Oral EGFR Inhibitor for Lung Cancer

Recruiting at 7 trial locations

Overseen By Avistone Clinical Study Information Center Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Avistone Biotechnology Co., Ltd.

Disqualifiers: Uncontrolled disease, Cardiovascular, Interstitial lung, others

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

Compensation: Varies

Number of Visits: Unknown

81 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase I, multicenter, open-label, dose escalation and dose expansion study to assess the safety and pharmacokinetic profile of PLB1004, a mono-anilino-pyrimidine compound, given alone in NSCLC patients with EGFR exon 20 insertion mutations，uncommon mutations, classical mutations (Ex19del and L858R), and drug-resistant mutation (T790M). Patients will be enrolled and dosed according to the most current protocol. This study is made of two Parts. Part 1 includes a dose escalation into 7 cohorts and patient allocation to these cohorts will be via slot allocation. Each cohort has a minimum of 3 and a maximum of 6 patients for a total of 21 - 42 patients. The patient population of the dose escalation phase will include patients with advanced NSCLC harboring EGFR classical mutations or Ex20ins mutations, or uncommon mutations. Part 2 includes an expansion phase and the expansion phase will explore one or more dose levels of PLB1004 in NSCLC patients with EGFR Ex20ins mutations, classical mutations, or uncommon mutations.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have used other experimental drugs within 2 weeks before starting the trial.

What data supports the effectiveness of the drug PLB1004 for lung cancer?

Research shows that drugs targeting the epidermal growth factor receptor (EGFR) are effective in treating non-small cell lung cancer (NSCLC). Additionally, combining EGFR inhibitors with polo-like kinase 1 (PLK1) inhibitors, like volasertib, has been shown to overcome resistance in NSCLC, suggesting potential benefits for similar treatments. ^{1 2 3 4 5}

What safety data exists for oral EGFR inhibitors in lung cancer treatment?

Oral EGFR inhibitors, used in lung cancer treatment, can cause side effects like skin rash and diarrhea. Serious adverse events were observed in some cases, but monitoring protocols can help manage these risks. ^{6 7 8 9 10}

What makes the drug PLB1004 unique for treating lung cancer?

PLB1004 is an oral drug that targets the epidermal growth factor receptor (EGFR), similar to other drugs like gefitinib and erlotinib, but it is part of a newer generation of EGFR inhibitors that aim to improve patient outcomes in non-small cell lung cancer (NSCLC). This newer generation of drugs is being developed to potentially offer better effectiveness and safety compared to earlier treatments. ^{1 11 12 13 14}

Research Team

Weizhe Xue, Ph.D

Principal Investigator

Avistone Biotechnology Co., Ltd.

Eligibility Criteria

Adults over 18 with Non-Small Cell Lung Cancer (NSCLC) and a specific EGFR mutation can join. They should be recovered from previous cancer treatments, have at least one measurable tumor, not have other recent cancers or significant illnesses, and agree to use birth control. Pregnant women and those with certain lung conditions or recent radiotherapy are excluded.

Inclusion Criteria

I have recovered from side effects of my previous cancer treatments.

You need to have at least one visible and measurable tumor according to specific guidelines.

My cancer has a specific EGFR mutation.

Exclusion Criteria

I have serious heart problems that are not under control.

I do not have any health issues that would prevent me from following the study's requirements.

I have not had any cancer treatments except for NSCLC in the last 3 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive PLB1004 in a dose escalation phase to assess safety and pharmacokinetics

8-12 weeks

Dose Expansion

Participants receive PLB1004 at one or more dose levels to further explore safety and efficacy

12-16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• PLB1004

Trial Overview The trial is testing PLB1004, an oral drug for NSCLC patients with a particular genetic change in their cancer cells. It's in Phase I where they're figuring out the right dose by starting small and increasing it across groups of patients before expanding to more people at the best doses found.

Participant Groups

Group I: PLB1004 Experimental Treatment 1 Intervention

PLB1004 given as a mono-therapy in dose escalation and dose expansion phase.

Who Is Running the Clinical Trial?

Avistone Biotechnology Co., Ltd.

Lead Sponsor

Trials

10

Recruited

1,400+

Findings from Research

Inhibiting EGFR signaling is an effective treatment strategy for non-small cell lung cancer (NSCLC), with first-generation drugs like gefitinib and erlotinib leading to significant advancements in research.

Four second-generation EGFR-targeted agents (EKB-569, HKI-272, CI-1033, and ZD6474) are currently being investigated in clinical trials, aiming to further enhance patient outcomes in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Sequist, LV.[2022]

A study involving 57 advanced non-small cell lung cancer (NSCLC) patients and 54 healthy subjects found that both groups valued oral epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) for their effectiveness and low toxicity, with a median willingness-to-pay of $100 CAD per month.

Despite recognizing the value of EGFR TKIs, many NSCLC patients face financial challenges, as most rely on disability or social assistance, raising concerns about their access to these potentially life-saving treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A willingness-to-pay study of oral epidermal growth factor tyrosine kinase inhibitors in advanced non-small cell lung cancer. Leighl, NB., Tsao, WS., Zawisza, DL., et al.[2018]

The maximum tolerated doses (MTD) for volasertib combined with afatinib were determined to be 300 mg and 30 mg for Schedule A, and 70 mg for Schedule B, indicating a safe dosage range for this combination therapy in patients with advanced solid tumors.

While the combination therapy had manageable side effects, including neutropenia and diarrhea, it showed limited antitumor activity, with only 6.9% of patients achieving a partial response and stable disease in others, suggesting that further investigation is needed to enhance efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of volasertib combined with afatinib, in advanced solid tumors. Machiels, JP., Peeters, M., Herremans, C., et al.[2018]

Inhibiting polo-like kinase 1 (PLK1) can effectively overcome resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with T790M mutations or undergoing epithelial-mesenchymal transition (EMT), as shown in both in vitro and in vivo studies.

The combination of the PLK1 inhibitor volasertib with the EGFR inhibitor erlotinib significantly enhances treatment efficacy, leading to greater tumor size reduction and increased apoptosis compared to either drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations. Wang, Y., Singh, R., Wang, L., et al.[2023]

In a study of 95 patients with relapsed stage IIIB/IV non-small cell lung cancer, BI 2536 showed modest efficacy with a median progression-free survival of 8.3 weeks and overall survival of 28.7 weeks, indicating it may provide some clinical benefit.

The treatment was generally safe, with 37% of patients experiencing grade 4 neutropenia and some nonhematologic side effects like fatigue and nausea; however, two deaths were linked to the drug, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open-label, randomized phase II clinical trial. Sebastian, M., Reck, M., Waller, CF., et al.[2023]

A study of 130 treatment courses in 111 patients revealed that safety monitoring activities (SMAs) for EGFR and ALK inhibitors were inconsistently conducted, with prevalence ranging from 10.0% to 84.6%, and 31.5% of courses had no SMAs performed.

EGFR inhibitors were associated with a higher likelihood of SMAs being conducted compared to ALK inhibitors, highlighting the need for clinicians to closely follow FDA guidelines to ensure patient safety and monitor for serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Monitoring Activity During EGFR or Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients With Lung Cancer. Singh, AM., Rubiera-Pebe, R., Ahmad, Y., et al.[2023]

Targeted therapies like gefitinib and erlotinib have been developed to inhibit the epidermal growth factor receptor (EGFR) in advanced non-small-cell lung cancer (NSCLC), but combining them with platinum chemotherapy has not shown increased effectiveness.

Patient selection based on molecular markers is crucial for the success of these therapies, as they are effective in only a small subset of NSCLC patients, prompting research into newer drugs that target multiple receptor pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EGFR inhibitors in lung cancer. Buter, J., Giaccone, G.[2018]

Targeted therapies for non-small cell lung cancer (NSCLC) have significantly improved treatment options, but their effectiveness can be compromised by issues like poor patient adherence and adverse events.

The review highlights the need for standardized monitoring protocols for the various toxicities associated with these therapies, which can include skin, gastrointestinal, lung, and heart-related side effects, to ensure better patient management and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Toxicities: Protocols for Monitoring the Adverse Events of Targeted Therapies Used in the Treatment of Non-Small Cell Lung Cancer. Hines, JB., Bowar, B., Levine, E., et al.[2023]

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]

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]

Erlotinib is an effective oral EGFR tyrosine kinase inhibitor approved for treating locally advanced non-small cell lung cancer (NSCLC) after chemotherapy failure and for first-line treatment of advanced pancreatic cancer, based on major Phase III studies.

The drug is generally well-tolerated, but ongoing research is necessary to personalize treatment and optimize dosing, particularly in special populations like smokers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of erlotinib--an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor. Iyer, R., Bharthuar, A.[2018]

Gefitinib, an EGFR inhibitor, has been shown to be as effective as docetaxel chemotherapy in overall survival for pretreated non-small-cell lung cancer (NSCLC) patients, while offering a better quality of life and a more favorable toxicity profile.

In chemotherapy-naive patients with adenocarcinoma, especially those with EGFR mutations, gefitinib significantly improves progression-free survival compared to standard chemotherapy, highlighting the importance of genetic testing in optimizing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gefitinib for the treatment of non-small-cell lung cancer. Campbell, L., Blackhall, F., Thatcher, N.[2018]

Erlotinib, an oral inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, has shown promising results in clinical trials for treating non-small cell lung cancer, particularly in combination with other chemotherapy agents like paclitaxel and carboplatin, and gemcitabine and cisplatin.

The National Cancer Institute of Canada--Clinical Trials Group BR21 study was significant as it was the first to demonstrate a survival benefit for EGFR inhibitors like erlotinib in patients with non-small cell lung cancer, highlighting its potential as an effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erlotinib in the treatment of non-small cell lung cancer. Brown, ER., Shepherd, FA.[2022]

Erlotinib and gefitinib, two small molecule EGFR inhibitors, have shown a 10-20% response rate and a 30-50% improvement in symptoms for patients with advanced non-small cell lung cancer (NSCLC) who have not responded to chemotherapy.

A phase III study indicated that erlotinib can improve median survival by two months in metastatic NSCLC patients receiving second or third line treatment, highlighting its potential as a targeted therapy in this challenging cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer. Cascone, T., Morelli, MP., Ciardiello, F.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. [2022]

2. Ireland pubmed.ncbi.nlm.nih.gov

A willingness-to-pay study of oral epidermal growth factor tyrosine kinase inhibitors in advanced non-small cell lung cancer. [2018]

3. Germany pubmed.ncbi.nlm.nih.gov

A phase I study of volasertib combined with afatinib, in advanced solid tumors. [2018]

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

Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations. [2023]

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

The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open-label, randomized phase II clinical trial. [2023]

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

Safety Monitoring Activity During EGFR or Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients With Lung Cancer. [2023]

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

EGFR inhibitors in lung cancer. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Targeted Toxicities: Protocols for Monitoring the Adverse Events of Targeted Therapies Used in the Treatment of Non-Small Cell Lung Cancer. [2023]

9. Spain pubmed.ncbi.nlm.nih.gov

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

10. Ireland pubmed.ncbi.nlm.nih.gov

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

11. England pubmed.ncbi.nlm.nih.gov

A review of erlotinib--an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor. [2018]

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

Gefitinib for the treatment of non-small-cell lung cancer. [2018]

13. England pubmed.ncbi.nlm.nih.gov

Erlotinib in the treatment of non-small cell lung cancer. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer. [2020]