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: Dose 1: Utomilumab 20 mg IV + ado-trastuzumab emtansine (T-DM1) 3.6 mg/kg IV every
3 weeks. Dose 2: Dose Level 2 - Utomilumab 100 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV
every 3 weeks
COHORT 2: Dose 1: Utomilumab 20 mg IV + trastuzumab 6 mg/kg IV every 3 weeks. Dose Level 2 -
Utomilumab 100 mg IV + trastuzumab 6 mg/kg IV every 3 weeks.
- 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
- Subjects in Cohort 2 must have received at least 1 prior therapy including
- 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
- 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.
- Previously discontinued either trastuzumab or ado trastuzumab emtansine due to
- 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
- 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:
- 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