PDR001 + Trametinib/Dabrafenib for Thyroid Cancer

Recruiting at 9 trial locations

Overseen By David G Pfister, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Dabrafenib

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Autoimmune disease, Active hepatitis, HIV, 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

Compensation: Varies

Number of Visits: 4

Duration: 12 months

19 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether a drug called PDR001, combined with either trametinib or dabrafenib, is a safe and effective treatment for thyroid cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot have had chemotherapy or targeted therapy within 4 weeks before starting the trial, except for dabrafenib, which can be continued if you are enrolling in Cohort B. If you are on systemic chronic steroid therapy or immunosuppressive therapy, you must stop at least 7 days before starting the trial.

What data supports the effectiveness of the drug combination PDR001 + Trametinib/Dabrafenib for thyroid cancer?

Research shows that the combination of dabrafenib and trametinib is effective in treating certain types of thyroid cancer, particularly those with a specific mutation called BRAF V600E. Studies have demonstrated that this drug combination can improve survival rates and help manage advanced thyroid cancers. ^{1 2 3 4 5}

What is the safety profile of Dabrafenib and Trametinib in thyroid cancer treatment?

The combination of Dabrafenib and Trametinib has been generally well tolerated in patients with BRAF V600E-mutated anaplastic thyroid cancer, with common side effects including fatigue, fever, and nausea. No new safety concerns were identified in the studies, and there were no treatment-related deaths. ^{1 2 5 6 7}

What makes the drug PDR001 + Trametinib/Dabrafenib unique for thyroid cancer?

The combination of PDR001 with Trametinib and Dabrafenib is unique because it targets BRAF V600E mutations, which are common in certain aggressive thyroid cancers. This approach is particularly novel as it combines targeted therapies with an immune checkpoint inhibitor (PDR001), potentially enhancing the body's immune response against the cancer. ^{1 2 3 4 7}

Research Team

Alan L Ho, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults with certain types of thyroid cancer that have progressed despite previous treatments and can't be cured with surgery or radiation. They must not have a specific mutation (BRAFV600-), should be in good physical condition, able to swallow pills, and not on immunosuppressive drugs. Pregnant women or those who might become pregnant without contraception are excluded.

Inclusion Criteria

Patients must have a measurable disease according to RECIST v1.1 guidelines.

I can swallow pills without any major stomach or intestine problems.

I have tissue samples from my cancer available for study.

Exclusion Criteria

I have an autoimmune disease, but it might be an exception.

I have a history of lung disease not caused by infections.

I have symptoms from cancer spread to my brain or its coverings.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive PDR001 in combination with trametinib or dabrafenib for thyroid cancer

12 months

IV administration every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dabrafenib
• PDR001
• Trametinib

Trial Overview The trial is testing the effectiveness of PDR001 combined with trametinib or dabrafenib for treating advanced thyroid cancer. It aims to determine if this combination therapy is safe and beneficial for patients whose cancer has continued to progress after other treatments.

Participant Groups

Group I: Cohort B-BRAF Mutant Experimental Treatment 2 Interventions

Cohort B (BRAF Mutant, resistant to previous BRAF inhibitors): dabrafenib (D) 150 mg twice daily (OR at dose the patient previously tolerated) plus PDR001 400mg IV every 4 weeks.

Group II: Cohort A-BRAF WT tumors Experimental Treatment 2 Interventions

Cohort A (BRAF WT tumors): trametinib (T) 2mg by mouth daily plus PDR001 400mg IV every 4 weeks

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

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]

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]

The use of neoadjuvant therapy with dabrafenib and trametinib in a patient with locally advanced recurrent differentiated thyroid carcinoma (DTC) led to a significant radiographic response, allowing for a less invasive partial laryngectomy instead of a total laryngectomy.

This approach not only preserved the patient's voice and allowed for early resumption of oral feeding but also demonstrated that neoadjuvant treatment can effectively reduce the extent of surgery needed, potentially lowering associated complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant dabrafenib and trametinib for functional organ preservation in recurrent BRAF V600E-mutated papillary thyroid cancer. Farlow, JL., McCrary, HC., Sipos, JA., et al.[2023]

In a study of 27 patients with anaplastic thyroid carcinoma (ATC), those treated with the combination of Dabrafenib and Trametinib (DT) had a median overall survival of 475 days, significantly longer than the 156 days for multimodal therapy and 39 days for compassionate care (P < .001).

The DT group also demonstrated a median progression-free survival of 270 days, compared to less than 32 days for BRAF wild type patients, with no severe adverse events reported, indicating a strong safety and efficacy profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target therapy for BRAF mutated anaplastic thyroid cancer: a clinical and molecular study. da Silva, TN., Rodrigues, R., Saramago, A., et al.[2023]

In a phase II trial involving 16 patients with BRAF V600E-mutated anaplastic thyroid cancer, the combination of dabrafenib and trametinib showed a high overall response rate of 69%, indicating significant efficacy in a cancer type with previously limited treatment options.

The treatment was well tolerated, with common side effects including fatigue, fever, and nausea, and no new safety concerns were identified, marking a promising advancement for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. Subbiah, V., Kreitman, RJ., Wainberg, ZA., 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]

References

1. 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]

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. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant dabrafenib and trametinib for functional organ preservation in recurrent BRAF V600E-mutated papillary thyroid cancer. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Case report: Visibly curative effect of dabrafenib and trametinib on advanced thyroid carcinoma in 2 patients. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Target therapy for BRAF mutated anaplastic thyroid cancer: a clinical and molecular study. [2023]

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

Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. [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]