Larotrectinib for Solid Cancers

(NAVIGATE Trial)

No longer recruiting at 185 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well the drug larotrectinib treats various solid cancers with specific genetic changes in the NTRK genes. Larotrectinib aims to block these gene changes to halt cancer growth. It suits individuals with solid tumor cancer that has spread and not responded to standard treatments. Participants should have these specific gene changes in their cancer and have exhausted typical treatment options without success. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that larotrectinib is generally safe for individuals with TRK fusion-positive solid tumors. Most experience only mild side effects, such as tiredness, dizziness, and nausea, while serious side effects remain rare.

One study found that larotrectinib is safe for individuals with various tumors linked to NTRK gene fusions. The FDA has approved this treatment for other conditions, which supports its safety in humans.

Although this trial is in an early stage, current evidence suggests that larotrectinib is a promising and manageable option for many patients. It is important to discuss with a doctor what joining a trial could mean. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for cancer?

Larotrectinib is unique because it specifically targets NTRK gene fusions, which are abnormal connections between genes that can drive cancer growth. Most cancer treatments, like chemotherapy or radiation, attack rapidly dividing cells in general, but larotrectinib zeroes in on these specific genetic abnormalities. This precision allows it to potentially be more effective and cause fewer side effects compared to standard treatments. Researchers are excited because this targeted approach could provide new hope for patients with various solid tumors that have NTRK fusions, offering a more personalized and potentially more effective treatment option.

What evidence suggests that this trial's treatments could be effective for solid cancers?

Research has shown that larotrectinib effectively treats cancers with NTRK gene fusions. Studies have demonstrated that larotrectinib produces strong and lasting effects against tumors in patients of all ages and cancer types. The drug blocks the activity of NTRK genes, which often promote cancer growth. Many patients with TRK fusion–positive cancers experienced significant tumor shrinkage. The U.S. FDA fully approved larotrectinib due to its proven tumor-fighting ability. Overall, this treatment has shown promising results in targeting specific genetic changes in cancer cells. Participants in this trial will receive larotrectinib to evaluate its effectiveness across various solid tumor types with NTRK fusions. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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 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, 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 (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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02576431

NCT02576431 | A Study to Test the Effect of the Drug ... Allowed conditions may include, but are not limited to in situ cancers of cervix, breast, or skin, superficial bladder cancer, limited-stage prostate cancer, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5857389/

Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in ... Larotrectinib had marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or of the tumor type.

3. bayer.com bayer.com/en/us/news-stories/approval-of-vitrakvi

U.S. FDA Grants Full Approval of VITRAKVI® (larotrectinib ... ... NTRK gene fusion-positive cancers. This milestone reinforces Bayer's ... In in vitro and in vivo tumor models, VITRAKVI demonstrated anti-tumor ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02122913

NCT02122913 | A Study to Test the Safety of ... This research study is done to test the safety of the drug larotrectinib in adult cancer patients. The drug may be used to treat cancer with a change in a ...

5. esmoopen.com esmoopen.com/article/S2059-7029(25)00979-2/fulltext

Efficacy and safety of larotrectinib as first-line treatment for ... Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours ... Efficacy of larotrectinib in TRK fusion-positive cancers ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32105622/

Larotrectinib in patients with TRK fusion-positive solid tumours Interpretation: These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active.

7. vitrakvi-us.com vitrakvi-us.com/

VITRAKVI® (larotrectinib) | Official Patient Website VITRAKVI can work in a variety of tumor types as long as the tumor is caused by an NTRK gene fusion ... solid tumors (cancer) that: are caused by certain ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0959804925001194

Efficacy and safety of larotrectinib in patients with TRK ... NTRK gene fusions occur with varying frequencies from up to 90 % in rare cancers (e.g., secretory breast carcinoma and infantile fibrosarcoma), ...