Repotrectinib for Solid Tumors

(TRIDENT-1 Trial)

Recruiting at 358 trial locations

Overseen By Katherine Scilla, Site 2133

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Turning Point Therapeutics, Inc.

Disqualifiers: Symptomatic brain metastases, Cardiovascular disease, Active infections, 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

500 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests repotrectinib (TPX-0005), a new treatment for advanced solid tumors with specific gene changes, such as ROS1 or NTRK rearrangements. The main goal is to determine the right dose and evaluate its effectiveness against these tumors. Individuals with advanced solid tumors featuring these gene changes, who can safely take the medication, might be suitable candidates for the trial. 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.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that you cannot participate in another therapeutic clinical trial at the same time, and certain heart medications might be a concern due to potential heart-related side effects.

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

Research has shown that repotrectinib was tested in 426 patients with ROS1-positive non-small cell lung cancer (NSCLC) and other solid tumors. In these studies, most patients tolerated the treatment well. Common side effects included dizziness, fatigue, and nausea, which were generally manageable.

Serious side effects were rare but possible. These studies help doctors understand the safety and effectiveness of a treatment. Since repotrectinib is already used for similar conditions, this offers some reassurance about its safety. However, treatments can affect individuals differently, so staying informed and consulting a healthcare provider is crucial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Repotrectinib is unique because it's designed to tackle solid tumors with specific genetic markers, like ROS1 and NTRK fusions, in a way that existing treatments may not fully address. Unlike standard options that often involve chemotherapy or older tyrosine kinase inhibitors (TKIs), repotrectinib is a next-generation TKI that works by targeting these specific genetic abnormalities more precisely. Researchers are excited about its potential to be more effective in patients who have become resistant to previous treatments, offering hope for those with limited options. Additionally, its oral administration makes it more convenient compared to some traditional therapies.

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

Research shows that repotrectinib holds promise for treating advanced solid tumors with specific gene changes. In patients with ROS1-positive non-small cell lung cancer (NSCLC), repotrectinib has demonstrated long-lasting effectiveness, including activity in the brain. Studies have found improvements in patient response and the duration of that response. This trial tests repotrectinib as a treatment option for advanced ROS1-positive NSCLC and NTRK-positive solid tumors. These findings suggest that repotrectinib may effectively target and manage these specific cancer types. ^{2 4 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?

Adults with advanced solid tumors that have specific gene rearrangements (ALK, ROS1, NTRK1-3) can join this trial. They should have at least one measurable tumor and a life expectancy of over 3 months. Prior cancer treatments are okay if side effects are minimal now. People with certain heart conditions, active infections, significant lung disease or recent major surgery cannot participate.

Inclusion Criteria

My cancer is advanced and tests show specific gene changes.

I can swallow pills without breaking them.

All side effects from my previous cancer treatments, except for hair loss, are mild or gone.

Exclusion Criteria

I have had cancer before, but it was either skin cancer treated successfully or another type that was completely removed and didn’t need treatment in the last 2 years.

I do not have moderate or severe numbness, tingling, or pain in my hands or feet.

I haven't had radiation therapy (except for bone pain relief) in the last 2 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Phase 1 dose escalation to determine dose-limiting toxicities, maximum tolerated dose, and recommended Phase 2 dose of repotrectinib

4 weeks

Multiple visits for dose escalation and monitoring

Phase 2 Treatment

Phase 2 to determine the confirmed Overall Response Rate (ORR) and other secondary outcomes in expansion cohorts

Approximately 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 (TPX-0005)

Trial Overview The study is testing the safety and effectiveness of an oral drug called repotrectinib in two phases: first to find the safest dose and then to see how well it works against tumors. It also looks into how repotrectinib affects another drug's breakdown in the body.

How Is the Trial Designed?

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

Phase 1 Oral repotrectinib (TPX-0005): Phase 1a dose escalation, Phase 1b food-effect sub-study, and Phase 1c dose escalation with food, and Midazolam drug-drug interaction sub-study. Phase 2 Oral repotrectinib (TPX-0005): 6 distinct expansion cohorts * EXP-1: ROS1 TKI-naïve ROS1+ NSCLC * EXP-2: 1 Prior ROS1 TKI and 1 Platinum based chemo ROS1+ NSCLC * EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) * EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) * EXP-5: TRK TKI-naïve NTRK+ solid tumors * EXP-6: TRK TKI-pretreated NTRK+ solid tumors

Repotrectinib (TPX-0005) is already approved in United States for the following indications:

Approved in United States as Augtyro for:

• Locally advanced or metastatic ROS1-positive non-small cell lung cancer

Who Is Running the Clinical Trial?

Turning Point Therapeutics, Inc.

Lead Sponsor

Trials

10

Recruited

790+

Zai Lab (Shanghai) Co., Ltd.

Industry Sponsor

Trials

30

Recruited

3,800+

Published Research Related to This Trial

Repotrectinib, a third-generation ALK inhibitor, effectively inhibits the signaling of various ALK mutant variants found in neuroblastoma, suggesting its potential as a targeted therapy for this cancer.

In preclinical studies, repotrectinib demonstrated strong antitumor effects in a neuroblastoma xenograft model, indicating promising efficacy for treating neuroblastoma in patients with ALK aberrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells. Cervantes-Madrid, D., Szydzik, J., Lind, DE., et al.[2021]

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]

ROS1 tyrosine kinase inhibitors (TKIs) are effective for treating advanced ROS1-positive non-small cell lung cancer (NSCLC), but resistance often develops, necessitating new treatment options.

In a patient with NSCLC who had developed the F2004V mutation after failing treatment with entrectinib and crizotinib, the next-generation TKI repotrectinib successfully led to a disease response, demonstrating its effectiveness against this specific resistance mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repotrectinib Overcomes F2004V Resistance Mutation in ROS1-Rearranged NSCLC: A Case Report. Pizzutilo, EG., Agostara, AG., Roazzi, L., 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]

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]

Three novel RET fusion-positive lung cancer cell lines were developed, showing different sensitivities to RET inhibitors, which can help understand patient variability in treatment responses.

The study revealed that while CUTO42 cells were effectively inhibited by the RET inhibitor BLU-667, CUTO32 cells were resistant, suggesting the need for alternative therapies for certain RET+ patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Human-Derived RET Fusion NSCLC Cell Lines Have Heterogeneous Responses to RET Inhibitors and Differential Regulation of Downstream Signaling. Schubert, L., Le, AT., Estrada-Bernal, A., et al.[2021]

Repotrectinib, a next-generation ROS1 tyrosine kinase inhibitor, demonstrated strong antitumor activity in both treatment-naïve and ROS1G2032R mutation models, outperforming crizotinib and other available treatments in preclinical studies.

Repotrectinib effectively penetrated the blood-brain barrier, showing significant activity against brain metastases, and delayed tumor recurrence after treatment withdrawal, indicating its potential as a first-line therapy and after progression from other ROS1 TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer. Yun, MR., Kim, DH., Kim, SY., et al.[2023]

Citations

1. augtyrohcp.com augtyrohcp.com/ros1

AUGTYRO® (repotrectinib) for ROS1+ NSCLC | HCP Website The major efficacy outcome measures were ORR and DOR (assessed by BICR per RECIST v1. ... AUGTYRO was assessed in 426 patients with ROS1+ NSCLC and other solid ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11623886/

a promising new therapy for advanced nonsmall cell lung ... This study reveals the efficacy of repotrectinib, in regular clinical use with increased survival rates and tolerability outcomes, which significantly advocates ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03093116

NCT03093116 | A Study of Repotrectinib (TPX-0005) in ... A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1). ClinicalTrials.gov ID ...

4. onclive.com onclive.com/view/repotrectinib-demonstrates-durable-efficacy-in-tki-naive-and--pretreated-ros1-nsclc

Repotrectinib Demonstrates Durable Efficacy in TKI-Naive ... Repotrectinib (Augtyro) showcased durable efficacy and intracranial activity in patients with ROS1-positive non–small cell lung cancer ...

5. news.bms.com news.bms.com/news/details/2024/Bristol-Myers-Squibb-Receives-Positive-CHMP-Opinion-for-Repotrectinib-for-the-Treatment-of-Advanced-ROS1-Positive-Non-Small-Cell-Lung-Cancer-and-Advanced-NTRK-Positive-Solid-Tumors/default.aspx

Bristol Myers Squibb Receives Positive CHMP Opinion for ... Repotrectinib has the potential to be a best-in-class treatment for patients with advanced ROS1 -positive non-small cell lung cancer in the European Union.

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

augtyro - accessdata.fda.gov The pooled safety population described in WARNINGS AND PRECAUTIONS and below reflects exposure to AUGTYRO in 426 patients with ROS1-positive NSCLC (n=320), ...

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 with ROS1-positive NSCLC or in children younger than 12 years of age with NTRK-positive solid ...

8. ema.europa.eu ema.europa.eu/en/medicines/human/EPAR/augtyro

Augtyro | European Medicines Agency (EMA) In an ongoing main study, 323 adults with advanced ROS1-positive NSCLC and 120 adults with advanced solid tumors with NTRK gene fusion were ...