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

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ClinicalTrials.gov Identifier: NCT03364348
Recruitment Status : Recruiting
First Posted : December 6, 2017
Last Update Posted : January 26, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
George W. Sledge Jr., Stanford University

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.

Condition or disease Intervention/treatment Phase
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 Drug: Utomilumab Drug: Trastuzumab Drug: Trastuzumab Emtansine Phase 1

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: Patients receive trastuzumab emtansine intravenously (IV) over 30 minutes on day 0 of course 1 and day 1 of subsequent courses, and utomilumab IV over 1 hour on day 1.

COHORT 2: Patients receive trastuzumab IV over 90 minutes on day 0 of course 1 and day 1 of subsequent courses, and utomilumab IV over 1 hour on day 1.

In both cohorts, treatment repeats every 21 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up to 60 days, then every 9 weeks for up to 6 months. Tumor assessments per the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 criteria.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 79 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B Dose Escalation Trial of Human Anti-4-1BB Agonistic Antibody PF-05082566 in Combination With Adotrastuzumab-Emtansine or Trastuzumab in Patients With HER2-Positive Advanced Breast Cancer
Actual Study Start Date : October 30, 2017
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Cohort 1 (trastuzumab emtansine + utomilumab)

Participants receive trastuzumab emtansine intravenously (IV) over 30 minutes on Day 0 of Cycle and Day 1 of subsequent cycles, and utomilumab IV over 1 hour on day 1.

Treatment cycles are 21 days, and may repeat for up to 24 cycles, in the absence of disease progression or unacceptable toxicity.

Drug: Utomilumab
Given IV
Other Names:
  • 4-1BB Agonist Monoclonal Antibody PF-05082566
  • PF-05082566
  • PF-2566

Drug: Trastuzumab Emtansine
Given IV
Other Names:
  • Ado Trastuzumab Emtansine
  • Kadcyla
  • PRO132365
  • RO5304020
  • T-DM1
  • Trastuzumab-DM1
  • Trastuzumab-MCC-DM1
  • Trastuzumab-MCC-DM1 Antibody-Drug Conjugate
  • Trastuzumab-MCC-DM1 Immunoconjugate

Experimental: Cohort 2 (trastuzumab + utomilumab)
Participants receive trastuzumab intravenously (IV) over 90 minutes on Day 0 of Cycle 1 and Day 1 of subsequent cycles, and utomilumab IV over 1 hour on day 1. Treatment cycles are 21 days, and may repeat for up to 24 cycles, in the absence of disease progression or unacceptable toxicity.
Drug: Utomilumab
Given IV
Other Names:
  • 4-1BB Agonist Monoclonal Antibody PF-05082566
  • PF-05082566
  • PF-2566

Drug: Trastuzumab
Given IV
Other Names:
  • 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




Primary Outcome Measures :
  1. Incidence of Dose-limiting toxicities (DLTs) [ Time Frame: 2 months ]
    Incidence of dose-limiting toxicities (DLTs) within the first 2 cycles (up to about 2 months) reported for the Dose-finding Cohorts 1 (ado-trastuzumab emtansine) and 2 (trastuzumab). Subjects lost-to-follow-up before completion of first 2 cycles due to reasons unrelated to treatment-related adverse events are not evaluable for DLT.


Secondary Outcome Measures :
  1. Objective tumor response (ORR) [ Time Frame: 2 months ]

    Objective tumor response (ORR) after 2 cycles for subjects in Expansion Phase 1B Cohorts 1 (ado trastuzumab emtansine) and 2 (trastuzumab), per RECIST v1.1:

    • Complete Response (CR): Complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed.
    • Partial Response (PR): ≥ 30% decrease in the sum of diameters of all 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): All target lesions assessed, but not CR, PR, or PD.
    • Indeterminate. Progression has not been documented; and

      • 1+ target measurable lesions have not been assessed; or
      • Assessment methods inconsistent with baseline; or
      • 1+ target lesions cannot be measured accurately; or
      • 1+ target lesions excised or irradiated, and have not reappeared or increased.

  2. Time-to-tumor response (TTR) [ Time Frame: 4 months ]

    Time-to-tumor response (TTR), per RECIST v1.1, in subjects who have at least 1 on-study tumor assessment and respond within 4 months.

    RECIST v1.1:

    • Complete Response (CR): Complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed.
    • Partial Response (PR): ≥ 30% decrease in the sum of diameters of all 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): All target lesions assessed, but not CR, PR, or PD.
    • Indeterminate. Progression has not been documented; and

      • 1+ target measurable lesions have not been assessed; or
      • Assessment methods inconsistent with baseline; or
      • 1+ target lesions cannot be measured accurately; or
      • 1+ target lesions excised or irradiated, and have not reappeared or increased.

  3. Duration of response (DR) [ Time Frame: Up to 5 years ]

    Duration of response (DR) in subjects who have 1+ on-study tumor assessment and have a clinical response, through up to 5 years after treatment, per RECIST v1.1:

    • Complete Response (CR): Complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed.
    • Partial Response (PR): ≥ 30% decrease in the sum of diameters of all 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): All target lesions assessed, but not CR, PR, or PD.
    • Indeterminate. Progression has not been documented; and

      • 1+ target measurable lesions have not been assessed; or
      • Assessment methods inconsistent with baseline; or
      • 1+ target lesions cannot be measured accurately; or
      • 1+ target lesions excised or irradiated, and have not reappeared or increased

  4. Progression-ree survival (PFS) [ Time Frame: Up to 5 years ]

    Progression-free survival (PFS) of subjects (percentage) who initiate treatment and have in subjects who have at least 1 on-study tumor assessment, reported as the number who remain alive without progression 5 years after treatment. Subjects withdrawn for treatment related AEs, or lost to follow up before 5 years, will report as the last date known alive.

    RECIST v1.1 Progression Disease (PD): Increase in lesion size ≥ 5 mm and ≥ 20% increase in the sum of diameters of target measurable lesions.


  5. Adverse Event Incidence [ Time Frame: Up to 3 years ]
    Incidence of adverse events (not including laboratory abnormalities) while receiving treatment and within 30 days, reported by treatment group for severity (as graded by NCI CTCAE v.4.03), seriousness (YES/no), and relationship to the study treatments

  6. Laboratory abnormality Incidence [ Time Frame: Up to 3 years ]
    Incidence of laboratory abnormalities reported by treatment group for severity (as graded by NCI CTCAE v.4.03)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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].

    • Cohort 1 participants must have received trastuzumab and a taxane in the advanced/metastatic setting or must have developed disease recurrence during or within 6 months of completing adjuvant therapy.
    • Cohort 2 participants must have received at least 2 prior therapies in the advanced/metastatic setting.
    • Potential participants who discontinued prior trastuzumab or ado-trastuzumab emtansine due to progressive or refractory disease are eligible for enrollment.
  • Available tumor samples

    • A formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from a de novo tumor biopsy obtained during screening will be required (biopsied tumor lesion should not be a target lesion). An archival FFPE tumor tissue block (cut slides not acceptable) from a primary or metastatic tumor resection or biopsy can be provided if the following criteria are met:

      1. The biopsy or resection was performed within 1 year of enrollment AND
      2. Not received any intervening systemic anti-cancer treatment from the time the tissue was obtained and randomization onto the current study.
    • Availability of an archival FFPE tumor tissue block from primary tumor resection specimen (if not provided per above). If an FFPE tissue block cannot be provided, a minimum of 10 unstained slides (15 preferable) will be acceptable.
  • Participants must have evaluable OR measurable disease, as defined by RECIST v1.1.
  • Women or men, age ≥ 18 years old.
  • Performance status 0 to 1 (by Eastern Cooperative Oncology Group [ECOG] scale).
  • Absolute neutrophil count (ANC) ≥ 1.5 × 10e9/L (≥ 1500/µL)
  • Platelet count ≥ 100 × 10e9/L (≥ 100,000/µL)
  • Hemoglobin ≥ 9.0 g/dL
  • Potential participants 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
  • Serum creatinine ≤ 1.5 × the upper limit of normal (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
  • Not pregnant or breastfeeding.
  • Signed an informed consent document stating that they understand the investigational nature of the proposed treatment.
  • Not receiving any other investigational agents within 30 days of registration.
  • Left ventricular ejection fraction determined by echocardiogram or multiple gated acquisition scan (MUGA) (cardiac scan) must be 50% or higher.

EXCLUSION CRITERIA:

  • Intolerance to prior trastuzumab or ado-trastuzumab emtansine
  • Central nervous system (CNS) metastases, unless previously treated by either radiation therapy and/or surgical resection, clinically stable for at least 60 days and off corticosteroids. Potential participants 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);
    • No additional treatment planned for brain metastases;
    • Clinically stable;
    • Not receiving corticosteroids.
  • 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 v4.03) 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 5 mg daily for therapeutic and not adrenal replacement indications (maintenance steroid use for adrenal insufficiency is permitted).
  • History of bleeding diathesis.
  • Any co-morbid medical condition that may put the subject at significant risk for toxicity.
  • Known sensitivity to any of the products to be administered during dosing.
  • Any 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. Chronic, systemic corticosteroid use for palliative or supportive purpose is not permitted. Use of corticosteroids as symptomatic treatment may be allowed on individual basis and upon discussion. Acute emergency administration, topical applications, inhaled sprays, eye drops or local injections of corticosteroids are allowed.
  • 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, a 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03364348


Contacts
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Contact: Oshra Sedan 650-723-0628 osedan@stanford.edu

Locations
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United States, California
Stanford University, School of Medicine Recruiting
Palo Alto, California, United States, 94304
Contact: Oshra Sedan    650-723-0628    osedan@stanford.edu   
Principal Investigator: George W. Sledge, MD         
Sponsors and Collaborators
George W. Sledge Jr.
National Cancer Institute (NCI)
Investigators
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Principal Investigator: George Sledge, MD Stanford Cancer Institute

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Responsible Party: George W. Sledge Jr., Principal Investigator, Stanford University
ClinicalTrials.gov Identifier: NCT03364348     History of Changes
Other Study ID Numbers: BRS0070
NCI-2016-01881 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
BRS0070 ( Other Identifier: Stanford Cancer Institute )
IRB-37299 ( Other Identifier: Stanford Cancer Institute )
First Posted: December 6, 2017    Key Record Dates
Last Update Posted: January 26, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoconjugates
Immunoglobulin G
Trastuzumab
Antineoplastic Agents, Immunological
Ado-trastuzumab emtansine
Maytansine
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action