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

NCT03364348 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: IRB-37299NCI-2016-01881BRS0070
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Objective Tumor Response (ORR)

  3 months

• Time-to-tumor Response (TTR)

  3 months

• Duration of Response (DoR)

  up to 260 weeks

• Progression-free Survival (PFS)

  128 weeks

• Adverse Events by Severity Grade 1 to 5

  Up to 128 weeks

Other Outcomes (1)

• Laboratory Value Abnormalities

  Up to 128 weeks

Study Arms (4)

Cohort 1A (trastuzumab + utomilumab)

EXPERIMENTAL

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; Drug: Trastuzumab

Cohort 1B (trastuzumab + utomilumab)

EXPERIMENTAL

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

Drug: Utomilumab; Drug: Trastuzumab

Cohort 2A (ado-trastuzumab emtansine + utomilumab)

EXPERIMENTAL

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

Drug: Utomilumab; Drug: Ado-Trastuzumab Emtansine

Cohort 2B (ado-trastuzumab emtansine + utomilumab)

EXPERIMENTAL

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

Drug: Utomilumab; Drug: Ado-Trastuzumab Emtansine

Interventions

Utomilumab DRUG

Given IV

Also known as: 4-1BB Agonist Monoclonal Antibody PF-05082566, PF-05082566, PF-2566

Cohort 1A (trastuzumab + utomilumab); Cohort 1B (trastuzumab + utomilumab); Cohort 2A (ado-trastuzumab emtansine + utomilumab); Cohort 2B (ado-trastuzumab emtansine + utomilumab)

Trastuzumab DRUG

Given IV

Also known as: ABP 980, Anti-c-ERB-2, Anti-c-erbB2 Monoclonal Antibody, Anti-ERB-2, Anti-erbB-2, Anti-erbB2 Monoclonal Antibody, Anti-HER2/c-erbB2 Monoclonal Antibody, Anti-p185-HER2, c-erb-2 Monoclonal Antibody, HER2 Monoclonal Antibody, Herceptin, Herceptin Biosimilar PF-05280014, Herceptin Trastuzumab Biosimilar PF-05280014, MoAb HER2, Monoclonal Antibody c-erb-2, Monoclonal Antibody HER2, PF-05280014, rhuMAb HER2, RO0452317, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar PF-05280014

Cohort 1A (trastuzumab + utomilumab); Cohort 1B (trastuzumab + utomilumab)

Ado-Trastuzumab Emtansine DRUG

Given IV

Also known as: Trastuzumab Emtansine, Kadcyla, PRO132365, RO5304020, T-DM1, Trastuzumab-DM1, Trastuzumab-MCC-DM1, Trastuzumab-MCC-DM1 Antibody-Drug Conjugate, Trastuzumab-MCC-DM1 Immunoconjugate

Cohort 2A (ado-trastuzumab emtansine + utomilumab); Cohort 2B (ado-trastuzumab emtansine + utomilumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• George W. Sledge Jr.: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Stanford University, School of Medicine

Palo Alto, California, 94304, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

utomilumab; Trastuzumab; PF-05280014; Ado-Trastuzumab Emtansine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Sinyoung Park
• Organization: Stanford Medicine at Stanford University

sinyoung@stanford.edu

650-721-4485

Study Officials

• George Sledge, MD

  Stanford Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 10, 2017
• First Posted: December 6, 2017
• Study Start: October 30, 2017
• Primary Completion: February 15, 2021
• Study Completion: February 14, 2022
• Last Updated: October 19, 2022
• Results First Posted: October 19, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)