Larotrectinib for Advanced or Metastatic Cancer

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Tyrosine kinase inhibitors

Disqualifiers: Uncontrolled infection, Cardiovascular disease, 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: Unknown

Duration: 28 days per cycle

13 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests larotrectinib, a treatment designed to stop the growth of cancer cells in individuals with advanced or metastatic solid tumors that have a specific gene change called NTRK amplification. The goal is to evaluate larotrectinib's effectiveness in blocking enzymes that promote cancer cell growth. Suitable candidates for this trial have solid tumors that have spread, tested positive for NTRK gene changes, and have not responded to standard treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong CYP3A4 inhibitors or inducers before starting treatment. If you're on such medications, you may need to discuss alternatives with your doctor.

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 certain types of cancer. Studies have found that most people tolerate this drug well, and side effects are usually manageable. For instance, in patients with TRK fusion cancers who have not received prior treatment, larotrectinib has led to lasting improvements and longer survival while maintaining a good safety record. Long-term data confirm that larotrectinib continues to work quickly and effectively, with consistent safety over time. Although all medications can have side effects, evidence suggests that larotrectinib is safe for most patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Larotrectinib is unique because it specifically targets a genetic feature called a TRK fusion, found in various advanced or metastatic cancers. Unlike traditional chemotherapy or radiation that attacks rapidly dividing cells indiscriminately, larotrectinib focuses on this specific genetic anomaly, potentially leading to fewer side effects and more precise treatment. Researchers are excited about larotrectinib because it represents a shift towards personalized medicine, offering hope for patients whose cancers are driven by TRK fusions, regardless of the cancer's location in the body.

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

Research has shown that larotrectinib effectively treats cancers with specific genetic changes known as TRK fusions. In earlier studies, patients with TRK fusion-positive cancers experienced long-lasting responses and extended survival when treated with larotrectinib. The treatment is generally safe and well-tolerated. This trial will focus on NTRK gene amplifications, and positive results in similar cases suggest potential effectiveness. Overall, larotrectinib has successfully targeted and halted the growth of certain cancer cells. ^{1 2 3 6 7}

Who Is on the Research Team?

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults (16+) with solid tumors that have spread and show NTRK gene amplification. Participants must have tried standard treatments, or be unlikely to benefit from them, and should not have progressed on TRK inhibitors before. They need stable organ function, measurable tumor lesions, no uncontrolled infections or diseases, and agree to use two birth control methods.

Inclusion Criteria

I've had radiation or chemotherapy for my cancer, with radiation ending more than 12 weeks ago.

I've had standard treatment for my cancer or it's believed I won't benefit from it.

I agree to use two forms of birth control during and 3 months after the study.

Exclusion Criteria

I've previously had cancer treatment that didn't work, but stopped if it was intolerable within 28 days.

I haven't taken any cancer drugs or been in a trial for at least 2 weeks.

I do not have any uncontrolled infections or unstable heart conditions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive larotrectinib sulfate orally twice daily on days 1-28. Cycles repeat every 28 days in the absence of unacceptable toxicity.

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 4 weeks, and then every 3 months for 2 years.

2 years

Extension

Patients who experience disease progression and are deriving clinical benefit from larotrectinib may continue treatment per physician discretion.

What Are the Treatments Tested in This Trial?

Interventions

• Larotrectinib

Trial Overview The trial tests Larotrectinib's effectiveness in blocking enzymes needed for cell growth in patients with advanced solid tumors positive for NTRK gene amplification. It's a phase II study where all participants receive the same drug to see how well it works against their cancer.

How Is the Trial Designed?

Group I: Treatment (larotrectinib sulfate) Experimental Treatment 1 Intervention

Patients receive larotrectinib sulfate PO BID on days 1-28. Cycles repeat every 28 days in the absence of unacceptable toxicity. Patients who experience disease progression and are deriving clinical benefit from larotrectinib may continue treatment per physician discretion.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

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]

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 (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 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]

Citations

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

The potential long-term comparative effectiveness of ... The tyrosine receptor kinase (TRK) inhibitor larotrectinib demonstrated improvements in life expectancy and health utility in patients with TRK fusion–positive ...

2. 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 ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12151180/

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.

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

NCT02122913 | A Study to Test the Safety of ... This research study is done to test the safety of the drug larotrectinib in adult cancer patients. The drug may be used to treat cancer with a change in a ...

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

Outcomes of larotrectinib compared with real-world data ... Results: In total,164 pts with TRK fusion cancer were matched (82 in each cohort). Balance in the baseline covariates was achieved after ...

6. 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.

7. 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 ...