Larotrectinib for Brain Cancer

(CONNECT1903 Trial)

Recruiting at 23 trial locations

Overseen By Kelsey H Troyer, PhD

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Nationwide Children's Hospital

Must not be taking: Investigational drugs, Anti-cancer agents, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Infection, Organ transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 8 weeks

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of Larotrectinib for treating brain cancer in children, specifically targeting high-grade glioma with a genetic change called TRK fusion. Participants will receive Larotrectinib either before surgery or with chemotherapy, and researchers aim to observe the cancer's response after two treatment cycles. Children with a recent diagnosis of high-grade glioma with TRK fusion, who have not previously undergone chemotherapy, might be eligible for this trial. As an Early Phase 1 trial, this research seeks to understand how Larotrectinib works in children, offering participants the opportunity to be among the first to receive this treatment.

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

The trial requires that you avoid strong CYP3A4 inhibitors or inducers (medications that affect how drugs are processed in the body) from 7 days before joining the study until the end. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

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

Research shows that larotrectinib is usually well-tolerated by patients with TRK fusion-positive cancers, including those affecting the brain. Studies have found that it has a good safety record, with most people not experiencing serious side effects. Some adults with these cancers have taken the drug and lived longer with minimal side effects. In these studies, many patients experienced tumor shrinkage, indicating that the drug is effective.

For children with TRK fusion-positive central nervous system (CNS) tumors, research has shown quick and lasting improvements, suggesting the drug's long-term effectiveness. Although the trial you might join is in its early stages, these findings offer reassurance about the treatment's safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for brain cancer, such as surgery, radiation, and chemotherapy, Larotrectinib targets a specific genetic feature called TRK fusion, which is found in some tumors. This targeted approach allows Larotrectinib to attack cancer cells more precisely, potentially leading to fewer side effects and better outcomes. Researchers are excited because this precision could mean a more effective treatment with a quicker response, offering new hope for patients with TRK fusion-positive brain tumors.

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

Research has shown that larotrectinib effectively treats various cancers with TRK fusions, including brain tumors. In patients with TRK fusion-positive brain tumors, larotrectinib quickly and effectively controlled the disease, with many tumors shrinking significantly. One study found that 75% of patients experienced a noticeable reduction in tumor size. This treatment targets and blocks the TRK fusion proteins that help tumors grow. In this trial, participants in the Feasibility Cohort will receive larotrectinib on a 28-day cycle schedule, while those in the Surgical Cohort will receive larotrectinib before surgery and continue on the same cycle schedule. Although specific data on brain cancer is limited, the positive results in other TRK fusion cancers suggest it could also be effective for aggressive brain tumors like high-grade gliomas. ^{1 2 3 5 6}

Who Is on the Research Team?

Susan Chi, MD

Principal Investigator

Dana Farber/ Boston Children's Cancer and Blood Disorders Center

Maryam Fouladi, MD

Principal Investigator

Nationwide Children's Hospital

Are You a Good Fit for This Trial?

This trial is for children up to 21 years old with a specific type of brain tumor called high-grade glioma that has NTRK fusion. They must not have had cancer treatment before and should be healthy enough for chemotherapy or radiation, based on certain medical criteria. Pregnant individuals or those who've taken other experimental drugs are excluded.

Inclusion Criteria

I have a spinal tumor and am receiving chemotherapy or targeted radiation, but not full spine radiation.

I have DIPG or HGG and am only receiving chemotherapy, with no plans for craniospinal radiation.

My high-grade brain tumor has a specific genetic change called NTRK fusion.

Exclusion Criteria

Pregnant or breast-feeding women

I am currently taking or have taken cancer treatment drugs.

Patients who have previously received or are currently receiving another investigational drug

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 2 cycles of larotrectinib monotherapy, each cycle lasting 28 days

8 weeks

Maintenance Therapy

Participants with CCR or CR continue to receive larotrectinib monotherapy for a total of 12 cycles

24 weeks

Combination Therapy

Participants ≤ 48 months with PR or SD receive combination therapy with standard backbone chemotherapy or focal radiation therapy

Varies

Surgical Cycle

Participants in the surgical cohort receive larotrectinib pre-surgery for 3-5 days, followed by definitive surgery

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 months

What Are the Treatments Tested in This Trial?

Interventions

• Larotrectinib
• Larotrectinib surgical

Trial Overview The study tests Larotrectinib's effects after two cycles in treating newly-diagnosed high-grade gliomas with NTRK fusion in children. It examines the drug's safety alongside chemotherapy and after focal radiation therapy.

How Is the Trial Designed?

Group I: Surgical Cohort Experimental Treatment 2 Interventions

Larotrectinib administered PO, BID @100 mg/m2 3-5 days prior to definitive surgery, followed by Larotrectinib administered PO, BID @100 mg/m2 on a 28-day cycle schedule.

Group II: Feasibility Cohort Experimental Treatment 1 Intervention

Larotrectinib administered PO, BID @100 mg/m2 on a 28-day cycle schedule.

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?

Nationwide Children's Hospital

Lead Sponsor

Trials

354

Recruited

5,228,000+

Published Research Related to This Trial

Larotrectinib showed a 30% objective response rate in 33 patients with TRK fusion-positive primary CNS tumors, indicating its efficacy in this specific cancer type.

The treatment demonstrated a high disease control rate of 73% and favorable safety profile, with only 3 patients experiencing severe adverse events, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Doz, F., van Tilburg, CM., Geoerger, B., 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 (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]

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, 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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9159442/

Efficacy and safety of larotrectinib in TRK fusion-positive ... One prior case report demonstrated activity of larotrectinib in a child with a high-grade glioma harboring an NTRK gene fusion, but there is otherwise a paucity ...

2. braintumor.org braintumor.org/news/new-fda-approval-uses-genetic-mutation-not-tumor-site-to-guide-treatment/

New FDA Approval Uses Genetic Mutation, Not Tumor Site, ... Thus, there is little data from these three trials that speak to the potential efficacy of Vitrakvi specifically in brain tumor patients.

3. 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 ...

4. cancer.gov cancer.gov/news-events/cancer-currents-blog/2018/larotrectinib-effective-across-cancer-types

Targeted Therapy Larotrectinib Shows Promise in Early Trials Larotrectinib was shown to be highly effective at either shrinking tumors or keeping them from progressing, often for long periods.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.3141

Larotrectinib long-term efficacy and safety in adult patients ... Larotrectinib continues to demonstrate rapid and durable responses, extended survival, and a favorable safety profile in adults with TRK fusion cancer.

6. nejm.org nejm.org/doi/full/10.1056/NEJMoa1714448

Efficacy of Larotrectinib in TRK Fusion–Positive Cancers ... Larotrectinib had marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or of the tumor type.