Entrectinib for Solid Tumors

(STARTRK-2 Trial)

Recruiting at 189 trial locations

Overseen By Reference Study ID Number: GO40782 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Hoffmann-La Roche

Must not be taking: Trk, ROS1, ALK inhibitors

Disqualifiers: Congestive heart failure, QTc, 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 months

534 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, multicenter, global Phase 2 basket study of entrectinib (RXDX-101) for the treatment of patients with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene fusion. Patients will be assigned to different baskets according to tumor type and gene fusion.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require a break of at least 2 weeks or 5 half-lives after prior chemotherapy or targeted therapy, and 4 weeks after antibody therapy. You should discuss your specific 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 or 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 (a kidney function marker), muscle pain, swelling, vomiting, joint pain, anemia (low red blood cell count), and increased AST (a liver enzyme). ^{2 3 4 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 adults with advanced solid tumors that have specific gene rearrangements (NTRK1/2/3, ROS1, or ALK). Participants must have measurable disease, may include those with brain involvement if controlled. They should be past certain treatments by at least 2 weeks and have good organ function. People can't join if they've had certain other cancers, bone disorders, heart failure recently, severe neuropathy, active infections or are in another clinical trial.

Inclusion Criteria

My cancer can be measured or seen on tests.

Other protocol specified criteria

I finished my radiotherapy more than 14 days ago.

Exclusion Criteria

I have been treated with specific inhibitors for my cancer due to certain gene changes.

I have a family or personal history of bone disorders.

I am still recovering from a recent surgery.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral entrectinib (RXDX-101) for the treatment of solid tumors with specific gene fusions

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Long-term follow-up

Participants are monitored for overall survival and progression-free survival

36 months

Treatment Details

Interventions

• Entrectinib

Trial Overview The study tests Entrectinib's effectiveness on various tumor types with NTRK1/2/3, ROS1 or ALK gene fusions. It's a global Phase 2 trial where patients are grouped based on their tumor type and genetic changes to receive the open-label drug Entrectinib.

Participant Groups

Group I: ROS1-rearranged other solid tumor Experimental Treatment 1 Intervention

Oral entrectinib (RXDX-101)

Group II: ROS1-rearranged mCRC Experimental Treatment 1 Intervention

Oral entrectinib (RXDX-101)

Group III: ROS1-rearranged NSCLC Experimental Treatment 1 Intervention

Oral entrectinib (RXDX-101)

Group IV: NTRK1/2/3-rearranged other solid tumor Experimental Treatment 1 Intervention

Oral entrectinib (RXDX-101)

Group V: NTRK1/2/3-rearranged NSCLC Experimental Treatment 1 Intervention

Oral entrectinib (RXDX-101)

Group VI: NTRK/1/2/3-rearranged mCRC Experimental Treatment 1 Intervention

Oral entrectinib (RXDX-101)

Group VII: ALK-rearranged other solid tumor Experimental Treatment 1 Intervention

Oral entrectinib (RXDX-101)

Group VIII: ALK-rearranged mCRC Experimental Treatment 1 Intervention

Oral entrectinib (RXDX-101)

Group IX: ALK- or ROS1-rearranged NSCLC Experimental Treatment 1 Intervention

with CNS-only progression previously treated with crizotinib (NOTE: The ALK-rearranged portion of this arm is now closed to enrollment.) 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 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]

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]

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]

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]

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: First Global Approval. [2020]

3. 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]

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

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

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

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

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. England pubmed.ncbi.nlm.nih.gov

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

10. 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]

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. 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]