Larotrectinib for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, TRK inhibitors

Disqualifiers: Hypersensitivity to larotrectinib, 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

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

Compensation: Varies

Number of Visits: 4

Duration: Up to 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of larotrectinib for patients with cancer that includes specific genetic changes. Larotrectinib, a kinase inhibitor, stops cancer cells from multiplying by blocking certain proteins. The trial targets patients whose cancer has an altered NTRK gene. Ideal candidates have an NTRK gene fusion in their cancer and have not received similar drugs before. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

You may need to stop taking certain medications, especially if they are strong CYP3A4 inhibitors or inducers, as the trial excludes patients who cannot discontinue these before starting treatment.

Is there any evidence suggesting that larotrectinib (LOXO-101) is likely to be safe for humans?

Research has shown that larotrectinib is generally safe for people with certain types of cancer. Studies have found that it has a good safety record, meaning most people can take it without serious side effects. Larotrectinib blocks abnormal proteins that help cancer cells grow, which can slow down or stop the cancer.

In past studies, patients responded well to this treatment. Most side effects were mild and manageable, such as fatigue or dizziness, which are common with many cancer treatments. Larotrectinib has been used in both adults and children, with children often responding very well.

Overall, the treatment has been well-tolerated. For specific concerns, discussing them with a doctor is advisable. They can help explain how this treatment might work for an individual. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Larotrectinib is unique because it specifically targets a genetic mutation known as TRK fusion, which is found in various types of cancer. Unlike traditional chemotherapy that attacks rapidly dividing cells indiscriminately, larotrectinib zeroes in on this specific genetic alteration, potentially leading to fewer side effects and a more personalized treatment approach. Researchers are excited about larotrectinib because it offers a tailored therapy option that could work across different cancer types that share this genetic feature, providing new hope for patients with TRK fusion-positive cancers.

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

Research shows that larotrectinib, the treatment under study in this trial, effectively treats cancers with an NTRK gene fusion. Studies have found that 77% of patients with this cancer type experienced tumor shrinkage. In children, the response was even better, with 90% experiencing tumor reduction. Those treated with larotrectinib tend to live longer than those receiving other treatments. Overall, it has demonstrated lasting effects against tumors and generally manageable side effects. ^{1 4 5 6 7}

Who Is on the Research Team?

David S Hong

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for cancer patients with specific genetic changes in the NTRK gene. It's open to those with lymphoma, multiple myeloma, or solid tumors that have not responded well to standard treatments. Participants must be able to undergo procedures like biopsies and scans.

Inclusion Criteria

Patients must have met applicable eligibility criteria in the Master MATCH Protocol EAY131/ NCI-2015-00054 prior to registration to treatment subprotocol

Patients must fulfill all eligibility criteria of MATCH Master Protocol at the time of registration to treatment step (Step 1, 3, 5, 7)

My cancer has an NTRK gene fusion.

Exclusion Criteria

I can stop taking strong CYP3A4 inhibitors or inducers before starting treatment.

I have not taken any TRK inhibitor medications.

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 larotrectinib (LOXO-101) orally twice daily on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 3 years

Bi-weekly visits for imaging and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 3 months for 2 years and then every 6 months for 1 year.

3 years

Every 3 months for 2 years, then every 6 months for 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Larotrectinib (LOXO-101)

Trial Overview The study tests larotrectinib (LOXO-101), a kinase inhibitor aimed at blocking abnormal proteins from multiplying cancer cells. The trial includes diagnostic procedures such as MRI and CT scans, along with biospecimen collection to monitor effects.

How Is the Trial Designed?

Group I: Treatment (larotrectinib [LOXO-101]) Experimental Treatment 5 Interventions

Patients receive larotrectinib (LOXO-101) PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT or MRI during screening and on study, as well as during follow-up as clinically necessary. Patients also undergo biopsies and blood sample collection on study.

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

Larotrectinib and entrectinib, first-generation TRK inhibitors, are effective first-line treatments for advanced non-small cell lung cancer (NSCLC) with TRK gene fusions, showing rapid and long-lasting clinical benefits.

A safety analysis of 807 reports revealed that the most common adverse reactions were dizziness and pain, with no significant long-term safety concerns noted, indicating a favorable risk-benefit profile for these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Safety Profiles of Two First-Generation NTRK Inhibitors: Analysis of Individual Case Safety Reports from the FDA Adverse Event Reporting System (FAERS) Database. Liguori, V., Gaio, M., Zinzi, A., et al.[2023]

Larotrectinib shows promising efficacy for treating solid tumors with NTRK gene fusions, with a 12-month progression-free survival (PFS) rate of 66.6% consistent between 2018 predictions and 2020 observed data from 102 patients across 15 tumor types.

While long-term PFS predictions varied due to differences in tumor responses, the overall survival (OS) predictions were reliable, with a 48-month OS rate of 67.2% aligning closely with observed data, indicating larotrectinib's potential for sustained effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimating Long-Term Survival Outcomes for Tumor-Agnostic Therapies: Larotrectinib Case Study. Briggs, A., Paracha, N., Rosettie, K., et al.[2022]

Larotrectinib is a small-molecule kinase inhibitor specifically designed to target NTRK fusions found in various cancers, showcasing its potential effectiveness across multiple tumor types.

It is the first treatment to receive FDA approval as 'tumor-agnostic,' meaning its use is based on specific genetic markers rather than the location of the cancer, highlighting a significant advancement in personalized medicine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Tumor-Agnostic NTRK (TRK) Inhibitor. Huang, FW., Feng, FY.[2020]

Larotrectinib showed a 30% objective response rate in 33 patients with TRK fusion-positive primary CNS tumors, indicating its efficacy in this specific cancer type.

The treatment demonstrated a high disease control rate of 73% and favorable safety profile, with only 3 patients experiencing severe adverse events, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Doz, F., van Tilburg, CM., Geoerger, B., et al.[2022]

Larotrectinib (VITRAKVI®) is a targeted therapy specifically designed to inhibit tropomyosin receptor kinases (TRK) in patients with cancers that have neurotrophic receptor tyrosine kinase (NTRK) gene fusions, making it a promising option for both adults and children.

Approved in November 2018 in the USA, larotrectinib is indicated for metastatic solid tumors with NTRK gene fusions when no other satisfactory treatments are available, highlighting its role as a critical option for patients with limited alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Larotrectinib: First Global Approval. Scott, LJ.[2020]

Elacridar significantly increases the oral availability and brain penetration of larotrectinib, suggesting it could enhance the drug's therapeutic effects in treating NTRK fusion-positive cancers.

Both rifampin and ritonavir also improve the systemic exposure of larotrectinib, indicating that these drugs can be used to optimize larotrectinib's effectiveness by inhibiting specific transporters and enzymes involved in its metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rifampin and ritonavir increase oral availability and elacridar enhances overall exposure and brain accumulation of the NTRK inhibitor larotrectinib. Wang, Y., Sparidans, RW., Wang, J., et al.[2022]

Larotrectinib (VITRAKVI) is a highly effective treatment for patients with Trk fusion-positive cancers, showing a remarkable response rate of 75% regardless of cancer type, age, or gender.

The study developed a new LC-MS/MS method for accurately measuring Larotrectinib levels and assessing its metabolic stability, revealing a moderate extraction ratio and a half-life of approximately 48.8 minutes in human liver microsomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry. Attwa, MW., Kadi, AA., Darwish, HW.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5857389/

Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in ... Larotrectinib had marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or of the tumor type.

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

Efficacy and safety of larotrectinib as first-line treatment ... In a combined analysis of three phase I/II trials, larotrectinib achieved a robust objective response rate and durable antitumour efficacy, ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3105

Outcomes of larotrectinib compared with real-world data ... Conclusions: In adult pts with TRK fusion cancer, treatment with laro was associated with longer OS and all measured time-to-event endpoints ( ...

4. targetedonc.com targetedonc.com/view/larotrectinib-shows-robust-efficacy-and-safety-in-trk-fusion-cancer

Larotrectinib Shows Robust Efficacy and Safety in TRK ... Larotrectinib demonstrated a high ORR of 77% in TRK fusion cancer, with pediatric patients showing a higher ORR of 90% compared to adults at 68% ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0959804925001194

Efficacy and safety of larotrectinib in patients with TRK ... Larotrectinib demonstrated long durability, extended survival and manageable safety in patients with TRK fusion GI cancer, including those with MSI-H CRC.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40408921/

Efficacy and safety of larotrectinib as first-line treatment for ... Larotrectinib achieved extremely durable responses, extended survival and had a favourable safety profile in treatment-naïve patients with TRK fusion cancers.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.3148

Efficacy and safety of larotrectinib in patients with non- ... Laro continues to demonstrate rapid and durable responses, extended survival, clinical benefit, and a favorable safety profile in pts with TRK fusion cancer.