Larotrectinib for Solid Cancers

(NAVIGATE Trial)

Recruiting at 143 trial locations

Overseen By Bayer Clinical Trials Contact

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Bayer

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Uncontrolled infection, Unstable cardiovascular, HIV, 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: Up to 120 months

215 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests how well larotrectinib works for children and adults with advanced solid tumors that have specific gene changes. The drug blocks the actions of these genes to stop cancer growth.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take strong CYP3A4 inhibitors or inducers. If you are on such medications, you may need to stop them before starting the trial.

What data supports the effectiveness of the drug Larotrectinib for solid cancers?

Larotrectinib has shown a high response rate of 75% and strong anticancer activity in patients with TRK fusion-positive cancers, regardless of the type of cancer, age, or gender. ^{1 2 3 4 5}

What makes the drug Larotrectinib unique for treating solid cancers?

Larotrectinib is unique because it is an oral drug specifically designed to target and inhibit tropomyosin receptor kinase (Trk) proteins, which are involved in cancer growth when they have a specific genetic change called NTRK gene fusion. This makes it effective across different types of solid tumors, regardless of the patient's age or gender, as long as the tumors have this genetic feature. ^{1 2 3 4 6}

Eligibility Criteria

This trial is for adults and children with solid tumors that have a specific gene change (NTRK1, NTRK2 or NTRK3). Participants must have tried standard treatments without success or be unlikely to benefit from them. They need at least one measurable tumor lesion, stable organ function, and no uncontrolled illnesses. People with certain infections or recent heart issues can't join.

Inclusion Criteria

I've had standard treatments for my cancer or there are no good options left for me.

I have a brain tumor, treated before, with stable symptoms and measurable disease.

I can take care of myself but can't do any physical work or I have a brain tumor and can still do some daily activities.

Exclusion Criteria

Known or suspected hypersensitivity to the active substance or any IMP ingredients

I haven't taken any cancer drugs or been in a trial for 2 weeks.

My cancer progressed despite TRK inhibitor treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive larotrectinib for the treatment of advanced solid tumors with NTRK fusions

Up to 120 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Larotrectinib

Trial Overview The study tests larotrectinib's effectiveness on cancers with an NTRK gene fusion. Larotrectinib aims to block these genes in cancer cells to treat the disease. The trial includes patients who've had prior treatments like chemotherapy or radiation.

Participant Groups

Group I: Arm 9_Solid tumors without confirmed NTRK fusion Experimental Treatment 1 Intervention

Patients eligible for arms 1 to 8, but with documented NTRK fusion from a laboratory where CLIA or equivalent certification cannot be confirmed by the sponsor at the time of consent (arm closed)

Group II: Arm 8_Other tumors Experimental Treatment 1 Intervention

Patients with e.g. kidney cancer, squamous cell cancer of head or neck or ovarian solid tumors harboring NTRK fusions (arm closed)

Group III: Arm 7_Primary CNS Experimental Treatment 1 Intervention

Patients with solid tumors in the primary central nervous system (CNS) harboring NTRK fusions (arm closed)

Group IV: Arm 6_Biliary Experimental Treatment 1 Intervention

Patients with solid biliary tumors harboring NTRK fusions (arm closed)

Group V: Arm 5_Salivary Experimental Treatment 1 Intervention

Patients with solid salivary tumors harboring NTRK fusions (arm closed)

Group VI: Arm 4_Colorectal Experimental Treatment 1 Intervention

Patients with solid colorectal tumors harboring NTRK fusions (arm closed)

Group VII: Arm 3_Sarcoma Experimental Treatment 1 Intervention

Patients with soft-tissue sarcoma harboring NTRK fusions (arm closed)

Group VIII: Arm 2_Thyroid Experimental Treatment 1 Intervention

Patients with solid thyroid tumors harboring NTRK fusions (arm closed)

Group IX: Arm 1_NSCLC Experimental Treatment 1 Intervention

Patients with solid non-small cell lung cancer (NSCLC) harboring NTRK fusions (arm closed)

Group X: Arm 11_Bone health cohort Experimental Treatment 1 Intervention

Patients with all tumor types harboring NTRK fusions, not eligible for the main prospective cohort, including patients with non-measurable disease

Group XI: Arm 10_Prospective cohort Experimental Treatment 1 Intervention

Patients with melanoma, non secretory breast and colorectal cancer or other tumor types harboring NTRK fusions, except soft tissue sarcoma, salivary gland and thyroid cancer (arm closed)

Larotrectinib is already approved in United States, European Union for the following indications:

Approved in United States as Vitrakvi for:

• Solid tumors with NTRK gene fusions

Approved in European Union as Vitrakvi for:

• Solid tumors with NTRK gene fusions

Who Is Running the Clinical Trial?

Bayer

Lead Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

Findings from Research

Larotrectinib (VITRAKVI®) is a targeted therapy specifically designed to inhibit tropomyosin receptor kinases (TRK) in patients with cancers that have neurotrophic receptor tyrosine kinase (NTRK) gene fusions, making it a promising option for both adults and children.

Approved in November 2018 in the USA, larotrectinib is indicated for metastatic solid tumors with NTRK gene fusions when no other satisfactory treatments are available, highlighting its role as a critical option for patients with limited alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Larotrectinib: First Global Approval. Scott, LJ.[2020]

Larotrectinib (VITRAKVI) is a highly effective treatment for patients with Trk fusion-positive cancers, showing a remarkable response rate of 75% regardless of cancer type, age, or gender.

The study developed a new LC-MS/MS method for accurately measuring Larotrectinib levels and assessing its metabolic stability, revealing a moderate extraction ratio and a half-life of approximately 48.8 minutes in human liver microsomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry. Attwa, MW., Kadi, AA., Darwish, HW.[2022]

Elacridar significantly increases the oral availability and brain penetration of larotrectinib, suggesting it could enhance the drug's therapeutic effects in treating NTRK fusion-positive cancers.

Both rifampin and ritonavir also improve the systemic exposure of larotrectinib, indicating that these drugs can be used to optimize larotrectinib's effectiveness by inhibiting specific transporters and enzymes involved in its metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rifampin and ritonavir increase oral availability and elacridar enhances overall exposure and brain accumulation of the NTRK inhibitor larotrectinib. Wang, Y., Sparidans, RW., Wang, J., et al.[2022]

Larotrectinib, an FDA-approved treatment for certain cancers, is significantly affected by transporters like ABCB1 and ABCG2, which limit its oral availability and ability to penetrate the brain and testis, potentially impacting its therapeutic effectiveness.

The study found that the uptake transporter OATP1A/1B and the enzyme CYP3A also restrict larotrectinib's systemic exposure and oral availability, suggesting that understanding these mechanisms could enhance its clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OATP1A/1B, CYP3A, ABCB1, and ABCG2 limit oral availability of the NTRK inhibitor larotrectinib, while ABCB1 and ABCG2 also restrict its brain accumulation. Wang, Y., Sparidans, RW., Li, W., et al.[2022]

Larotrectinib is a small-molecule kinase inhibitor specifically designed to target NTRK fusions found in various cancers, showcasing its potential effectiveness across multiple tumor types.

It is the first treatment to receive FDA approval as 'tumor-agnostic,' meaning its use is based on specific genetic markers rather than the location of the cancer, highlighting a significant advancement in personalized medicine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Tumor-Agnostic NTRK (TRK) Inhibitor. Huang, FW., Feng, FY.[2020]

Larotrectinib shows promising efficacy for treating solid tumors with NTRK gene fusions, with a 12-month progression-free survival (PFS) rate of 66.6% consistent between 2018 predictions and 2020 observed data from 102 patients across 15 tumor types.

While long-term PFS predictions varied due to differences in tumor responses, the overall survival (OS) predictions were reliable, with a 48-month OS rate of 67.2% aligning closely with observed data, indicating larotrectinib's potential for sustained effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimating Long-Term Survival Outcomes for Tumor-Agnostic Therapies: Larotrectinib Case Study. Briggs, A., Paracha, N., Rosettie, K., et al.[2022]

References

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

Larotrectinib: First Global Approval. [2020]

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

Metabolic Stability Assessment of Larotrectinib Using Liquid Chromatography Tandem Mass Spectrometry. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Rifampin and ritonavir increase oral availability and elacridar enhances overall exposure and brain accumulation of the NTRK inhibitor larotrectinib. [2022]

4. England pubmed.ncbi.nlm.nih.gov

OATP1A/1B, CYP3A, ABCB1, and ABCG2 limit oral availability of the NTRK inhibitor larotrectinib, while ABCB1 and ABCG2 also restrict its brain accumulation. [2022]

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

A Tumor-Agnostic NTRK (TRK) Inhibitor. [2020]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Estimating Long-Term Survival Outcomes for Tumor-Agnostic Therapies: Larotrectinib Case Study. [2022]