NVL-655 for NSCLC

Recruiting at 69 trial locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Nuvalent Inc.

Must not be taking: Anticancer therapy

Disqualifiers: Other oncogenic driver, Allergy, others

No Placebo Group

Breakthrough Therapy

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called NVL-655 to see if it is safe and effective for patients with advanced ALK-positive lung cancer and other solid tumors. The drug works by blocking a protein that helps cancer cells grow. The study focuses on patients who have specific genetic changes and may not respond well to standard treatments. Newer treatments have been shown to improve outcomes in ALK-translocated lung cancer compared to older treatments.

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.

What data supports the effectiveness of the drug NVL-655 for NSCLC?

Research on a similar drug, NVP-BEZ235, shows it can slow down tumor growth and improve survival in various cancers by targeting specific pathways that help cancer cells grow. This suggests that NVL-655 might also be effective in treating non-small cell lung cancer (NSCLC) by working in a similar way. ^{1 2 3 4 5}

Research Team

Viola Zhu, MD, PHD

Principal Investigator

Nuvalent Inc.

Eligibility Criteria

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 18 years old or older.

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

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.

Trial Timeline

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

Treatment Details

Interventions

• NVL-655 (Monoclonal Antibodies)

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.

Participant Groups

Group I: Phase 1 dose escalation Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Nuvalent Inc.

Lead Sponsor

Trials

6

Recruited

1,400+

Findings from Research

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 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 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]

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]

References

1. Ireland 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. [2021]

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

Dual inhibitor of PI3K and mTOR (NVP-BEZ235) augments the efficacy of fluorouracil on gastric cancer chemotherapy. [2022]

3. Switzerland 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. [2021]

4. Greece 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. [2020]

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

NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/mTOR phosphorylation. [2022]