Repotrectinib for Solid Tumors

(TRIDENT-1 Trial)

Recruiting at 396 trial locations

Overseen By Scott Moerdler, M.D.

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

Trial Summary

What is the purpose of this trial?

Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction. Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. The secondary objective will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

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.

What data supports the effectiveness of the drug Repotrectinib (TPX-0005) for solid tumors?

Research shows that Repotrectinib is effective in treating cancers with specific genetic changes, like ROS1, ALK, and NTRK mutations, especially when other treatments stop working. It has shown strong antitumor effects in neuroblastoma and lung cancer models, even overcoming certain resistance mutations. ^{1 2 3 4 5}

Is Repotrectinib safe for human use?

Repotrectinib has been tested in early-phase clinical trials and has shown confirmed responses in patients with certain types of cancer, indicating it is generally safe for human use. However, as with any medication, there may be side effects, and its safety profile is still being evaluated in ongoing studies. ^{1 3 4 6 7}

What makes the drug Repotrectinib unique for treating solid tumors?

Repotrectinib is a next-generation drug that targets specific mutations in cancer cells, making it effective against tumors that have become resistant to earlier treatments. It is particularly potent against mutations in ROS1, TRK, and ALK genes, which are common in certain types of cancer, and it can overcome resistance caused by these mutations, offering a new option for patients who have relapsed on other therapies. ^{2 3 4 5 7}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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-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]

References

1. United States 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. [2021]

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

Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front-Mutant ROS1-Rearranged Non-Small Cell Lung Cancer. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Repotrectinib (TPX-0005), effectively reduces growth of ALK driven neuroblastoma cells. [2021]

4. 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]

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

Repotrectinib Overcomes F2004V Resistance Mutation in ROS1-Rearranged NSCLC: A Case Report. [2023]

6. 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]

7. China pubmed.ncbi.nlm.nih.gov

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