Larotrectinib for Brain Cancer

(CONNECT1903 Trial)

Recruiting at 17 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

Trial Summary

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.

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

Larotrectinib has shown a high response rate of 75% in patients with TRK fusion-positive cancers, regardless of the type of cancer, age, or gender. It is approved for treating TRK fusion-positive tumors, including those in the central nervous system, which suggests its potential effectiveness for brain cancer. ^{1 2 3 4 5}

Is larotrectinib safe for use in humans?

Larotrectinib has been evaluated for safety, with common side effects including dizziness and pain. No major long-term safety concerns have been identified, and it has a favorable risk-benefit profile, but continuous monitoring is recommended. ^{1 2 3 6 7}

What makes the drug Larotrectinib unique for treating brain cancer?

Larotrectinib is unique because it is a highly selective TRK inhibitor that targets cancers with NTRK gene fusions, regardless of the cancer type, making it a tumor-agnostic therapy. This means it can be used for various cancers, including brain cancer, if they have this specific genetic feature. ^{1 2 3 5 8}

What is the purpose of this trial?

This is a pilot study that will evaluate disease status in children that have been newly diagnosed high-grade glioma with TRK fusion. The evaluation will occur after 2 cycles of the medication (Larotrectinib) have been given. The study will also evaluate the safety of larotrectinib when given with chemotherapy in your children; as well as the safety larotrectinib when given post-focal radiation therapy.

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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, 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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. [2022]

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

Larotrectinib: First Global Approval. [2020]

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

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

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

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

5. 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]

6. 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]

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. 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]