NX-019 for EGFR-Mutant Cancer

Recruiting at 13 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

258 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing NX-019, a new drug, in patients with advanced or metastatic EGFR-mutant cancer. The drug aims to block a protein that helps cancer cells grow, potentially slowing down or stopping the cancer. NRC-AN-019 has shown better antitumor activity than Lapatinib in pre-clinical breast cancer models.

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.

What data supports the effectiveness of the drug NX-019 for EGFR-Mutant Cancer?

EGFR inhibitors, like gefitinib and cetuximab, have shown effectiveness in treating certain cancers by blocking signals that help cancer cells grow. These drugs have been effective in some patients with non-small cell lung cancer, suggesting that NX-019, as an EGFR inhibitor, might also be effective for EGFR-mutant cancers. ^{1 2 3 4 5}

What data supports the effectiveness of the drug NX-019 for EGFR-mutant cancer?

EGFR inhibitors, like gefitinib and cetuximab, have shown promise in treating certain cancers by blocking signals that help cancer cells grow. These drugs have been effective in some patients with non-small cell lung cancer, suggesting that NX-019, as an EGFR inhibitor, might also be effective for EGFR-mutant cancers. ^{1 2 3 4 5}

What safety data exists for NX-019 or similar EGFR inhibitors in humans?

The safety profile of similar EGFR inhibitors, like AZD9291, shows they are generally well-tolerated in patients with non-small cell lung cancer, with common side effects including rash and diarrhea. Afatinib, another EGFR inhibitor, also shows similar side effects and is considered well-tolerated. ^{6 7 8 9 10}

What safety data exists for NX-019 or similar EGFR inhibitors in humans?

The safety profile of similar EGFR inhibitors, like AZD9291, has been described as encouraging, with common side effects including rash and diarrhea. Afatinib, another EGFR inhibitor, is generally well tolerated but can cause similar side effects such as diarrhea, rash, acne, and mouth sores. ^{6 7 8 9 10}

What makes the drug NX-019 unique for treating EGFR-mutant cancer?

NX-019 is unique because it is a mutant-selective inhibitor that specifically targets EGFR mutations, including those resistant to other treatments, while sparing the normal (wild-type) EGFR, potentially reducing side effects compared to other EGFR inhibitors. ^{11 12 13 14 15}

What makes the drug NX-019 unique for treating EGFR-mutant cancer?

NX-019 is unique because it is a mutant-selective inhibitor that specifically targets EGFR mutations, including those resistant to other treatments, while sparing the normal (wild-type) EGFR, potentially reducing side effects compared to other EGFR inhibitors. ^{11 12 13 14 15}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

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]

References

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

Biomarkers for prediction of sensitivity to EGFR inhibitors in non-small cell lung cancer. [2022]

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

Outcomes after combined modality therapy for EGFR-mutant and wild-type locally advanced NSCLC. [2022]

3. England pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

Identification of small-molecule EGFR allosteric inhibitors by high-throughput docking. [2019]

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

Autocrine production of amphiregulin predicts sensitivity to both gefitinib and cetuximab in EGFR wild-type cancers. [2022]

6. United States 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. [2022]

7. Ireland pubmed.ncbi.nlm.nih.gov

Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. [2022]

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

Afatinib for the treatment of metastatic non-small cell lung cancer. [2022]

9. England pubmed.ncbi.nlm.nih.gov

HERTHENA-Lung02: phase III study of patritumab deruxtecan in advanced EGFR-mutated NSCLC after a third-generation EGFR TKI. [2023]

10. United States 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. [2023]

11. United States 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. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Partial response to carboplatin in an RRx-001 pretreated patient with EGFR-inhibitor-resistance and T790M-negative NSCLC. [2020]

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

NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor. [2020]

14. Spain pubmed.ncbi.nlm.nih.gov

The epidermal growth factor receptor pathway and its inhibition as anticancer therapy. [2022]

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

The reversible fourth-generation EGFR tyrosine kinase inhibitor OBX02-011 overcomes C797S-mediated resistance in lung cancer. [2022]