Osimertinib + Chemotherapy for Lung Cancer

Recruiting at 7 trial locations

Overseen By Mark Kris, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Osimertinib

Disqualifiers: Pregnancy, Small cell histology, others

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

Compensation: Varies

Number of Visits: 2

11 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety of combining Osimertinib with either Cisplatin or Carboplatin (at different dose levels) and Etoposide, to find out what effects, if any, this combination of drugs has on people with EGFR mutant lung cancer.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Osimertinib in treating lung cancer?

Osimertinib has shown effectiveness in treating non-small cell lung cancer (NSCLC) with specific genetic mutations, particularly the EGFR T790M mutation, which is a common resistance mechanism to earlier treatments. It has been approved by the FDA for patients with this mutation who have not responded to previous therapies, demonstrating good activity and less toxicity compared to other treatments. ^{1 2 3 4 5}

What safety data exists for the combination of Osimertinib and Chemotherapy in humans?

The combination of etoposide (VP-16) and cisplatin has been studied, showing some antitumor effects but also significant side effects like myelosuppression (reduced bone marrow activity), nausea, vomiting, and hair loss. In some studies, the combination was associated with acceptable toxicity levels, but there were instances of severe side effects, including two drug-related deaths due to infections. ^{6 7 8 9 10}

What makes the drug combination of Osimertinib, Etoposide, and Platinum unique for lung cancer treatment?

The combination of Osimertinib, Etoposide, and Platinum is unique because it combines a targeted therapy (Osimertinib, which blocks specific proteins in cancer cells) with chemotherapy agents (Etoposide and Platinum) that have shown synergy in treating non-small cell lung cancer, potentially enhancing effectiveness compared to using these drugs individually. ^{11 12 13 14 15}

Research Team

Helena Yu, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults over 18 with advanced non-small cell lung cancer that has specific mutations (EGFR, RB1, P53). They should have good physical function and organ health, be able to swallow pills, and not have had certain treatments or surgeries recently. Pregnant women and those with small cell lung cancer are excluded.

Inclusion Criteria

Written informed consent

My cancer has a specific genetic change known as an EGFR mutation.

I have either not started EGFR TKI treatment or began osimertinib less than 9 weeks ago.

Exclusion Criteria

Pregnant or lactating women

I have not had any radiation therapy in the week before starting the treatment.

I have not had major surgery within the last week.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Participants receive osimertinib 80mg orally daily for 9 weeks

9 weeks

Regular visits as per protocol

Combination Chemotherapy

Participants receive osimertinib with cisplatin or carboplatin and etoposide for cycles 4-7

12 weeks

Visits every cycle

Osimertinib Monotherapy

Participants continue with osimertinib monotherapy from cycle 8 onward

Indefinite

Every 2 cycles post-chemo (Cycles 8, 10, 12, etc.)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Etoposide
• Osimertinib
• Platinum

Trial Overview The study tests the safety of Osimertinib combined with platinum-based drugs (Cisplatin or Carboplatin) and Etoposide in patients. It aims to find the best dose levels and see how this drug mix affects people with EGFR mutant lung cancers.

Participant Groups

Group I: Osimertinib, Platinum (cisplatin or carboplatin) and Etoposide Experimental Treatment 3 Interventions

Initially, 6 patients will be enrolled and will begin treatment with osimertinib 80mg orally daily (3 who will be receiving cisplatin and 3 who will be receiving carboplatin). Cisplatin or carboplatin treatment will be decided by the treating physician prior to study registration. After 9 weeks (+/- 1 week)( 3 cycles) on osimertinib alone, carboplatin or cisplatin and etoposide will be added. Carboplatin is doses at an AUC of 5 or cisplatin at 60mg/m2 will be given on C4D1. Etoposide is dosed at 100mg/m2 given on Days 1-3 of C4. Only patients on osimertinib 80mg orally daily at the start of cycle 4 will be included in the 3+3 dose de-escalation portion of the study. Chemotherapy and osimertinib will be administered concurrently during cycles 4-7, and from cycle 8 onward, osimertinib monotherapy will be continued. Patients will present every 2 cycles post-chemo (Cycles 8, 10, 12, etc.)

Etoposide is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Etoposide for:

• Testicular cancer
• Small cell lung cancer
• Non-Hodgkin lymphoma
• Acute myeloid leukemia

Approved in European Union as Etoposide for:

• Testicular cancer
• Small cell lung cancer
• Non-Hodgkin lymphoma
• Acute myeloid leukemia

Approved in Canada as Etoposide for:

• Testicular cancer
• Small cell lung cancer
• Non-Hodgkin lymphoma
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

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 (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, 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]

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 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]

In a phase II trial involving 51 patients with non-small cell lung cancer (NSCLC), VP16-213 showed minimal activity, with only 4% of patients achieving partial responses lasting 5 to 6 months.

The main side effects of VP16-213 included myelosuppression, which was the dose-limiting toxicity, along with other adverse effects like nausea, vomiting, and chills during infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of VP16-213 in non-small cell lung cancer (NSCLC). Chapman, R., Itri, L., Gralla, R., et al.[2019]

The combination of etoposide (VP 16) and cis-diamminedichloroplatinum (DDP) showed poor overall antitumor effects against Lewis lung carcinoma cell lines, with high acute toxicity observed.

Administering VP 16 before DDP resulted in a significant reduction in metastasis while maintaining acceptable levels of toxicity, suggesting a potential strategy for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide prior to cis-diamminedichloroplatinum in combination chemotherapy: in vitro and in vivo studies. Zupi, G., Greco, C., Sacchi, A., et al.[2019]

In a phase II trial involving 51 patients with metastatic non-small-cell lung cancer (NSCLC), VP-16-213 showed a low overall response rate of only 4%, with partial responses occurring exclusively in previously untreated patients.

The treatment was associated with significant side effects, including myelosuppression and two drug-related deaths from septicemia, indicating that while it has minimal efficacy, it also poses safety risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of VP-16-213 in non-small-cell lung cancer. Itri, LM., Gralla, RJ., Chapman, RA., et al.[2013]

VP 16-213, a new semisynthetic epipodophyllotoxin, demonstrated clinically valuable antitumor activity in a phase II trial involving 33 patients with solid tumors and acute leukemias, particularly showing promising results in patients with oat cell carcinoma of the lung.

The drug was generally well tolerated, but it commonly caused side effects like leukothrombopenia and hair loss, indicating a need for further studies to optimize its dosage and explore its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapeutic experiences using the new podophyllotoxin derivative VP 16-213 in malignant human tumors]. Jungi, WF., Senn, HJ., Beckmann, C., et al.[2013]

Temozolomide combined with olaparib shows promise as a treatment option for patients with small-cell lung cancer who have progressive disease after standard etoposide and platinum-based therapy.

The study emphasizes the use of co-clinical trials with patient-derived xenografts to enhance biomarker discovery, potentially leading to more personalized and effective treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide plus PARP Inhibition in Small-Cell Lung Cancer: Could Patient-Derived Xenografts Accelerate Discovery of Biomarker Candidates? Pacheco, JM., Byers, LA.[2019]

References

1. 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]

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

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

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

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

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

Osimertinib: First Global Approval. [2022]

5. 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]

6. Germany pubmed.ncbi.nlm.nih.gov

Phase II trial of VP16-213 in non-small cell lung cancer (NSCLC). [2019]

7. England pubmed.ncbi.nlm.nih.gov

Etoposide prior to cis-diamminedichloroplatinum in combination chemotherapy: in vitro and in vivo studies. [2019]

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

Phase II trial of VP-16-213 in non-small-cell lung cancer. [2013]

9. Switzerland pubmed.ncbi.nlm.nih.gov

[Therapeutic experiences using the new podophyllotoxin derivative VP 16-213 in malignant human tumors]. [2013]

10. England pubmed.ncbi.nlm.nih.gov

Phase I and pharmacologic study of the arotinoid Ro 40-8757 in combination with cisplatin and etoposide in patients with non-small cell lung cancer. [2019]

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

Chemotherapy for metastatic non-small cell bronchogenic carcinoma: cyclophosphamide, doxorubicin, and etoposide versus mitomycin and vinblastine (EST 2575, generation IV). [2013]

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

The European Organization for Research and Treatment of Cancer (EORTC) trials of new agents for advanced non-small cell lung cancer. [2018]

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

Temozolomide plus PARP Inhibition in Small-Cell Lung Cancer: Could Patient-Derived Xenografts Accelerate Discovery of Biomarker Candidates? [2019]

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

VP-16 and cisplatin in the treatment of non-small-cell lung cancer. [2013]

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

Etoposide in the management of non-small cell lung cancer. [2019]