Larotrectinib for TRK Fusion Cancers and Acute Leukemia

Recruiting at 86 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Oncology Group

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Breastfeeding, High grade gliomas, 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: Up to 24 months

31 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the side effects and how well larotrectinib works in treating patients with previously untreated TRK fusion solid tumors and TRK fusion acute leukemia that has come back. Larotrectinib may stop the growth of cancer cells with TRK fusions by blocking the TRK enzymes needed for cell growth.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop all current medications, but certain medications are not allowed. You cannot take other anti-cancer agents, strong CYP3A4 inducers or inhibitors, or medications to prevent graft-versus-host disease. If you are on corticosteroids for leukemia, you can continue them until 24 hours before starting the trial treatment.

What data supports the effectiveness of the drug Larotrectinib for TRK fusion cancers?

Larotrectinib has shown significant effectiveness in treating TRK fusion-positive cancers in both children and adults, as demonstrated in clinical trials. It works by targeting specific genetic changes in cancer cells, leading to tumor shrinkage and control of the disease. ^{1 2 3 4 5}

Is larotrectinib safe for use in humans?

Larotrectinib has shown a favorable safety profile in clinical trials for TRK fusion-positive cancers, with common side effects including dizziness and pain. Long-term safety data suggests no major concerns, but continuous monitoring is recommended. ^{1 3 4 6 7}

What makes the drug Larotrectinib unique for treating TRK fusion cancers and acute leukemia?

Larotrectinib is unique because it is an oral drug specifically designed to target and inhibit TRK proteins, which are involved in the growth of cancers with NTRK gene fusions. This makes it effective across various cancer types, regardless of the patient's age or gender, and it has shown a high response rate in patients with these specific genetic mutations. ^{1 3 8 9 10}

Research Team

Theodore W Laetsch

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for patients under 30 with untreated TRK fusion solid tumors or relapsed acute leukemia. They must have no prior cancer treatment except surgery, meet blood and organ function criteria, not be pregnant or breastfeeding, able to swallow capsules or have gastric access, and not on certain medications.

Inclusion Criteria

I am 30 years old or younger.

My seizures are well controlled and I've been on the same medication for at least 14 days.

My leukemia has come back or didn't respond to treatment, and tests show NTRK fusion.

Exclusion Criteria

You have had an organ transplant in the past.

I am taking medication to prevent rejection after a bone marrow transplant.

Patients currently receiving another investigational drug

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive larotrectinib orally or by nasogastric or gastric tube twice daily on days 1-28. Treatment repeats every 28 days for up to 26 cycles.

Up to 24 months

Monthly visits for each cycle

Surgical Resection

Patients whose tumors shrink sufficiently may undergo surgical resection of their tumor while on study.

Follow-up

Participants are monitored for safety and effectiveness after treatment completion at 3, 6, 12, 18, 24, 30, 36, and 48 months and annually thereafter for up to 5 years.

Up to 5 years

Treatment Details

Interventions

• Larotrectinib

Trial Overview The study tests Larotrectinib's effectiveness in blocking TRK enzymes to stop cancer cell growth in those with specific genetic markers (NTRK1, NTRK2, NTRK3 fusions). It includes young patients who haven't tried other treatments and whose disease has measurable indicators of progress.

Participant Groups

Group I: Treatment (larotrectinib) Experimental Treatment 1 Intervention

Patients receive larotrectinib PO or by NG or G-tube BID on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity, or complete surgical resection of tumor.

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?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

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 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 (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 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

Antitumor activity of larotrectinib in tumors harboring NTRK&#160;gene fusions: a short review on the current evidence. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers. [2022]

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

Larotrectinib: First Global Approval. [2020]

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

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. [2022]

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

Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. [2022]

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

Larotrectinib OK'd for Cancers with TRK Fusions. [2019]

7. 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]

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

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

9. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. [2022]