Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Carcinoma

Breast Neoplasms

Recurrence

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Breast Diseases

Skin Diseases

All Drugs and Chemicals

Antineoplastic Agents

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Antibodies

Antibodies, Monoclonal

Trastuzumab

Immunoconjugates

Immunoglobulins

Ado-Trastuzumab Emtansine

Adenosine

Antineoplastic Agents, Immunological

Maytansine

Immunoglobulins, Intravenous

Immunoglobulin G

Immunologic Factors

Tubulin Modulators

Antimitotic Agents

Immunotoxins

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).

Utomilumab 100 mg IV + trastuzumab 6 mg/kg IV every 3 weeks.

Utomilumab 20 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks.

Utomilumab 100 mg IV + ado-trastuzumab emtansine 3.6 mg/kg IV every 3 weeks.

Utomilumab

George Sledge, MD

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.

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.

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

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

Adverse events that were laboratory value abnormalities that occurred during treatment or within 30 days, were assessed by treatment group. The outcome is reported as the number of laboratory abnormalities by treatment group that were laboratory value abnormalities (Yes) or not (No), numbers without dispersion.

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.

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.

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).

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).

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.

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.

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.

National Cancer Institute (NCI)

George W. Sledge Jr.

Principal Investigator

Cohort 1A (Trastuzumab + Utomilumab)

Cohort 1B (Trastuzumab + Utomilumab)

Cohort 2A (Ado-trastuzumab Emtansine + Utomilumab)

Cohort 2B (Ado-trastuzumab Emtansine + Utomilumab)

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Sinyoung Park

Dose-limiting Toxicities (DLTs)

Complete Response (CR)

Partial Response (PR)

Progressive Disease (PD)

Stable Disease (SD)

Objective Tumor Response (ORR)

Not all participants in Cohort 2B achieved a clinical response within 4 cycles (3 months).

Time-to-tumor Response (TTR)

This analysis includes only those Cohort 2B participants who had a Complete Response (CR) or a Partial Response (PR).

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

Trial Identification

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Study Description

Keywords

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