Entrectinib for Brain Tumors

Overseen By Daniel Moreira, MD, MEd

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Enzyme-inducing antiepileptics

Disqualifiers: Congestive heart failure, uncontrolled infection, 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: 24 cycles (approximately 24 months)

52 Participants Needed

Trial Summary

What is the purpose of this trial?

This clinical trial tests how well entrectinib works to treat patients less than 3 years of age with NTRK 1/2/3 or ROS1 fused, high grade glioma or other central nervous system (CNS) tumors.

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

The trial requires that participants not be on enzyme-inducing antiepileptic drugs (EIAEDs) and not have had any prior cancer therapy, including chemotherapy, targeted therapy, immunotherapy, cellular therapy, or radiation. If you are on these medications, you may need to stop them to participate.

What data supports the effectiveness of the drug Entrectinib (Rozlytrek) for brain tumors?

Entrectinib has shown effectiveness in treating solid tumors with specific genetic changes (NTRK and ROS1 fusions) and has been particularly effective in patients with brain metastases (cancer spread to the brain). It is approved for use in both adults and children with these genetic changes, indicating its potential to treat brain tumors with similar characteristics. ^{1 2 3 4 5}

Is Entrectinib safe for humans?

Entrectinib, also known as Rozlytrek, has been generally well tolerated in clinical trials for various solid tumors, including those in the brain. It has a manageable safety profile, meaning that while some side effects may occur, they can usually be controlled or treated. ^{1 2 3 4 5}

What makes the drug Entrectinib unique for treating brain tumors?

Entrectinib is unique because it is an oral medication that can penetrate the central nervous system (CNS) and targets specific genetic changes (NTRK, ROS1, and ALK gene fusions) in tumors, making it effective for brain tumors with these genetic features, especially in patients with existing or potential CNS metastases. ^{1 2 3 4 5}

Research Team

Daniel Moreira, MD, MEd

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children under 3 with high-grade glioma or other CNS tumors that have specific genetic markers (NTRK1/2/3 or ROS1). To join, they must not have had previous treatments and should be able to undergo MRI scans. Children with certain health conditions or taking drugs that interfere with entrectinib are excluded.

Inclusion Criteria

COHORT 1: AST and ALT ≤2.5x the upper limit of normal (ULN)

COHORT 1: Bilirubin ≤ 1.5 x ULN

My new brain tumor is located above the cerebellum.

Exclusion Criteria

I do not have any stomach or intestine problems that affect how drugs are absorbed.

COHORT 1 AND 2: Clinically significant medical disorder that could compromise the ability to tolerate study therapy or would interfere with the study procedures or results history

I have previously undergone chemotherapy or radiotherapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive entrectinib enterally once daily on days 1-28 of each cycle. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

24 cycles (approximately 24 months)

Surgical Intervention

A gross total resection or significant debulking may become possible if a response to entrectinib is seen. If surgical resection is performed and a gross total resection is achieved, 24 cycles of entrectinib will be completed, including those before and after surgery.

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up continues for 5 years to assess long-term outcomes such as progression-free survival and overall survival.

5 years

Treatment Details

Interventions

• Entrectinib

Trial Overview The trial is testing the effectiveness of entrectinib alone in young children with particular brain tumors. It's an early study to see how well this drug works as a first treatment option before trying surgery or chemotherapy like Carboplatin, Etoposide, Cyclophosphamide, and supportive care drugs Pegfilgrastim and G-CSF.

Participant Groups

Group I: Entrectinib therapy, Cohort 1 and Cohort 2 Experimental Treatment 7 Interventions

Cohort 1: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused high-grade glioma (HGG) will receive therapy as outline in Detailed Description. Cohort 2: Patients who are younger than 3 years of age diagnosed with NTRK1/2/3- or ROS1-fused CNS tumors other than HGG will receive therapy as outline in Detailed Description.

Entrectinib is already approved in United States, European Union, Japan for the following indications:

Approved in United States as Rozlytrek for:

• Metastatic non-small cell lung cancer (mNSCLC) with a neurotrophic receptor tyrosine kinase (NTRK) gene fusion
• Solid tumors with a NTRK gene fusion

Approved in European Union as Rozlytrek for:

• Solid tumours with a NTRK gene fusion
• Metastatic non-small cell lung cancer (NSCLC) with a NTRK gene fusion

Approved in Japan as Rozlytrek for:

• Solid tumours with a NTRK gene fusion

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Hoffmann-La Roche

Industry Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Findings from Research

Entrectinib is an effective treatment for adults and pediatric patients with NTRK fusion-positive solid tumors and ROS1 fusion-positive non-small-cell lung cancer, showing durable responses even in patients with CNS metastases.

The drug has a manageable safety profile, making it a valuable option for patients with advanced cancers, particularly those at risk for or already having brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC. Frampton, JE.[2022]

Entrectinib shows significant efficacy in treating ROS1 fusion-positive non-small cell lung cancer (NSCLC), with a 68% objective response rate and a median overall survival of 47.8 months in treatment-naïve patients, based on a study of 168 patients with a median follow-up of 29.1 months.

In patients with CNS-only progression after crizotinib, entrectinib demonstrated modest activity, with an intracranial objective response rate of 14%, indicating limited effectiveness in this specific group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion-Positive NSCLC. Drilon, A., Chiu, CH., Fan, Y., et al.[2022]

Entrectinib demonstrated a 57.7% objective response rate in pediatric patients with solid tumors that have NTRK or ROS1 fusions, indicating its efficacy in this specific group.

The treatment was generally well-tolerated, although some patients experienced dose-limiting toxicities, with weight gain being the most common side effect (48.8%) and 20.9% experiencing bone fractures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Desai, AV., Robinson, GW., Gauvain, K., et al.[2023]

Entrectinib is an oral medication that selectively inhibits certain tyrosine kinases associated with specific gene fusions (NTRK and ROS1), showing promise for treating various solid tumors, including those in the central nervous system.

In June 2019, entrectinib received its first global approval in Japan for treating advanced or recurrent solid tumors with NTRK fusions, and it is also under review for ROS1-positive non-small cell lung cancer, indicating its potential as a targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entrectinib: First Global Approval. Al-Salama, ZT., Keam, SJ.[2020]

Entrectinib is a potent and selective inhibitor for treating ROS1-positive non-small cell lung cancer and NTRK gene fusion-positive solid tumors, with pharmacokinetics characterized in a study of 276 cancer patients.

The study developed a robust population pharmacokinetic model showing linear absorption and elimination for entrectinib and its active metabolite M5, which will support its use in clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of entrectinib in pediatric and adult patients with advanced/metastatic solid tumors: support of new drug application submission. González-Sales, M., Djebli, N., Meneses-Lorente, G., et al.[2021]

References

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

Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC. [2022]

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

Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion-Positive NSCLC. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). [2023]

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

Entrectinib: First Global Approval. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of entrectinib in pediatric and adult patients with advanced/metastatic solid tumors: support of new drug application submission. [2021]