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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and optimal dosage of combining two drugs, dabrafenib (a BRAF inhibitor) and lapatinib, to treat thyroid cancer that cannot be removed by surgery and has not responded to standard treatments. Dabrafenib and lapatinib block certain enzymes that help cancer cells grow, potentially stopping or slowing tumor growth. Suitable candidates for this trial have thyroid cancer with a specific BRAF mutation and have not had success with other treatments like radioactive iodine. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that taking dabrafenib and lapatinib together is generally safe and well-tolerated. In studies, patients who took dabrafenib at 150 mg twice a day and lapatinib at 1500 mg daily did not experience severe side effects. These drugs block proteins that help cancer cells grow, and most patients managed the treatment well. This combination has been tested in individuals who had previous treatments, and results showed consistent safety. Although this trial is in the early stages, current data suggest that the treatment is fairly safe for humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for thyroid cancer, which often involve surgery, radioactive iodine, or chemotherapy, dabrafenib and lapatinib offer a targeted therapy approach. These drugs work differently by homing in on specific proteins involved in cancer cell growth. Dabrafenib targets the BRAF protein, while lapatinib targets the HER2/EGFR pathways, making them potentially more effective for certain genetic profiles of thyroid cancer. Researchers are excited because this combination could lead to more personalized and effective treatment options with possibly fewer side effects compared to traditional methods.

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

Research has shown that using dabrafenib and lapatinib together may help treat thyroid cancer. In this trial, participants will receive dabrafenib, which targets a specific gene called BRAF linked to cancer growth, and lapatinib, which blocks certain proteins that aid cancer cell growth. Studies have found that lapatinib can make cancer cells more responsive to dabrafenib, potentially enhancing the treatment's effectiveness. Early findings suggest that this drug combination is safe and well-tolerated. The goal of using these drugs together is to stop cancer cells from growing by blocking essential enzymes they need to survive. ^{1 2 3 6 7}

Who Is on the Research Team?

Eric J Sherman

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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.

PT/INR and PTT =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with PT/INR/PTT established within the therapeutic range prior to randomization; subjects will be eligible if it is determined by a hematologist that the cause is not associated with clinical bleeding (e.g., deficiency of factor XII), within 2 weeks of the first dose of study treatment

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01947023?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(GSK-2118436B)))&rank=5

Dabrafenib and Lapatinib in Treating Patients With ... This phase I trial studies the side effects and best dose of lapatinib when given together with dabrafenib in treating patients with thyroid ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01947023?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(GSK-2118436A))))&rank=3

Study Details | Dabrafenib and Lapatinib in Treating ... This phase I trial studies the side effects and best dose of lapatinib when given together with dabrafenib in treating patients with thyroid cancer that ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.6087

Combination of dabrafenib (DAB) and lapatinib (LAP) for ... The addition of LAP, a HER2/HER3 kinase inhibitor, sensitizes the cell to growth suppression by BRAF inhibitors (Cancer Discov 5(3):520, 2013).

4. asco.org asco.org/abstracts-presentations/ABSTRACT224263

Combination of dabrafenib (DAB) and lapatinib (LAP) for ... The combination of DAB 150 mg bid and LAP 1500 mg daily was safe and well-tolerated. Despite the number of subjects with prior treatment (including with BRAF ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7226736/

Combinatorial Therapies in Thyroid Cancer: An Overview of ... Their first conclusion was that the inhibition of BRAFV600E by dabrafenib could be effective against cancer cells harboring active alterations in both MAPK and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6770736/

BRAF Inhibitors in Thyroid Cancer: Clinical Impact ... Dabrafenib achieved partial responses and stable disease in, respectively, 29% and 45% of patients; the median PFS was 11.3 months and 50% of ...

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT01947023/

Clinical Trial: NCT01947023 - Thyroid Cancer Dabrafenib and lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Related Conditions: Thyroid ...