4-1BB Agonist Monoclonal Antibody PF-05082566 With Trastuzumab Emtansine or Trastuzumab in Treating Patients With Advanced HER2-Positive Breast Cancer

Study Overview
=================
Brief 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.

Detailed Description
-----------------
PRIMARY OBJECTIVE: 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. SECONDARY OBJECTIVES: 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.

Official Title
-----------------
A Phase 1B Dose Escalation Trial of Human Anti 4 1BB Agonistic Antibody Utomilumab (PF 05082566) in Combination With Ado Trastuzumab Emtansine or Trastuzumab in Patients With HER2 Postive Advanced Breast Cancer

Conditions
-----------------
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

Intervention / Treatment
-----------------
* Drug: Utomilumab
* Drug: Trastuzumab
* Drug: Ado-Trastuzumab Emtansine


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1A (trastuzumab + utomilumab)<br>Utomilumab 20 mg IV + trastuzumab 6 mg/kg IV every 3 weeks. 3 subjects will be treated at this dose level. If no DLT events are recorded, then utomilumab dose will be increased to 100 mg (Dose Level 1B). | Drug: Utomilumab<br>* Given IV<br>* Other names: PF-2566;Drug: Trastuzumab<br>* Given IV<br>* Other names: Trastuzumab Biosimilar PF-05280014;|
| Experimental: Cohort 1B (trastuzumab + utomilumab)<br>Utomilumab 100 mg IV + trastuzumab 6 mg/kg IV every 3 weeks. | Drug: Utomilumab<br>* Given IV<br>* Other names: PF-2566;Drug: Trastuzumab<br>* Given IV<br>* Other names: Trastuzumab Biosimilar PF-05280014;|
| Experimental: Cohort 2A (ado-trastuzumab emtansine + utomilumab)<br>Utomilumab 20 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks. | Drug: Utomilumab<br>* Given IV<br>* Other names: PF-2566;Drug: Ado-Trastuzumab Emtansine<br>* Given IV<br>* Other names: Trastuzumab-MCC-DM1 Immunoconjugate;|
| Experimental: Cohort 2B (ado-trastuzumab emtansine + utomilumab)<br>Utomilumab 100 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks. | Drug: Utomilumab<br>* Given IV<br>* Other names: PF-2566;Drug: Ado-Trastuzumab Emtansine<br>* Given IV<br>* Other names: Trastuzumab-MCC-DM1 Immunoconjugate;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicities (DLTs) | Dose-limiting toxicities (DLTs) within the first 2 cycles (6 weeks) of treatment were assessed. DLTs are treatment-related adverse events defined as: Neutropenia Grade (Gr) 4 >7 days Febrile neutropenia, defined as absolute neutrophil count <1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for >1 hour Neutropenic infection ≥Gr 3 Thrombocytopenia ≥Gr 4, or with bleeding Gr 3 Non-laboratory toxicities ≥Gr 3, except nausea, vomiting, or diarrhea recovering to <Gr 2 within 48 hours. Laboratory abnormalities [other than aspartate aminotransferase / alanine aminotransferase (AST/ALT)] ≥Gr 3, if: Medical intervention required Hospitalization required, or >24 hours AST & ALT Gr 4, or >3×ULN Total bilirubin >2×ULN, with no elevation of alkaline phosphatase The outcome is reported as the number of DLTs observed per group, a number with dispersion. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response (ORR) | Objective tumor response (ORR) per RECIST v1.1 was assessed after 4 cycles (3 months) of treatment. RECIST v1.1 was assessed on target lesions as: Complete Response (CR): Complete disappearance of all lesions with the exception of nodal disease. All target lymph nodes must decrease to normal size (short axis < 10 mm). Partial Response (PR): ≥ 30% decrease in the sum of diameters of all measurable lesions. Progressive Disease (PD): Increase in lesion size ≥ 5 mm and ≥ 20% increase in the sum of diameters of measurable lesions. Stable Disease (SD): All lesions assessed, but not CR, PR, or PD. Per protocol, the outcome is reported for participants in Cohort 2B (ado-trastuzumab emtansine + utomilumab) as the number of participants with the indicated clinical response, a number without dispersion. | 3 months | 
| Time-to-tumor Response (TTR) | Time-to-tumor response (TTR) was assessed per RECIST v1.1, in participants who have at least 1 on-study tumor assessment & respond within 4 cycles (3 months). RECIST v1.1 was assessed as: Complete Response (CR): Complete disappearance of target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). Partial Response (PR): ≥ 30% decrease in the sum of diameters of target measurable lesions. By definition, TTR an assessment of the tumor response, meaning a CR or a PR. Per protocol, the outcome is reported as the median with full range for participants in Cohort 2B (ado-trastuzumab emtansine + utomilumab) achieving a clinical response within 4 cycles (3 months). | 3 months | 
| Duration of Response (DoR) | Duration of response (DoR) was assessed in participants who have 1+ on-study tumor assessment(s) and have a clinical response, through up to 5 years after treatment. RECIST v1.1 was assessed as: Complete Response (CR): Complete disappearance of target lesions with the exception of nodal disease. Target nodes must decrease to normal size (short axis < 10 mm). Partial Response (PR): ≥ 30% decrease in the sum of diameters of target measurable lesions. Progression Disease (PD): Increase in lesion size ≥ 5 mm and ≥ 20% increase in the sum of diameters of target measurable lesions. Stable Disease (SD): Target lesions assessed, but not CR, PR, or PD. By definition, DoR is an assessment of tumor response, meaning the participants achieved a CR or a PR. Per protocol, the outcome is reported as the median with full range for participants in Cohort 2B (ado-trastuzumab emtansine + utomilumab) achieving a clinical response within 5 years (260 weeks). | up to 260 weeks | 
| Progression-free Survival (PFS) | Progression-free survival (PFS) means the participants remained alive without disease progression (DP). DP was defined per RECIST v1.1 as an increase in lesion size ≥ 5 mm or ≥ 20% increase in the sum of diameters of target measurable lesions. The outcome is reported as the median time that participants survived without DP, with full range. | 128 weeks | 
| Adverse Events by Severity Grade 1 to 5 | Adverse events while receiving treatment and within 30 days were assessed by treatment group for severity (as graded by NCI CTCAE v5). The outcome is reported by treatment group as the numbers of adverse events by treatment group, numbers without dispersion. | Up to 128 weeks | 
| Adverse Event Relationship to Study Drugs | Adverse events while receiving treatment and within 30 days were assessed by treatment group for relationship to the study treatments. The outcome is reported as the numbers of related adverse events by treatment group, numbers without dispersion. | Up to 128 weeks |