Clinical Trials /

Encorafenib and Binimetinib With or Without Nivolumab in Treating Patients With Metastatic Radioiodine Refractory BRAF V600 Mutant Thyroid Cancer

NCT04061980

Description:

This phase II trial studies how well encorafenib and binimetinib given with or without nivolumab works in treating patients with BRAF V600 mutation positive thyroid cancer that has spread to other places in the body (metastatic) and does not respond to radioiodine treatment (refractory). Encorafenib and 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. The trial aims to find out if the combination of encorafenib and binimetinib, with and without study nivolumab, is a safe and effective way to treat metastatic radioiodine refractory thyroid cancer.

Related Conditions:
  • Poorly Differentiated Thyroid Gland Carcinoma
  • Well-Differentiated Thyroid Gland Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Encorafenib and Binimetinib With or Without Nivolumab in Treating Patients With Metastatic Radioiodine Refractory BRAF V600 Mutant Thyroid Cancer
  • Official Title: Encorafenib/Binimetinib With or Without Nivolumab for Patients With Metastatic BRAF V600 Mutant Thyroid Cancer

Clinical Trial IDs

  • ORG STUDY ID: STUDY00019481
  • SECONDARY ID: NCI-2019-04212
  • SECONDARY ID: IST-818-210X
  • SECONDARY ID: SOL-19084-L
  • SECONDARY ID: CA209-73R
  • SECONDARY ID: STUDY00019481
  • SECONDARY ID: P30CA069533
  • NCT ID: NCT04061980

Conditions

  • BRAF NP_004324.2:p.V600M
  • BRAF V600E Mutation Present
  • Metastatic Thyroid Gland Carcinoma
  • Refractory Thyroid Gland Carcinoma
  • Stage IV Differentiated Thyroid Gland Carcinoma AJCC v8
  • Stage IVA Differentiated Thyroid Gland Carcinoma AJCC v8
  • Stage IVB Differentiated Thyroid Gland Carcinoma AJCC v8

Interventions

DrugSynonymsArms
BinimetinibARRY-162, ARRY-438162, MEK162, MektoviArm I (encorafenib, binimetinib)
EncorafenibBraftovi, LGX 818, LGX-818, LGX818Arm I (encorafenib, binimetinib)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm II (encorafenib, binimetinib, nivolumab)

Purpose

This phase II trial studies how well encorafenib and binimetinib given with or without nivolumab works in treating patients with BRAF V600 mutation positive thyroid cancer that has spread to other places in the body (metastatic) and does not respond to radioiodine treatment (refractory). Encorafenib and 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. The trial aims to find out if the combination of encorafenib and binimetinib, with and without study nivolumab, is a safe and effective way to treat metastatic radioiodine refractory thyroid cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the overall rate of response among study participants treated with the
      combination of encorafenib and binimetinib, with or without nivolumab.

      SECONDARY OBJECTIVES:

      I. To assess the progression-free survival (PFS) among study participants treated with the
      combination of encorafenib and binimetinib with or without nivolumab.

      II. To assess the overall survival (OS) among study participants treated with the combination
      of encorafenib and binimetinib with or without nivolumab.

      III. To evaluate the duration of response (DOR). IV. To evaluate the safety and tolerability
      of study participants treated with the combination of encorafenib and binimetinib with or
      without nivolumab.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive encorafenib orally (PO) once daily (QD) and binimetinib PO twice
      daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression
      or unacceptable toxicity.

      ARM II: Patients receive encorafenib PO QD and binimetinib PO BID as in arm I. Patients also
      receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles with nivolumab repeat
      every 28 days for up to 2 years in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment patients are followed up at 30 days and then every 6
      months for up to 12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (encorafenib, binimetinib)ExperimentalPatients receive encorafenib PO QD and binimetinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Binimetinib
  • Encorafenib
Arm II (encorafenib, binimetinib, nivolumab)ExperimentalPatients receive encorafenib PO QD and binimetinib PO BID as in arm I. Patients also receive nivolumab IV over 30 minutes on day 1. Cycles with nivolumab repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Binimetinib
  • Encorafenib
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Histologically (or cytologically) confirmed diagnosis of metastatic, radioiodine (RAI)
             refractory, BRAFV600E/M mutant differentiated thyroid cancer (DTC)

               -  Note: RAI refractoriness is defined as:

                    -  The absence of uptake of RAI on either a low-dose diagnostic whole body
                       scan, or a post-treatment RAI scan in measurable lesions

                    -  Radiographic progression of disease within 12 months of the last course of
                       RAI treatment, or

                    -  Having a cumulative lifetime administered dose of > 600 mCi of RAI

          -  Measurable disease meeting the following criteria and confirmed by radiography review:

               -  At least 1 lesion of >= 1.0 cm in the longest diameter for a non-lymph node or >
                  1.5 cm in the short-axis diameter for a lymph node metastasis that is serially
                  measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
                  using computed tomography/magnetic resonance imaging (CT/MRI). If there is only 1
                  target lesion and it is a non-lymph node, it should have a longest diameter of >=
                  1.5 cm

               -  Lesions that have had external beam radiotherapy or locoregional therapies such
                  as radiofrequency (RF) ablation must show evidence of progressive disease based
                  on RECIST 1.1 to be deemed a target lesion.

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

          -  Hemoglobin (Hgb) >= 9 g/dL

          -  Platelets (PLT) >= 75 x 10^9/L

          -  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2.5 x upper
             limit of normal (ULN); participants with liver metastases =< 5 x ULN

          -  Total bilirubin =< 1.5 x ULN

               -  Note: Individuals who have a total bilirubin level > 1.5 x ULN will be allowed if
                  their indirect bilirubin level is =< 1.5 x ULN (i.e., participants with suspected
                  or known diagnosis of Gilbert?s syndrome)

          -  Serum creatinine =< 1.5 x ULN, or calculated creatinine clearance (determined as per
             Cockcroft-Gault) >= 40 mL/min at screening

          -  Left ventricular ejection fraction (LVEF) >= 50% as determined by a multigated
             acquisition (MUGA) scan or echocardiogram

          -  Triplicate average baseline corrected QT (QTc) interval =< 480 ms

          -  Participants of childbearing potential must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
             [HCG]) within 72 hours prior to the start of assigned study intervention

          -  Participants of child-bearing potential agree to use highly effective methods of
             contraception starting with the first dose of assigned study intervention through 6
             months after the last dose of study therapy

          -  Participants of childbearing potential are those who are not proven postmenopausal.
             Postmenopausal is defined as any of the following:

               -  Amenorrheic for 1 year or more following cessation of exogenous hormonal
                  treatments

               -  Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the
                  post-menopausal range for women under 50

               -  Radiation-induced oophorectomy with last menses > 1 year ago

               -  Chemotherapy-induced menopause with > 1 year interval since last menses

               -  Surgical sterilization (bilateral oophorectomy or hysterectomy)

          -  Male participants must agree to use an adequate method of contraception starting with
             the first dose of study therapy through 6 months after the last dose of study therapy

        Exclusion Criteria:

          -  Currently participating and receiving study therapy or has participated in a study of
             an investigational agent and received study therapy or used an investigational
             agent/device within 4 weeks of first dose of study intervention

               -  Note: Individuals in the follow-up phase of a prior investigational study may
                  participate as long as it has been 4 weeks since last dose of the previous
                  investigational agent of device

          -  Participants with active, known, or suspected autoimmune disease. Participants with
             type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only
             requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or
             alopecia) not requiring systemic treatment are permitted to enroll

          -  Prior treatment with selective/potent BRAF/MEK inhibitors including vemurafenib,
             dabrafenib, encorafenib, selumetinib, trametinib, cobimetinib, binimetinib.

               -  Note: Prior therapy with oral multikinase inhibitors (e.g., lenvatinib,
                  sorafenib, cabozantinib, pazopanib, sunitinib, etc.) remain eligible for study
                  participation.

          -  Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4
             antibody (including ipilimumab or any other antibody or drug specifically targeting T
             cell co-stimulation or immune checkpoint pathways)

          -  Participants with a condition requiring systemic treatment with either corticosteroids
             (>= 10 mg daily prednisone or equivalent) or other immunosuppressive medications
             within 14 days of study drug administration. Inhaled or topical steroids are permitted
             in the absence of active autoimmune disease

          -  History of allergy or hypersensitivity to any monoclonal antibody

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

          -  Previous or concurrent malignancy within 3 years of study entry, with the following
             exceptions:

               -  Adequately treated basal or squamous cell skin cancer, superficial bladder
                  cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or
                  other noninvasive or indolent malignancy; OR

               -  Other solid tumors treated curatively in which the expected rate of recurrence
                  within 5 years is < 5%

          -  Impaired cardiovascular function or clinically significant cardiovascular diseases,
             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 prior to screening

               -  Symptomatic congestive heart failure (i.e. grade 2 or higher), history or current
                  evidence of clinically significant cardiac arrhythmia and/or conduction
                  abnormality < 6 months prior to screening. Exceptions include
                  asymptomatic/well-controlled atrial fibrillation/flutter or paroxysmal
                  supraventricular tachycardia

               -  Uncontrolled hypertension defined as persistent elevation of systolic blood
                  pressure >= 150 mmHg or diastolic blood pressure >= 100 mmHg, despite medical
                  therapy

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

          -  Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,
             and/or active hepatitis C infection

          -  Known history of acute or chronic pancreatitis

          -  Impaired gastrointestinal function or disease that may significantly alter the
             absorption of encorafenib or binimetinib (e.g., uncontrolled vomiting or malabsorption
             syndrome)

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

          -  Current use of a prohibited medication (including herbal medications, supplements, or
             foods), as described, or use of a prohibited medication =< 1 week prior to the start
             of study treatment

          -  Any other condition that would, in the investigator?s judgment, contraindicate an
             individual?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

          -  Participants who have undergone major surgery (e.g., intracranial, intrathoracic, or
             intra-abdominal surgery) =< 3 weeks prior to starting study drug or who have not
             recovered from side effects of such procedure

          -  Participants that are pregnant or nursing (lactating)

          -  Prisoners or individuals who are involuntarily incarcerated

          -  Medical, psychiatric, cognitive or other conditions that may compromise the
             participant?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:Overall response rate (ORR)
Time Frame:From the start of randomization up to 6 months from first dose of study drugs
Safety Issue:
Description:ORR is defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria. ORR at 6 months will be assessed using the efficacy evaluable analysis set. A point and 90% exact binomial confidence interval will be provided for each arm.

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:From date of randomization until either tumor progression (per RECIST v1.1) or death, assessed for up to 12 months
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate PFS and the summary statistics (e.g., 12-month survival, median survival, 95% confidence intervals) will be provided for each arm.
Measure:Overall survival
Time Frame:From date of randomization until the date of death from any cause, assessed for up to 1 year
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate OS and the summary statistics (e.g., 12-month survival, median survival, 95% confidence intervals) will be provided for each arm.
Measure:Duration of response (DOR)
Time Frame:From date of first documented CR or PR up to first documented progression or death due to any cause, assessed for up to 1 year
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate DOR, and the summary statistics (e.g., 12-month survival, median survival, 95% confidence intervals) will be provided for each arm. DOR will be estimated only among responders (i.e. participants achieving at least once CR or PR). Data visualization tools such as waterfall plots (% change in tumor size) or swimmer plot (DOR) will be used to display the data.
Measure:Incidence of grade >= 3 toxicities
Time Frame:From the first dose of assigned study intervention until 90 days from the last dose of assigned study intervention
Safety Issue:
Description:Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Using the safety evaluable analysis set, the incidence of having grade >= 3 adverse events will be determined for study participants that received at least one dose of their assigned treatment. The point estimate and 95% confidence interval will be reported for each arm.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:OHSU Knight Cancer Institute

Trial Keywords

  • Encorafenib
  • Binimetinib
  • Nivolumab
  • BRAF V600
  • Thyroid cancer
  • Radiodine refractory Thyroid Cancer
  • Phase 2
  • IST-818-210X
  • CA209-73R

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