PDR001 + Trametinib/Dabrafenib for Thyroid Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a new drug, PDR001, combined with trametinib (Mekinist) or dabrafenib (Tafinlar), can safely and effectively treat thyroid cancer. It targets two groups: one with a specific gene change (BRAF mutation) and another without it. People with thyroid cancer that is growing or causing symptoms, and who aren’t eligible for surgery or radiation, might be suitable candidates. Participants must have certain types of thyroid cancer and show evidence of disease progression. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of people.

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.

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

Research has shown that trametinib and dabrafenib, when combined with PDR001, have been studied for safety in treating certain types of thyroid cancer. These studies indicate that this combination is already approved for treating advanced thyroid cancer, suggesting it is generally well-tolerated.

In earlier studies, serious side effects were rare. Severe fatigue occurred in about 4% of patients, while slight increases in weight, diarrhea, and joint pain affected about 1-2% of patients. This data suggests that the treatments are mostly safe, with serious side effects being uncommon.

Since the current trial is in Phase 2, the drugs have demonstrated a reasonable level of safety in earlier studies. While no drug is without risk, these findings are promising for those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about PDR001 combined with trametinib or dabrafenib for thyroid cancer because these treatments offer a fresh approach compared to standard therapies. While most thyroid cancer treatments focus on traditional chemotherapy or radioactive iodine, PDR001 is an immune checkpoint inhibitor that enhances the body's own immune response to attack cancer cells. Trametinib and dabrafenib, on the other hand, target specific proteins involved in cancer cell growth, with trametinib inhibiting the MEK pathway and dabrafenib targeting the BRAF mutation. This combination therapy provides a tailored approach, especially for patients with BRAF mutations or those resistant to previous treatments, potentially improving outcomes where existing treatments fall short.

What evidence suggests that this trial's treatments could be effective for thyroid cancer?

Research has shown that combining PDR001 with trametinib or dabrafenib may help treat thyroid cancer. In this trial, participants with BRAF wild-type tumors will receive PDR001 with trametinib, while those with BRAF mutant tumors resistant to previous BRAF inhibitors will receive PDR001 with dabrafenib. Studies have found that dabrafenib, especially when combined with trametinib, can be effective for patients with a specific gene change called BRAF V600E, with about 50% of patients responding to the treatment. This combination has also proven effective for other types of cancer, suggesting it might help with thyroid cancer too. Early results indicate that these drugs, when used with PDR001, are generally safe and can lead to significant improvements. This treatment targets certain proteins in cancer cells, potentially stopping their growth. ^{2 6 7 8 9}

Who Is on the Research Team?

Alan L Ho, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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 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. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4291160/

BRAF Inhibitor Dabrafenib in Patients with Metastatic BRAF ... Conclusions: Dabrafenib was well tolerated and resulted in durable responses in BRAF-mutant differentiated thyroid carcinoma patients. Introduction. Effective ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04544111

PDR001 Combination Therapy for Radioiodine-Refractory ... 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 ...

3. academic.oup.com academic.oup.com/edrv/article/40/6/1573/5535574

Targeted Therapy for Advanced Thyroid Cancer: Kinase ... Updated efficacy and safety data of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated anaplastic thyroid cancer (ATC) [abstract].

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)03529-4/pdf

1929P Dabrafenib and trametinib (D+T) in ... Conclusions: Longer duration of dabrafenib and trametinib appears to be safe and more effective on resensitization of BRAF-mutated iodine refractory DTC.

5. cancer.osu.edu cancer.osu.edu/news/targeted-therapies-show-initial-effectiveness-in-subset-of-papillary-thyroid-cancer

Targeted Therapies Show Initial Effectiveness in Subset of ... Initial data shows that both dabrafenib alone and combined dabrafenib/trametinib therapy are well tolerated by patients, resulting in a 50 to 54 percent ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/202806s022lbl.pdf

TAFINLAR (dabrafenib) - accessdata.fda.gov Patients with melanoma, thyroid cancer, or CRC were excluded. BRAF. V600E mutation status for enrollment was determined either by central or local laboratory ...

7. novartis.com novartis.com/us-en/sites/novartis_us/files/tafinlar.pdf

tafinlar.pdf TAFINLAR is indicated, in combination with trametinib, for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7341904/

Targeted Therapy for Advanced Thyroid Cancer: Kinase ... Higher-grade adverse events were rare and included grade 3 fatigue (4%), weight increase (2%), diarrhea and arthralgia (both 1%), and grade 4 eosinophilic ...

9. researchgate.net researchgate.net/publication/328500172_1821PDUpdated_efficacy_and_safety_data_of_dabrafenib_D_and_trametinib_T_in_patients_pts_with_BRAF_V600E-mutated_anaplastic_thyroid_cancer_ATC

1821PDUpdated efficacy and safety data of dabrafenib (D) ... 1821PDUpdated efficacy and safety data of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated anaplastic thyroid cancer ...