4-1BB Agonist Monoclonal Antibody PF-05082566 With Trastuzumab Emtansine or Trastuzumab in Treating Patients With Advanced HER2-Positive Breast Cancer
- Conditions
- HER2 Positive Breast CarcinomaRecurrent Breast CarcinomaStage III Breast CancerStage IIIA Breast CancerStage IIIB Breast CancerStage IIIC Breast CancerStage IV Breast Cancer
- Interventions
- Registration Number
- NCT03364348
- Lead Sponsor
- George W. Sledge Jr.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 18
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 1A (trastuzumab + utomilumab) Utomilumab 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). Cohort 1B (trastuzumab + utomilumab) Utomilumab Utomilumab 100 mg IV + trastuzumab 6 mg/kg IV every 3 weeks. Cohort 1B (trastuzumab + utomilumab) Trastuzumab Utomilumab 100 mg IV + trastuzumab 6 mg/kg IV every 3 weeks. Cohort 2B (ado-trastuzumab emtansine + utomilumab) Ado-Trastuzumab Emtansine Utomilumab 100 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks. Cohort 2A (ado-trastuzumab emtansine + utomilumab) Utomilumab Utomilumab 20 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks. Cohort 2A (ado-trastuzumab emtansine + utomilumab) Ado-Trastuzumab Emtansine Utomilumab 20 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks. Cohort 2B (ado-trastuzumab emtansine + utomilumab) Utomilumab Utomilumab 100 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks. Cohort 1A (trastuzumab + utomilumab) Trastuzumab 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).
- Primary Outcome Measures
Name Time Method Dose-limiting Toxicities (DLTs) 6 weeks 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.
- Secondary Outcome Measures
Name Time Method Progression-free Survival (PFS) 128 weeks 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.
Duration of Response (DoR) up to 260 weeks 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).Objective Tumor Response (ORR) 3 months 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.Adverse Event Relationship to Study Drugs Up to 128 weeks 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.
Time-to-tumor Response (TTR) 3 months 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).Adverse Events by Severity Grade 1 to 5 Up to 128 weeks 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.
Trial Locations
- Locations (1)
Stanford University, School of Medicine
🇺🇸Palo Alto, California, United States