Clinical Trials /

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

NCT03106415

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Binimetinib in Treating Patients With Locally Advanced or Metastatic Triple Negative Breast Cancer
  • Official Title: Phase I/II Trial of Pembrolizumab in Combination With Binimetinib in Unresectable Locally Advanced or Metastatic Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: MC1632
  • SECONDARY ID: NCI-2017-00496
  • SECONDARY ID: MC1632
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03106415

Conditions

  • 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

Interventions

DrugSynonymsArms
BinimetinibARRY-162, ARRY-438162, MEK162Treatment (binimetinib, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (binimetinib, pembrolizumab)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (binimetinib, pembrolizumab)ExperimentalPatients 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.
  • Binimetinib

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

Primary Outcome Measures

Measure: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)
Safety Issue:
Description: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

Measure:ORR by irRECIST
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure:OS
Time Frame:The time from study enrollment to death attributable to any cause, assessed up to 3 years
Safety Issue:
Description: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.
Measure:PFS
Time Frame:The time from study enrollment to date of progression, assessed up to 3 years
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

November 29, 2017