4-1BB Agonist Monoclonal Antibody PF-05082566 With Trastuzumab Emtansine or Trastuzumab in Treating Patients With Advanced HER2-Positive Breast Cancer
Condition: HER2 Positive Breast Carcinoma; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer
MeSH terms: Carcinoma; Breast Neoplasms
Intervention: Utomilumab; Trastuzumab; Ado-Trastuzumab Emtansine
Intervention description: Given IV; Given IV; Given IV
Intervention MeSH terms: Antineoplastic Agents, Immunological; Trastuzumab; Ado-Trastuzumab Emtansine; Maytansine; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G; Immunoconjugates
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This trial studies the best dose and side effects of utomilumab (4-1BB agonist monoclonal
      antibody PF-05082566) with trastuzumab emtansine or trastuzumab in treating patients with
      HER2-positive breast cancer that has spread to other places in the body. Monoclonal
      antibodies, such as utomilumab, trastuzumab emtansine, and trastuzumab may interfere with the
      ability of tumor cells to grow and spread.
    

Eligibility criteria:

        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 ASCO/CAP guidelines.

          -  Cohort 1 subjects must have received trastuzumab and a taxane separately or in
             combination (those who previously received ado-trastuzumab emtansine may accrue to
             Cohort 2).

          -  Subjects in Cohort 2 must have received at least 1 prior therapy including
             ado-trastuzumab emtansine.

          -  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 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 RECIST v1.1.

          -  Performance status 0 to 1 (by Eastern Cooperative Oncology Group [ECOG] scale).

          -  Laboratory parameters (must satisfy all): Absolute neutrophil count (ANC) ≥ 1.5 ×
             109/L (≥ 1500/µL) Platelet count ≥ 100 × 109/L (≥ 100,000 /µL) 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 (eg, on Coumadin with an 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 × the ULN or calculated
             creatinine clearance (by Cockcroft Gault formula) ≥ 60 mL/min Aspartate
             aminotransferase (AST) ≤ 2.5 × ULN Alanine aminotransferase (ALT) ≤ 2.5 × ULN
             Bilirubin ≤ 1.5 × 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 and/or bilateral oophorectomy or who has not
             been naturally postmenopausal for at least 24 consecutive months (ie, 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 v5) 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.

          -  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 2 highly effective method of contraceptive such as:

          -  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