Trastuzumab, Vinorelbine Tartrate, and Avelumab with or without Utomilumab in Treating Patients with HER2-Positive Metastatic Breast Cancer

Status: Active

Description

This phase II trial studies the how well trastuzumab, vinorelbine tartrate, and avelumab with or without utomilumab work in treating patients with HER2-positive breast cancer that has spread to other parts of the body. Monoclonal antibodies, such as trastuzumab, avelumab, and utomilumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as vinorelbine tartrate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving trastuzumab, vinorelbine tartrate, and avelumab with or without utomilumab may work better in treating patients with breast cancer.

Eligibility Criteria

Inclusion Criteria

  • 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.

Exclusion Criteria

  • 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.
  • Positive for human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
  • Positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] ribonucleic acid [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 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.

Locations & Contacts

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: Active
Contact: Erica M. Stringer-Reasor
Phone: 205-975-2816
Email: Esreasor@uabmc.edu

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: Active
Contact: Rita Nanda
Phone: 773-834-2756
Email: Rnanda@medicine.bsd.uchicago.edu
New Lenox
UC Comprehensive Cancer Center at Silver Cross
Status: Active
Contact: Rita Nanda
Phone: 773-834-2756
Email: Rnanda@medicine.bsd.uchicago.edu
Orland Park
University of Chicago Medicine-Orland Park
Status: Active
Contact: Rita Nanda
Phone: 773-834-2756
Email: Rnanda@medicine.bsd.uchicago.edu

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Roisin M Connolly
Phone: 410-955-8964
Email: Rconnol2@jhmi.edu

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: Approved
Contact: Neelam V. Desai
Phone: 617-667-2100
Email: ndesai@bidmc.harvard.edu
Brigham and Women's Hospital
Status: Active
Contact: Ian Elliott Krop
Phone: 617-632-5958
Email: ikrop@partners.org
Dana-Farber Cancer Institute
Status: Active
Contact: Ian Elliott Krop
Phone: 617-632-5958
Email: ikrop@partners.org

New York

Bronx
Montefiore Medical Center - Moses Campus
Status: Active
Contact: Sun Young Oh
Phone: 718-920-4057
Email: Suyoung@montefiore.org

North Carolina

Durham
Duke University Medical Center
Status: Active
Contact: Kelly Elizabeth Westbrook
Phone: 919-668-6688
Email: Kelly.westbrook@duke.edu

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: Active
Contact: Vandana Gupta Abramson
Phone: 615-343-6653
Email: Vandana.abramson@vanderbilt.edu

Texas

Houston
Baylor College of Medicine / Dan L Duncan Comprehensive Cancer Center
Status: Active
Contact: Mothaffar Fahed Rimawi
Phone: 713-798-1999
Email: Rimawi@bcm.edu
M D Anderson Cancer Center
Status: Active
Contact: Rashmi Krishna Murthy
Phone: 713-563-0779
Email: RMurthy1@mdanderson.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

I. To evaluate efficacy of the no immunotherapy arm (Arm A), single immunotherapy (Arm B) and doublet immunotherapy (Arm C) using objective response (ORR), defined as complete response or partial response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

II. To evaluate efficacy of the no immunotherapy arm (Arm A), single immunotherapy (Arm B) and doublet immunotherapy (Arm C) using duration of response (DOR).

III. To evaluate efficacy of the no immunotherapy arm (Arm A), single immunotherapy (Arm B) and doublet immunotherapy (Arm C) using overall survival, defined as time from randomization to death from any cause.

IV. To evaluate efficacy of the no immunotherapy arm (Arm A), single immunotherapy (Arm B) and doublet immunotherapy (Arm C) using 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.

V. To evaluate efficacy of the no immunotherapy arm (Arm A), single immunotherapy (Arm B) and doublet immunotherapy (Arm C) using safety and tolerability using National Cancer Institute (NCI)- Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

EXPLORATORY OBJECTIVES:

I. To determine efficacy of the combinations using PFS measures according to PD-L1 immunohistochemistry (IHC) status.

II. To determine efficacy of the combinations using PFS measures according to tumor infiltrating lymphocytes (TILs) level (baseline absolute levels and change).

III. To determine efficacy of the combinations using PFS measures as defined by immune modified RECIST.

IV. To determine efficacy of the combinations using ORR by PD-L1 IHC status and various categories.

V. To determine efficacy of the combinations using estimate two-year overall survival rate according to treatment arm.

VI. To assess if baseline PD-L1 IHC expression is associated with responders and if this differs by treatment arm.

VII. 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.

VIII. 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.

IX. To assess objectives VI-VIII by estrogen receptor (ER) status.

X. To determine if mutational profiles of material from baseline tumor biopsies are associated with efficacy and if this differs by treatment arm.

XI. 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.

XII. To determine if clonality and diversity derived from sequencing of the T cell receptor (TCR) in tumor and blood are associated with efficacy.

XIII. To track mutations in plasma to understand biomarkers of responders and nonresponders.

XIV. To determine if levels of T cell phenotypes (activated effector T cells in blood) are associated with efficacy.

XV. To determine if any biomarkers are associated with safety signals.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM A: Patients receive trastuzumab intravenously (IV) over approximately 30-90 minutes on days 1 and 15 and vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15. Courses 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. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive trastuzumab IV over approximately 30-90 minutes 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. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive trastuzumab IV over approximately 30-90 minutes 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. Courses 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 & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Ian Elliott Krop

Trial IDs

Primary ID 17-455
Secondary IDs NCI-2018-01455
Clinicaltrials.gov ID NCT03414658