Larotrectinib for Advanced Cancer

Recruiting at 130 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

9 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II Pediatric MATCH trial studies how well larotrectinib works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with NTRK fusions that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and have come back (relapased) or does not respond to treatment (refractory). Larotrectinib may stop the growth of cancer 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 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.

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

Larotrectinib has shown a high response rate of 75% in patients with cancers that have a specific genetic feature called NTRK gene fusion, regardless of the type of cancer, age, or gender. ^{1 2 3 4 5}

Is larotrectinib safe for humans?

Larotrectinib has been studied for safety, with common side effects including dizziness and pain. No major long-term safety concerns have been identified, but continuous monitoring is recommended to detect any new side effects. ^{1 2 3 5 6}

What makes the drug Larotrectinib unique for treating advanced cancer?

Larotrectinib is unique because it specifically targets a genetic mutation called TRK fusion, which can occur in various types of cancer, making it effective across different cancer types regardless of the tumor's location in the body. This is different from traditional treatments that are usually specific to the cancer's location or type. ^{7 8 9 10 11}

Research Team

Katherine A Janeway

Principal Investigator

Children's Oncology Group

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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, 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]

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]

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 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]

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. England 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. [2022]

4. 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]

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

The Safety Profiles of Two First-Generation NTRK Inhibitors: Analysis of Individual Case Safety Reports from the FDA Adverse Event Reporting System (FAERS) Database. [2023]

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

Octreotide long-acting repeatable use among elderly patients with carcinoid syndrome and survival outcomes: a population-based analysis. [2023]

8. Italy pubmed.ncbi.nlm.nih.gov

Shortened interval of long-acting octreotide administration is effective in patients with well-differentiated neuroendocrine carcinomas in progression on standard doses. [2022]

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

Long-acting octreotide for the treatment and symptomatic relief of bowel obstruction in advanced ovarian cancer. [2013]

10. England pubmed.ncbi.nlm.nih.gov

Treatment of gastroenteropancreatic neuroendocrine tumours with octreotide LAR. [2019]

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

Final results of a phase 2A study for the treatment of metastatic neuroendocrine tumors with a fixed activity of 90Y-DOTA-D-Phe1-Tyr3 octreotide. [2016]