NVL-655 for NSCLC

Recruiting at 94 trial locations

Overseen By Nuvalent Clinical Trial

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Nuvalent Inc.

Must not be taking: Anticancer therapy

Disqualifiers: Other oncogenic driver, Allergy, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

840 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called neladalkib (NVL-655) for individuals with advanced non-small cell lung cancer (NSCLC) and other solid tumors that have a specific genetic change known as ALK-positive. The main goals are to assess the safety and tolerability of this treatment and to evaluate its effectiveness against these tumors. The trial will test different doses and monitor how the cancer responds over time. Individuals with advanced ALK-positive NSCLC or other solid tumors who have tried other treatments might be suitable candidates. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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

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

Is there any evidence suggesting that NVL-655 is likely to be safe for humans?

Research has shown that NVL-655 (neladalkib) holds promise for treating advanced ALK-positive non-small cell lung cancer (NSCLC). In studies, patients have tolerated this treatment well, even those with extensive prior treatments. This suggests NVL-655 might be safe for individuals with this cancer type.

While detailed safety information on NVL-655 is still being collected, ongoing trials aim to determine the optimal dose with minimal side effects. So far, available studies have not reported any major severe side effects directly linked to this treatment. This is encouraging, but participants should still discuss potential risks with their healthcare providers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for NSCLC?

Researchers are excited about NVL-655 for treating non-small cell lung cancer (NSCLC) with ALK rearrangements because it targets cancer cells differently from existing options. Most standard treatments, like crizotinib or alectinib, are ALK inhibitors, but NVL-655 is designed to be more selective, potentially leading to fewer side effects. This specificity could help patients who have become resistant to other ALK inhibitors or who have limited options after trying multiple therapies. Plus, its oral dosing offers convenience compared to some existing treatments, making it easier for patients to maintain their treatment regimen.

What evidence suggests that NVL-655 might be an effective treatment for NSCLC?

Research shows that NVL-655 holds promise for treating advanced ALK-positive non-small cell lung cancer (NSCLC). This trial includes various cohorts, with participants receiving NVL-655 based on their prior treatments and specific cancer characteristics. Studies have found that NVL-655 works well for patients who have tried other treatments. It targets specific changes in cancer cells and effectively combats them. NVL-655 can also reach the brain, which is crucial because cancer can spread there. Early evidence suggests that it is well-tolerated, causing few side effects. ^{1 2 6 7 8}

Who Is on the Research Team?

Viola Zhu, MD, PHD

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 changes in a gene called ALK. Kids over 12 and weighing more than 40 kg can join one part of the study. Participants need to have measurable disease and good organ function but can't be on other cancer treatments or have allergies to NVL-655 components.

Inclusion Criteria

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

Phase 2: Must have measurable disease according to RECIST 1.1

My cancer is advanced or has spread, and tests show an ALK gene change.

Exclusion Criteria

You are currently participating in another clinical trial or receiving active treatment for a medical condition.

You are allergic to the inactive ingredients in NVL-655.

I have not had major surgery in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

Evaluate the overall safety and tolerability of NVL-655 and determine the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) if applicable.

Approximately 3 years

Phase 2: Dose Expansion

Determine the objective response rate (ORR) and evaluate secondary outcomes such as duration of response (DOR), progression-free survival (PFS), and overall survival (OS) at the RP2D.

Approximately 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-3 years

What Are the Treatments Tested in This Trial?

Interventions

• NVL-655

Trial Overview

NVL-655 is being tested in two phases: Phase 1 finds the safest dose by slowly increasing it, while Phase 2 tests how well this dose works using measures like tumor shrinkage rate, how long patients respond, survival without disease getting worse, overall survival time, and total benefit rate.

How Is the Trial Designed?

Group I: Phase 1 dose escalation Experimental Treatment 1 Intervention

Neladalkib (NVL-655) oral daily dosing

Group II: Cohort 2f Experimental Treatment 1 Intervention

Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.

Group III: Cohort 2e Experimental Treatment 1 Intervention

Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.

Group IV: Cohort 2d Experimental Treatment 1 Intervention

Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.

Group V: Cohort 2c Experimental Treatment 1 Intervention

Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed.

Group VI: Cohort 2b Experimental Treatment 1 Intervention

Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.

Group VII: Cohort 2a Experimental Treatment 1 Intervention

Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.

NVL-655 is already approved in United States for the following indications:

Approved in United States as NVL-655 for:

• Locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) in patients who have received at least 2 prior lines of ALK tyrosine kinase inhibitors

Who Is Running the Clinical Trial?

Nuvalent Inc.

Lead Sponsor

Trials

6

Recruited

1,400+

Published Research Related to This Trial

NVP-BEZ235, a dual inhibitor of PI3K and mTOR, significantly enhances the effectiveness of the chemotherapy drug fluorouracil (5-FU) in treating gastric cancer, as shown in both in vitro and in vivo studies with MKN-45 cells and xenograft models.

The combination treatment not only inhibited cancer cell proliferation and invasion but also increased apoptosis, indicating a synergistic effect, while also altering key signaling pathways related to cancer growth and survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual inhibitor of PI3K and mTOR (NVP-BEZ235) augments the efficacy of fluorouracil on gastric cancer chemotherapy. Li, L., Zhang, S., Xie, D., et al.[2022]

NVP-BEZ235, a dual PI3K/mTOR inhibitor, effectively inhibited osteosarcoma cell growth by causing G0/G1 cell cycle arrest without triggering cell death, indicating a unique mechanism of action.

In pre-clinical murine models, NVP-BEZ235 significantly slowed tumor progression, reduced tumor cell proliferation, and improved survival rates, suggesting its potential as a promising adjuvant treatment for osteosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NVP-BEZ235, a dual PI3K/mTOR inhibitor, inhibits osteosarcoma cell proliferation and tumor development in vivo with an improved survival rate. Gobin, B., Battaglia, S., Lanel, R., et al.[2021]

NVP-BEZ235, a dual PI3K/mTOR inhibitor, was found to be more effective than other treatments (RAD001 and NVP-BKM120) in inhibiting the growth of HTLV-1-infected T-cell lines, suggesting it could be a promising therapy for adult T-cell leukemia (ATL).

In animal models, NVP-BEZ235 significantly slowed tumor growth in mice with HTLV-1-infected cells, indicating its potential efficacy in treating ATL and supporting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of NVP-BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines. Ishikawa, C., Senba, M., Mori, N.[2020]

NVP-BEZ235 effectively inhibits the growth of gefitinib-resistant non-small cell lung cancer cells (H1975) both in vitro and in vivo, suggesting its potential as a therapeutic option for patients who develop resistance to EGFR TKIs.

The mechanism of action for NVP-BEZ235 involves downregulating the phosphorylation of key proteins in the PI3K/AKT/mTOR signaling pathway, which is crucial for tumor growth and migration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/mTOR phosphorylation. Sun, Z., Li, Q., Zhang, S., et al.[2022]

NVP-BEZ235 effectively inhibits the proliferation, migration, and invasion of oral cavity squamous cell carcinoma (OSCC) cells by targeting the phosphorylation of p70S6K, a key protein in the PI3K-AKT signaling pathway.

The study demonstrated that NVP-BEZ235's effects on OSCC cells were similar to those of a specific p70S6K inhibitor, suggesting that targeting this pathway could be a promising strategy for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NVP-BEZ235 Attenuated Cell Proliferation and Migration in the Squamous Cell Carcinoma of Oral Cavities and p70S6K Inhibition Mimics its Effect. Hsu, CM., Lin, PM., Lin, HC., et al.[2021]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05384626

NCT05384626 | A Study of Neladalkib (NVL-655) in ...

A Study of Neladalkib (NVL-655) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1).

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11609626/

NVL-655 Is a Selective and Brain-Penetrant Inhibitor of ...

In vitro, NVL-655 inhibits diverse ALK fusions, activating alterations, and resistance mutations, showing ≥100-fold improved potency against ALKG1202R single ...

3.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS8666

Neladalkib (NVL-655), a highly selective anaplastic ...

In the Phase 1/2 ALKOVE-1 study, neladalkib showed encouraging preliminary efficacy in patients with heavily pretreated ALK+ NSCLC, including in ...

4.

onclive.com

onclive.com/view/data-for-nvl-655-in-advanced-alk-nsclc-and-solid-tumors-from-the-alkove-1-trial

Data for NVL-655 in Advanced ALK+ NSCLC and Solid ...

Gregory J. Riely, MD, PhD, and Benjamin Besse, MD, discuss data for NVL-655 in ALK-positive NSCLC and other ALK-positive solid tumors.

5.

investors.nuvalent.com

investors.nuvalent.com/2024-02-12-Nuvalent-Initiates-the-Phase-2-Portion-of-ALKOVE-1-Clinical-Trial-for-Patients-with-ALK-Positive-NSCLC-and-other-Solid-Tumors

Nuvalent Initiates the Phase 2 Portion of ALKOVE-1 ...

Favorable tolerability of NVL-655 was observed at the 150 mg QD dose level, continuing to suggest the potential for a highly ALK-selective, TRK ...

6.

investors.nuvalent.com

investors.nuvalent.com/2024-09-09-Updated-Data-for-Nuvalents-ALK-Selective-Inhibitor,-NVL-655,-and-ROS1-Selective-Inhibitor,-Zidesamtinib,-Continue-to-Support-Potential-Best-in-Class-Profiles

Updated Data for Nuvalent's ALK-Selective Inhibitor, NVL- ...

Durable activity of NVL-655 and zidesamtinib in heavily pre-treated patient populations supports ongoing Phase 2 investigation in earlier lines of treatment.

7.

onclive.com

onclive.com/view/nvl-655-shows-strong-efficacy-in-heavily-pretreated-alk-nsclc

NVL-655 Shows Strong Efficacy in Heavily Pretreated ...

The novel ALK inhibitor NVL-655 demonstrated encouraging activity in heavily pretreated patients with advanced ALK-positive non–small cell lung cancer (NSCLC).

8.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06834074

Expanded Access Program of Neladalkib (NVL-655) for ...

The purpose of this Expanded Access Program is to provide investigational ALK inhibitor, neladalkib (NVL-655), for eligible patients with ALK-positive locally ...