NVL-520 for ROS1-Positive Solid Tumors

Recruiting in Palo Alto (17 mi)

+64 other locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Nuvalent Inc.

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

No Placebo Group

Trial Summary

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 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.

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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.

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Eligibility Criteria

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

Trial Timeline

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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Colorado Cancer Center Denver, CO

Memorial Sloan Kettering Cancer Center New York, NY

Sarah Cannon Research Institute Nashville, TN

Washington University School of Medicine Saint Louis, MO

More Trial Locations

Who Is Running the Clinical Trial?

Nuvalent Inc. Lead Sponsor

References

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

Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective. [2023] The ros1 kinase is an oncogenic driver in non-small-cell lung cancer (nsclc). Fusion events involving the ROS1 gene are found in 1%-2% of nsclc patients and lead to deregulation of a tyrosine kinase-mediated multi-use intracellular signalling pathway, which then promotes the growth, proliferation, and progression of tumour cells. ROS1 fusion is a distinct molecular subtype of nsclc, found independently of other recognized driver mutations, and it is predominantly identified in younger patients (<50 years of age), women, never-smokers, and patients with adenocarcinoma histology. Targeted inhibition of the aberrant ros1 kinase with crizotinib is associated with increased progression-free survival (pfs) and improved quality-of-life measures. As the sole approved treatment for ROS1-rearranged nsclc, crizotinib has been demonstrated, through a variety of clinical trials and retrospective analyses, to be a safe, effective, well-tolerated, and appropriate treatment for patients having the ROS1 rearrangement. Canadian physicians endorse current guidelines which recommend that all patients with nonsquamous advanced nsclc, regardless of clinical characteristics, be tested for ROS1 rearrangement. Future integration of multigene testing panels into the standard of care could allow for efficient and cost-effective comprehensive testing of all patients with advanced nsclc. If a ROS1 rearrangement is found, treatment with crizotinib, preferably in the first-line setting, constitutes the standard of care, with other treatment options being investigated, as appropriate, should resistance to crizotinib develop.

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

Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study. [2022] ROS1-rearranged (ROS1+) non-small-cell lung cancer (NSCLC) is a rare lung cancer with limited treatment options. Phase I-II studies with ROS1-tyrosine kinase inhibitors (TKIs) included small numbers of patients and real-world data are lacking. We investigate the efficacy and safety of lorlatinib, a third-generation TKI targeting ALK and ROS1, in patients with ROS1+ NSCLC treated through an expanded access program.

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

[ROS1-Translocations in Non-Small Cell Lung Cancer]. [2016] Summary of prevalence, testing and treatment approaches in patients with non-small cell lung cancer (NSCLC) and ROS1 activation.

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

Real-World Management and Outcomes of Crizotinib-Treated ROS1-Rearranged NSCLC: A Retrospective Canadian Cohort. [2022] The use, safety and effectiveness of crizotinib as part of the management of ROS1-rearranged NSCLC patients in a real-world Canadian clinical cohort was the focus of this retrospective review. Twenty-one ROS1-rearranged patients with advanced/metastatic disease receiving crizotinib between 2014-2020 were identified; crizotinib demonstrated tolerability and effectiveness in this population where outcomes were similar to those described in other crizotinib-treated real-world cohorts, but lower than those of the PROFILE 1001 clinical trial population. Systemic anti-cancer therapy prior to crizotinib initiation occurred in half of the study cohort, with platin-pemetrexed and immune checkpoint inhibitors being most common. Platin-pemetrexed showed good effectiveness in this cohort, but despite high prevalence of upregulated PD-L1 expression, immune checkpoint inhibitors showed poor effectiveness in his cohort. Among all systemic therapies received, crizotinib showed the most effective disease control, although longer intervals between diagnosis and crizotinib initiation were more common among those showing a lack of clinical response to crizotinib, and patients with brain metastases at the time of crizotinib initiation also showed increased diagnosis to crizotinib initiation intervals and decreased clinical response to crizotinib. This study reveals crizotinib has clinical benefit, but timely identification of ROS1-rearrangements and initiation targeted therapies appears important to maximize outcome in this population.

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] Patients with ROS1-rearranged non-small cell lung cancer (NSCLC) inevitably relapse after first-line targeted therapy with tyrosine kinase inhibitors. Efficacy of checkpoint inhibitor-based therapy on ROS1-positive NSCLC in second-line setting and change of immune factors during treatment are rarely studied. We report a ROS1-rearranged stage ⅢB lung adenocarcinoma patient who was resistant to ceritinib after developing a secondary ROS1 F2004L mutation. He received eight cycles of nivolumab plus chemotherapy and had an initial partial response, but brain metastases appeared in the seventh cycle. Lorlatinib was confirmed to have activity against CD74-ROS1 with F2004L in vitro, and was administered to this patient as the third-line therapy. The patient responded well to lorlatinib and had no relapse. We explored the tumor immune microenvironment (TIME) during immune-chemotherapy by multiplex immunohistochemistry, RNA sequencing, and multiplex plasma protein immunoassay. The results show that the TIME was active and plasma inflammatory factors were increased when the patient responded to immune-chemotherapy, while the plasma inhibitory checkpoint proteins, lymphocyte-activation gene 3, B and T lymphocyte attenuator, programmed cell death ligand 1 (PD-L1), and PD-1, were increased when the disease progressed. Moreover, the PD-L1 expression on tumor tissue was upregulated during treatment, predicting the limited benefit from immune-chemotherapy. This case report suggests that lorlatinib is a better choice than immune-chemotherapy in second-line setting for patients with similar genomic characteristics, and that monitoring the immune components during immunotherapy may help to predict disease response.

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

The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma. [2020] To determine the frequency and predictive impact of ROS1 rearrangements on treatment outcomes in never-smoking patients with lung adenocarcinoma.

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] ROS1 gene rearrangement was observed in around 1-2 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. Crizotinib, an ALK/ROS1/MET inhibitor, is highly effective against ROS1-rearranged lung cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1-rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged cancer in preclinical models, including crizotinib-resistant ROS1 positive cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors.

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] Some ALK inhibitors with good inhibition of ROS1 in preclinical studies have been reported to be possibly beneficial in ROS1-positive NSCLC. In this work, we studied the efficacy and safety of ensartinib in the treatment of patients with ROS1-positive NSCLC.