Clinical Trials /

Efficacy of MEK (Trametinib) and BRAFV600E (Dabrafenib) Inhibitors With Radioactive Iodine (RAI) for the Treatment of Refractory Metastatic Differentiated Thyroid Cancer

NCT03244956

Description:

This is a multicentric prospective non-randomized phase II trial, with two independent arms: one for patients with RAS mutation and one for patients with BRAFV600E mutation.

Related Conditions:
  • Poorly Differentiated Thyroid Gland Carcinoma
  • Thyroid Gland Follicular Carcinoma
  • Thyroid Gland Papillary Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Efficacy of MEK (Trametinib) and BRAFV600E (Dabrafenib) Inhibitors With Radioactive Iodine (RAI) for the Treatment of Refractory Metastatic Differentiated Thyroid Cancer
  • Official Title: Efficacy of a Selective MEK (Trametinib) and BRAFV600E (Dabrafenib) Inhibitors Associated With Radioactive Iodine (RAI) for the Treatment of Refractory Metastatic Differentiated Thyroid Cancer With RAS or BRAFV600E Mutation

Clinical Trial IDs

  • ORG STUDY ID: 2017-000742-21
  • SECONDARY ID: 2017/2527
  • NCT ID: NCT03244956

Conditions

  • Metastatic Radioactive Iodine Refractory Thyroid Cancer Patients With RAS or BRAF Mutation

Interventions

DrugSynonymsArms
Trametinibpatients with RAS mutation
Dabrafenibpatients with BRAFV600E mutation
rhTSHpatients with RAS mutation

Purpose

This is a multicentric prospective non-randomized phase II trial, with two independent arms: one for patients with RAS mutation and one for patients with BRAFV600E mutation.

Trial Arms

NameTypeDescriptionInterventions
patients with RAS mutationExperimental
  • Trametinib
  • rhTSH
patients with BRAFV600E mutationExperimental
  • Trametinib
  • Dabrafenib
  • rhTSH

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with thyroid carcinoma of follicular origin (papillary, follicular or poorly
             differentiated and their respective variants)

          -  Known positive RAS (NRAS or KRAS or HRAS) or BRAFV600E mutation (determined on a
             previous analysis and/or on a representative formalin-fixed paraffin embedded (FFPE)
             tumor samples sent for central testing or on a biopsy sample sent for central
             testing).

          -  Radioiodine-refractory disease defined by at least one of the following item:

               1. Distant metastasis without radioiodine uptake on a posttherapeutic radioactive
                  scan

               2. Distant metastasis disclosing RECIST progression within 12 months after a RAI
                  treatment

          -  Measurable disease with at least one lesion >/= 1.0 cm in the longest diameter for a
             non-lymph node or >/= 1.5 cm in the short axis for a lymph node, measured with spiral
             computed tomography (CT) without iv contrast injection or magnetic resonance imaging
             (MRI) according to RECIST 1.1

          -  Progressive disease according to RECIST 1.1 criteria within 18 months prior initiation
             of treatment

          -  Absence of metastatic lesion > 30mm

          -  Previous cumulated activity of radioactive iodine ≤ 300 mCi (11.1GBq)

          -  Patients may have received prior treatment with either 1 line of Tyrosine Kinase
             Inhibitor or 1 line of immunotherapy (excluding anti BRAF or anti MEK treatment such
             as sorafenib, dabrafenib, trametinib and selumitinib) but should be off treatment
             within 28 days prior to treatment start

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

          -  Blood pressure (BP) ≤ 140/90 mm Hg at screening with or without antihypertensive
             medications and no change in antihypertensive medications within 1 week prior to Cycle
             1/Day 1

          -  Creatinine clearance ≥50 mL/min according to the Cockcroft and Gault formula

          -  Adequate bone marrow function with :

               1. Absolute neutrophil count (ANC) ≥1.5 x 109/L

               2. Hemoglobin ≥9.0 g/dL

               3. Platelet count ≥100 x 109/L

               4. Normal blood coagulation function as evidenced by an International Normalized
                  Ratio (INR) ≤ 1.5

          -  Adequate liver function with:

               1. Bilirubin ≤1.5 × upper limit of normal (ULN) except for unconjugated
                  hyperbilirubinemia or Gilbert's syndrome,

               2. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate
                  aminotransferase (AST) ≤3 × ULN (≤5 × ULN if subject has liver metastases).

          -  Males or females age ≥ 18 years at the time of informed consent

          -  Women of childbearing potential must have a negative urine or serum β-HCG pregnancy
             test within 7 days prior to the administration of the first study treatment. Sexually
             active women of childbearing potential must agree to use a highly effective method of
             contraception during the study and for at least 12 months after the last study
             treatment administration. Sexually active males patients must agree to use condom
             during the study and for at least 12 months after the last study treatment
             administration. Also, it is recommended their women of childbearing potential partner
             use a highly effective method of contraception.

          -  In case of previous external beam radiation, all radiation therapy related toxicities
             must have resolved to < Grade 2 severity per Common Terminology Criteria for Adverse
             Events (CTCAE v 4.0), except alopecia and infertility.

          -  Voluntary agreement to provide written informed consent and the willingness and
             ability to comply with all aspects of the protocol

          -  Patient affiliated to a social security regimen or beneficiary of the same

        Exclusion Criteria:

          -  Undifferentiated or Medullary (MTC) carcinoma of the thyroid

          -  Brain metastases (including asymptomatic brain metastases)

          -  Major surgery within 4 weeks prior to the first dose of drug

          -  Subjects having > 1 + proteinuria on urine dipstick testing will undergo 24 h urine
             collection for quantitative assessment of proteinuria. Subjects with urine protein ≥ 1
             g/24 h will be ineligible.

          -  Need for locoregional treatment such as surgery, external beam radiation or
             thermoablation at inclusion

          -  Prior RAI therapy < 6 months prior initiation of treatment

          -  External beam radiation < 4 weeks prior initiation of treatment

          -  Iodine contamination defined by a urine ioduria ≥ 50 μg/dl

          -  Gastrointestinal malabsorption or any other condition that in the opinion of the
             investigator might affect the absorption of the drugs

          -  History of congestive heart failure greater or equal to than New York Heart
             association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6
             months of the first dose of drug, or cardiac arrhythmia associated with significant
             cardiovascular impairment and uncontrolled hypertension

          -  Electrocardiogram (ECG) with QT interval (QTc) interval ≥480 msec

          -  Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 2 months prior to
             the first dose of drug and any other active bleeding, coagulopathy or pathologic
             condition that would confer a high risk of bleeding.

          -  Active infection requiring systemic therapy

          -  Active malignancy (except for DTC, or definitively treated melanoma insitu, basal or
             squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder)
             within the past 24 months

          -  Any history of or concomitant medical condition that, in the opinion of the
             investigator, would compromise subject's ability to safely complete the protocol

          -  Females who are pregnant or breastfeeding

          -  Patients with an injection of radio-contrast agent within 8 weeks prior enrolment

          -  Previous history of retinal vein occlusion

          -  Previous history of central serious retinopathy

          -  Known hypersensitivity to the study drugs or to any of the excipients
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Evaluated 6 months after the first dose of trametinib or trametinib and dabrafenib followed by RAI treatment in each arms
Safety Issue:
Description:Propotion of patients with a best overall response of Complete Response (CR) or a Partial Response (PR)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Gustave Roussy, Cancer Campus, Grand Paris

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