Trial Title:
Vemurafenib and Cobimetinib for the Treatment of Patients With High Risk Differentiated Thyroid Carcinoma With BRAFV600E Mutation
NCT ID:
NCT06440850
Condition:
Thyroid Gland Follicular Carcinoma
Thyroid Gland Oncocytic Carcinoma
Thyroid Gland Papillary Carcinoma
Conditions: Official terms:
Carcinoma
Thyroid Neoplasms
Carcinoma, Papillary
Thyroid Cancer, Papillary
Adenocarcinoma, Follicular
Thyroid Diseases
Iodine
Cadexomer iodine
Vemurafenib
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Drug
Intervention name:
Cobimetinib
Description:
Given PO
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
Cotellic
Other name:
GDC-0973
Other name:
MEK Inhibitor GDC-0973
Other name:
XL518
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT scan
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Procedure
Intervention name:
Diagnostic Imaging
Description:
Undergo I-123 diagnostic scan
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
Medical Imaging
Intervention type:
Procedure
Intervention name:
I-131 Uptake Test
Description:
Undergo I-131 whole body scan
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
I 131 Uptake
Other name:
I-131 Uptake and Scan
Other name:
Radioactive Iodine Uptake
Intervention type:
Radiation
Intervention name:
Iodine I-131
Description:
Given PO
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
131-Iodine
Other name:
Bound Iodide I-131
Other name:
I 131
Other name:
I-131
Other name:
Iodide I-131
Other name:
Iodide, I-131
Other name:
Iodine 131
Other name:
Iodine-131
Other name:
Iodotope
Other name:
Iodotrope
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging (MRI)
Other name:
Magnetic resonance imaging (procedure)
Other name:
Magnetic Resonance Imaging Scan
Other name:
Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
Other name:
MR
Other name:
MR Imaging
Other name:
MRI
Other name:
MRI Scan
Other name:
MRIs
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Other name:
sMRI
Other name:
Structural MRI
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET scan
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
Medical Imaging, Positron Emission Tomography
Other name:
PET
Other name:
PET Scan
Other name:
Positron emission tomography (procedure)
Other name:
Positron Emission Tomography Scan
Other name:
Positron-Emission Tomography
Other name:
proton magnetic resonance spectroscopic imaging
Other name:
PT
Intervention type:
Biological
Intervention name:
Recombinant Thyrotropin Alfa
Description:
Given IM
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
Recombinant Thyrotropin Alpha
Other name:
Recombinant TSH Alpha
Other name:
Thyrogen
Other name:
Thyroid Stimulating Hormone Alpha
Other name:
Thyrotropin Alfa
Other name:
TSH-alpha
Intervention type:
Procedure
Intervention name:
Ultrasound Imaging
Description:
Undergo neck ultrasound
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
2-Dimensional Grayscale Ultrasound Imaging
Other name:
2-Dimensional Ultrasound Imaging
Other name:
2D-US
Other name:
Ultrasonography
Other name:
Ultrasound
Other name:
Ultrasound Test
Other name:
Ultrasound, Medical
Other name:
US
Intervention type:
Drug
Intervention name:
Vemurafenib
Description:
Given PO
Arm group label:
Treatment (vemurafenib and cobimetinib)
Other name:
BRAF (V600E) kinase inhibitor RO5185426
Other name:
BRAF(V600E) Kinase Inhibitor RO5185426
Other name:
PLX-4032
Other name:
PLX4032
Other name:
RG 7204
Other name:
RG7204
Other name:
RO 5185426
Other name:
Zelboraf
Summary:
This phase II trial tests how well vemurafenib and cobimetinib work in treating patients
with high risk differentiated thyroid carcinoma with BRAFV600E mutation, in preparation
for radioactive iodine therapy. Vemurafenib and cobimetinib are used in patients whose
cancer has a mutated (changed) form of a gene called BRAF. They are in a class of
medications called kinase inhibitors. They work by blocking the action of an abnormal
protein that signals cancer cells to multiply. This helps slow or stop the spread of
cancer cells. Giving vemurafenib and cobimetinib may work better to treat patients with
high risk differentiated thyroid carcinoma with BRAFV600E mutation, in preparation for
radioactive iodine therapy.
Detailed description:
PRIMARY OBJECTIVE:
I. The proportion of BRAF mutated high-risk differentiated thyroid carcinoma patients who
achieve excellent or indeterminate response with vemurafenib and cobimetinib treatment
prior to initial radioactive iodine (RAI) therapy as defined by American Thyroid
Association guideline.
SECONDARY OBJECTIVES:
I. The proportion of patients who had significant change on their I-123 scan before and
after the targeted therapy.
II. To evaluate the safety and tolerability as determined by adverse events related to
vemurafenib and cobimetinib combination therapy.
III. To evaluate the efficacy of vemurafenib and cobimetinib in enhancing RAI avidity by
assessing the progression-free survival.
IV. To evaluate the diagnostic and prognostic value of thyroglobulin level as determined
by thyroglobulin changes associated with treatment response.
V. To evaluate the tumor molecular characteristics in treatment responders as compared to
non-responders.
OUTLINE:
Patients receive vemurafenib orally (PO) twice per day (BID) for 6 weeks and cobimetinib
PO once per day (QD) for 3 weeks, followed by 1 week off, and then continuing for 2
weeks. Patients then receive iodine 131 PO followed by 3 additional days of vemurafenib
PO BID and cobimetinib PO QD. Patients receive thyrogen intramuscularly (IM) daily for 2
days followed by I-123 diagnostic scan during screening and on study. Patients also
undergo magnetic resonance imaging (MRI) during screening, positron emission tomography
(PET) scan or computed tomography (CT) scan and blood sample collection throughout the
study and ultrasound imaging and I-131 whole body scan during follow up.
After completion of study treatment, patients are followed up every 3 months for up to 12
months.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Documented informed consent of the participant and/or legally authorized
representative
- Willingness to be followed for about 14 months
- Males or females aged ≥ 18 years at the time of informed consent
- Patients with thyroid carcinoma of follicular origin (papillary, follicular or
Hurthle cell)
- Known positive BRAFV600E mutation (determined on a previous analysis and/or on a
representative formalin-fixed paraffin embedded (FFPE) tumor samples or on a biopsy
sample)
- High risk for recurrence according to the American Thyroid Association (ATA)
guideline defined as having one or more of the features below:
- Gross extrathyroidal extension
- FTC with extensive vascular invasion (> 4), although less likely to have BRAF
mutation
- PTC with vascular invasion
- Advanced nodal disease of (any node >3 cm, > 4 nodes, or extra-nodal extension)
- BRAF+TERT promoter mutation
- Post op thyroglobulin (TG) suggestive of distant metastasis
- Distant metastatic sites (only for exploratory arm)
- 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
treatment start
- Creatinine clearance ≥ 50 mL/min according to the Cockcroft and Gault formula
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Hemoglobin ≥ 9.0 g/dL
- Platelet count ≥ 100 x 109/L
- Normal blood coagulation function as evidenced by an International Normalized Ratio
(INR) ≤ 1.5
- Bilirubin ≤ 1.5 × upper limit of normal (ULN) except for unconjugated
hyperbilirubinemia or Gilbert's syndrome
- Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if subject has liver metastases)
- 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
- Agreement by women of childbearing potential (WOCBP) and males of childbearing
potential* to use an effective** method of birth control** for at least 3 months
prior to screening through 1 year of study follow-up.
- Childbearing potential defined as not being surgically sterilized (men and
women) or have not been free from menses for > 1 year (women only)
- Effective birth control defined as hormonal and/or barrier contraception
- Non-English speaking persons and adults lacking capacity to consent are not excluded
from participation
Exclusion Criteria:
- Prior RAI treatment
- Prior anti-BRAF, anti-MEK treatment such as sorafenib, dabrafenib, vemurafenib,
encorafenib, binimetinib, cobimetinib, trametinib, d selumitinib and other TKIs
like, lenvatinib, sunitinib, axitinib, cabozantenib, vandatinib, pazopanib use
- Low to intermediate risk differentiated thyroid cancer (DTC) cases (not having the
high-risk features as described above)
- RAI contraindication
- Undifferentiated or Medullary (MTC) carcinoma of the thyroid
- Major surgery within 4 weeks prior to the first dose of treatment
- 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
- External beam radiation, for thyroid cancer, <4 weeks prior initiation of treatment
- 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 treatment, 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 treatment 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 in-situ, 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 12 weeks prior to
enrollment (can be enrolled after 12 weeks)
- Previous history of retinal vein occlusion
- Previous history of central serious retinopathy
- Known hypersensitivity to the study drugs or to any of the excipients
- Any other condition (including psychosocial condition) that would, in the
Investigator's judgment, contraindicate the patient's participation in the clinical
study due to safety concerns with clinical study procedures
- Any other condition that would confound study results
- Noncompliance
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
City of Hope Medical Center
Address:
City:
Duarte
Zip:
91010
Country:
United States
Status:
Recruiting
Contact:
Last name:
Sasan Fazeli
Phone:
626-256-4673
Phone ext:
82251
Email:
sfazeli@coh.org
Investigator:
Last name:
Sasan Fazeli
Email:
Principal Investigator
Start date:
November 30, 2024
Completion date:
November 30, 2026
Lead sponsor:
Agency:
City of Hope Medical Center
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
City of Hope Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06440850
