menstrual period in the past 12 months or who have been on ovarian suppression in the past year.
- Participants of childbearing potential (males and females 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.
- Ability to understand and the willingness to sign a written informed consent document.
- Prior therapy with vinorelbine in any setting
- Prior therapy with any anti-PD-1, anti-PD-L1, L2, anti-4-1BB (CD137), or anti-CTLA 4 therapy.
- Known human immunodeficiency virus (HIV) positive (testing not required).
- Active or chronic hepatitis B or C (testing not required)
- 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 central nervous system [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 Sjogren’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 in the opinion of the treating investigator.
- No current 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 planned treatment start date.
- Unresolved or unstable adverse events from prior therapy, except alopecia (has not recovered to CTCAE v.4 =< grade 1 or baseline).
- Pregnant women or women who are lactating/breastfeeding due to the teratogenic potential of the study drugs.
- Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A are ineligible. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
- Live vaccines within 30 days prior to the first dose of trial therapy and during trial treatment.
District of Columbia
I. To determine whether the addition of avelumab to the combination of trastuzumab and vinorelbine tartrate (vinorelbine) will improve progression-free survival (PFS) compared to the trastuzumab and vinorelbine combination alone in patients with advanced HER2-positive breast cancer.
II. To determine whether the addition of utomilumab to the combination of avelumab, trastuzumab, and vinorelbine will improve progression-free survival (PFS) compared to the avelumab, trastuzumab, and vinorelbine combination alone in patients with advanced HER2-positive breast cancer.
I. To evaluate efficacy of the no immunotherapy arm (Arm A), single immunotherapy (Arm B) and doublet immunotherapy (Arm C) using the following endpoints:
Ia. Objective response (ORR), defined as complete response or partial response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Ib. Duration of response (DOR).
Ic. Overall survival, defined as time from randomization to death from any cause.
Id. Preliminary assessment of the clinical activity, as measured by ORR and PFS, of the cross-over regimen of trastuzumab, avelumab and utomilumab in patients who progress on vinorelbine/trastuzumab.
Ie. Safety and tolerability using National Cancer Institute (NCI)- Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
I. To determine efficacy of the combinations using the following endpoints:
Ia. PFS measures according to PD-L1 immunohistochemistry (IHC) status.
Ib. PFS measures according to tumor infiltrating lymphocytes (TILs) level (baseline absolute levels and change).
Ic. PFS measures as defined by immune modified RECIST.
Id. ORR by PD-L1 IHC status and various categories.
Ie. Estimate two-year overall survival rate according to treatment arm.
I. To assess if baseline PD-L1 IHC expression is associated with responders and if this differs by treatment arm.
II. To assess if baseline TIL (as determined on hematoxylin and eosin [H&E] slides) levels are associated with responders and if this differs by treatment arm.
III. To assess if baseline “activated” immune status (defined by high TILs/ high PD-L1 expression, messenger ribonucleic acid (mRNA) enrichment of interferon signaling) is associated with responders and if this differs by treatment arm.
IV. To assess objectives VI-VIII by estrogen receptor (ER) status.
V. To determine if mutational profiles of material from baseline tumor biopsies are associated with efficacy and if this differs by treatment arm.
VI. To determine if baseline levels or change in IHC or gene expression levels of immune biomarkers are associated with efficacy and if this differs by treatment arm.
VII. To determine if clonality and diversity derived from sequencing of the T cell receptor (TCR) in tumor and blood are associated with efficacy.
VIII. To track mutations in plasma to understand biomarkers of responders and nonresponders.
IX. To determine if levels of T cell phenotypes (activated effector T cells in blood) are associated with efficacy.
X. To determine if any biomarkers are associated with safety signals.
OUTLINE: Patients are randomized to 1 of 3 arms.
ARM A: Patients receive trastuzumab or biosimilar intravenously (IV) on days 1 and 15 and vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression, may crossover and receive trastuzumab IV over approximately 30-90 minutes on days 1 and 15, utomilumab IV over 60 minutes on days 1, and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive trastuzumab or biosimilar IV on days 1 and 15, vinorelbine tartrate IV over 6-10 minutes on days 1, 8 and 15, and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM C: Patients receive trastuzumab or biosimilar IV over on days 1 and 15, vinorelbine tartrate IV over 6-10 minutes on days 1, 8 and 15, utomilumab IV over 60 minutes on day 1, and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 9-12 weeks or annually thereafter.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Ian Elliott Krop
- Primary ID 17-455
- Secondary IDs NCI-2018-01455
- Clinicaltrials.gov ID NCT03414658