Vemurafenib + Cobimetinib for Thyroid Cancer
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: City of Hope Medical Center
Must not be taking: Anti-BRAF, Anti-MEK
Disqualifiers: Prior RAI treatment, Low risk DTC, Major surgery, Active infection, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, if you are on certain cancer treatments like anti-BRAF or anti-MEK drugs, you may not be eligible to participate.
What data supports the effectiveness of the drug Vemurafenib + Cobimetinib for thyroid cancer?
Vemurafenib, a BRAF inhibitor, has shown promising results in patients with papillary thyroid cancer that have the BRAF(V600E) mutation, leading to partial responses and stable disease. Additionally, the combination of vemurafenib and cobimetinib has improved survival in patients with BRAF V600-mutated melanoma, suggesting potential benefits for similar mutations in thyroid cancer.
12345Is the combination of Vemurafenib and Cobimetinib safe for humans?
The combination of Vemurafenib and Cobimetinib has been studied in patients with melanoma and is generally well tolerated, with common side effects including diarrhea, rash, fatigue, swelling, nausea, and vomiting. In a study involving patients with advanced solid tumors, dose-limiting side effects included severe rash and blurred vision, but the treatment was considered manageable.
12678How is the drug combination of Vemurafenib and Cobimetinib unique for thyroid cancer?
The combination of Vemurafenib and Cobimetinib is unique for thyroid cancer because it targets specific genetic mutations (BRAF V600) that are common in this cancer type, offering a personalized treatment approach. This combination is used off-label, meaning it's not the standard treatment for thyroid cancer, but it has shown promise in improving outcomes for patients with these mutations.
12349Eligibility Criteria
This trial is for patients with high-risk differentiated thyroid carcinoma that has a specific BRAFV600E gene mutation. It's aimed at those preparing for radioactive iodine therapy.Inclusion Criteria
I am 18 years old or older.
My thyroid cancer is of follicular origin.
My cancer has a positive BRAFV600E mutation.
Exclusion Criteria
My urine protein levels are below 1 g/24 h.
I need surgery or radiation therapy at the start of the trial.
I cannot undergo radioactive iodine treatment.
I have had serious heart issues or uncontrolled high blood pressure recently.
I have not had major surgery in the last 4 weeks.
I have not coughed up significant blood or had bleeding issues recently.
I am not pregnant or breastfeeding.
I have previously undergone radioactive iodine treatment.
I have taken medications like sorafenib or trametinib for cancer.
My thyroid cancer is of a specific type (undifferentiated or MTC).
I am currently on medication for an infection.
I have had a retinal vein occlusion before.
I have had central serious retinopathy in the past.
My thyroid cancer is not considered high risk.
Participant Groups
The effectiveness of vemurafenib and cobimetinib, both kinase inhibitors, is being tested to see if they can better prepare patients with the BRAFV600E mutation for radioactive iodine treatment by slowing cancer growth.
1Treatment groups
Experimental Treatment
Group I: Treatment (vemurafenib and cobimetinib)Experimental Treatment11 Interventions
Patients receive vemurafenib PO BID for 6 weeks and cobimetinib PO 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 IM daily for 2 days followed by I-123 diagnostic scan during screening and on study. Patients also undergo MRI during screening, PET scan or CT scan and blood sample collection throughout the study and ultrasound imaging and I-131 whole body scan during follow up.
Cobimetinib is already approved in European Union, United States, Canada, Switzerland, Japan for the following indications:
๐ช๐บ Approved in European Union as Cotellic for:
- Melanoma
๐บ๐ธ Approved in United States as Cotellic for:
- Melanoma
๐จ๐ฆ Approved in Canada as Cotellic for:
- Melanoma
๐จ๐ญ Approved in Switzerland as Cotellic for:
- Melanoma
๐ฏ๐ต Approved in Japan as Cotellic for:
- Melanoma
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
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Who is running the clinical trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
Efficacy and toxicity of vemurafenib and cobimetinib in relation to plasma concentrations, after administration via feeding tube in patients with BRAF-mutated thyroid cancer: a case series and review of literature. [2022]The combination of vemurafenib, a proto-oncogene B-Raf inhibitor (BRAFi) and cobimetinib, an inhibitor of mitogen-activated protein kinase kinase (MEKi) has shown to improve survival in patients with BRAF V600-mutated melanoma. BRAF mutations are also frequently detected driver mutations in other tumor types, including thyroid carcinoma. Since thyroid carcinoma is not a labeled indication for BRAF/MEKi, a cohort for patients with BRAF V600-mutated thyroid carcinoma was opened within the Drug Rediscovery Protocol (DRUP), a national ongoing pan-cancer multi-drug trial, in which patients receive off-label treatment with approved drugs based on their molecular tumor profile.
Sorafenib in radioactive iodine-refractory well-differentiated metastatic thyroid cancer. [2021]Recent Phase III data presented at the American Society of Clinical Oncology (ASCO) 2013 annual conference by Brose et al led to the US Food and Drug Administration (FDA) approval of sorafenib for the treatment of well-differentiated radioactive iodine-resistant metastatic thyroid cancer. This is the second drug in 40 years to be FDA approved for this indication. Recent reviews and a meta-analysis reveal a modest ability to induce a partial remission but substantial ability to halt disease progression. Given the significant activating mutations present in thyroid cancer, many of which are inhibited by sorafenib, the next logical approach may be to combine targeted rational therapies if permitted by collective toxicity profiles. This systematic review aims to summarize the recent Phase II/III data leading to the FDA approval of sorafenib for radioactive iodine therapy differentiated thyroid cancer and highlights recent novel combination therapy trials.
Efficacy and tolerability of vemurafenib in patients with BRAF(V600E) -positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience. [2022]Vemurafenib, a selective BRAF inhibitor, appears to have promising clinical activity in patients with papillary thyroid cancer (PTC) harboring the BRAF(V600E) mutation.
Vemurafenib Active in Iodine-Refractory Thyroid Cancer. [2019]A new study shows that the BRAF inhibitor vemurafenib may induce partial responses and stable disease in patients with papillary thyroid cancer that has become refractory to radioactive iodine. However, the drug led to a variety of serious adverse events in roughly 65% of patients, including the development of some squamous cell carcinomas.
A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer. [2023]To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation.
Efficacy and safety of multi-kinase inhibitors in patients with radioiodine-refractory differentiated thyroid cancer: a systematic review and meta-analysis of clinical trials. [2022]Radioiodine-refractory differentiated thyroid cancer (RAI-rDTC) has frequently been associated with poor prognosis. We conducted a meta-analysis of published randomized controlled trials to evaluate multi-kinase inhibitors' efficacy and safety profile treatment.
Cobimetinib Plus Vemurafenib: A Review in BRAF (V600) Mutation-Positive Unresectable or Metastatic Melanoma. [2019]The MEK inhibitor cobimetinib (Cotellic(ยฎ)) is indicated for the treatment of patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma, in combination with the BRAF inhibitor vemurafenib (Zelboraf(ยฎ)). In the pivotal coBRIM trial, previously untreated patients with BRAF (V600) mutation-positive unresectable, stage IIIC or stage IV melanoma received cobimetinib 60 mg once daily for the first 21 days of each 28-day cycle plus vemurafenib 960 mg twice daily or vemurafenib alone. Compared with vemurafenib alone, cobimetinib plus vemurafenib significantly prolonged progression-free survival (primary endpoint) and was associated with a significantly higher overall response rate and significantly prolonged overall survival. Cobimetinib plus vemurafenib had a manageable tolerability profile. In conclusion, cobimetinib plus vemurafenib is a valuable option for use in BRAF (V600) mutation-positive unresectable or metastatic melanoma.
A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. [2019]Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.
Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. [2022]About half of patients with papillary thyroid cancer have tumours with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer.