Repotrectinib for Solid Tumors in Young Patients

Recruiting at 108 trial locations

Overseen By First line of the email MUST contain the NCT# and Site #.

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Turning Point Therapeutics, Inc.

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: Neuroblastoma, Active infections, Cardiac issues, 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 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called repotrectinib (also known as Augtyro or TPX-0005) for young patients with advanced cancers that have specific genetic changes. The goal is to determine the safest dose and evaluate its effectiveness against tumors with alterations in genes like ROS1 and NTRK. Participants may qualify if they have a solid tumor with these genetic changes and face challenges in daily life due to their condition. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that repotrectinib is likely to be safe for humans?

Research has shown that repotrectinib has been tested in patients with certain gene changes, such as ALK, ROS1, and NTRK. In these studies, patients aged 12 and older generally tolerated repotrectinib well. The most common side effects included dizziness, tiredness, and nausea. Serious side effects were less common but did occur in some cases.

Repotrectinib is approved for use in certain conditions, indicating that its safety is somewhat established for those situations. However, its safety and effectiveness for children under 12 remain unknown. This trial aims to determine the safety of repotrectinib for younger patients with specific gene changes in their tumors. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Repotrectinib is unique because it targets genetic fusions involved in cancer growth, specifically NTRK and ROS1 gene fusions, with precision. Most existing treatments for solid tumors in young patients focus on broader approaches like chemotherapy or radiation. However, repotrectinib's mechanism of action as a tyrosine kinase inhibitor allows it to directly interfere with the signaling pathways that drive tumor growth. This targeted approach not only has the potential to be more effective but also might reduce side effects compared to traditional treatments. Researchers are excited about repotrectinib because it offers a new hope for patients who haven't responded to other therapies or who have specific genetic markers.

What evidence suggests that repotrectinib might be an effective treatment for solid tumors?

Studies have shown that repotrectinib can be effective for certain cancers, helping to shrink or eliminate tumors. This trial tests repotrectinib in young patients with solid tumors, focusing on those with specific genetic changes. For cancers with NTRK gene fusions, repotrectinib has been approved due to its effectiveness and lasting effects. Research also shows better outcomes for patients with ROS1-positive tumors. Overall, these findings suggest repotrectinib could help reduce tumors in young patients with these specific genetic changes. ^{3 5 6 7 8}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Repotrectinib

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.

How Is the Trial Designed?

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

Repotrectinib is already approved in United States for the following indications:

Approved in United States as Augtyro for:

• ROS1-positive non-small cell lung cancer (NSCLC)
• Solid tumors caused by certain abnormal NTRK genes

Who Is Running the Clinical Trial?

Turning Point Therapeutics, Inc.

Lead Sponsor

Trials

10

Recruited

790+

Published Research Related to This Trial

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 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, 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]

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]

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]

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]

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]

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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03093116

NCT03093116 | A Study of Repotrectinib (TPX-0005) in ... Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject ...

2. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-repotrectinib-adult-and-pediatric-patients-ntrk-gene-fusion-positive

FDA grants accelerated approval to repotrectinib for adult ... The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 as assessed by ...

3. augtyrohcp.com augtyrohcp.com/ntrk

NTRK Gene Fusion+ Solid Tumors - AUGTYRO® (repotrectinib) The major efficacy outcome measures were ORR and DOR according to RECIST v1. ... There are no data on the effects of AUGTYRO on healing of known fractures and ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05004116

NCT05004116 | A Study of Repotrectinib in Combination ... This study will test the safety of the study drug, repotrectinib, in combination with chemotherapy (irinotecan and temozolomide) in children and young adults

5. uspharmacist.com uspharmacist.com/article/study-explores-optimal-repotrectinib-dosing

Study Explores Optimal Repotrectinib Dosing The results demonstrated that the recommended dose of 160 mg QD/BID exhibited improved ORR and PFS compared with 160 mg QD in both ROS1-positive ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/218213s001lbl.pdf

augtyro - accessdata.fda.gov This includes data demonstrating that the exposure of repotrectinib in pediatric patients 12 years of age and older is expected to result in similar safety and ...

7. augtyro.com augtyro.com/

ROS1+ Non-Small Cell Lung Cancer & NTRK+ Cancer ... It is not known if AUGTYRO is safe and effective in children younger than 12 years of age with NTRK-positive solid tumors. 1 / ...

8. mayoclinic.org mayoclinic.org/drugs-supplements/repotrectinib-oral-route/description/drg-20559718

Repotrectinib (oral route) - Side effects & dosage For solid tumors: Adults and children 12 years of age and older—160 milligrams (mg) once a day for 14 days. Your doctor may adjust your dose ...