Repotrectinib for Solid Tumors in Young Patients

Recruiting at94 trial locations

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Turning Point Therapeutics, Inc.

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: Neuroblastoma, Active infections, Cardiac issues, others

No Placebo Group

Breakthrough Therapy

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

Phase 1 will evaluate the safety and tolerability at different dose levels of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring anaplastic lymphoma kinase (ALK), receptor tyrosine kinase encoded by the gene ROS1 (ROS1), or neurotrophic receptor kinase genes encoding TRK kinase family (NTRK1-3) alterations to estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the Pediatric Recommended Phase 2 Dose (RP2D). Phase 2 will determine the anti-tumor activity of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring ROS1 or NTRK1-3 alterations.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot be treated with strong CYP3A4 inhibitors or inducers.

What data supports the idea that Repotrectinib for Solid Tumors in Young Patients is an effective drug?

The available research shows that Repotrectinib is effective for patients with certain types of cancer that have specific genetic changes. In a clinical trial, Repotrectinib helped patients who had previously stopped responding to other treatments. This suggests that Repotrectinib can be a good option for those who have developed resistance to earlier treatments. It is particularly effective against cancers with specific genetic mutations, making it a promising choice for patients with these conditions. ^{1 2 3 4 5}

What safety data is available for Repotrectinib in treating solid tumors?

Repotrectinib (also known as TPX-0005) is a next-generation tyrosine kinase inhibitor (TKI) that has shown promise in overcoming resistance due to acquired solvent-front mutations in ROS1, NTRK1-3, and ALK. Safety data for Repotrectinib comes from an ongoing first-in-human phase I/II trial, where it has achieved confirmed responses in patients with ROS1 or NTRK3 fusion-positive cancers who relapsed on earlier-generation TKIs. This suggests that Repotrectinib may be a safe and effective option for patients with these mutations, although detailed safety profiles and adverse events from this trial are not provided in the available abstracts. ^{2 4 6 7 8}

Is the drug Repotrectinib a promising treatment for solid tumors in young patients?

Yes, Repotrectinib is a promising drug for treating solid tumors in young patients. It is designed to target specific genetic changes in tumors, helping patients who have not responded to other treatments. It has shown positive results in early trials, making it a potential option for those with certain types of cancer. ^{1 2 5 9 10}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for young individuals with advanced or metastatic cancers like brain tumors, solid tumors, and lymphoma that have specific genetic changes (ALK, ROS1, NTRK1-3). They should have had prior treatments but be in stable condition. It's not for those with certain heart risks, active infections, severe neuropathy or gastrointestinal conditions affecting drug absorption.

Inclusion Criteria

My advanced solid tumor is NTRK fusion positive and I haven't taken TRK inhibitors.

My blood, kidney, and liver functions are all within normal ranges.

I am under 12 for Phase 1 or between 12-25 for Phase 2.

Exclusion Criteria

I have a condition like Crohn's disease that affects how my body absorbs drugs.

You have any important irregularities in your heart's electrical activity when at rest.

I am taking or might need strong medication that affects liver enzymes.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Evaluation of safety and tolerability at different dose levels of repotrectinib to estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the Pediatric Recommended Phase 2 Dose (RP2D)

28 days

Multiple visits for dose escalation and monitoring

Phase 2 Treatment

Determination of anti-tumor activity of repotrectinib in subjects with advanced or metastatic malignancies

2-3 years

Regular visits for treatment and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 3 years

Treatment Details

Interventions

• Repotrectinib (Tyrosine Kinase Inhibitor)

Trial Overview The study tests different doses of an oral drug called repotrectinib to find the safest and most effective amount for children and young adults. Phase 1 focuses on safety and finding the right dose; Phase 2 checks how well it works against their cancer.

Participant Groups

Group I: Repotrectinib (TPX-0005) Experimental Treatment 1 Intervention

Phase 1 Oral repotrectinib (TPX-0005): Safety and tolerability at different dose levels Phase 2 Oral repotrectinib (TPX-0005): 3 cohorts Cohort 1: TKI-naive NTRK fusion Cohort 2: Prior TKI NTRK fusion Cohort 3: ROS1 gene fusions or other ROS1 aberrations

Who Is Running the Clinical Trial?

Turning Point Therapeutics, Inc.

Lead Sponsor

Trials

10

Recruited

790+

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]

Repotrectinib (TPX-0005) is a next-generation tyrosine kinase inhibitor that effectively targets ROS1, TRKA-C, and ALK, showing promise in overcoming resistance caused by specific mutations in patients with these rearranged tumors.

In an ongoing phase I/II trial, repotrectinib demonstrated confirmed responses in patients with ROS1 or NTRK3 fusion-positive cancers who had previously relapsed on earlier-generation TKIs, indicating its potential as a new treatment option for resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Drilon, A., Ou, SI., Cho, BC., et al.[2022]

Entrectinib, a ROS1 tyrosine kinase inhibitor, showed a high objective response rate of 67.1% in 161 patients with ROS1 fusion-positive non-small-cell lung cancer (NSCLC), with a median duration of response of 15.7 months.

The treatment was also effective in patients with CNS metastases, achieving an intracranial objective response rate of 79.2%, indicating its potential to address brain involvement in this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. Dziadziuszko, R., Krebs, MG., De Braud, F., et al.[2022]

NTRK gene fusions are rare oncogenic drivers found in less than 5% of most tumors but are highly prevalent (over 80%) in specific rare tumors like infantile fibrosarcoma, leading to the approval of TRK inhibitors like larotrectinib and entrectinib for treatment.

Phase I/II trials have shown that TRK inhibitors are effective and well-tolerated in both children and adults with TRK fusion cancers, suggesting that these therapies should be considered for pediatric patients with advanced or metastatic tumors that have not responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Pediatric Patients. Perreault, S., Chami, R., Deyell, RJ., 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]

ROS1-rearranged non-small-cell lung cancer, which affects about 1-2% of patients, can be effectively treated with targeted therapies like crizotinib and entrectinib, showing high response rates of approximately 70-80% and manageable side effects.

Newer drugs like lorlatinib, along with next-generation TKIs such as repotrectinib and DS-6051b, show promise for treating ROS1-rearranged lung cancer, especially in cases resistant to earlier treatments, potentially improving long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cases of ROS1-rearranged lung cancer: when to use crizotinib, entrectinib, lorlatinib, and beyond? Sehgal, K., Piper-Vallillo, AJ., Viray, H., et al.[2020]

In a phase 1 study involving 41 pediatric patients with solid tumors, regorafenib was found to have a maximum tolerated dose (MTD) of 82 mg/m2, demonstrating acceptable safety with manageable side effects compared to adults.

Regorafenib showed preliminary antitumor activity, with one patient experiencing a partial response and 15 patients maintaining stable disease for over 16 weeks, indicating potential for further investigation in treating pediatric cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies. Geoerger, B., Morland, B., Jiménez, I., et al.[2021]

A total of 3120 adverse event cases related to avapritinib were reported to the FDA, with 44% occurring within the first 30 days of treatment, highlighting the importance of monitoring patients closely during this period.

The study found that elderly male patients are at a higher risk for serious adverse events, indicating that clinicians should exercise caution when prescribing avapritinib to this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. Rong, L., Xie, M., Jiang, M., et al.[2023]

NTRK alterations are found in about 1% of pediatric solid tumors, and early trials of NTRK inhibitors like larotrectinib show promising results for treating these cancers.

In a case study of two toddlers with NTRK fusion-positive cancers, adjuvant maintenance treatment with larotrectinib after surgery resulted in both children being alive, in remission, and tolerating the treatment well after 15 months, suggesting its potential effectiveness in preventing recurrences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Maintenance Larotrectinib Therapy in 2 Children With NTRK Fusion-positive High-grade Cancers. Carter-Febres, M., Schneller, N., Fair, D., 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]

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

Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. [2022]

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

Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small-Cell Lung Cancer. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Pediatric Patients. [2023]

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

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

6. China pubmed.ncbi.nlm.nih.gov

Cases of ROS1-rearranged lung cancer: when to use crizotinib, entrectinib, lorlatinib, and beyond? [2020]

7. England pubmed.ncbi.nlm.nih.gov

Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies. [2021]

8. England pubmed.ncbi.nlm.nih.gov

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. [2023]

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

Adjuvant Maintenance Larotrectinib Therapy in 2 Children With NTRK Fusion-positive High-grade Cancers. [2022]

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

Entrectinib: First Global Approval. [2020]