NVL-520 for ROS1-Positive Solid Tumors

Recruiting at 64 trial locations

Overseen By Nuvalent

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Nuvalent Inc.

Disqualifiers: Other oncogenic drivers, Allergy, Major surgery, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

359 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests NVL-520, a new drug, for safety and effectiveness in patients with advanced ROS1-positive cancers. It targets those who haven't responded well to other treatments by blocking a protein that helps cancer cells grow. NVL-520 is being tested for its effectiveness in treating advanced ROS1-positive cancers, a targetable mutation in non-small cell lung cancer (NSCLC) that has seen various treatments like crizotinib and entrectinib.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, it does mention that ongoing anticancer therapy is an exclusion criterion, which might imply that you need to stop such treatments before joining.

What makes the drug NVL-520 unique for treating ROS1-positive solid tumors?

NVL-520 (Zidesamtinib) is unique because it is designed to target ROS1-positive tumors, potentially offering a new option for patients who have developed resistance to existing treatments like crizotinib, which is a common issue. This drug may provide an alternative for patients with specific mutations that make other treatments less effective. ^{1 2 3 4 5}

What data supports the effectiveness of the drug NVL-520, Zidesamtinib for ROS1-Positive Solid Tumors?

Research on similar drugs like crizotinib and lorlatinib, which target ROS1-positive tumors, shows they can be effective in treating certain types of lung cancer by slowing tumor growth and improving patient outcomes. This suggests that NVL-520, Zidesamtinib might also be effective for ROS1-positive solid tumors. ^{1 3 6 7 8}

Who Is on the Research Team?

Vivek Upadhyay, MD, MBI

Principal Investigator

Nuvalent Inc.

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors, especially non-small cell lung cancer (NSCLC), that have a specific genetic change called ROS1 rearrangement. Patients should have tried other cancer treatments unless they're in one special group. They need to be healthy enough overall and not currently on another clinical study or recent major surgery.

Inclusion Criteria

I am 12 years or older and weigh more than 40 kg.

My advanced cancer has a confirmed ROS1 rearrangement.

My organs and bone marrow are functioning well.

Exclusion Criteria

My cancer is driven by a specific genetic change, not ROS1.

I am allergic to ingredients in NVL-520.

Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Determine the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) of NVL-520 in patients with advanced ROS1-positive solid tumors

Approximately 4-8 weeks

Phase 2 Expansion

Evaluate the objective response rate (ORR) and other secondary outcomes such as duration of response (DOR), progression-free survival (PFS), and overall survival (OS) in patients with advanced ROS1-positive NSCLC and other solid tumors

2-3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 3 years

What Are the Treatments Tested in This Trial?

Interventions

• NVL-520

Trial Overview NVL-520 is being tested to see how safe it is and what dose works best against these cancers. The first phase figures out the right dose; the second checks how well it shrinks tumors using independent reviews, also looking at survival times and other health benefits.

How Is the Trial Designed?

Group I: Phase 1 dose escalation Experimental Treatment 1 Intervention

NVL-520 oral daily dosing

Group II: Cohort 2e Experimental Treatment 1 Intervention

ROS1+ solid tumor and progressed on any prior therapy

Group III: Cohort 2d Experimental Treatment 1 Intervention

ROS1+ NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy

Group IV: Cohort 2c Experimental Treatment 1 Intervention

ROS1+ NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy

Group V: Cohort 2b Experimental Treatment 1 Intervention

ROS1+ NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy

Group VI: Cohort 2a Experimental Treatment 1 Intervention

ROS1+ NSCLC naïve to TKI therapy and up to 1 prior chemotherapy and/or immunotherapy

Who Is Running the Clinical Trial?

Nuvalent Inc.

Lead Sponsor

Trials

6

Recruited

1,400+

Published Research Related to This Trial

ROS1 fusion events occur in 1%-2% of non-small-cell lung cancer (NSCLC) patients and are associated with specific patient demographics, including younger individuals, women, and non-smokers, indicating a distinct molecular subtype of NSCLC.

Crizotinib is the only approved treatment for ROS1-rearranged NSCLC, showing significant benefits in progression-free survival and quality of life, and is recommended as the standard first-line therapy for patients with this genetic alteration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective. Bebb, DG., Agulnik, J., Albadine, R., et al.[2023]

In a study of 80 patients with advanced ROS1+ non-small-cell lung cancer (NSCLC), lorlatinib demonstrated a median progression-free survival of 7.1 months and an overall survival of 19.6 months, indicating its efficacy as a treatment option.

The treatment showed a high central nervous system response rate of 72% and an overall response rate of 45%, with a manageable safety profile, as 13% of patients discontinued due to toxicity, consistent with previous studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study. Girard, N., Galland-Girodet, S., Avrillon, V., et al.[2022]

ROS1 translocations occur in 1-2% of all non-small cell lung cancer (NSCLC) cases and 3-6% of pulmonary adenocarcinoma cases, and can be detected using in situ hybridization techniques.

Treatment with the ROS1 inhibitor crizotinib shows a high response rate of 70-80% and a median progression-free survival of about 19 months, indicating that targeted therapy is effective and generally well tolerated for patients with ROS1-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[ROS1-Translocations in Non-Small Cell Lung Cancer]. Warth, A., Weichert, W., Reck, M., et al.[2016]

In a study of 21 patients with ROS1-rearranged non-small cell lung cancer (NSCLC) treated with crizotinib from 2014 to 2020, crizotinib demonstrated good tolerability and effectiveness, although outcomes were lower than those seen in clinical trials.

The study highlighted the importance of timely initiation of crizotinib therapy, as delays in treatment, especially in patients with brain metastases, were associated with poorer clinical responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Management and Outcomes of Crizotinib-Treated ROS1-Rearranged NSCLC: A Retrospective Canadian Cohort. Gibson, AJW., Box, A., Cheung, WY., et al.[2022]

A patient with ROS1-rearranged non-small cell lung cancer (NSCLC) showed a good response to lorlatinib after failing immune-chemotherapy, suggesting that lorlatinib may be a more effective second-line treatment for similar patients.

Monitoring immune factors during treatment revealed that increased PD-L1 expression in tumor tissue could predict limited benefits from immune-chemotherapy, highlighting the importance of assessing the tumor immune microenvironment for better treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term response to immune-chemotherapy and immune features of a ceritinib-resistant patient with ROS1-rearranged lung adenocarcinoma. Yue, D., Qian, J., Chen, Z., et al.[2022]

In a study of 208 never-smoking patients with lung adenocarcinoma, 3.4% had ROS1 rearrangements, which were associated with a significantly higher objective response rate (60.0%) and longer progression-free survival when treated with pemetrexed compared to those without ROS1/ALK rearrangements.

The findings suggest that ROS1 rearrangements are more common in selected patients than previously thought, indicating that testing for ROS1 can help identify patients who may benefit from targeted therapies, especially in East-Asian populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma. Kim, HR., Lim, SM., Kim, HJ., et al.[2020]

DS-6051b is a new selective inhibitor that shows significant effectiveness against ROS1- or NTRK-rearranged cancers, including those resistant to crizotinib due to mutations like ROS1-G2032R.

In preclinical models, DS-6051b demonstrated strong growth inhibition in both wild type and G2032R mutant ROS1-rearranged cancers, suggesting it could be a promising treatment option for patients with crizotinib-resistant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models. Katayama, R., Gong, B., Togashi, N., et al.[2021]

In a phase 2 study involving 59 patients with ROS1-positive non-small cell lung cancer (NSCLC), ensartinib demonstrated a modest objective response rate of 27% and a median progression-free survival of 4.6 months, indicating its potential efficacy in this patient population.

The treatment was generally well-tolerated, with most adverse events being mild to moderate (grades 1-2), and only 25.4% of patients experiencing severe (grade 3 or higher) treatment-related adverse events, suggesting an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety but Limited Efficacy of Ensartinib in ROS1-Positive NSCLC: A Single-Arm, Multicenter Phase 2 Study. Ai, X., Wang, Q., Cheng, Y., et al.[2021]

Citations

1. Switzerland pubmed.ncbi.nlm.nih.gov

Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

[ROS1-Translocations in Non-Small Cell Lung Cancer]. [2016]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Management and Outcomes of Crizotinib-Treated ROS1-Rearranged NSCLC: A Retrospective Canadian Cohort. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Short-term response to immune-chemotherapy and immune features of a ceritinib-resistant patient with ROS1-rearranged lung adenocarcinoma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma. [2020]

7. England pubmed.ncbi.nlm.nih.gov

The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models. [2021]

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

Safety but Limited Efficacy of Ensartinib in ROS1-Positive NSCLC: A Single-Arm, Multicenter Phase 2 Study. [2021]