Estimate the maximum tolerated dose (MTD) and determine the recommended dose (RP2D) of
utomilumab in combination with ado-rastuzumab emtansine (T-DM1) or trastuzumab in subjects
with HER2 positive advanced breast cancer.
- Determine the objective tumor response (ORR)
- Determine the time to tumor response (TTR)
- Determine the duration of response (DR)
- Determine progression free survival (PFS)
- Assess the safety and tolerability of utomilumab in combination with ado-trastuzumab
emtansine or trastuzumab
OUTLINE: Patients are randomized to 1 of 2 cohorts.
COHORT 1: Patients receive trastuzumab emtansine intravenously (IV) over 30 minutes on day 0
of course 1 and day 1 of subsequent courses, and utomilumab IV over 1 hour on day 1.
COHORT 2: Patients receive trastuzumab IV over 90 minutes on day 0 of course 1 and day 1 of
subsequent courses, and utomilumab IV over 1 hour on day 1.
In both cohorts, treatment repeats every 21 days for up to 24 courses 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. Tumor assessments per the Response Evaluation Criteria In Solid Tumors
(RECIST) v1.1 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].
- Cohort 1 participants must have received trastuzumab and a taxane in the
advanced/metastatic setting or must have developed disease recurrence during or
within 6 months of completing adjuvant therapy.
- Cohort 2 participants must have received at least 2 prior therapies in the
- Potential participants who discontinued prior trastuzumab or ado-trastuzumab
emtansine due to progressive or refractory disease are eligible for enrollment.
- Available tumor samples
- A formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from a de novo
tumor biopsy obtained during screening will be required (biopsied tumor lesion
should not be a target lesion). An archival FFPE tumor tissue block (cut slides
not acceptable) from a primary or metastatic tumor resection or biopsy can be
provided if the following criteria are met:
1. The biopsy or resection was performed within 1 year of enrollment AND
2. Not received any intervening systemic anti-cancer treatment from the time
the tissue was obtained and randomization onto the current study.
- Availability of an archival FFPE tumor tissue block from primary tumor resection
specimen (if not provided per above). If an FFPE tissue block cannot be provided,
a minimum of 10 unstained slides (15 preferable) will be acceptable.
- Participants must have evaluable OR measurable disease, as defined by RECIST v1.1.
- Women or men, age ≥ 18 years old.
- Performance status 0 to 1 (by Eastern Cooperative Oncology Group [ECOG] scale).
- Absolute neutrophil count (ANC) ≥ 1.5 × 10e9/L (≥ 1500/µL)
- Platelet count ≥ 100 × 10e9/L (≥ 100,000/µL)
- Hemoglobin ≥ 9.0 g/dL
- Potential participants 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
- Serum creatinine ≤ 1.5 × the upper limit of normal (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
- Not pregnant or breastfeeding.
- Signed an informed consent document stating that they understand the investigational
nature of the proposed treatment.
- Not receiving any other investigational agents within 30 days of registration.
- Left ventricular ejection fraction determined by echocardiogram or multiple gated
acquisition scan (MUGA) (cardiac scan) must be 50% or higher.
- Intolerance to prior trastuzumab or ado-trastuzumab emtansine
- Central nervous system (CNS) metastases, unless previously treated by either radiation
therapy and/or surgical resection, clinically stable for at least 60 days and off
corticosteroids. Potential participants 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);
- No additional treatment planned for brain metastases;
- Clinically stable;
- Not receiving corticosteroids.
- 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
- Toxicities related to prior anticancer treatment (except alopecia) that have not
resolved to ≤ Grade 1 according to Common Terminology Criteria for Adverse Events
(CTCAE v4.03) 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 5 mg daily for therapeutic
and not adrenal replacement indications (maintenance steroid use for adrenal
insufficiency is permitted).
- History of bleeding diathesis.
- Any co-morbid medical condition that may put the subject at significant risk for
- Known sensitivity to any of the products to be administered during dosing.
- Any 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. Acute emergency administration, topical applications, inhaled sprays, eye
drops or local injections of corticosteroids are allowed.
- 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, a
highly-effective method of contraceptive such as:
- 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.