Entrectinib for Solid Tumors

(STARTRK-2 Trial)

Not currently recruiting at 216 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests entrectinib, an oral medication, to evaluate its effectiveness for people with solid tumors that have specific gene changes, such as NTRK1/2/3, ROS1, or ALK fusions. Participants will be grouped by tumor type and gene change. This trial suits those with advanced solid tumors featuring these genetic fusions, especially if they have previously tried other cancer treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that entrectinib is generally safe for patients. Studies indicate that its side effects are usually mild or manageable. For instance, in patients with certain solid tumors with NTRK gene changes, entrectinib proved safe. Similarly, in patients with ROS1-positive non-small cell lung cancer, entrectinib was well-tolerated. These findings suggest that entrectinib is a safe treatment option for solid tumors with specific gene changes. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for solid tumors often rely on chemotherapy or targeted therapies that may not address specific genetic rearrangements. Entrectinib is unique because it specifically targets tumors with genetic rearrangements in ROS1, NTRK1/2/3, and ALK. This precision allows for a more tailored approach, potentially leading to better outcomes with fewer side effects. Researchers are excited about entrectinib because it can cross the blood-brain barrier, which might make it effective against tumors that have spread to the brain, a common challenge with other treatments.

What evidence suggests that this trial's treatments could be effective for solid tumors?

Research has shown that entrectinib effectively treats solid tumors with specific gene changes, such as ROS1, NTRK, and ALK. In this trial, participants will join different treatment arms based on these gene rearrangements. For patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC), entrectinib provided a lasting response, with effects averaging 13 months. In tumors with NTRK gene changes, entrectinib was very effective, with 59% of patients experiencing significant tumor shrinkage. For tumors with ALK gene changes, 57% of patients responded well to the treatment. These findings suggest that entrectinib offers significant benefits in managing these specific types of solid tumors. ^{4 6 7 8 9}

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 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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5380583/

Combined Results from Two Phase 1 Trials (ALKA-372-001 ... In seven ALK-rearranged solid tumors, the ORR was 57% (95% CI: 25, 84), and responses were observed in ALK-rearranged NSCLC, renal cell carcinoma, and ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02568267

NCT02568267 | Basket Study of Entrectinib (RXDX-101) ... 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 ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0753332222003638

Entrectinib, a new multi-target inhibitor for cancer therapy The current research results show that entrectinib is safe and well-tolerated, and has good clinical effects on locally advanced or metastatic solid tumors that ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/28/7/1302/682220/Updated-Integrated-Analysis-of-the-Efficacy-and

Updated Integrated Analysis of the Efficacy and Safety of ... With additional clinical experience, entrectinib treatment continues to achieve high ORR (61.2%) and sustained responses (median DoR 20.0 months) in patients ...

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2019/212725Orig1s000,%20212726Orig1s000MultidisciplineR.pdf

Multi-Discipline Review - accessdata.fda.gov ... solid tumors. Conclusions on the Substantial Evidence of Effectiveness. In the opinion of the review team, the submitted evidence meets the ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33871816/

Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ ... Entrectinib was generally well tolerated, with a manageable safety profile. Thus, entrectinib expands the range of treatment options for ...

7. 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 ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0169500223009807

Updated efficacy and safety of entrectinib in NTRK fusion ... Entrectinib had a manageable safety profile in patients with NTRK-fp NSCLC. •. Data confirm that entrectinib is a relevant drug for patients with NTRK-fp NSCLC.

9. nature.com nature.com/articles/s41591-024-03008-4

Entrectinib in ROS1-positive advanced non-small cell lung ... We present efficacy and safety data from Cohort D of BFAST, an evaluation of entrectinib in treatment-naive patients with ROS1-positive NSCLC ...