Osimertinib Rechallenge for Lung Cancer

(OCELOT Trial)

Recruiting at9 trial locations

Overseen by Mark Vincent, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Mark Vincent

Must be taking: Osimertinib

Must not be taking: CYP3A4 inducers

Disqualifiers: Pregnancy, Uncontrolled diseases, Brain metastases, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase II single-armed study will examine the clinical utility of retreating patients with osimertinib, in the third-line, following first-line treatment with osimertinib and second-line treatment with platinum and pemetrexed chemotherapy. The current standard of care for first-line Epidermal Growth Factor Receptor (EGFR) mutated Advanced Non-Small Cell Lung Cancer (aNSCLC) is osimertinib, followed by cytotoxic chemotherapy. The repeat of osimertinib following previous treatment failure is investigational, although supported by scientific rationale. The dosing and scheduling of osimertinib follows its use in approved settings. The investigators examine its tolerability and efficacy in this setting to ensure osimertinib is a safe third-line option for patients with Epidermal Growth Factor Receptor mutated (EGFR+) Advanced Non-Small Cell Lung Cancer(aNSCLC).

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications or herbal supplements that are known to strongly affect a liver enzyme called CYP3A4 at least 3 weeks before starting the study treatment. It's best to discuss your current medications with the study team to see if any need to be adjusted.

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

Osimertinib has shown effectiveness in treating non-small cell lung cancer (NSCLC) with specific genetic mutations, particularly in patients who have developed resistance to earlier treatments. It has been approved for use in these cases due to its ability to target the EGFR T790M mutation, and clinical trials have demonstrated its ability to prolong disease-free survival in patients with early-stage NSCLC. ^{1 2 3 4 5}

Is osimertinib safe for humans?

Osimertinib is generally well tolerated in humans, with common side effects including diarrhea, rash, dry skin, and nail issues. Serious side effects occurred in 28% of patients, and 5.6% stopped treatment due to these effects. Overall, it has a manageable safety profile with no new safety concerns identified. ^{1 3 5 6 7}

How is the drug Osimertinib unique for treating lung cancer?

Osimertinib is unique because it specifically targets and inhibits a protein called EGFR (epidermal growth factor receptor) that is often mutated in lung cancer, making it effective for patients with these specific mutations. This targeted approach can be more effective and have fewer side effects compared to traditional chemotherapy, which attacks all rapidly dividing cells. ^{8 9 10 11 12}

Research Team

Mark Vincent, MD

Principal Investigator

London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

Eligibility Criteria

Adults with advanced non-small cell lung cancer (NSCLC) and specific EGFR mutations can join this trial. They must have had osimertinib as a first treatment, platinum plus pemetrexed chemotherapy second, and be fit for third-line therapy. Key requirements include measurable disease by CT/MRI, life expectancy over 12 weeks, ECOG/WHO-PS of 0-3, and use of effective contraception if applicable.

Inclusion Criteria

Patients enrolling for the third-line osimertinib rechallenge need to have specific information about their medical history and previous treatments available. They must have received a certain type of chemotherapy in the second-line treatment, and have measurable disease that can be accurately assessed by CT or MRI scans at baseline and follow-up visits.

I have all my basic health information and specific dates related to my lung cancer treatment ready.

I am not pregnant, not breastfeeding, and using effective birth control or am not able to have children.

Exclusion Criteria

If you have not started treatment with osimertinib yet, you should not have had any previous systemic therapy for EGFR+ advanced Non-Small Cell Lung Cancer. Additionally, your heart should not have certain abnormalities, and you should not have any factors that increase the risk of heart rhythm abnormalities.

I don't have severe side effects from past treatments, except for hair loss or mild nerve pain from platinum-based therapy.

Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

First-line Treatment

Participants receive osimertinib, 80 mg, oral, daily as first-line treatment

Variable, based on progression

Second-line Treatment

Participants receive platinum (carboplatin or cisplatin) + pemetrexed chemotherapy as second-line treatment

Variable, based on progression

Third-line Treatment

Participants receive osimertinib rechallenge, 80 mg, oral, daily as third-line treatment

Variable, based on progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Osimertinib (Tyrosine Kinase Inhibitor)
• Platinum + Pemetrexed (Chemotherapy)

Trial Overview The study tests the effectiveness of reusing osimertinib in third-line treatment after it was used first-line followed by platinum-pemetrexed chemo. It's a phase II trial to see if retreating with osimertinib is safe and works well for patients whose cancer has progressed despite previous treatments.

Participant Groups

Group I: Treatment Arm Experimental Treatment 3 Interventions

First-line treatment = osimertinib, 80 mg, oral, daily; Second-line treatment = platinum (carboplatin or cisplatin) + pemetrexed chemotherapy, prescribed as per institutional standards; Third-line treatment = osimertinib rechallenge, 80 mg, oral, daily. Patients may enter the study at first-line treatment, second-line treatment, or third-line treatment. This is dependent on meeting the eligibility criteria.

Who Is Running the Clinical Trial?

Mark Vincent

Lead Sponsor

Trials

1

Recruited

200+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

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]

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 significantly improves disease-free survival (DFS) in adults with completely resected, early-stage EGFR mutation-positive non-small cell lung cancer (NSCLC), as shown in the pivotal ADAURA trial, regardless of prior adjuvant chemotherapy.

The treatment is well tolerated with a manageable safety profile, and it does not negatively impact health-related quality of life, making it a suitable option for adjuvant therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC. Frampton, JE.[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 (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 (Tagrisso) is an approved adjuvant treatment for non-small cell lung cancer patients with specific tumor mutations, highlighting its targeted therapeutic approach.

Common side effects of osimertinib include blood-related issues like leukopenia and thrombocytopenia, as well as gastrointestinal and skin reactions, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Drug for Lung Cancer. Aschenbrenner, DS.[2023]

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]

Carboplatin has shown comparable efficacy to cisplatin in treating non-small cell lung cancer (NSCLC) and can be effectively used in combination chemotherapy, providing similar survival benefits.

Ongoing clinical trials are exploring various strategies to optimize carboplatin use, including dose adjustments, combinations with other treatments like stem-cell support and radiation therapy, and interactions with new agents like TAXOL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin in the treatment of non-small cell lung cancer: a review. Comis, RL.[2018]

In a study of 58 patients with recurrent advanced non-small cell lung cancer (NSCLC), platinum doublet re-challenge chemotherapy showed a disease control rate of 70.7% and a median survival time of 470 days, indicating its potential efficacy as a treatment option.

The treatment was particularly effective for patients who had a partial response to first-line chemotherapy or a treatment-free interval of over 90 days, with manageable toxicity levels, except for one case of drug-induced pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Evaluation of the Efficacy and Safety of Platinum Doublet Re-Challenge Chemotherapy in Patients with Recurrent Advanced Non-Small Cell Lung Cancer]. Mori, A., Hirose, T., Tamura, A., et al.[2016]

In a multicenter phase II trial involving 80 patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy, docetaxel demonstrated antitumor activity, with a partial response rate of 16% and a median survival time of 7 months.

Docetaxel was generally well tolerated, although 77% of patients experienced grade IV neutropenia; however, this was usually of short duration, and there were no fatal infections reported, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of docetaxel in platinum-treated non-small-cell lung cancer: results of a phase II multicenter trial. Gandara, DR., Vokes, E., Green, M., et al.[2018]

In a systematic review of 11 studies involving 607 non-small cell lung cancer (NSCLC) patients, TAXs-based doublets showed a significantly higher overall response rate of 37.8% compared to 22% for PEM-based combinations, indicating that TAXs may be more effective as second-line therapy after platinum-based chemotherapy failure.

The median progression-free survival (PFS) was also better for TAXs at 5.3 months compared to 3.9 months for PEM, suggesting that TAXs-based treatments may provide a more favorable outcome for patients relapsing after initial treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platinum rechallenge in patients with advanced NSCLC: a pooled analysis. Petrelli, F., Coinu, A., Cabiddu, M., et al.[2022]

In a study of 37 heavily pretreated patients with advanced non-small cell lung cancer (NSCLC), pemetrexed demonstrated a disease control rate of 54.1%, indicating its effectiveness as a salvage therapy beyond second-line treatment.

The median progression-free survival was 8.05 months and overall survival was 19.29 months, suggesting that pemetrexed is both efficacious and tolerable for patients with advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of pemetrexed as second-line therapy or beyond in patients with advanced non-small cell lung cancer]. Li, J., Wang, J., Hao, X., et al.[2021]

References

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

Osimertinib: First Global Approval. [2022]

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

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

3. France pubmed.ncbi.nlm.nih.gov

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC. [2022]

4. 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]

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

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

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

New Adjuvant Drug for Lung Cancer. [2023]

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

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

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

Carboplatin in the treatment of non-small cell lung cancer: a review. [2018]

9. Japan pubmed.ncbi.nlm.nih.gov

[Evaluation of the Efficacy and Safety of Platinum Doublet Re-Challenge Chemotherapy in Patients with Recurrent Advanced Non-Small Cell Lung Cancer]. [2016]

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

Activity of docetaxel in platinum-treated non-small-cell lung cancer: results of a phase II multicenter trial. [2018]

11. Ireland pubmed.ncbi.nlm.nih.gov

Platinum rechallenge in patients with advanced NSCLC: a pooled analysis. [2022]

12. China pubmed.ncbi.nlm.nih.gov

[Efficacy of pemetrexed as second-line therapy or beyond in patients with advanced non-small cell lung cancer]. [2021]