Larotrectinib for Thyroid Cancer

Recruiting at 4 trial locations

Overseen By Meghan Donnelly

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Theodore Laetsch

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Breastfeeding, Prior systemic therapy, 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: Unknown

13 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for individuals with papillary thyroid cancer that has spread to the lungs and hasn't responded well to standard treatment. Researchers are combining larotrectinib, a targeted therapy, with traditional radioactive iodine therapy (also known as 131I therapy) to determine if this combination is more effective. Participants should have undergone thyroid surgery and have cancer nodules in their lungs, along with a specific gene fusion identified by their doctor. The trial aims to offer a better solution for those who haven't received previous systemic treatments like TRK inhibitors or radioactive iodine. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, providing participants a chance to benefit from potentially more effective therapies.

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 take strong CYP3A4 inducers or inhibitors starting 14 days before and during the study.

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

Research has shown that larotrectinib is generally safe and well-tolerated. In studies, patients with thyroid cancer, including papillary thyroid cancer, responded well to larotrectinib, with 71% experiencing tumor shrinkage.

Larotrectinib is considered safe because its side effects are usually mild and manageable. Common side effects may include dizziness, nausea, or tiredness, which are not severe and often improve over time.

Traditional treatments for thyroid cancer, such as 131I therapy, can sometimes cause lung problems or increase the risk of other cancers later. However, the FDA has already approved larotrectinib for other conditions, indicating it has undergone safety review.

Overall, evidence suggests that larotrectinib is a safe option for thyroid cancer patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for thyroid cancer, which often includes surgery and radioactive iodine (131I) therapy, larotrectinib offers a targeted approach by specifically inhibiting TRK fusion proteins. These proteins can drive cancer growth, and larotrectinib's ability to block them makes it a promising option for patients with TRK fusion-positive thyroid cancer. Researchers are excited because this targeted mechanism has the potential to provide more effective treatment with fewer side effects compared to non-specific therapies. Additionally, larotrectinib can be used in combination with existing treatments like 131I, offering a comprehensive strategy to manage the disease.

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

Research has shown that larotrectinib effectively treats thyroid cancer with a specific genetic feature called TRK fusion. In studies, 71% of patients with this cancer type experienced tumor reduction or disappearance. The treatment's effects are long-lasting, providing extended benefits. Larotrectinib is already approved for various TRK fusion cancers, including differentiated thyroid cancer. This trial will evaluate larotrectinib monotherapy followed by 131I therapy, suggesting potential effectiveness for papillary thyroid cancer as well. ^{1 6 7 8 9}

Who Is on the Research Team?

Theodore W. Laetsch

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for people of any age over 1 year with a specific type of thyroid cancer, who've had surgery and possibly other treatments for neck metastases. They must have certain lung nodules seen on CT scans and an NTRK gene fusion without resistance mutations. Good performance status and organ function are required, including specific blood cell counts and creatinine levels.

Inclusion Criteria

I am at least 1 year old.

I am 16 years old or older.

My organs are functioning well.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Larotrectinib Treatment

Participants receive larotrectinib monotherapy for 6 months at the FDA-approved dose

6 months

131I Therapy

Participants receive 131I therapy after 6 months of larotrectinib. Larotrectinib is continued for 5 days after RAI therapy

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

18 months

What Are the Treatments Tested in This Trial?

Interventions

• 131I therapy
• Larotrectinib

Trial Overview The study tests Larotrectinib's ability to improve the effectiveness of radioactive iodine (RAI) therapy in treating advanced differentiated thyroid cancer after surgery. It aims to see if this drug can help those who don't fully respond to RAI, which has risks like pulmonary fibrosis and secondary cancers.

How Is the Trial Designed?

Group I: Larotrectinib monotherapy with 131I therapy Experimental Treatment 2 Interventions

Patients will receive larotrectinib monotherapy for 6 months at the FDA-approved dose. Patients will receive 131I therapy after 6 months of larotrectinib. Larotrectinib will be continued for 5 days after RAI therapy and then patients will enter a wait and see period off treatment. Patients who experience disease progression at any point while on larotrectinib will proceed to 131I therapy and discontinue larotrectinib.

131I therapy is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Radioactive Iodine Therapy for:

• Thyroid cancer
• Hyperthyroidism

Approved in European Union as Radioactive Iodine Therapy for:

• Thyroid cancer
• Hyperthyroidism

Approved in Canada as Radioactive Iodine Therapy for:

• Thyroid cancer
• Hyperthyroidism

Who Is Running the Clinical Trial?

Theodore Laetsch

Lead Sponsor

Trials

4

Recruited

80+

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Bayer

Industry Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

Published Research Related to This Trial

Sorafenib has been FDA approved for treating well-differentiated radioactive iodine-resistant metastatic thyroid cancer, marking it as the second drug approved for this condition in 40 years, based on Phase III data presented at the ASCO 2013 conference.

While sorafenib shows a modest ability to induce partial remission, it is particularly effective at halting disease progression, suggesting that combining it with other targeted therapies could enhance treatment outcomes given the presence of activating mutations in thyroid cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sorafenib in radioactive iodine-refractory well-differentiated metastatic thyroid cancer. McFarland, DC., Misiukiewicz, KJ.[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]

Real-world data confirms that sorafenib and lenvatinib are effective in improving progression-free survival and possibly overall survival in patients with radioiodine-resistant differentiated thyroid carcinomas (RAIR-DTC).

Safety profiles from real-world studies align with clinical trial data, showing manageable adverse events, which supports the use of these multikinase inhibitors as viable treatment options, particularly in second-line settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multikinase inhibitors for the treatment of radioiodine refractory thyroid cancer: what have we learned from the 'real-world' experience? Costante, G.[2021]

Radioiodine (RAI)-refractory thyroid cancer is rare, with a very low 10-year survival rate of less than 10%, particularly affecting older patients and those with aggressive tumor characteristics.

Multikinase inhibitors (MKIs) like sorafenib and lenvatinib have shown promise in improving progression-free survival in patients with RAI-refractory thyroid cancer, but they have not yet demonstrated an overall survival benefit, highlighting the need for careful patient selection and timing of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radioactive iodine-refractory differentiated thyroid cancer: an uncommon but challenging situation. Schmidt, A., Iglesias, L., Klain, M., et al.[2023]

Combining multikinase inhibitors (MKIs) like lenvatinib with radioactive iodine (RAI) may enhance treatment efficacy for radioactive iodine-refractory differentiated thyroid cancer, potentially leading to better outcomes than using either treatment alone.

Early preclinical studies suggest that this combination could also result in lower toxicity rates, but further validation through ongoing clinical trials is necessary before widespread application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of multikinase inhibitors/lenvatinib concomitant with radioiodine for the treatment of radioiodine refractory differentiated thyroid cancer. Herranz, UA.[2023]

Larotrectinib, a selective TRK inhibitor, led to a complete response in a patient with rapidly progressing NTRK3 fusion-positive thyroid cancer, sustained for 11 months after just 2 months of treatment.

The treatment also resulted in complete responses in metastatic brain lesions after 7 months, suggesting larotrectinib could be a valuable option for patients with radioactive iodine-refractory thyroid cancer who have limited alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete response to larotrectinib treatment in a patient with papillary thyroid cancer harboring an ETV6-NTRK3 gene fusion. Pitoia, F.[2023]

Thyroid cancer is the most common type of endocrine tumor, and treatment options for advanced or metastatic cases include radioactive iodine (RAI) and multikinase inhibitors like lenvatinib and sorafenib.

Lenvatinib is specifically highlighted for its role in treating RAI-refractory differentiated thyroid cancer, emphasizing the importance of targeted therapy in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of multikinase inhibitors/lenvatinib in singular thyroid cancer scenarios. Zafón, C., Castelo, B.[2022]

Lenvatinib has been approved as a second targeted therapy for patients with radioactive iodine refractory, locally advanced, or metastatic differentiated thyroid carcinoma, showing a median progression-free survival (PFS) of 18.3 months compared to just 3.6 months for placebo, indicating a significant improvement in treatment efficacy.

The overall response rate (ORR) for lenvatinib was 64.7%, vastly higher than the 1.5% seen in the placebo group, highlighting its effectiveness in managing this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib in Advanced, Radioactive Iodine-Refractory, Differentiated Thyroid Carcinoma. Yeung, KT., Cohen, EE.[2015]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12165012/

The potential long-term comparative effectiveness of ... Larotrectinib is approved for patients with metastatic TRK fusion cancers, including differentiated thyroid (DTC), colorectal cancer (CRC), and soft tissue ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.6094

Efficacy and safety of larotrectinib in patients with TRK ... The 6-year OS rate was 71% (95% CI 50–91) for pts with DTC and 17% (95% CI 0–46) for pts with ATC. Median duration of treatment was 31 months ( ...

3. targetedonc.com targetedonc.com/view/larotrectinib-shows-durable-responses-safety-in-trk-fusion-thyroid-carcinoma

Larotrectinib Shows Durable Responses, Safety in TRK ... Of the 31 patients included in the analysis, the overall response rate (ORR) was 65% (95% CI, 45%-81%), which included 3 (10%) complete ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38824630/

Projecting long-term clinical outcomes with larotrectinib ... Results: In NSCLC, larotrectinib resulted in gains of 5.87 and 5.91 LYs compared to nivolumab and pembrolizumab, respectively, which translated to gains of 3.53 ...

5. onclive.com onclive.com/view/updated-efficacy-and-safety-of-larotrectinib-in-patients-with-advanced-tropomyosin-receptor-kinase-trk-fusion-positive-thyroid-carcinoma

Updated Efficacy and Safety of Larotrectinib in Patients ... Larotrectinib is a highly selective TRK inhibitor which has shown a 71% overall response rate (ORR) in 28 investigator-evaluable patients with ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9066591/

Efficacy and safety of larotrectinib in patients with TRK ... In the current study, the highly selective TRK inhibitor larotrectinib showed durable antitumour efficacy and a favourable safety profile in patients with TRK ...

7. esmoopen.com esmoopen.com/article/S2059-7029(25)00979-2/fulltext

Efficacy and safety of larotrectinib as first-line treatment ... Outcomes of larotrectinib compared with real-world data from non-TRK inhibitor therapies in patients with TRK fusion cancer: VICTORIA study.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11145004/

Projecting long-term clinical outcomes with larotrectinib ... In metastatic NSCLC and DTC, larotrectinib may produce substantial life expectancy and QALY gains compared to immune checkpoint inhibitors.

9. bayer2019tf.q4web.com bayer2019tf.q4web.com/news/news-details/2021/Updated-Vitrakvi-larotrectinib-Sub-Analysis-at-ATA-2021-Supports-Efficacy-and-Safety-in-Adult-and-Pediatric-TRK-Fusion-Thyroid-Cancer-Patients/default.aspx

Updated Vitrakvi® (larotrectinib) Sub-Analysis at ATA 2021 ... Overall response rate (ORR) of 71% (95% confidence interval [CI] 51—87) among those with all types of thyroid cancers (n=28), ...