Minnelide + Osimertinib for Lung Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Osimertinib

Must not be taking: CYP3A4 inducers, Antiarrhythmics, Herbal meds

Disqualifiers: HIV, Hepatitis B/C, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests Minnelide and Osimertinib together to treat advanced lung cancer with a specific gene mutation. Minnelide becomes an active drug in the body, and Osimertinib blocks a protein needed for cancer growth. This combination aims to help patients whose cancer grows faster due to this specific gene mutation. Osimertinib is a third-generation medication approved for treating a type of lung cancer with specific gene mutations.

Will I have to stop taking my current medications?

The trial requires stopping certain medications before starting, including strong CYP3A4 inducers/inhibitors, some antiarrhythmic agents, herbal and alternative medications, and specific drugs like clarithromycin, loperamide, and ondansetron. If you're taking any of these, you may need to stop them before joining the trial.

What data supports the effectiveness of the drug combination Minnelide and Osimertinib for lung cancer?

Osimertinib has shown effectiveness in treating non-small-cell lung cancer (NSCLC) with specific mutations, particularly the EGFR T790M mutation, which is a common resistance mechanism to earlier treatments. It has demonstrated efficacy in clinical trials and real-world settings for patients with EGFR-mutant NSCLC. ^{1 2 3 4 5}

Is the combination of Minnelide and Osimertinib safe for humans?

Osimertinib has been studied for lung cancer and common side effects include diarrhea, rash, dry skin, and nail issues. Serious side effects occurred in about 28% of patients, with some stopping treatment due to these effects. There is no specific safety data available for Minnelide in combination with Osimertinib. ^{2 5 6 7 8}

What makes the drug combination of Minnelide and Osimertinib unique for lung cancer treatment?

The combination of Minnelide and Osimertinib is unique because it pairs a novel compound, Minnelide, with Osimertinib, a third-generation drug specifically targeting a mutation in lung cancer cells that often leads to resistance against other treatments. This combination aims to enhance effectiveness by addressing resistance mechanisms in non-small cell lung cancer. ^{2 3 4 9 10}

Research Team

Erminia Massarelli, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

Adults with advanced non-small cell lung cancer that has spread and have specific EGFR gene mutations. They must have had tumor progression after standard osimertinib treatment, be able to swallow pills, not be pregnant or breastfeeding, use effective birth control, and agree to research biopsies. Excluded are those with certain heart conditions, active infections requiring systemic therapy, recent use of strong CYP3A4 inducers/inhibitors or antiarrhythmic agents.

Inclusion Criteria

My tumor has a specific EGFR mutation sensitive to certain treatments.

My liver function test is within the required range.

My blood clotting time is within the target range for my anticoagulant therapy.

Exclusion Criteria

I have not taken strong CYP3A4 drugs in the last 14 days.

I have a history of HIV or hepatitis B/C.

I have a serious health condition that is not under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive minnelide orally once daily on days 1-21 and osimertinib once daily on days 1-28. Cycles repeat every 28 days for 6 months.

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 3 months for 2 years.

2 years

Treatment Details

Interventions

• Minnelide
• Osimertinib

Trial Overview The trial is testing the combination of Minnelide (which turns into triptolide in the body) and Osimertinib for treating advanced lung cancer with EGFR mutations. It aims to find the best dose of Minnelide while checking how well it works alongside Osimertinib by blocking a protein needed for cancer cell growth.

Participant Groups

Group I: Treatment (minnelide, osimertinib) Experimental Treatment 3 Interventions

Patients receive minnelide PO QD on days 1-21 and osimertinib PO QD on days 1-28. Cycles repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 240 advanced non-small-cell lung cancer (NSCLC) patients with acquired resistance to EGFR TKIs, 52.9% had the T790M mutation after rebiopsy, highlighting the mutation's prevalence in treatment resistance.

Patients with the T790M mutation who had previously used osimertinib experienced significantly longer post-progression survival (42.6 months) compared to those without osimertinib (18.0 months) or without the mutation (18.8 months), suggesting osimertinib's effectiveness as a standard treatment for T790M-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Progression Survival in Secondary EGFR T790M-Mutated Non-Small-Cell Lung Cancer Patients With and Without Osimertinib After Failure of a Previous EGFR TKI. Chiang, CL., Huang, HC., Shen, CI., et al.[2022]

Osimertinib is an oral medication specifically designed to target the EGFR T790M mutation in advanced non-small cell lung cancer (NSCLC), which helps overcome resistance to previous EGFR TKI therapies.

It received accelerated approval in the USA in November 2015 for patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed after EGFR TKI treatment, and is currently undergoing further development for broader treatment applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib: First Global Approval. Greig, SL.[2022]

In a retrospective analysis of 32 patients with EGFR T790M-mutant non-small-cell lung cancer, osimertinib showed a 50% objective response rate and a median progression-free survival of 11.3 months, indicating its efficacy in clinical practice.

The median overall survival was 18.3 months, with better outcomes observed in patients without cerebral metastases and those with better performance status, highlighting the importance of these factors in treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland. Knetki-Wróblewska, M., Kowalski, DM., Czyżewicz, G., et al.[2022]

Osimertinib, an irreversible tyrosine kinase inhibitor, showed excellent activity in treating a 69-year-old man with metastatic EGFR-mutated non-small cell lung cancer, leading to a rapid treatment response despite initial severe pancytopenia.

After experiencing pancytopenia, the patient's dose of osimertinib was reduced from 80 mg to 40 mg daily, which allowed for continued effective treatment without further adverse events, demonstrating the potential for safe dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. Di Marino, P., Chiapperino, C., Primavera, FC., et al.[2022]

In a study of 94 patients with advanced non-small-cell lung cancer (NSCLC) who had previously been treated, osimertinib showed a 47.3% overall objective response rate and a 90.1% disease control rate, indicating its effectiveness in this population.

Patients with the T790M mutation experienced significantly longer progression-free survival (PFS) compared to those without the mutation, highlighting osimertinib's targeted efficacy, especially in those with specific genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study. Mu, Y., Xing, P., Hao, X., et al.[2022]

Osimertinib (TAGRISSO) received accelerated FDA approval for treating metastatic non-small cell lung cancer with the EGFR T790M mutation, showing significant tumor response rates of 57% and 61% in two major trials involving 411 patients.

While osimertinib demonstrated promising efficacy, common side effects included diarrhea (42%) and rash (41%), with 28% of patients experiencing severe adverse events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib for the Treatment of Metastatic EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. Khozin, S., Weinstock, C., Blumenthal, GM., et al.[2022]

Osimertinib (Tagrisso) is a targeted therapy approved by the FDA for patients with metastatic non-small cell lung cancer (NSCLC) who have the EGFR T790M mutation and have progressed after previous treatments.

The drug received special designations from the FDA, including breakthrough therapy and priority review, highlighting its significance in treating resistant forms of NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. Skoulidis, F., Papadimitrakopoulou, VA.[2022]

Osimertinib significantly improves progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation, showing a median PFS of 10.1 months compared to 4.4 months with chemotherapy in a trial of 419 patients.

The safety profile of osimertinib is favorable compared to other EGFR tyrosine kinase inhibitors and chemotherapy, with common side effects including diarrhea and rash, making it a viable treatment option for patients who have progressed on previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. Odogwu, L., Mathieu, L., Goldberg, KB., et al.[2022]

The study established an osimertinib-resistant cell line (HCC827/OSIR) from EGFR-sensitive HCC827 cells, demonstrating that these resistant cells have higher resistance to multiple EGFR tyrosine kinase inhibitors compared to the original cells.

Increased expression of IRE1α was identified as a potential mechanism for resistance to osimertinib, and targeting IRE1α with an inhibitor showed promise in reducing the number of viable resistant cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased Expression of IRE1α Associates with the Resistant Mechanism of Osimertinib (AZD9291)-resistant non-small Cell Lung Cancer HCC827/OSIR Cells. Tang, ZH., Su, MX., Guo, X., et al.[2022]

Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, was effective for 2.5 years in a 78-year-old woman with T790M-positive lung cancer, but she eventually experienced disease progression due to the emergence of a new resistance mutation (C797G).

The case highlights the potential of liquid biopsy and next-generation sequencing to monitor clonal evolution and identify novel resistance mechanisms in patients treated with osimertinib, which could inform future treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report. DE Carlo, E., Schiappacassi, M., Pelizzari, G., et al.[2022]

References

1. France pubmed.ncbi.nlm.nih.gov

Post-Progression Survival in Secondary EGFR T790M-Mutated Non-Small-Cell Lung Cancer Patients With and Without Osimertinib After Failure of a Previous EGFR TKI. [2022]

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

Osimertinib: First Global Approval. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland. [2022]

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

Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. [2022]

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

Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study. [2022]

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

Osimertinib for the Treatment of Metastatic EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. [2022]

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

Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Increased Expression of IRE1α Associates with the Resistant Mechanism of Osimertinib (AZD9291)-resistant non-small Cell Lung Cancer HCC827/OSIR Cells. [2022]

10. Greece pubmed.ncbi.nlm.nih.gov

Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report. [2022]