Vemurafenib for Thyroid Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Antiangiogenics, Chemotherapy

Disqualifiers: Non-PTC histology, Hepatitis, Pregnancy, Brain metastases, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 88

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how vemurafenib affects thyroid cancer, specifically papillary thyroid cancer (PTC), by targeting and blocking a gene mutation that promotes cancer growth. The study aims to determine if vemurafenib can reduce the cancer's size or halt its growth. Participants may receive the drug before surgery, after surgery, or without surgery, depending on their condition. This trial might suit individuals with PTC who have a specific BRAF mutation and require surgery or have been informed that surgery isn't currently an option. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop any antiangiogenic therapy (medications that affect blood vessel growth) at least 14 days before starting the study. Additionally, you must not have had chemotherapy or targeted therapy within 14 days or 5 half-lives of the drug before starting the trial. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

Is there any evidence suggesting that vemurafenib is likely to be safe for humans?

Research has shown that vemurafenib is already FDA-approved to treat certain types of melanoma, a skin cancer with a specific genetic change, indicating a known safety record for that condition. In studies with thyroid cancer patients who have a similar genetic change, vemurafenib helped shrink tumors and slow disease progression.

Most participants in these studies tolerated the treatment well. Common side effects included joint pain, rash, and fatigue. More serious side effects, such as skin reactions and liver issues, were less common but did occur. Prospective trial participants should weigh these possible side effects against the potential benefits.

Consulting with healthcare providers is crucial to understand how this information may relate to individual health. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for thyroid cancer?

Researchers are excited about vemurafenib for thyroid cancer because it targets a specific mutation known as BRAF V600E, which is not directly addressed by current standard treatments like surgery and radioactive iodine therapy. Unlike traditional therapies that often rely on physical removal or general radiation, vemurafenib works at the molecular level to inhibit the abnormal protein caused by this mutation. This targeted approach can lead to a more effective treatment with potentially fewer side effects, offering hope for improved outcomes in patients whose cancers are driven by this genetic change.

What evidence suggests that vemurafenib might be an effective treatment for thyroid cancer?

Research has shown that vemurafenib, a drug targeting the BRAF gene mutation, may help treat thyroid cancer. Studies have found that it controls the disease in 73% of patients with this mutation. On average, patients live about 18.2 months without cancer progression. Vemurafenib also works in 25% to 50% of patients with papillary thyroid cancer unresponsive to iodine treatment. In this trial, participants may receive vemurafenib before surgery, after surgery, or as a continuous treatment if not scheduled for surgery. This suggests vemurafenib could be a useful option for some thyroid cancer patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Maria E. Cabanillas, M.D.

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced papillary thyroid cancer (PTC) that's inoperable may join this trial. They should have the BRAF V600E mutation, be new to MAPK pathway therapies, and have their major organs functioning well. Pregnant women, those with significant heart disease or untreated brain metastases, or recent chemotherapy/targeted therapy users are excluded.

Inclusion Criteria

Your blood creatinine level is within a certain range.

Your absolute neutrophil count is at least 1.0 x 10^9 per liter.

Your hemoglobin level is higher than 9 mg/dL.

Exclusion Criteria

I have severe nausea, vomiting, or issues absorbing food due to bowel surgery.

I have brain metastases that have not been treated.

I haven't had chemotherapy or targeted therapy within the last 14 days or 5 half-lives, whichever is longer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Vemurafenib 960 mg by mouth twice a day for 56 days prior to surgery or biopsy

8 weeks

Baseline visit, Day 28 visit, Day 56 visit

Surgery/Biopsy

Participants undergo surgery or core biopsy depending on group assignment

1 day

Day 56 visit

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up visits every 4-8 weeks depending on group

1 year

Every 4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Vemurafenib

Trial Overview The study tests vemurafenib's effects on PTC biomarkers before surgery (neoadjuvant). All participants receive vemurafenib; Group A and C continue post-surgery. The drug aims to block a gene mutation responsible for cancer growth.

How Is the Trial Designed?

Group I: Vemurafenib - Group C Experimental Treatment 1 Intervention

Patients not scheduled for surgical resection undergo a CT scan and core biopsy at day 56, Vemurafenib 960 mg by mouth twice a day unless there is evidence of progressive disease on day 56 CT scan. Patients evaluated for resectability after each CT scan is performed. If scheduled for resection, patient continues vemurafenib until surgery and follows same treatment schema as patients in Groups A and B.

Group II: Vemurafenib - (Presurgery) Experimental Treatment 3 Interventions

All Groups: Vemurafenib 960 mg by mouth 2 times a day for 56 days prior to surgery (patients not planned for surgical resection will have a core biopsy at day 56 +/- 7 days).

Group III: Vemurafenib (Post Surgery) - Group A Experimental Treatment 1 Intervention

Vemurafenib 960 mg by mouth two times a day 2 weeks post-surgery, or if patients have not sufficiently recovered at that point, as soon as their condition permits. Patients in Group A restaged 8 weeks after resuming drug. If patients in Group A demonstrate either stable or regressing disease, they will continue on vemurafenib with restaging occurring every 8 weeks until no longer benefitting from the drug.

Group IV: Post Surgery - Group B Active Control 1 Intervention

Post Surgery - Group B: Patients discontinue vemurafenib after surgery but will be restaged with CT neck 8 weeks after surgery.

Vemurafenib is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Zelboraf for:

• Unresectable or metastatic melanoma with BRAF V600E mutation
• Erdheim-Chester Disease (ECD) with BRAF V600 mutation

Approved in European Union as Zelboraf for:

• Adults with BRAF V600E mutation positive unresectable or metastatic melanoma

Approved in Canada as Zelboraf for:

• Unresectable or metastatic melanoma with BRAF V600E mutation

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In a retrospective study of 17 patients with advanced papillary thyroid cancer (PTC) and the BRAF(V600E) mutation, vemurafenib showed a partial response in 47% of patients and stable disease in 53%, indicating its potential efficacy as a treatment.

Despite some adverse events, including fatigue and weight loss, vemurafenib was generally well-tolerated, with a durable response rate of 67% and a median time to treatment failure of 13 months, supporting its use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of vemurafenib in patients with BRAF(V600E) -positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience. Dadu, R., Shah, K., Busaidy, NL., et al.[2022]

Vemurafenib demonstrated antitumor activity in patients with BRAF(V600E)-positive papillary thyroid cancer, showing a partial response in 38.5% of patients who had not previously received multikinase inhibitors, based on a phase 2 trial involving 51 participants.

While the treatment was effective, it was associated with significant adverse events, with 65% of patients experiencing grade 3 or 4 side effects, including serious conditions like squamous cell carcinoma of the skin and lymphopenia, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Brose, MS., Cabanillas, ME., Cohen, EE., et al.[2022]

Multi-kinase inhibitors (MKIs) significantly improve progression-free survival (PFS) and overall survival (OS) in patients with radioiodine-refractory differentiated thyroid cancer (RAI-rDTC), with a median PFS hazard ratio of 0.30 and OS hazard ratio of 0.70 based on a meta-analysis of randomized controlled trials.

While MKIs are effective, they are associated with a higher incidence of adverse events compared to control treatments, highlighting the need for careful patient evaluation to balance treatment benefits against potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of multi-kinase inhibitors in patients with radioiodine-refractory differentiated thyroid cancer: a systematic review and meta-analysis of clinical trials. Su, J., Wang, M., Fu, Y., et al.[2022]

PLX4032, a BRAFV600E-specific inhibitor, effectively reduces the growth of BRAFV600E-positive papillary thyroid cancer cells while having the opposite effect on normal BRAF-wild-type thyroid cells, indicating its targeted efficacy.

The anti-proliferative effects of PLX4032 in BRAF-mutated cells are linked to its ability to inhibit key signaling molecules in the MAPK pathway, suggesting a potential for combination therapies in treating thyroid cancer with this mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disruption of mutated BRAF signaling modulates thyroid cancer phenotype. Hanly, EK., Rajoria, S., Darzynkiewicz, Z., et al.[2021]

Vemurafenib, a BRAF inhibitor, has shown the potential to induce partial responses and maintain stable disease in patients with papillary thyroid cancer that no longer responds to radioactive iodine treatment.

However, the treatment is associated with significant safety concerns, as approximately 65% of patients experienced serious adverse events, including the development of squamous cell carcinomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vemurafenib Active in Iodine-Refractory Thyroid Cancer. [2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3967415/

Clinical Responses to Vemurafenib in Patients with Metastatic ... In a first-in-human phase I study of vemurafenib, 81% of patients had a significant tumor reduction with a confirmed response rate of 56% among patients with ...

2. erc.bioscientifica.com erc.bioscientifica.com/view/journals/erc/30/11/ERC-22-0392.xml

Vemurafenib activates the sonic hedgehog pathway and ... B-Raf kinase inhibitors such as vemurafenib (PLX4032) and dabrafenib have limited therapeutic efficacy on BRAF-mutated thyroid cancer. Cancer stem cells (CSCs) ...

3. onclive.com onclive.com/view/vemurafenib-effective-for-brafmutant-thyroid-cancer

Vemurafenib Effective for BRAF-Mutant Thyroid Cancer The overall disease control rate was 73%. The median progression-free survival (PFS) with vemurafenib was 18.2 months and the median overall survival (OS) was ...

4. aacrjournals.org aacrjournals.org/cancerdiscovery/article/6/10/OF4/5222/Vemurafenib-Active-in-Iodine-Refractory-Thyroid

Vemurafenib Active in Iodine-Refractory Thyroid Cancer A new study suggests that the BRAF inhibitor vemurafenib (Zelboraf; Genentech) may be effective in the 25% to 50% of patients with papillary thyroid cancer who ...

5. academic.oup.com academic.oup.com/jcem/article/100/1/E77/2812864

Efficacy and Tolerability of Vemurafenib in Patients with BRAF ... Vemurafenib, a selective BRAF inhibitor, appears to have promising clinical activity in patients with papillary thyroid cancer (PTC) harboring the BRAFV600E ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK535429/

Vemurafenib - StatPearls - NCBI Bookshelf - NIH Vemurafenib is a selective BRAF inhibitor approved by the US Food and Drug Administration (FDA) for treating metastatic and unresectable melanoma with a BRAF V ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01709292?cond=Cancer&aggFilters=funderType%3Aindustry%2CstudyType%3Aint

Vemurafenib Neoadjuvant Trial in Locally Advanced ... The goal of this clinical research study is to learn about how vemurafenib may affect certain biomarkers in patients with PTC.

8. medchemexpress.com medchemexpress.com/Vemurafenib.html?srsltid=AfmBOorlISRxzLZmwsGDMZrqKZPQuNwzPpwiO6ZFuhJRztAMHzdiS29g

Vemurafenib (PLX4032) | B-Raf Inhibitor Targeting Autophagy Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib.J Clin Endocrinol Metab. ... SAFETY DATA SHEET (SDS). English - EN (393 KB) ...

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Vemurafenib in patients with BRAF(V600E)-positive ... - PubMed Vemurafenib showed antitumour activity in patients with progressive, BRAF(V600E)-positive papillary thyroid cancer refractory to radioactive iodine.

10. reference.medscape.com reference.medscape.com/drug/zelboraf-vemurafenib-999679

Zelboraf (vemurafenib) dosing, indications, interactions, ... Orphan Designations. Thyroid cancer: Treatment of anaplastic thyroid carcinoma and advanced papillary thyroid cancer whose tumors harbor a BRAF V600 mutation.