NX-019 for EGFR-Mutant Cancer

Recruiting in Palo Alto (17 mi)

+13 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Waitlist Available

Sponsor: Nalo Therapeutics Inc.

No Placebo Group

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.

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 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 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}

Research Team

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.

Treatment Details

Interventions

• NX-019 (Other)

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

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]

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]

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]