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Avelumab With Binimetinib, Utomilumab, or Anti-OX40 Antibody PF-04518600 in Treating Triple Negative Breast Cancer (InCITe)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03971409
Recruitment Status : Recruiting
First Posted : June 3, 2019
Last Update Posted : July 28, 2020
Sponsor:
Collaborators:
Translational Breast Cancer Research Consortium
Hoosier Cancer Research Network
Array BioPharma
Pfizer
Breast Cancer Research Foundation
Johns Hopkins University
Information provided by (Responsible Party):
Hope Rugo, MD, University of California, San Francisco

Brief Summary:

This phase II trial studies how well avelumab in combination with binimetinib, utomilumab, or anti-OX40 antibody PF-04518600 works in treating patients with triple negative breast cancer that is stage IV or is not able to be removed by surgery (unresectable) and has come back (recurrent). Immunotherapy with checkpoint inhibitors like avelumab require activation of the patients immune system.

This trial includes a two week induction or lead-in of medications that can stimulate the immune system. It is our hope that this induction will improve the response to immunotherapy with avelumab. Patients on this trial will receive two weeks of treatment with one of three treatments to stimulate the bodies immune system, including the monoclonal antibodies, utomilumab, and the anti-OX40 antibody PF-04518600 which may help the body's immune system attack the cancer, and could interfere with the ability of tumor cells to grow and spread. The third medication is called binimetinib , which may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and may help activate the immune system. It is not yet known whether giving avelumab in combination with binimetinib, utomilumab, or anti-OX40 antibody PF-04518600 will work better in treating patients with triple negative breast cancer


Condition or disease Intervention/treatment Phase
Stage III Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer Invasive Breast Carcinoma Recurrent Breast Carcinoma Triple-Negative Breast Carcinoma Biological: Anti-OX40 Antibody PF-04518600 Drug: Avelumab Drug: Binimetinib Biological: Utomilumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Innovative Combination Immunotherapy for Metastatic Triple Negative Breast Cancer (TNBC): A Multicenter, Multi-Arm Translational Breast Cancer Research Consortium Study
Actual Study Start Date : July 8, 2019
Estimated Primary Completion Date : July 30, 2021
Estimated Study Completion Date : July 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Arm I (binimetinib, avelumab)
Patients will receive a 15-day lead-in of binimetinib, followed by binimetinib PO BID and avelumab IV over 60 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Drug: Binimetinib
Given PO
Other Names:
  • ARRY-162
  • ARRY-438162
  • MEK162

Experimental: Arm II (anti-OX40 antibody PF-04518600, avelumab)
Patients will receive a 15-day lead-in of anti-OX40 antibody PF-04518600, followed by anti-OX40 antibody PF-04518600 IV over 60 minutes and avelumab IV over 60 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Biological: Anti-OX40 Antibody PF-04518600
Given IV
Other Name: PF-04518600

Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Experimental: Arm III (utomilumab, avelumab)
Patients will receive a 15-day lead-in of utomilumab, followed by utomilumab IV over 60 minutes every 4 weeks and avelumab IV over 60 minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Biological: Utomilumab
Given IV
Other Names:
  • PF 05082566
  • PF 5082566
  • PF-05082566
  • PF-2566




Primary Outcome Measures :
  1. Best Overall Response Rate (BORR) Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: From initiation of study treatment until the date disease progression is first observed, an estimated average of 1 year ]
    Will be defined as the percentage of patients achieving complete response or partial response by RECIST version 1.1 and will be reported for each arm along with 95% two-sided confidence intervals.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) Assessed by Immune-Related RECIST (iRECIST) [ Time Frame: From initiation of study treatment until the date disease progression is first observed, an estimated average of 1 year ]
    Will be assessed by Immune-related Response Evaluation Criteria in Solid Tumors. Will be summarized by arm and 95% two-sided confidence intervals for each percentage will be reported.

  2. Clinical Benefit Rate (CBR) Assessed by RECIST Version 1.1 [ Time Frame: At 6 months ]
    Will be defined as lack of disease progression at 6 months. Will be summarized by arm and 95% two-sided confidence intervals for each percentage will be reported.

  3. Median Progression-free Survival (PFS) Assessed by RECIST Version 1.1 [ Time Frame: From initiation of study treatment until the date disease progression is first observed, an estimated average of 1 year ]
    The distribution of PFS per each arm will be estimated using the Kaplan-Meier method with censoring used as needed. Median time to event and corresponding confidence intervals will be reported along with Kaplan-Meier curves.

  4. Median Overall Survival [ Time Frame: At 12 months ]
    Will be summarized by arm and 95% two-sided confidence intervals for each percentage will be reported.

  5. Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 [ Time Frame: Up to 30 days after completion of study treatment ]
    An unacceptable toxicity is defined as any unexpected and clinically relevant drug-related grade 3 toxicity, or any drug-related grade 4-5 adverse event within the first cycle of therapy assessed via National Cancer Institute CTCAE version 5 criteria. Safety will be evaluated by estimating the percentage of patients who experience a clinically relevant toxicity (both patient and physician reported) for each arm with 95% two-sided confidence intervals. All adverse events will be tabulated and summarized with descriptive statistics.

  6. Change in Quality of Life at 8 Weeks Assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Measure [ Time Frame: Baseline up to 8 weeks ]
    Will be measured the PROMIS Global Short Form. Change scores will be compared across treatment arms using one way analysis of variance (ANOVA) with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn's adjustment for multiple comparisons.

  7. Change in Quality of Life Over Treatment Duration Assessed by PROMIS Global Health Measure [ Time Frame: From baseline until the date disease progression is first observed, an estimated average of 1 year ]
    Will be measured the PROMIS Global Short Form. Change scores will be compared across treatment arms using one way analysis of variance (ANOVA) with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn's adjustment for multiple comparisons.

  8. Change in Symptoms (Self-Reported Toxicities) at 8 Weeks Assessed by Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE) [ Time Frame: Baseline up to 8 weeks ]
    Will be measured by the PRO-CTCAE criteria . The data will be presented descriptively using summary statistics and graphical representations across time points. Will assess symptom burden using Likert scores. Each attribute will be presented descriptively using summary statistics and graphical representations across time points.

  9. Change in Symptoms (Self-Reported Toxicities) Over Treatment Duration Assessed by PRO-CTCAE [ Time Frame: From baseline until the date disease progression is first observed, an estimated average of 1 year ]
    Will be measured by the PRO-CTCAE criteria . The data will be presented descriptively using summary statistics and graphical representations across time points. Will assess symptom burden using Likert scores. Each attribute will be presented descriptively using summary statistics and graphical representations across time points.

  10. Change in Ability to Participate in Social Roles and Activities at 8 Weeks Assessed by PROMIS [ Time Frame: Baseline up to 8 weeks ]
    The data will be presented descriptively using summary statistics and graphical representations across time points. Change scores will be compared across treatment arms using one way ANOVA with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn?s adjustment for multiple comparisons.

  11. Change in Ability to Participate in Social Roles and Activities Over Treatment Duration Assessed by PROMIS [ Time Frame: From baseline until the date disease progression is first observed, an estimated average of 1 year ]
    The data will be presented descriptively using summary statistics and graphical representations across time points. Change scores will be compared across treatment arms using one way ANOVA with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn?s adjustment for multiple comparisons.

  12. Change in Treatment Satisfaction at 8 Weeks Assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) [ Time Frame: Baseline up to 8 weeks ]
    Will be assessed by TSQM Questionnaire. Change scores will be compared across treatment arms using one way ANOVA with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn?s adjustment for multiple comparisons.

  13. Change in Treatment Satisfaction Over Treatment Duration Assessed by the TSQM [ Time Frame: From baseline until the date disease progression is first observed, an estimated average of 1 year ]
    Will be assessed by TSQM Questionnaire. Change scores will be compared across treatment arms using one way ANOVA with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn?s adjustment for multiple comparisons.



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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:

  • Signed and dated written informed consent
  • Subjects >= 18 years of age
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Clinical stage IV invasive mammary carcinoma or unresectable locoregional recurrence of invasive mammary carcinoma that is:

    • Estrogen receptor (ER)/progesterone receptor (PR)-negative (=< 5% cells) by immunohistochemistry (IHC) and human epidermal growth factor receptor 2 (HER2) negative [by IHC or fluorescence in situ hybridization (FISH)]
    • Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria and which can be followed by computed tomography (CT) or magnetic resonance imaging (MRI). A measureable lytic bone lesion(s) and/or skin lesion(s) are allowed. Skin lesions must also be followed by photography with measuring tools within the photograph at each tumor evaluation time point
    • Amenable to biopsy at the time of study entry
    • Known tumor/immune cell PD-L1 status by any assay
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Hemoglobin >= 9/g/dL (may have been transfused)
  • Total serum bilirubin =< 1.5 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) [serum glutamic oxaloacetic transaminase (SGOT)] and alanine aminotransferase (ALT) [serum glutamate pyruvate transaminase (SGPT)] =< 2.5 x ULN (or =< 5 x ULN if liver metastases are present)
  • Serum creatinine =< 1.5 x ULN or estimated creatinine clearance >= 50 mL/min as calculated using the Cockcroft-Gault (CG) equation
  • Thyroid stimulating hormone (TSH) within institutional normal limits
  • Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN
  • Amylase =< 1 x ULN
  • Lipase =< 1 x ULN
  • Male and female patients of childbearing potential must agree to use at least two methods of acceptable contraception from 15 days prior to first trial treatment administration until at least 30 days after study participant's final dose of study drug(s). See sub-protocols for additional arm specific details

    • Note: Females of childbearing potential are defined as those who are not surgically sterile or post-menopausal (i.e. patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months without an alternative medical cause). Post-menopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women
  • Patients unable to read/write in English are eligible to participate in the overall study but will not participate in the patient-reported outcome questionnaires throughout the trial
  • Re-enrollment of a subject that has discontinued the study as a pre-treatment screen failure (i.e. a consented patient who did not receive avelumab) is permitted. If re-enrolled, the subject must be re-consented. Only the screening procedures performed outside of protocol-specified timing must be repeated; if biopsies and correlative blood samples were already obtained, they do not need to be repeated

Exclusion Criteria:

  • More than 3 lines of chemotherapy in the metastatic setting
  • More than 1 prior line of checkpoint inhibitor therapy in the metastatic setting
  • Concurrent anticancer therapy. Required washout from prior therapies are as follows:

    • Chemotherapy: >= 14 days
    • Major surgery: >=14 days (provided wound healing is adequate)
    • Radiation: >= 7 days
    • Investigational/biologic therapy (half-life =< 40 hours): >= 14 days
    • Investigational/biologic therapy (half-life > 40 hours): >= 28 days
    • Use of corticosteroids or immunosuppressive medication is exclusionary, except the following in the absence of active autoimmune disease:

      • Subjects are permitted the use of corticosteroids with minimal systemic absorption (e.g. topical, ocular, intra-articular, intranasal, and inhaled)
      • Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent are permitted
      • Adrenal replacement steroid doses including doses > 10 mg daily prednisone are permitted
      • A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. CT scan premedication against contrast dye allergy) or for treatment of nonautoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by a contact allergen) is permitted
  • Previous malignant disease other than breast cancer within the last 5 years, with the exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, or low-risk cancers considered curatively treated (i.e. complete remission achieved at least 2 years prior to first dose of study drugs AND additional therapy not required while receiving study treatment)
  • All subjects with brain metastases, except those meeting the following criteria:

    • Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment
    • No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
    • Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent)
  • Receipt of any organ transplantation including allogeneic stem-cell transplantation
  • Significant acute or chronic infections including, among others:

    • Known history of testing positive for human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)
    • A history of a positive test for hepatitis B virus (HBV) surface antigen (and/or core antibody) and/or confirmatory hepatitis C virus (HCV) ribonucleic acid (RNA) (if anti-HCV antibody tested positive); testing is not required for this protocol
  • Active autoimmune disease with reasonable possibility of clinically significant deterioration when receiving an immunostimulatory agent:

    • Subjects with type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
    • Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses =< 10 mg or 10 mg equivalent prednisone per day
    • Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable
  • History of interstitial lung disease that is symptomatic or which may interfere with the detection or management of suspected drug-related pulmonary toxicity
  • Uncontrolled asthma (defined as having 3 or more of the following features of partially controlled asthma within 28 days prior to starting study treatment: Daytime symptoms more than twice per week, any limitation of activities, any nocturnal symptoms/awaking, need for reliever/rescue inhaler more than twice per week, or known lung function [peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV1)] without administration of a bronchodilator that is < 80% predicted or personal best [if known])
  • Current symptomatic congestive heart failure (New York Heart Association > class II), unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest discomfort), uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100mmHg), or known cardiac ejection fraction below the lower limit of institutional normal. Or any of the following occurring within 6 months (180 days) prior to first dose of avelumab: Myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack. (Use of antihypertensive medication to control blood pressure is allowed.)
  • Patients who have neuromuscular disorders that are associated with elevated creatine kinase (CK)
  • History of acute or chronic pancreatitis
  • History or current evidence of retinal vein occlusion (RVO), or current risk factors for RVO including uncontrolled glaucoma, ocular hypertension, history of hyperviscosity, or hypercoagulability syndromes; history of retinal degenerative disease
  • Requirement of anticoagulant therapy with oral vitamin K antagonists such as Coumadin (warfarin). Low-dose anticoagulants for the maintenance of patency in a central venous access device or the prevention of deep vein thrombosis or pulmonary embolism is allowed. Therapeutic use of low molecular weight heparin is allowed provided patients are safely able to interrupt it prior to biopsy procedures
  • Persisting toxicity related to prior therapy that has not reduced to grade 1 (National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI CTCAE] version 5.0); however, alopecia and sensory neuropathy grade =< 2 is acceptable
  • Known severe (grade >= 3 NCI-CTCAE v5.0) hypersensitivity reactions to monoclonal antibodies, or history of anaphylaxis
  • Vaccination within 28 days of the first dose of study drugs and while on trial is prohibited, except for administration of inactivated vaccines (for example, inactivated influenza vaccine)
  • Pregnant or breastfeeding females
  • Known current alcohol or drug abuse
  • Prisoners or subjects who are involuntarily incarcerated
  • Known psychiatric condition, social circumstance, or other medical condition reasonably judged by the patient's study physician to unacceptably increase the risk of study participation; or to prohibit the understanding or rendering of informed consent or anticipated compliance with scheduled visits, treatment schedule, laboratory tests and other study requirements

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): NCT03971409


Contacts
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Contact: Hope Rugo, MD 877-827-3222 Cancertrials@ucsf.edu
Contact: Amy DeLuca 415-353-7288 Amy.Deluca@ucsf.edu

Locations
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United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Felicia Witherspoon    205-934-4317    fwithers@uab.edu   
Principal Investigator: Ahmed Elkhanany, MD         
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Hope Rugo, MD    877-827-3222    cancertrials@ucsf.edu   
Contact: Amy DeLuca    415-353-7288    Amy.Deluca@ucsf.edu   
Principal Investigator: Hope Rugo, MD         
United States, District of Columbia
Georgetown University Recruiting
Washington, District of Columbia, United States, 20057
Contact: Antonella Novielli    202-683-0716    noviella@georgetown.edu   
Principal Investigator: Filipa Lynce, MD         
United States, Minnesota
Mayo Clinic Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: Minetta C. Liu    507-293-0526    liu.minetta@mayo.edu   
Principal Investigator: Minetta C. Liu         
United States, North Carolina
UNC Lineberger Comprehensive Cancer Center Not yet recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Charles M. Perou    919-843-5740    chuck_perou@med.unc.edu   
Principal Investigator: Charles M. Perou         
United States, Tennessee
Vanderbilt University/Ingram Cancer Center Not yet recruiting
Nashville, Tennessee, United States, 37232
Contact: Ingrid A. Mayer    615-936-2033    ingrid.mayer@vanderbilt.edu   
Principal Investigator: Ingrid A. Mayer         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Chava Kankana    713-798-1911    Kankana.Chava@bcm.edu   
Principal Investigator: Valentina Hoyos Velez, MD         
Sponsors and Collaborators
Hope Rugo, MD
Translational Breast Cancer Research Consortium
Hoosier Cancer Research Network
Array BioPharma
Pfizer
Breast Cancer Research Foundation
Johns Hopkins University
Investigators
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Principal Investigator: Hope Rugo, MD University of California, San Francisco
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Responsible Party: Hope Rugo, MD, Principal Investigator, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03971409    
Other Study ID Numbers: 187519
NCI-2019-01531 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
TBCRC 047 ( Other Identifier: Translational Breast Cancer Research Consortium )
BRE16-279 ( Other Identifier: Hoosier Cancer Research Network )
First Posted: June 3, 2019    Key Record Dates
Last Update Posted: July 28, 2020
Last Verified: July 2020
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
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antibodies
Antibodies, Monoclonal
Immunoglobulin G
Immunologic Factors
Physiological Effects of Drugs