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Pembrolizumab and Binimetinib in Treating Patients With Locally Advanced or Metastatic Triple Negative Breast Cancer

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03106415
Recruitment Status : Suspended (DSMC Recommendation)
First Posted : April 10, 2017
Last Update Posted : December 11, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
This phase I/II trial studies the best dose of pembrolizumab and binimetinib and how well it works when giving together with pembrolizumab in treating patients with triple negative breast cancer that has spread to other parts of the body. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and binimetinib may work better in treating patients with triple negative breast cancer.

Condition or disease Intervention/treatment Phase
Breast Adenocarcinoma Estrogen Receptor Negative HER2/Neu Negative Progesterone Receptor Negative Stage III Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer Triple-Negative Breast Carcinoma Drug: Binimetinib Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of binimetinib in combination with pembrolizumab. (Phase I) II. To evaluate the objective response rate (ORR) of binimetinib in combination with pembrolizumab in patients with unresectable locally advanced or metastatic triple negative breast cancer by Response Evaluation Criteria in Solid Tumors (RECIST). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of binimetinib in combination with pembrolizumab.

II. To evaluate the ORR by immune-related RECIST criteria (irRECIST). III. To evaluate the progression free survival (PFS), duration of response (DoR), and disease control rate (DCR) by RECIST and irRECIST.

IV. To assess overall survival (OS).

TERTIARY OBJECTIVES:

I. To assess the correlation between ORR, progression free survival (PFS), or overall survival (OS) and baseline and/or change in tumor infiltrating lymphocytes (TILs).

II. To assess the correlation between ORR, PFS, or OS and baseline and/or change in immune related gene signature and PDJ amplification.

III. To assess the change in immunoregulatory cells (IRC). IV. To assess the change in the cytokine profile. V. To assess the change in circulating tumor cells (CTC).

OUTLINE: This is phase I, dose-escalation study of binimetinib followed by a phase II study.

Patients receive binimetinib orally (PO) twice daily (BID) on days 1-14 of course 1 and on days 1-21 of course 2 and subsequent courses. Patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Course 1 equals 14 days. Courses 2 and beyond repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 or 6 months for up to 3 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Pembrolizumab in Combination With Binimetinib in Unresectable Locally Advanced or Metastatic Triple Negative Breast Cancer
Actual Study Start Date : September 26, 2017
Estimated Primary Completion Date : May 15, 2020
Estimated Study Completion Date : May 15, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Treatment (binimetinib, pembrolizumab)
Patients receive binimetinib PO BID on days 1-14 of course 1 and on days 1-21 of course 2 and subsequent courses. Patients also receive pembrolizumab IV over 30 minutes on day 1. Course 1 equals 14 days. Courses 2 and beyond repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Binimetinib
Given PO
Other Names:
  • ARRY-162
  • ARRY-438162
  • MEK162

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. MTD of pembrolizumab in combination with binimetinib using the standard 3+3 design assessed by Common Terminology Criteria for Adverse Events version 4.0 (Phase I) [ Time Frame: Up to course 2 (35 days) ]
  2. ORR as assessed by RECIST (Phase II) [ Time Frame: Up to 3 years ]
    Will utilize Simon's Two-Stage Optimal Design to test the null hypothesis. Will be estimated using the approach of Jung and Kim. The 90% lower confidence bound will be calculated using the approach of Koyama and Chen.


Secondary Outcome Measures :
  1. ORR by irRECIST [ Time Frame: Up to 3 years ]
    Will be estimated as a binomial proportion with a 2-sided 95% confidence intervals. Baseline TILs and percent change in TILs from baseline will be summarized. Logistic regression models will be used to assess the correlation between these biomarkers and ORR in order to assess their prognostic significance.

  2. OS [ Time Frame: The time from study enrollment to death attributable to any cause, assessed up to 3 years ]
    Patients who are alive (including those lost to follow-up) at the time of data analysis will be censored at the last known alive date. A Kaplan-Meier curve will be used to summarize the OS experience of this patient cohort. Cox Proportional Hazard models will be used to assess baseline TILs and percent change in TILs from baseline and their correlation with OS.

  3. PFS [ Time Frame: The time from study enrollment to date of progression, assessed up to 3 years ]
    Patients who are alive (including those lost to follow-up) at the time of data analysis will be censored at the last known alive date. A Kaplan-Meier curve will be used to summarize the PFS experience of this patient cohort. Cox Proportional Hazard models will be used to assess baseline TILs and percent change in TILs from baseline and their correlation with PFS.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Histological confirmation of adenocarcinoma of the breast
  • Estrogen receptor (ER) and progesterone receptor (PR) negative; defined as ER =< 10% and PR =< 10% staining by immunohistochemistry (IHC)
  • HER2 negative in the primary or metastatic tumor tissue defined as:

    • Immunohistochemistry (IHC) grade 0 as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within =< 10% of the invasive tumor cell; OR
    • IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of the invasive tumor cell; OR
    • IHC grade 2+ staining intensity by means of IHC analysis with no gene amplification below; OR
    • No gene amplification on in situ hybridization (ISH) based on:

      • Single-probe average HER2 copy number < 4.0 signals/cell OR
      • Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell
  • =< 3 prior lines of treatment in the metastatic setting for the current breast cancer
  • Measurable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
  • Hemoglobin >= 9.0 g/dL (must be >= 7 days after most recent transfusion)
  • Absolute neutrophil count (ANC) >= 1500/mm^3 or >= 1.5 x 10^9/L
  • Platelet count >= 100,000/mm^3 or >= 100 x 10^9/L (must be >= 7 days after most recent transfusion)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate transaminase (AST) and/or alanine transaminase (ALT) =< 2.5 x ULN or =< 5 x ULN for patients with liver metastases
  • Creatinine =< 1.5 x ULN OR
  • Calculated creatinine clearance must be >= 50 ml/min using the Cockcroft-Gault formula
  • International normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Adequate cardiac function:

    • Left ventricular ejection fraction (LVEF) >= 50% as determined by multigated acquisition (MUGA) scan or echocardiogram (echo)
    • Corrected QT (QTc) interval =< 480 ms
  • Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Able to swallow oral medication
  • Both female and male patients of reproductive potential must agree to avoid pregnancy or impregnating a partner (respectively) while receiving drug and for 120 days after last dose of study drug
  • Provide written informed consent
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  • Willing to provide mandatory tissue and blood for correlative research purposes

Exclusion Criteria:

  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm OR participated in a study of an investigational agent, received study therapy or used an investigational device =< 4 weeks prior to registration
  • Received prior therapy with anti-PD-1, anti-PD-L1 or anti-PD-L2 agent or MEK inhibitor
  • Immunocompromised patients and patients with known immunodeficiency; or receiving systemic steroid therapy or any other immunosuppressive therapy =< 7 days prior to registration; NOTE: inhaled steroids and low-dose corticosteroids are allowed
  • History of active tuberculosis (TB), human immunodeficiency virus (HIV), active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) and/or active hepatitis C infection (e.g. hepatitis C virus [HCV] ribonucleic acid [RNA] qualitative is detected)
  • Received a live vaccine =< 30 days prior to registration; NOTE: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines, and are not allowed
  • Hypersensitivity to pembrolizumab, binimetinib, or any excipients of either drug
  • Prior anti-cancer therapy with a monoclonal antibody (mAb) =< 4 weeks prior to registration OR failure to recover (to =< grade 1) from adverse events (AE) attributable to agents received > 4 weeks prior to registration
  • Prior therapy including chemotherapy, targeted small molecule therapy or radiation therapy =< 2 weeks prior to registration OR failure to recover (to =< grade 1 or to baseline) from adverse events (AE) attributable to agents received > 4 weeks prior to registration; NOTE: exception for neuropathy =< grade 2, which is allowed
  • Any active central nervous system (CNS) lesion (i.e., those with radiographically unstable, symptomatic lesions) and/or leptomeningeal metastases; NOTE: patients treated with stereotactic radiotherapy or surgery are eligible if no evidence of CNS disease progression >= 4 weeks and patients must be off corticosteroid therapy for >= 3 weeks; NOTE: carcinomatous meningitis is excluded regardless of clinical stability
  • Active autoimmune disease requiring systemic treatment in the past 2 years (i.e. use of disease modifying agents, corticosteroids or immunosuppressive drugs); NOTE: replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Known history of, or any evidence of active, non-infectious pneumonitis
  • Active infection requiring systemic therapy
  • Known history of acute or chronic pancreatitis
  • History of or current evidence of retinal vein occlusion (RVO) or predisposing factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
  • History of retinal degenerative disease
  • History of Gilbert's syndrome
  • Other active malignancy =< 3 years prior to registration; EXCEPTIONS: adequately treated non-melanotic skin cancer (adequate wound healing is required prior to study entry) or carcinoma-in-situ of the cervix; NOTE: if there is a history of prior solid tumor malignancy, it must have been treated curatively with no evidence of recurrence =< 3 years prior to registration
  • Impaired cardiovascular function or clinically specific cardiovascular disease including any of the following:

    • History of acute coronary syndromes (including myocardial infarction unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) =< 6 months; OR
    • Symptomatic chronic heart failure history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality < 6 months prior to screening; except atrial fibrillation and paroxysmal supraventricular tachycardia
  • Uncontrolled arterial hypertension defined as persistent elevation of systolic blood pressure >= 150 mmHg or diastolic blood pressure >= 100 mmHg despite medical treatment
  • History of neuromuscular disorders that are associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  • Planning to embark on a new strenuous exercise regimen after first dose of study treatment; NOTE: muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on binimetinib treatment
  • Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection); NOTE: gastric bypass is allowed
  • Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/psychological issues, etc.
  • Major surgery =< 3 weeks prior to registration or failure to adequately recover from surgery
  • Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study

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): NCT03106415


Locations
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United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Saranya Chumsri Mayo Clinic

Additional Information:
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Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT03106415    
Other Study ID Numbers: MC1632
NCI-2017-00496 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1632 ( Other Identifier: Mayo Clinic in Florida )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: April 10, 2017    Key Record Dates
Last Update Posted: December 11, 2019
Last Verified: December 2019

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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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Breast Neoplasms
Adenocarcinoma
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents