NX-019 for EGFR-Mutant Cancer

Not currently recruiting at 17 trial locations

Overseen By Nalo Therapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Nalo Therapeutics Inc.

Must not be taking: Strong CYP3A inhibitors, Proton pump inhibitors

Disqualifiers: C797X EGFR mutations, Uncontrolled diabetes, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called NX-019, an EGFR mutant-selective inhibitor, for individuals with advanced cancer that has a specific EGFR gene mutation. Researchers aim to determine if NX-019 is safe and effective for patients whose cancer has spread or advanced, particularly after other treatments have failed. The trial consists of two parts: first, to identify a safe dose, and then to assess the treatment's effectiveness at that dose. Individuals with advanced non-small cell lung cancer (NSCLC) who have specific EGFR mutations and have tried other treatments might be suitable candidates. As a Phase 1 trial, this research focuses on understanding how NX-019 works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop using certain medications, such as strong CYP3A inhibitors or inducers, proton pump inhibitors, and specific drugs with a narrow therapeutic window like digoxin, at least 7 days before starting the study and throughout its duration. If you are on these medications, you will need to discuss alternatives with your doctor.

Will I have to stop taking my current medications?

The trial requires that you stop using certain medications, such as strong CYP3A inhibitors or inducers, proton pump inhibitors, and specific drugs with a narrow therapeutic window like digoxin, starting 7 days before the first dose and throughout the study. If you are taking any of these, you will need to stop them.

Is there any evidence suggesting that NX-019 is likely to be safe for humans?

Research shows that NX-019 is being tested for safety in people with EGFR-mutant cancer. This marks the first use of NX-019 in humans, so information about its safety remains limited. However, similar treatments for this cancer type have shown promise in other studies.

Early trials like this one primarily aim to find a safe dose. Researchers closely monitor side effects and adjust doses to minimize them. Since this is the initial human test of NX-019, it is too early to determine its tolerability. Participants receive close monitoring for any unwanted effects.

Because this trial is in its early stages, safety information is still being gathered. Participants play a crucial role in helping researchers assess the safety of NX-019 for future patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about NX-019 because it offers a new approach to treating EGFR-mutant cancer. Unlike standard therapies that often target EGFR mutations in a broad manner, NX-019 is designed to target specific mutations more precisely. This precision could potentially lead to fewer side effects and better outcomes for patients. Additionally, the dose-escalation and dose-expansion strategies used in its development aim to optimize its effectiveness and minimize toxicity, setting it apart from existing treatments.

What evidence suggests that NX-019 might be an effective treatment for EGFR-mutant cancer?

Research has shown that NX-019, the investigational treatment in this trial, targets specific changes in a protein called EGFR, which plays a role in cell growth and is often present in certain cancers. Early lab studies demonstrated that NX-019 was highly effective against many types of these EGFR changes. This is promising because the treatment is designed to reach the brain, potentially benefiting patients with cancer that has spread there. EGFR inhibitors typically help 10 to 28% of patients with advanced non-small cell lung cancer (NSCLC) who haven't improved with other treatments. NX-019 aims to surpass this by being more precise and powerful against these changes. Although human studies have provided limited information, early results offer hope for its effectiveness. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

Adults with advanced EGFR-mutant cancer, specifically non-small cell lung cancer (NSCLC), who have progressed after standard therapy or are intolerant to it. Participants must have measurable disease, a life expectancy of at least 3 months, and adequate organ function. They should not be pregnant or breastfeeding and must agree to effective birth control during the study.

Inclusion Criteria

My NSCLC has an EGFR mutation and doesn't fit other specific group criteria.

Specific Inclusion Criteria for Expansion Cohorts:

My organs and bone marrow are working well.

Exclusion Criteria

I have not had radiation therapy in the last 4 weeks.

I am currently taking medication that strongly affects liver enzyme activity.

My cancer has a specific EGFR mutation or another known driver.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive NX-019 in multiple ascending cohorts to evaluate safety and determine the maximum tolerated dose

8-12 weeks

Dose Expansion

Participants receive NX-019 at the recommended expansion doses to confirm safety and assess preliminary efficacy

12-16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• NX-019

Trial Overview The trial is testing NX-019's safety, tolerability, and preliminary effectiveness in patients with advanced cancers that have a mutation in the epidermal growth factor receptor (EGFR). It's an open-label study where all participants receive NX-019.

How Is the Trial Designed?

Group I: Part 2: NX-019 Dose Expansion Experimental Treatment 1 Intervention

Patients will be treated with the REDs of NX-019 as determined in Part 1.

Group II: Part 1: NX-019 Dose Escalation Experimental Treatment 1 Intervention

Patients will be treated with NX-019 in multiple ascending cohorts.

Who Is Running the Clinical Trial?

Nalo Therapeutics Inc.

Lead Sponsor

Trials

1

Recruited

260+

Published Research Related to This Trial

In a phase 1 clinical trial involving 108 patients with advanced NSCLC, YK-029A demonstrated a manageable safety profile with no dose-limiting toxicities and common side effects including anemia (50.9%) and diarrhea (49.1%).

Among 28 treatment-naive patients with EGFR exon 20 insertion mutations, YK-029A showed promising efficacy with an objective response rate of 73.1% and a disease control rate of 92.3%, indicating strong antitumor activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of YK-029A in Treatment-Naive Patients With Advanced NSCLC Harboring EGFR Exon 20 Insertion Mutations: A Phase 1 Trial. Duan, J., Wu, L., Yang, K., et al.[2023]

The novel irreversible EGFR-TKI CNX-2006 shows effectiveness against non-small cell lung cancer (NSCLC) with EGFR mutations, particularly the T790M mutation, while sparing the wild-type receptor, indicating a targeted approach to treatment.

Inhibition of the NF-κB pathway is crucial for overcoming resistance to EGFR-TKIs, suggesting that combining NF-κB inhibitors with EGFR-TKIs could be a promising strategy for patients who develop resistance after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor. Galvani, E., Sun, J., Leon, LG., et al.[2020]

In a pooled analysis of 21 clinical trials involving 1468 patients with EGFR mutation-positive non-small cell lung cancer, afatinib was found to cause significantly more severe adverse events, such as rash and diarrhea, compared to erlotinib and gefitinib.

Gefitinib was associated with a higher frequency of severe hepatotoxicity compared to the other two drugs, while the overall rates of severe interstitial lung disease were low and similar across all three EGFR-TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Takeda, M., Okamoto, I., Nakagawa, K.[2022]

The novel EGFR inhibitor EGF816 (nazartinib) shows promise as a mutant-selective treatment for lung cancer, effectively targeting both oncogenic and T790M-resistant EGFR mutations, which are common causes of resistance in existing therapies.

In preclinical studies, EGF816 demonstrated good selectivity for mutant EGFR over wild-type EGFR, suggesting it may reduce dose-limiting toxicities while maintaining efficacy, making it a strong candidate for clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers. Lelais, G., Epple, R., Marsilje, TH., et al.[2019]

OBX02-011 is a newly discovered reversible fourth-generation EGFR TKI that effectively targets the C797S mutation, which is a major cause of resistance to osimertinib in advanced non-small cell lung cancer (NSCLC).

In preclinical studies, OBX02-011 demonstrated strong anticancer effects and significantly inhibited tumor growth in mouse models with the C797S mutation, suggesting it could improve survival outcomes for patients with this resistance mechanism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The reversible fourth-generation EGFR tyrosine kinase inhibitor OBX02-011 overcomes C797S-mediated resistance in lung cancer. Choi, YJ., Kim, DS., Hoon Sung, Y., et al.[2022]

EGFR-targeting agents like C225 and ZD1839 show promise in treating cancers such as non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), with C225 demonstrating synergy with chemotherapy and radiation in preclinical models.

Despite initial positive responses in phase I trials, large phase III studies of ZD1839 combined with chemotherapy did not show an increase in survival for advanced NSCLC patients, highlighting the need for further research into effective treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The epidermal growth factor receptor pathway and its inhibition as anticancer therapy. Janmaat, ML., Giaccone, G.[2022]

EGFR inhibitors show a response rate of 10 to 28% in advanced non-small cell lung cancer (NSCLC) patients who have not responded to chemotherapy, with about 30% achieving stable disease.

Increased EGFR gene copy number, assessed through FISH analysis, is currently the best predictive marker for determining which patients will benefit from EGFR inhibitors, suggesting a need for further large-scale studies to refine patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers for prediction of sensitivity to EGFR inhibitors in non-small cell lung cancer. Hirsch, FR., Witta, S.[2022]

In a study of 123 patients with locally advanced non-small cell lung cancer (NSCLC), those with EGFR mutations had a significantly higher 2-year overall survival rate (92.6%) compared to those with wild-type EGFR (69.0%).

EGFR-mutant patients also experienced a significantly lower locoregional recurrence rate (17.8%) compared to wild-type patients (41.7%), suggesting that EGFR mutations may enhance sensitivity to radiation therapy and chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes after combined modality therapy for EGFR-mutant and wild-type locally advanced NSCLC. Mak, RH., Doran, E., Muzikansky, A., et al.[2022]

Targeting the epidermal growth factor receptor (EGFR) is a promising strategy in cancer therapy, as it plays a crucial role in processes like cancer cell growth and metastasis, with several anti-EGFR drugs currently in advanced clinical development.

Cetuximab and gefitinib are two key anti-EGFR drugs that have shown efficacy in treating specific types of cancer, such as advanced colorectal cancer and chemoresistant non-small cell lung cancer, respectively, highlighting their potential in improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epidermal growth factor receptor inhibitors in cancer treatment. Ciardiello, F.[2018]

A new high-throughput docking protocol was developed to identify allosteric inhibitors of the EGFR protein, which is crucial for treating non-small-cell lung cancer, especially in cases of drug resistance.

The most promising compound identified was confirmed to effectively inhibit both the wild-type and drug-resistant mutant forms of EGFR, demonstrating potential for treating resistant non-small-cell lung cancer cell lines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of small-molecule EGFR allosteric inhibitors by high-throughput docking. Caporuscio, F., Tinivella, A., Restelli, V., et al.[2019]

In a study of 10 EGFR wild-type NSCLC cell lines and 4 head and neck squamous cell carcinoma cell lines, higher levels of amphiregulin were linked to greater growth inhibition by EGFR-targeted therapies like gefitinib and cetuximab.

Patients with NSCLC who had higher amphiregulin expression were more likely to achieve stable disease after treatment with gefitinib or erlotinib, suggesting that amphiregulin could be a useful biomarker for predicting treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers. Yonesaka, K., Zejnullahu, K., Lindeman, N., et al.[2022]

AZD9291 is an irreversible inhibitor specifically designed to target both sensitizing mutations and the T790M resistance mutation in EGFR, showing promise in treating non-small-cell lung cancer (NSCLC) patients who have developed resistance to previous therapies.

In early clinical trials, AZD9291 demonstrated significant tumor inhibition and an encouraging safety profile, suggesting it may be a more effective option with fewer side effects compared to traditional EGFR inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. Finlay, MR., Anderton, M., Ashton, S., et al.[2022]

A 71-year-old female patient with T790M-negative non-small cell lung cancer (NSCLC) showed a positive response to carboplatin after previously failing multiple treatments, including EGFR-TKIs and chemotherapy, suggesting potential for therapeutic rechallenge.

The case introduces the concept of 'episensitization,' which challenges the belief that cancer resistance is permanent, indicating that reintroducing certain treatments may still be effective in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Partial response to carboplatin in an RRx-001 pretreated patient with EGFR-inhibitor-resistance and T790M-negative NSCLC. Carter, CA., Oronsky, B., Caroen, S., et al.[2020]

Afatinib, an irreversible pan-ErbB inhibitor, has been approved for treating advanced non-small cell lung cancer (NSCLC) with specific EGFR mutations, showing promise in overcoming resistance to first-generation EGFR inhibitors like gefitinib and erlotinib.

Clinical studies indicate that afatinib is well tolerated, with side effects similar to those of first-generation EGFR TKIs, including diarrhea and rash, while providing effective treatment options for patients with sensitizing mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Afatinib for the treatment of metastatic non-small cell lung cancer. Joshi, M., Rizvi, SM., Belani, CP.[2022]

HER3-DXd shows promising antitumor activity and manageable safety in patients with EGFR-mutated NSCLC who have progressed on EGFR TKI therapy, indicating it may be a more effective treatment option than traditional platinum-based chemotherapy.

The HERTHENA-Lung02 phase III trial is the first to compare HER3-DXd with platinum-based chemotherapy, aiming to establish its safety and efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HERTHENA-Lung02: phase III study of patritumab deruxtecan in advanced EGFR-mutated NSCLC after a third-generation EGFR TKI. Mok, T., Jänne, PA., Nishio, M., et al.[2023]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS9159

A first-in-human, open-label, dose escalation and ... A first-in-human, international, open-label study designed to evaluate single-agent NX-019 in patients with EGFR-mutant, locally advanced or metastatic NSCLC.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05514496

NCT05514496 | A Study of NX-019 in Patients with ... This is a 2-part, first-in-human, open-label study to determine the safety and tolerability of NX-019 and preliminary efficacy in patients with locally advanced ...

3. annalsofoncology.org annalsofoncology.org/article/S0923-7534(22)04603-8/fulltext

374P NX-019, a brain penetrant, mutation selective EGFR ... NX-019 was optimized for enhanced CNS penetration and potency against a broad range of EGFR mutations. Preclinical studies in multiple mutant EGFR disease ...

4. ovid.com ovid.com/journals/anonc/pdf/10.1016/j.annonc.2022.10.412~nx-019-a-brain-penetrant-mutation-selective-egfr-inhibitor

374P NX-019, a brain penetrant, mutation selective EGFR ... Conclusions: High-dose Aumolertinib is effective in pts with NSCLC Harboring un- common EGFR Mutations other than 20 ins. The up to date data suggested CK ...

5. withpower.com withpower.com/trial/phase-1-egfr-mutation-related-tumors-8-2022-46943

NX-019 for EGFR-Mutant Cancer · Info for Participants EGFR inhibitors show a response rate of 10 to 28% in advanced non-small cell lung cancer (NSCLC) patients who have not responded to chemotherapy, with about 30% ...

6. patents.google.com patents.google.com/patent/WO2024039691A1/en

1h-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (nx-019 ... [0007] This disclosure describes a clinical study of patients having EGFR mutant cancer to demonstrate the efficacy and safety of NX-019 when it is ...