Dabrafenib + Lapatinib for Thyroid Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Antibiotics, Anticonvulsants, Antifungals, others

Disqualifiers: HIV, Hepatitis, Cardiovascular risks, others

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

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

Compensation: Varies

Number of Visits: 2

Duration: 28 days per cycle

21 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing the combination of lapatinib and dabrafenib in patients with hard-to-treat thyroid cancer. The drugs work by blocking proteins that help cancer cells grow. The goal is to find the best dose and observe any anti-tumor activity. Dabrafenib has shown antitumor activity in various cancers, including thyroid cancer, and lapatinib is a tyrosine kinase inhibitor used in breast cancer treatment.

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking certain medications that strongly affect specific liver enzymes (CYP3A and CYP2C8) and some herbal remedies like St. John's wort. You should consult with the trial team to review your current medications and see if any need to be stopped.

What data supports the effectiveness of the drug combination Dabrafenib and Lapatinib for thyroid cancer?

Research shows that Dabrafenib, a BRAF inhibitor, is effective in treating certain types of thyroid cancer with BRAF mutations, such as papillary and anaplastic thyroid cancer. It has been shown to inhibit cancer cell growth and improve outcomes in patients with these mutations. ^{1 2 3 4 5}

Is the combination of Dabrafenib and Lapatinib safe for humans?

Dabrafenib has been studied for safety in thyroid cancer and other conditions, showing common side effects like skin issues, fever, and high blood sugar. No treatment-related deaths were reported in these studies, suggesting it is generally safe for humans. ^{2 4 5 6 7}

What makes the drug combination of Dabrafenib and Lapatinib unique for treating thyroid cancer?

The combination of Dabrafenib and Lapatinib is unique for treating thyroid cancer because it targets specific genetic mutations (BRAF mutations) that are often found in aggressive forms of the disease, like papillary and anaplastic thyroid cancer. This approach is novel as it combines two drugs that inhibit different pathways, potentially improving treatment effectiveness compared to using a single drug. ^{1 2 4 6 8}

Research Team

Eric J Sherman

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for patients with thyroid cancer that's spread or can't be removed by surgery, and hasn't improved after standard treatments. Participants must have a specific BRAF V600E or V600K mutation in their tumor, good organ function, no recent cancer treatments, and an ability to swallow pills. Women who can have children need to use non-hormonal birth control during the study.

Inclusion Criteria

My PET scan shows a highly active lesion with an SUVmax of 3 or more.

I haven't had radioactive iodine therapy in the last 3 months.

My cancer does not absorb radioactive iodine well, as confirmed by a specialist.

Exclusion Criteria

Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or DMSO

You cannot have taken any experimental drugs in the 28 days (or five half-lives, whichever is shorter, with a minimum of 14 days from the last dose) before starting the study and during the study.

Medical or psychiatric illness/social situations that would limit compliance with study requirements

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive dabrafenib orally twice daily for 28 days, followed by the addition of lapatinib once daily, with cycles repeating every 28 days

28 days per cycle

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks

1 visit (in-person)

Long-term follow-up

Participants are followed up annually after the initial follow-up period

Annually

Treatment Details

Interventions

• Dabrafenib
• Lapatinib

Trial Overview The trial is testing the combination of two drugs: Dabrafenib and Lapatinib. These drugs are believed to block enzymes important for cancer cell growth. The study aims to find the best dose with acceptable side effects for patients whose thyroid cancer has not been controlled by other treatments.

Participant Groups

Group I: Treatment (lapatinib, dabrafenib) Experimental Treatment 11 Interventions

Patients receive dabrafenib PO BID on days 1-28 of each cycle. After two weeks of single agent dabrafenib, patients also start receiving lapatinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo tumor biopsy, blood sample collection, ECHO or MUGA, as well as PET, CT, and/or MRI during screening and on study.

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

Approved in European Union as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in United States as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600E mutation
• Adjuvant treatment of melanoma with a BRAF V600E or V600K mutation
• Metastatic non-small cell lung cancer with a BRAF V600E mutation

Approved in Canada as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation
• Adjuvant treatment of melanoma with a BRAF V600 mutation

Approved in Japan as Tafinlar for:

• Unresectable or metastatic melanoma with a BRAF V600 mutation

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase II trial involving 24 patients with radioactive iodine refractory metastatic differentiated thyroid cancer, dabrafenib and trametinib treatment led to a partial response in 38% of patients at 6 months, indicating its efficacy in restoring iodine uptake in BRAF p.V600E-mutated cases.

The treatment was associated with a high rate of adverse events (96%), although only 10 patients experienced severe (grade 3-4) adverse effects, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer. Leboulleux, S., Do Cao, C., Zerdoud, S., et al.[2023]

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 phase 2 trial involving 53 patients with BRAF-mutated radioactive iodine refractory differentiated thyroid cancer, both dabrafenib monotherapy and the combination of dabrafenib + trametinib showed similar objective response rates, with 42% and 48% respectively, indicating no significant advantage of the combination therapy.

The most common side effects included skin disorders and fever, but there were no treatment-related deaths, suggesting that both treatment options are relatively safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial. Busaidy, NL., Konda, B., Wei, L., et al.[2023]

In a study of 36 patients with BRAF V600E-mutant anaplastic thyroid cancer, the combination of dabrafenib and trametinib showed a significant overall response rate of 56%, with three patients achieving complete responses.

The treatment demonstrated manageable safety, with no new adverse effects identified, and improved median progression-free survival of 6.7 months and overall survival of 14.5 months, indicating it is a promising option for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Subbiah, V., Kreitman, RJ., Wainberg, ZA., et al.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Targeting SHP2 reverses BRAF inhibitor tolerance in anaplastic thyroid carcinoma. [2023]

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

A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer. [2023]

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

Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. [2022]

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

BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. [2022]

5. 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]

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

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

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

Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. [2022]