Clinical Trials /

Binimetinib and Nivolumab for the Treatment of Locally Advanced Unresectable or Metastatic BRAF V600 Wildtype Melanoma

NCT04375527

Description:

This phase II trial studies how well binimetinib and nivolumab work in treating patients with BRAF V600 wildtype melanoma that has spread to nearby tissues or lymph nodes and cannot be removed by surgery (locally advanced unresectable) or has spread to other places in the body (metastatic). Binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving binimetinib and nivolumab together may work better in treating patients with melanoma compared to nivolumab alone.

Related Conditions:
  • Cutaneous Melanoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Binimetinib and Nivolumab for the Treatment of Locally Advanced Unresectable or Metastatic BRAF V600 Wildtype Melanoma
  • Official Title: A Phase 2 Study of Combination Treatment of Binimetinib and Nivolumab for Advanced V600BRAF Wildtype Melanoma With Innate Anti-PD-1 Resistance

Clinical Trial IDs

  • ORG STUDY ID: 19-002060
  • SECONDARY ID: NCI-2020-02590
  • SECONDARY ID: 19-002060
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT04375527

Conditions

  • Clinical Stage III Cutaneous Melanoma AJCC v8
  • Clinical Stage IV Cutaneous Melanoma AJCC v8
  • Locally Advanced Cutaneous Melanoma
  • Metastatic Cutaneous Melanoma
  • Pathologic Stage III Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIA Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIB Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIID Cutaneous Melanoma AJCC v8
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8
  • Unresectable Cutaneous Melanoma

Interventions

DrugSynonymsArms
BinimetinibARRY-162, ARRY-438162, MEK162, MektoviTreatment (binimetinib, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (binimetinib, nivolumab)

Purpose

This phase II trial studies how well binimetinib and nivolumab work in treating patients with BRAF V600 wildtype melanoma that has spread to nearby tissues or lymph nodes and cannot be removed by surgery (locally advanced unresectable) or has spread to other places in the body (metastatic). Binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving binimetinib and nivolumab together may work better in treating patients with melanoma compared to nivolumab alone.

Detailed Description

      PRIMARY OBJECTIVE:

      I. Objective response rate (ORR), which is defined as the proportion of response-evaluable
      participants either with a confirmed complete response (CR) or partial response (PR) per
      Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as determined by the investigator
      assessment, at best overall response.

      SECONDARY OBJECTIVE:

      I. Progression-free survival (PFS), clinical benefit rate (CR + PR + stable disease [SD]
      among response-evaluable participants, per RECIST 1.1), overall survival (OS) and duration of
      response (DOR).

      EXPLORATORY OBJECTIVE:

      I. Evaluation of histologic evidence of response (p-ERK reduction in residual tumor cells and
      CD8 T cell or tumor infiltrating lymphocytes or tumor infiltrating lymphocyte [TIL]
      infiltration induced by combination treatment) using pretreatment and early on-treatment
      tumor biopsies.

      OUTLINE:

      Patients receive binimetinib orally (PO) twice daily (BID) on days 1-28 and nivolumab
      intravenously (IV) over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 12
      cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for up to 1
      year, then annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (binimetinib, nivolumab)ExperimentalPatients receive binimetinib PO BID on days 1-28 and nivolumab IV over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Binimetinib
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Males or females age >= 18 years

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

          -  Histologically confirmed locally advanced/unresectable or metastatic cutaneous
             melanoma

          -  Measurable disease per RECIST version (v.) 1.1 criteria using imaging scans, OR
             peripheral lesions that can be adequately documented with a picture and a ruler even
             if they do not meet RECIST criteria

          -  Patient must have failed prior alphaPD-1 or alphaPD-1 + alphaCTLA-4 therapy in the
             metastatic setting

          -  V600BRAF wildtype tumor status confirmed by Clinical Laboratory Improvement Act (CLIA)
             approved lab

          -  Hemoglobin >= 8.0 g/dL

          -  Whole blood cell count (WBC) >= 2,000/mm^3

          -  Absolute neutrophil count >= 1,500/mm^3

          -  Platelet count >= 75,000/mm^3

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x
             institutional upper limit of normal (ULN), (=< 5.0 x ULN in those with hepatic
             metastases)

          -  Bilirubin =< 1.5 x ULN; for subjects with documented/suspected Gilbert's disease,
             bilirubin =< 3 x ULN

          -  Albumin >= 2.5 g/dl

          -  Serum creatinine =< 2.0 x upper limit of normal (ULN)

          -  Left ventricular ejection fraction (LVEF) >= 50% assessed by echocardiogram (ECHO) or
             multiple-gated acquisition (MUGA) scan completed =< 180 days (6 months) before
             initiation of protocol treatment

          -  Patients must be willing to submit blood and tissue specimens for translational
             medicine studies

          -  Patients must have a site of disease amenable to biopsy and be a candidate for biopsy

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
             [HCG]) at screening and within 24 hours prior to the start of study drug

          -  Women of childbearing potential (WOCBP) must be willing to use either two adequate
             barrier methods or a barrier method plus a hormonal method of contraception to prevent
             pregnancy, or to abstain from heterosexual activity (complete abstinence) throughout
             the study, starting with visit 1 through 5 months after the last dose of study
             therapy. Approved contraceptive methods include, for example, intrauterine device,
             diaphragm with spermicide, cervical cap with spermicide, male condoms, female condoms
             with spermicide, or oral contraceptives. Spermicides alone are not an acceptable
             method of contraception. Should a woman become pregnant or suspect she is pregnant
             while she or her partner is participating in this study, she should inform her
             treating physician immediately

          -  Male patients must agree to use an adequate method of contraception, or to abstain
             from heterosexual activity (complete abstinence) starting with the first dose of study
             drug through 5 months after the last dose of study therapy

        Exclusion Criteria:

          -  Contraindications to tumor biopsy (coagulopathy, known history of keloid formation,
             etc.)

          -  Women who are pregnant or breastfeeding

          -  Prior therapy with a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib)

          -  Known hypersensitivity or contraindication to any component of binimetinib or its
             excipients

          -  Inability to swallow and retain study drug

          -  Patients who have received prior lines of systemic therapy in the advanced/metastatic
             setting (not including, neoadjuvant, adjuvant, or maintenance therapy)

          -  Received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic
             biologic therapy (e.g., erlotinib, cetuximab, bevacizumab etc.), within 14 days prior
             to start of study treatment or exposure to any investigational drug within 7 days
             prior to screening visit or for which 5 half-lives have not elapsed

          -  Participants who have undergone major surgery (e.g., in-patient procedures) =< 6 weeks
             prior to start of study treatment or who have not recovered from side effects of such
             procedure

          -  Participants who have had radiotherapy =< 14 days prior to start of study treatment or
             who have not recovered from side effects of such procedure. Note: Palliative radiation
             therapy must be complete 7 days prior to the first dose of study treatment

          -  Participants who have not recovered to =< grade 1 from toxic effects of prior therapy
             before starting study treatment

               -  Note: Stable chronic conditions (=< grade 2) that are not expected to resolve
                  (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies)
                  are exceptions and may enroll

          -  Uncontrolled or symptomatic brain metastases or leptomeningeal carcinomatosis that are
             not stable, require steroids, are potentially life-threatening or have required
             radiation within 28 days prior to starting study drug. Note: Patients with previously
             treated brain metastases may participate provided they are stable (e.g., without
             evidence of progression by radiographic imaging for at least 28 days before the first
             dose of study treatment and neurologic symptoms have returned to baseline), and have
             no evidence of new or enlarging brain metastases or central nervous system (CNS)
             edema, and does not require steroids at least 7 days before the first dose of study
             treatment

          -  Subjects with active, known, or suspected autoimmune disease. Subjects with type I
             diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
             (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or
             conditions not expected to recur in the absence of an external trigger are permitted
             to enroll

          -  Uncontrolled or significant cardiovascular disease including, but not limited to, any
             of the following:

               -  Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6
                  months prior to consent

               -  Uncontrolled angina within the 3 months prior to consent

               -  Any history of clinically significant arrhythmias (such as ventricular
                  tachycardia, ventricular fibrillation, torsades de pointes, or poorly controlled
                  atrial fibrillation)

               -  Corrected QT (QTc) prolongation > 480 msec

               -  History of other clinically significant cardiovascular disease (i.e.,
                  cardiomyopathy, congestive heart failure with New York Heart Association [NYHA]
                  functional classification III-IV, pericarditis, significant pericardial effusion,
                  significant coronary stent occlusion, poorly controlled deep venous thrombosis,
                  etc)

               -  Cardiovascular disease-related requirement for daily supplemental oxygen

               -  History of two or more myocardial infarctions OR two or more coronary
                  revascularization procedures

               -  Subjects with history of myocarditis, regardless of etiology

               -  History of thromboembolic or cerebrovascular events =< 12 weeks prior to the
                  first dose of study treatment. Examples include transient ischemic attacks,
                  cerebrovascular accidents, hemodynamically significant (i.e. massive or
                  sub-massive) deep vein thrombosis or pulmonary emboli

                    -  Note: Patients with either deep vein thrombosis or pulmonary emboli that
                       does not result in hemodynamic instability are allowed to enroll as long as
                       they are on a stable dose of anticoagulants for at least 4 weeks

                    -  Note: Patients with thromboembolic events related to indwelling catheters or
                       other procedures may be enrolled

          -  A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year
             prior to informed consent

          -  Participants with a condition requiring systemic treatment with corticosteroids (> 10
             mg daily prednisone or equivalent)

          -  Subjects receiving any other investigational or standard antineoplastic agents

          -  Patients with severe grade 3-4 toxicities due to anti-PD-1 monotherapy during first
             line. Toxicities due to combination PD-1/CTLA-4 blockade will not be exclusionary

          -  Inability to give informed consent

          -  History of malignancies except cured basal cell carcinoma, cutaneous squamous cell
             carcinoma, melanoma in situ, superficial bladder cancer or carcinoma in situ of the
             cervix; for other malignancies, must be documented to be free of cancer for >= 2
             years. All other cases can be considered on a case by case basis at the discretion of
             the principal investigator

          -  Any condition that might interfere with the subject's participation in the study,
             safety, or in the evaluation of the study results

          -  Concurrent enrollment in another clinical study, unless it is an observational
             (non-interventional) clinical study or the follow-up period of an interventional study

          -  Active or prior documented inflammatory bowel disease

          -  History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required
             steroids or has current ILD/pneumonitis or where suspected ILD/pneumonitis cannot be
             ruled out by imaging at screening

          -  Impairment of gastrointestinal function or disease which may significantly alter the
             absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or
             diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal
             absorption), or recent (=< 3 months) history of a partial or complete bowel
             obstruction, or other conditions that will interfere significantly with the absorption
             of oral drugs

          -  Concurrent neuromuscular disorder that is associated with elevated creatine kinase
             (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
             sclerosis, spinal muscular atrophy)

          -  History or current evidence of retinal venous occlusion (RVO) or current risk factors
             for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
             or hypercoagulability syndromes); history of retinal degenerative disease

          -  Prisoners or subjects who are involuntarily incarcerated

               -  Note: under certain specific circumstances a person who has been imprisoned may
                  be included or permitted to continue as a subject

               -  Subjects who are compulsorily detained for treatment of either a psychiatric or
                  physical (e.g., infectious disease) illness
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 26 months
Safety Issue:
Description:Will be defined as the total number of patients with confirmed responses of either complete response or partial response divided by the total number of subjects in the enrolled population per Response Evaluation Criteria in Solid Tumors 1.1 by investigator assessment. Will be calculated along with the corresponding exact one-sided 95% Clopper-Pearson confidence interval.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:From first dose of study drug to the date of progressive disease first documented disease progression or death due to any cause by investigator assessment, or the start of secondary antitumor therapy, whichever occurs first, assessed up to 26 months
Safety Issue:
Description:Will be assessed per Response Evaluation Criteria in Solid Tumors 1.1. Will be summarized using the Kaplan Meier method. Will be summarized descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum). Figures showing the Kaplan-Meier estimates will also be presented.
Measure:Clinical benefit rate
Time Frame:Up to 26 months
Safety Issue:
Description:Will be defined as the proportion of response-evaluable participants who have achieved a confirmed complete response, partial response, and stable disease per Response Evaluation Criteria in Solid Tumors 1.1, as determined by the investigator assessment. Clinical benefit rate and the individual rates for complete response/partial response/stable disease will be summarized with the frequency count and the percentage of subjects in each category along with a 2-sided 95% exact confidence interval.
Measure:Overall survival
Time Frame:From first dose of study drug and death due to any cause, assessed up to 26 months
Safety Issue:
Description:Will be summarized using the Kaplan Meier method. The Kaplan Meier estimates for the 1 year OS rates and the 2-sided 95% confidence interval of the rates using the Greenwood's formula will be reported. Will be summarized descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum). Figures showing the Kaplan-Meier estimates will also be presented.
Measure:Duration of response
Time Frame:From the time measurement criteria is met for complete response/partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 26 months
Safety Issue:
Description:Will be summarized using the Kaplan Meier method. Will be summarized descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum). Figures showing the Kaplan-Meier estimates will also be presented.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

Last Updated

May 1, 2020