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Utomilumab with Trastuzumab Emtansine or Trastuzumab in Treating Patients with Advanced HER2-Positive Breast Cancer

Trial Status: Active

This phase I trial studies the best dose and side effects of utomilumab with trastuzumab emtansine or trastuzumab in treating patients with HER2-positive breast cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as utomilumab and trastuzumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Trastuzumab emtansine is a monoclonal antibody, where trastuzumab is linked to a chemotherapy drug called DM1. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers DM1 to kill them.

Inclusion Criteria

  • History of biopsy-proven HER2-overexpressing breast cancer and radiographic evidence of metastatic disease, or locally recurrent unresectable disease; the HER2 status can be determined either by immunohistochemistry (IHC) (IHC score, 3+) or by fluorescence in situ hybridization (FISH) (as defined by HER2/CEP-17 ratio >= 2.0, or HER2 copy number >= 6), or as otherwise defined by 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines * Cohort 1 subjects must have received prior trastuzumab and a taxane separately or in combination * Subjects in Cohort 2 must have received at least 1 prior therapy in the advanced/metastatic setting * Subjects who discontinued prior trastuzumab or ado-trastuzumab emtansine due to progressive or refractory disease are eligible for enrollment
  • Available tumor samples; for eligibility, if no unstained slides remain, stained pathology slides may be reviewed at the treating institution; however, a tumor sample is required for research evaluations per the following (any of item 1; 2; or 3, in order of preference) * A formalin-fixed paraffin-embedded (FFPE) tumor tissue block from a de novo fresh tumor biopsy obtained during screening will be requested, though not mandated * A recently-obtained archival FFPE tumor tissue block (or 10 to 15 unstained slides) from a primary or metastatic tumor resection or biopsy if the following criteria are met: ** The biopsy or resection was performed within 1 year of enrollment OR ** The subject has not received any intervening systemic anti-cancer treatment from the time the tissue was obtained and enrolled onto the current study OR * Any archival FFPE tumor tissue block (or unstained slides) from primary tumor resection specimen (if not provided per above); the archival sample may have been collected at any time prior to the current study, regardless of any intervening therapy; if an FFPE tissue block cannot be provided, a minimum of 10 unstained slides (15 preferable) will be acceptable
  • Subjects must have evaluable OR measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
  • Performance status 0-1 (by Eastern Cooperative Oncology Group [ECOG] scale)
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 /uL)
  • Platelet count >= 100 x 10^9/L (>= 100,000 /uL)
  • Hemoglobin >= 9.0 g/dL; subjects on therapeutic anticoagulation are eligible if there is no bleeding and they are on a stable dose of anticoagulation therapy (e.g., on Coumadin with an international normalized ratio [INR] of 2 to 3) for at least 7 days before registration (prior to the start of therapy, or stable heparin or factor Xa inhibitor dose)
  • Serum creatinine =< 1.5 x the upper limit of normal (ULN) or calculated creatinine clearance (by Cockcroft-Gault formula) >= 60 mL/min
  • Aspartate aminotransferase (AST) =< 2.5 x ULN
  • Alanine aminotransferase (ALT) =< 2.5 x ULN
  • Bilirubin =< 1.5 x ULN
  • Subjects must not be pregnant or breastfeeding; a pregnancy test will be obtained if the subject is a woman of child-bearing potential, defined as a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months) with 2 pregnancy tests, one at screening and another immediately preceding the initiation of treatment
  • Subjects must have signed an informed consent document stating that they understand the investigational nature of the proposed treatment
  • Left ventricular ejection fraction determined by echocardiogram or multiple-gated acquisition scan (MUGA) (cardiac scan) must be 50% or higher

Exclusion Criteria

  • Previously discontinued either trastuzumab or ado-trastuzumab emtansine due to intolerance
  • Received any other investigational agents within 30 days of registration
  • Central nervous system (CNS) metastases, unless previously treated by either radiation therapy and/or surgical resection, clinically stable for at least 60 days and on a stable corticosteroid dose of =< 4 mg/day decadron (or equivalent steroid regimen) for at least 1 month; subjects with a history of CNS metastases that are both treated and stably controlled are eligible if all of the following apply * Therapy has been administered (surgery and/or radiation therapy) * There is no additional treatment planned for brain metastases * The subject is clinically stable * The subject is on a stable corticosteroid dose of =< 4 mg/day decadron (or equivalent steroid regimen) for at least 1 month
  • Prior malignancy (other than in situ cervical cancer, or basal cell or squamous cell carcinoma of the skin), unless treated with curative intent and without evidence of disease for 3 years or longer
  • Administration of other prior anticancer therapies within 4 weeks of enrollment, except ongoing administration of a bisphosphonate drug or denosumab as treatment for bone metastasis
  • Toxicities related to prior anticancer treatment (except alopecia) that have not resolved to =< grade 1 according to common terminology criteria for adverse events (CTCAE version [v] 5) before registration or prior to start of therapy
  • Currently receiving systemic antibiotic, antiviral, or antifungal therapy for the treatment of an active infection
  • Systemic corticosteroid therapy at doses of greater than prednisone 5 mg daily (or dose-equivalent chronic steroid regimen) for therapeutic and not adrenal replacement indications (maintenance steroid use for adrenal insufficiency is permitted); acute emergency administration, topical applications, inhaled sprays, eye drops or local injections of corticosteroids are allowed
  • History of bleeding diathesis
  • Any co-morbid medical condition deemed by the treating or principal investigator to possibly put the subject at significant risk for toxicity
  • Subject has known sensitivity to any of the products to be administered during dosing
  • Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures
  • Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • History of venous thromboembolism within prior 6 months; chronic, systemic corticosteroid use for palliative or supportive purpose is not permitted; use of corticosteroids as symptomatic treatment may be allowed on individual basis and upon discussion with the sponsor; acute emergency administration, topical applications, inhaled sprays, eye drops or local injections of corticosteroids are allowed
  • Subject with reproductive potential who will not agree to use, during the study and for 60 days after the last dose of utomilumab or 6 months for ado-trastuzumab emtansine or trastuzumab two highly effective method of contraceptive such a: * Implants * Injectables * Intrauterine devices (IUDs) such as copper T or levonorgestrel-releasing intrauterine system (LNG-IUS * Sexual abstinence * Vasectomized partner * Condom or occlusive cap (diaphragm or cervical/vault cap) supplemented with the use of a spermicide during treatment


Palo Alto
Stanford Cancer Institute Palo Alto
Status: ACTIVE
Contact: George W. Sledge
Phone: 650-724-4397


I. To estimate the maximum tolerated dose (MTD) and determine the recommended dose (RP2D) of utomilumab in combination with trastuzumab emtansine (ado-trastuzumab emtansine [T-DM1]) or trastuzumab in patients with HER2-positive advanced breast cancer.


I. Determine the objective tumor response rate (ORR).

II. Determine the time-to-tumor response (TTR).

III. Determine the duration of response (DR).

IV. Determine progression-free survival (PFS).

V. Assess the safety and tolerability of utomilumab in combination with ado-trastuzumab emtansine or trastuzumab.


I. Evaluate the pharmacokinetics (PK) of utomilumab and ado-trastuzumab emtansine or trastuzumab when given in combination.

II. Evaluate preliminary evidence of antitumor activity of utomilumab in combination with ado-trastuzumab emtansine or trastuzumab.

III. Evaluate the immunogenicity of utomilumab and ado-trastuzumab emtansine or trastuzumab when given in combination.

IV. Assess the presence of CD8+ T cells in HER2-positive tumors.

V. Evaluate the modulation of immune activity biomarkers by utomilumab in combination with ado-trastuzumab emtansine or trastuzumab.

OUTLINE: This is a dose-escalation study of utomilumab. Patients are assigned to 1 of 2 cohorts.

COHORT 1: Patients receive trastuzumab emtansine intravenously (IV) over 30 minutes on day 0 of cycle 1 and day 1 of subsequent cycles, and utomilumab IV over 1 hour on day 1.

COHORT 2: Patients receive trastuzumab IV over 90 minutes on day 0 of cycle 1 and day 1 of subsequent cycles, and utomilumab IV over 1 hour on day 1.

In both cohorts, treatment repeats every 21 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up to 60 days, then every 9 weeks for up to 6 months.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Stanford Cancer Institute Palo Alto

Principal Investigator
George W. Sledge

  • Primary ID BRS0070
  • Secondary IDs NCI-2016-01881
  • ID NCT03364348