Clinical Trials /

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

NCT03364348

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: BRS0070
  • SECONDARY ID: NCI-2016-01881
  • SECONDARY ID: BRS0070
  • SECONDARY ID: IRB-37299
  • NCT ID: NCT03364348

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

Interventions

DrugSynonymsArms
Utomilumab4-1BB Agonist Monoclonal Antibody PF-05082566, PF-05082566, PF-2566Cohort 1 (trastuzumab emtansine + utomilumab)
TrastuzumabABP 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-05280014Cohort 2 (trastuzumab + utomilumab)
Trastuzumab EmtansineAdo Trastuzumab Emtansine, Kadcyla, PRO132365, RO5304020, T-DM1, Trastuzumab-DM1, Trastuzumab-MCC-DM1, Trastuzumab-MCC-DM1 Antibody-Drug Conjugate, Trastuzumab-MCC-DM1 ImmunoconjugateCohort 1 (trastuzumab emtansine + utomilumab)

Purpose

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: 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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 (trastuzumab emtansine + utomilumab)ExperimentalParticipants 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.
  • Utomilumab
  • Trastuzumab Emtansine
Cohort 2 (trastuzumab + utomilumab)ExperimentalParticipants 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.
  • Utomilumab
  • Trastuzumab

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].

               -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Dose-limiting toxicities (DLTs)
Time Frame:2 months
Safety Issue:
Description: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

Measure:Objective tumor response (ORR)
Time Frame:2 months
Safety Issue:
Description: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.
Measure:Time-to-tumor response (TTR)
Time Frame:4 months
Safety Issue:
Description: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.
Measure:Duration of response (DR)
Time Frame:Up to 5 years
Safety Issue:
Description: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
Measure:Progression-ree survival (PFS)
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Adverse Event Incidence
Time Frame:Up to 3 years
Safety Issue:
Description: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
Measure:Laboratory abnormality Incidence
Time Frame:Up to 3 years
Safety Issue:
Description:Incidence of laboratory abnormalities reported by treatment group for severity (as graded by NCI CTCAE v.4.03)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:George W. Sledge Jr.

Last Updated

January 24, 2018