Clinical Trials /

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

NCT03971409

Description:

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

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Avelumab With Binimetinib, Utomilumab, or Anti-OX40 Antibody PF-04518600 in Treating Triple Negative Breast Cancer
  • Official Title: Innovative Combination Immunotherapy for Metastatic Triple Negative Breast Cancer (TNBC): A Multicenter, Multi-Arm Translational Breast Cancer Research Consortium Study

Clinical Trial IDs

  • ORG STUDY ID: 187519
  • SECONDARY ID: NCI-2019-01531
  • SECONDARY ID: TBCRC 047
  • SECONDARY ID: BRE16-279
  • NCT ID: NCT03971409

Conditions

  • 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

Interventions

DrugSynonymsArms
Anti-OX40 Antibody PF-04518600PF-04518600Arm II (anti-OX40 antibody PF-04518600, avelumab)
AvelumabBavencio, MSB-0010718C, MSB0010718CArm I (binimetinib, avelumab)
BinimetinibARRY-162, ARRY-438162, MEK162Arm I (binimetinib, avelumab)
UtomilumabPF 05082566, PF 5082566, PF-05082566, PF-2566Arm III (utomilumab, avelumab)

Purpose

This phase II trial studies if avelumab in combination with binimetinib, utomilumab, or anti-OX40 antibody PF-04518600 is safe and effective for 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 monoclonal antibodies, such as avelumab, utomilumab, and anti-OX40 antibody PF-04518600 may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Anti-tumor effect of avelumab in combination with different targeted agents explored in
      the sub-protocols of the trial.

      SECONDARY OBJECTIVES:

      I. Additional anti-tumor effects. II. Safety and tolerability of avelumab single-agent and in
      combination with different targeted agents explored in the sub-protocols of the trial.

      III. Patient reported outcomes (PRO) between baseline and cycle 3 day 1 across arms.

      IV. Longitudinal trends in PRO outcomes across treatment arms. V. Differences in PRO outcomes
      for patients who respond compare to those who do not respond.

      CORRELATIVE OBJECTIVES:

      I. To determine the therapeutic predictive role of the following on clinical outcome:

      I a. Programmed cell death-ligand 1 (PD-L1) expression and immune 'hot-spots'. I b. Tumor
      infiltrating lymphocyte (TIL)s, and cluster of differentiation 8 (CD8) and cluster of
      differentiation 4 (CD4) positivity in TIL.

      I c. Human leukocyte antigen (HLA)-A (MHC-I) and HLA-DR (MHC-II), FoxP3, OX40 and OX40L,
      Phosphatase and tensin homolog (PTEN), and myelocytomatosis oncogene (MYC) expression.

      I d. Number/levels of expressed predicted class I and class II neoantigens, central memory
      T-cells and T-cells.

      I e. Expression of effector/regulatory immune gene, innate Programmed cell death protein 1
      (PD-1) resistance signature (IPRES), and B cell, T cell, and/or macrophage signatures.

      I f. Basal or claudin-low molecular subtypes. I g. T cell receptor (TCR) clonality in the
      tumor and peripheral blood. I h. Genomic mutational burden. I i. PD-L1 positivity in
      circulating tumor cells (CTCs). I j. Soluble B7-H1 (sB7-H1) levels. II. To determine if
      circulating tumor deoxyribonucleic acid (DNA) (ctDNA) results will discriminate
      pseudo-progression from true progression.

      III. To determine if certain genomic alterations detected in tumor tissue or ctDNA are
      potentially associated with resistance to the tested drug combinations.

      OUTLINE: Patients are randomized to 1 of 3 arms.

      Arm I: Patients receive binimetinib orally (PO) twice daily (BID) and avelumab IV over 60
      minutes every 2 weeks. Cycles repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      Arm II: Patients receive 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.

      Arm III: Patients receive 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.

      After completion of study treatment, patients have a follow-up at 30 days after treatment
      ends and then every 6 months for a minimum of one year following start of study therapy or
      until the study is stopped.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (binimetinib, avelumab)ExperimentalPatients receive 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.
  • Avelumab
  • Binimetinib
Arm II (anti-OX40 antibody PF-04518600, avelumab)ExperimentalPatients receive 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.
  • Anti-OX40 Antibody PF-04518600
  • Avelumab
Arm III (utomilumab, avelumab)ExperimentalPatients receive 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.
  • Avelumab
  • Utomilumab

Eligibility Criteria

        Inclusion Criteria:

          -  Signed and dated written informed consent

          -  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)

               -  Amenable to biopsy at the time of study entry

          -  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

          -  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 60 days after study participant?s final dose of study drug(s)

               -  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:

          -  Prior therapy with anti-programmed cell death-ligand 1 (PD-L1) and anti-programmed
             cell death protein 1 (PD1) antibodies

          -  More than 3 lines of chemotherapy 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
             4.03); however, alopecia and sensory neuropathy grade =< 2 is acceptable

          -  Known severe (grade >= 3 NCI-CTCAE) 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best Overall Response Rate 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
Safety Issue:
Description: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

Measure:Best Overall Response Rate 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
Safety Issue:
Description: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.
Measure:Clinical Benefit Rate Assessed by RECIST Version 1.1
Time Frame:At 6 months
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Median Overall Survival
Time Frame:At 12 months
Safety Issue:
Description:Will be summarized by arm and 95% two-sided confidence intervals for each percentage will be reported.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Change in Ability to Participate in Social Roles and Activities at 8 Weeks Assessed by PROMIS
Time Frame:Baseline up to 8 weeks
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Change in Treatment Satisfaction at 8 Weeks Assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM)
Time Frame:Baseline up to 8 weeks
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Hope Rugo, MD

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