Entrectinib for Solid Tumors

(STARTRK-NG Trial)

Not currently recruiting at 58 trial locations

Overseen By Reference Study ID Number: CO40778 https://forpatients.roche.com/

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Hoffmann-La Roche

Must not be taking: Enzyme inducing antiepileptics

Disqualifiers: Congenital long QT, Heart failure, Infections, Bone disorders, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests entrectinib, a drug targeting specific gene fusions, in children with hard-to-treat solid tumors. It aims to determine if entrectinib can benefit patients whose tumors have gene changes like NTRK1/2/3 or ROS1 fusions, which can promote cancer growth. The trial targets children with relapsed or stubborn tumors, particularly those affecting the brain or other body parts, that have not responded to other treatments. Participants must have a diagnosis of these specific gene fusions and have previously tried other treatments without success. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on Enzyme Inducing Antiepileptic Drugs (EIAEDs) within 14 days of starting the trial. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatment is likely to be safe?

Research has shown that entrectinib is generally safe for children with certain types of tumors. It acts quickly and effectively on tumors with specific gene changes, such as NTRK or ROS1 fusions. Studies also find that most patients tolerate entrectinib well, with side effects usually being manageable. Common side effects include fatigue, dizziness, or changes in taste. These findings reassure that entrectinib is safe for tumors with these genetic markers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about entrectinib for treating solid tumors because it uniquely targets specific genetic alterations within tumors, such as NTRK, ROS1, and ALK gene fusions. Unlike traditional chemotherapy, which attacks rapidly dividing cells indiscriminately, entrectinib precisely targets these genetic drivers, potentially leading to more effective treatment with fewer side effects. Moreover, entrectinib is administered orally, making it more convenient compared to intravenous therapies. This precision and ease of administration make entrectinib a promising option for personalized cancer treatment.

What evidence suggests that entrectinib could be an effective treatment for solid tumors?

Studies have shown that entrectinib can quickly and effectively help children with solid tumors that have specific genetic changes, such as NTRK or ROS1 fusions. One analysis revealed that 57.4% of patients with these genetic changes experienced tumor shrinkage, indicating positive results for more than half of the participants. In this trial, participants with CNS tumors, extracranial solid tumors, and neuroblastoma will receive entrectinib to evaluate its effectiveness. Entrectinib has proven effective in treating both brain tumors and other solid tumors outside the brain. For neuroblastoma, a type of cancer that develops in nerve tissue, entrectinib significantly slowed tumor growth in animal studies. Overall, these findings suggest that entrectinib works well against tumors with certain genetic markers. ^{1 2 6 7 8}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

This trial is for children and adolescents with advanced or metastatic solid tumors or primary CNS tumors that have specific gene fusions (NTRK1/2/3 or ROS1) and no satisfactory treatment options. They must have a certain level of physical function, recovered from previous treatments, adequate organ function, not be pregnant or breastfeeding, and agree to use contraception.

Inclusion Criteria

Participants must have measurable or evaluable disease, as defined by RANO for Phase 2 portion Part B

Participants must have archival tumor tissue from diagnosis or relapse

My cancer can be measured or evaluated by specific medical criteria.

Exclusion Criteria

I do not have any severe health or mental conditions that could worsen by joining this study.

I have a family or personal history of bone disorders or weak bones.

I have not taken any seizure medications that affect enzymes in the last 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Dose escalation study in pediatric patients with relapsed or refractory extracranial solid tumors

6 months

Phase 2 Treatment

Expansion cohorts in patients with primary brain tumors and extracranial solid tumors harboring NTRK1/2/3 or ROS1 gene fusions

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Entrectinib

Trial Overview Entrectinib is being tested in this study which includes two phases: Phase 1 focuses on dose escalation in patients with relapsed/refractory extracranial solid tumors; Phase 2 expands to include those with brain tumors harboring specific gene fusions. The goal is to determine the appropriate dosage and assess its effectiveness.

How Is the Trial Designed?

Group I: CNS tumors harboring- NTRK1/2/3, ROS1, ALK Active Control 1 Intervention

Arm closed for further enrollment molecular alterations, including gene fusions Oral entrectinib (RXDX-101)

Group II: Extracranial solid tumors harboring NTRK1/2/3, Active Control 1 Intervention

Arm closed for further enrollment ROS1, ALK non-gene fusion molecular alterations Oral entrectinib (RXDX-101)

Group III: Non-neuroblastoma, extracranial solid tumors Active Control 1 Intervention

Arm closed for further enrollment harboring - NTRK1/2/3, ROS1, ALK gene fusions Oral entrectinib (RXDX-101)

Group IV: Neuroblastoma Active Control 1 Intervention

Arm closed for further enrollment Oral entrectinib (RXDX-101)

Group V: Any participant unable to swallow capsules Active Control 1 Intervention

Arm closed for further enrollment Any participant who otherwise meet all other eligibility criteria Oral entrectinib (RXDX-101)

Group VI: Expansion: CNS tumors harboring NTRK1/2/3, ROS1 Active Control 1 Intervention

gene fusions Oral entrectinib (RXDX-101)

Group VII: Expansion: Extracranial solid tumors harboring NTRK1/2/3, ROS1 Active Control 1 Intervention

NTRK 1,2,3 and ROS1 fusions Oral entrectinib (RXDX-101)

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?

Hoffmann-La Roche

Lead 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

Published Research Related to This Trial

Lazertinib, a new EGFR tyrosine kinase inhibitor, is being tested as a first-line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutations and brain metastases, with a total of 75 patients participating in this phase II trial.

The trial aims to evaluate lazertinib's efficacy in improving progression-free survival and intracranial progression-free survival, potentially offering better outcomes than existing treatments due to its higher selectivity and ability to penetrate the blood-brain barrier.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of lazertinib for symptomatic or asymptomatic brain metastases in treatment-naive patients with advanced EGFR mutation-positive non-small cell lung cancer: Protocol of an open-label, single-arm phase II trial. Lee, B., Ji, W., Lee, JC., et al.[2023]

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]

In vitro studies identified the BRAF G469A mutation as a key mechanism of acquired resistance to osimertinib in non-small cell lung cancer cells, indicating that this mutation allows cancer cells to continue growing despite treatment.

Treatment with selumetinib and trametinib was effective in restoring sensitivity to osimertinib and increasing cell death in resistant clones, suggesting potential strategies to overcome resistance in patients with this mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acquired BRAF G469A Mutation as a Resistance Mechanism to First-Line Osimertinib Treatment in NSCLC Cell Lines Harboring an EGFR Exon 19 Deletion. La Monica, S., Minari, R., Cretella, D., et al.[2022]

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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40086048/

Efficacy and safety of entrectinib in children with ... Integrated data from three trials confirm entrectinib induces rapid and durable responses in children with NTRK or ROS1 fusion-positive tumours.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0959804925000899

Efficacy and safety of entrectinib in children with ... Integrated data from three trials confirm entrectinib induces rapid and durable responses in children with NTRK or ROS1 fusion-positive tumours.

3. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK601790/

Clinical Review - Entrectinib (Rozlytrek) - NCBI Bookshelf - NIH Entrectinib is indicated for the treatment of adult patients who have unresectable, locally advanced or metastatic extracranial solid tumours (including brain ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.10050

Updated efficacy and safety of entrectinib in children with ... Entrectinib is a TRK and ROS1 inhibitor that has shown rapid and durable responses in children with NTRK1/2/3 or ROS1 fusion-positive (fp) extracranial solid ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02568267

NCT02568267 | Basket Study of Entrectinib (RXDX-101) ... Efficacy and safety of entrectinib in children with extracranial solid or central nervous system (CNS) tumours harbouring NTRK or ROS1 fusions. Eur J Cancer.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/212725s011lbl.pdf

212725s011lbl.pdf - accessdata.fda.gov The safety of ROZLYTREK was evaluated was evaluated in pediatric patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(23)02689-3/fulltext

666P Updated efficacy and safety data of entrectinib in ... Updated efficacy and safety data of entrectinib in patients (pts) with locally advanced/metastatic NTRK fusion-positive (fp) solid tumours.

8. gene.com gene.com/medical-professionals/medicines/rozlytrek

Rozlytrek® (entrectinib) - Information for Healthcare ... entrectinib. Full Prescribing Information. Safety Data Sheets (3 SDS) ... solid tumors that: have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion ...