Entrectinib for Solid Tumors

(STARTRK-NG Trial)

Recruiting at 54 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

69 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, Phase 1/2 multicenter dose escalation study in pediatric patients with relapsed or refractory extracranial solid tumors (Phase 1), with additional expansion cohorts (Phase 2) in patients with primary brain tumors harboring NTRK1/2/3 or ROS1 gene fusions, and extracranial solid tumors harboring NTRK1/2/3 or ROS1 gene fusions.

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.

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

Entrectinib has been shown to be effective in treating solid tumors with specific genetic changes (NTRK and ROS1 gene fusions) and is approved for use in both adults and children. It has demonstrated meaningful and lasting responses in patients, including those with cancer that has spread to the brain. ^{1 2 3 4 5}

Is Entrectinib safe for humans?

Entrectinib, also known as Rozlytrek, is generally well tolerated in humans, with a manageable safety profile. Common side effects include changes in taste, tiredness, dizziness, constipation, diarrhea, nausea, weight gain, tingling sensations, increased creatinine levels, muscle pain, swelling, vomiting, joint pain, anemia, and increased liver enzymes. ^{2 4 5 6 7}

How is the drug Entrectinib unique for treating solid tumors?

Entrectinib is unique because it targets specific genetic changes in tumors, known as NTRK, ROS1, and ALK gene fusions, which are not commonly targeted by other treatments. This makes it a personalized treatment option for patients with these specific genetic alterations in their solid tumors. ^{8 9 10 11 12}

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

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

Participants must have measurable or evaluable disease, as defined by RECIST v1.1 for Phase 2 portion Part D

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

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

Treatment Details

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.

Participant Groups

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

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 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]

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]

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]

References

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

Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors. [2022]

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

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

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

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

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]

6. England pubmed.ncbi.nlm.nih.gov

The European Medicines Agency review of entrectinib for the treatment of adult or paediatric patients with solid tumours who have a neurotrophic tyrosine receptor kinase gene fusions and adult patients with non-small-cell lung cancer harbouring ROS1 rearrangements. [2021]

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

Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. [2022]

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

MUC1-C Is a Common Driver of Acquired Osimertinib Resistance in NSCLC. [2023]

9. Singapore 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. [2023]

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

EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer. [2022]

11. France 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. [2022]

12. Ireland pubmed.ncbi.nlm.nih.gov

High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from the phase 2 multicenter POSITION20 trial. [2022]