Larotrectinib for Advanced Cancer

Not currently recruiting at 138 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 drugs, Anticancer agents

Disqualifiers: Pregnancy, Uncontrolled infection, Organ transplant, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of larotrectinib (also known as Vitrakvi, LOXO-101, or ARRY-470) for patients with advanced cancers featuring specific gene changes called NTRK fusions. Larotrectinib blocks certain enzymes that cancer cells need to grow. The trial targets patients whose solid tumors, non-Hodgkin lymphoma, or histiocytic disorders have recurred or not responded well to previous treatments. Suitable candidates have cancers with NTRK fusions that have spread and not improved with other treatments. 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?

The trial requires that you stop taking certain medications before enrolling. You cannot be on other anti-cancer agents, investigational drugs, or medications that strongly affect the liver enzyme CYP3A4. If you're on corticosteroids, you need to be on a stable or decreasing dose for at least 7 days before joining.

Is there any evidence suggesting that larotrectinib is likely to be safe for humans?

Research has shown that larotrectinib is generally safe for patients with TRK fusion cancers. Serious side effects rarely occur, and most people experience only mild or moderate ones, such as fatigue, nausea, dizziness, or a cough.

Larotrectinib has proven effective in treating various types of cancer. It blocks certain enzymes that cancer cells need to grow, which may help stop or slow the disease.

Larotrectinib is already approved for patients with TRK fusion cancers, indicating it has undergone careful safety testing in previous studies. Prospective trial participants should consult their doctor to ensure it aligns with their health needs. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Larotrectinib is unique because it specifically targets a genetic abnormality known as a TRK fusion, which is found in various types of advanced cancers. Unlike traditional chemotherapy that attacks rapidly dividing cells indiscriminately, larotrectinib zeroes in on cancer cells with this specific mutation, potentially leading to fewer side effects. Researchers are excited about this treatment because it represents a more personalized approach, offering hope for patients whose cancers have specific genetic characteristics.

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

Research has shown that larotrectinib, which participants in this trial will receive, effectively treats cancers with NTRK fusions. Studies indicate that it can lead to better life outcomes compared to standard treatments for similar cancers. In patients with TRK fusion cancer, larotrectinib demonstrated better results than treatments that do not target TRK in real-world settings. This drug blocks certain enzymes that help cancer cells grow, potentially stopping or slowing the disease's spread. This makes it a promising option for people with advanced, hard-to-treat cancers. ^{1 4 6 7 8}

Who Is on the Research Team?

Katherine A Janeway

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for young patients aged 12 months to 21 years with advanced solid tumors, non-Hodgkin lymphoma, or histiocytic disorders that have NTRK fusions and are relapsed or refractory. They must not have used other NTRK inhibitors before, should be recovered from previous cancer treatments' side effects, and meet specific health criteria like adequate kidney function and blood counts.

Inclusion Criteria

All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

I have not taken any NTRK inhibitor medications.

My bilirubin levels are within the normal range for my age.

Exclusion Criteria

Patients who have received a prior solid organ transplantation are not eligible

I am not taking medication that strongly affects liver enzyme CYP3A4.

I am not taking medication to prevent GVHD after a bone marrow transplant.

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 sulfate orally or via NG- or G-tube twice per day on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Regular visits for imaging and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and periodically thereafter.

30 days initially, then periodically

What Are the Treatments Tested in This Trial?

Interventions

• Larotrectinib

Trial Overview The study tests larotrectinib's effectiveness on various advanced cancers in youth with a genetic change called an NTRK fusion. It examines if this drug can halt cancer growth by blocking enzymes needed for cell proliferation. The trial includes imaging tests like MRI and CT scans to monitor the disease.

How Is the Trial Designed?

Group I: Treatment (larotrectinib sulfate) Experimental Treatment 8 Interventions

Patients receive larotrectinib sulfate PO or via NG- or G-tube BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, MRI, an x-ray, bone scan, and/or MIBG scintigraphy during screening and on study. Patients also undergo bone marrow aspiration and/or biopsy during screening and may undergo blood sample collection on study.

Larotrectinib is already approved in United States, European Union for the following indications:

Approved in United States as Vitrakvi for:

• Solid tumors with NTRK gene fusions

Approved in European Union as Vitrakvi for:

• Solid tumors with NTRK gene fusions

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 (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]

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 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]

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 is a cost-effective treatment for patients with tropomyosin receptor kinase fusion-positive cancers in the Netherlands, showing an incremental cost-effectiveness ratio of €41,424 per quality-adjusted life year (QALY), which is below the €80,000/QALY threshold.

The analysis indicates that larotrectinib provides significant health benefits, resulting in an increase of 5.61 QALYs compared to standard care, with an 88% probability of being cost-effective at the established willingness-to-pay threshold.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Evaluation of a Tumour-Agnostic Therapy: Dutch Economic Value of Larotrectinib in TRK Fusion-Positive Cancers. Michels, RE., Arteaga, CH., Peters, ML., et al.[2022]

Larotrectinib, an FDA-approved treatment for certain cancers, is significantly affected by transporters like ABCB1 and ABCG2, which limit its oral availability and ability to penetrate the brain and testis, potentially impacting its therapeutic effectiveness.

The study found that the uptake transporter OATP1A/1B and the enzyme CYP3A also restrict larotrectinib's systemic exposure and oral availability, suggesting that understanding these mechanisms could enhance its clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OATP1A/1B, CYP3A, ABCB1, and ABCG2 limit oral availability of the NTRK inhibitor larotrectinib, while ABCB1 and ABCG2 also restrict its brain accumulation. Wang, Y., Sparidans, RW., Li, W., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02576431

NCT02576431 | A Study to Test the Effect of the Drug ... The primary objective of this study is to investigate the efficacy of larotrectinib for the treatment of advanced solid tumors harboring a fusion of ...

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

The potential long-term comparative effectiveness of ... CONCLUSIONS: Compared with standard of care in metastatic TRK wild-type cancers, larotrectinib is estimated to result in improved LY and QALY outcomes based on ...

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

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

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02122913

NCT02122913 | A Study to Test the Safety of ... The objectives of the study are to determine the safety, pharmacokinetic profile, recommended dose and efficacy of orally administered larotrectinib in patients ...

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

Outcomes of larotrectinib compared with real-world data ... Outcomes of larotrectinib compared with real-world data from non-TRK inhibitor therapies in patients with TRK fusion cancer: VICTORIA study.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11265530/

Larotrectinib Efficacy and Safety in Adult Patients With ... These results show that larotrectinib demonstrated significant activity in patients with TRK fusion cancer, regardless of tumor type, and was well-tolerated ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2059702925009792

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.

8. annalsofoncology.org annalsofoncology.org/article/S0923-7534(22)01120-6/fulltext

SO-31 Long-term efficacy and safety of larotrectinib in ... In this expanded dataset with longer follow-up, larotrectinib continues to demonstrate rapid, durable responses, extended survival and a favourable safety ...