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

Trial Summary

What is the purpose of this trial?

This phase II trial studies the effect of larotrectinib in treating patients with NTRK gene amplification positive solid tumors that have spread to nearby tissues or lymph nodes (locally advanced) or other places in the body (metastatic). Larotrectinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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.

What data supports the effectiveness of the drug Larotrectinib for advanced or metastatic cancer?

Larotrectinib has shown a high response rate of 75% in patients with TRK fusion-positive cancers, meaning it works well for many people with this specific genetic feature in their cancer, regardless of the type of cancer, age, or gender. ^{1 2 3 4 5}

How is the drug Larotrectinib unique for treating advanced or metastatic cancer?

Larotrectinib is unique because it is a 'tumor-agnostic' drug, meaning it targets a specific genetic feature (NTRK gene fusions) found in various types of cancer, rather than being specific to one type of cancer. It is taken orally and is effective regardless of the patient's age or gender, offering a new option for those with these specific genetic mutations. ^{1 2 4 5 6}

Research Team

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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.

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 (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 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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Larotrectinib: First Global Approval. [2020]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Economic Evaluation of a Tumour-Agnostic Therapy: Dutch Economic Value of Larotrectinib in TRK Fusion-Positive Cancers. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

A Tumor-Agnostic NTRK (TRK) Inhibitor. [2020]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Rifampin and ritonavir increase oral availability and elacridar enhances overall exposure and brain accumulation of the NTRK inhibitor larotrectinib. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Estimating Long-Term Survival Outcomes for Tumor-Agnostic Therapies: Larotrectinib Case Study. [2022]