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

24 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to learn about how vemurafenib may affect certain biomarkers in patients with PTC. Biomarkers are in the blood/tissue and may be related to your reaction to the study drug. The safety of this drug will also be studied. Vemurafenib is designed to block the BRAF gene mutation. This mutation causes cancer and cancer growth. By blocking this mutation, the drug may kill the cancer cells with the mutation and/or stop the tumor from growing.

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.

What data supports the effectiveness of the drug Vemurafenib for thyroid cancer?

Research shows that Vemurafenib, a drug targeting the BRAF(V600E) mutation, has shown promising results in patients with papillary thyroid cancer, especially those whose cancer no longer responds to radioactive iodine. It has been effective in inducing partial responses and stabilizing the disease in some patients, although it can cause serious side effects in about 65% of cases. ^{1 2 3 4 5}

Is Vemurafenib safe for use in humans?

Vemurafenib has been associated with serious side effects in about 65% of patients, including the development of some skin cancers, when used for thyroid cancer that does not respond to radioactive iodine. ^{1 2 3 6 7}

How is the drug Vemurafenib unique for treating thyroid cancer?

Vemurafenib is unique for treating thyroid cancer because it specifically targets the BRAF(V600E) mutation, which is present in about half of papillary thyroid cancers, offering a targeted approach for tumors that are resistant to standard radioactive iodine treatment. ^{1 2 3 4 5}

Research Team

Maria E. Cabanillas, M.D.

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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, 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]

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]

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]

References

1. England 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. [2022]

2. United States 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. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

Disruption of mutated BRAF signaling modulates thyroid cancer phenotype. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Extended Antitumor Response of a BRAF V600E Papillary Thyroid Carcinoma to Vemurafenib. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

BRAF inhibitors: experience in thyroid cancer and general review of toxicity. [2022]

7. England 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. [2022]