Osimertinib Rechallenge for Lung Cancer

(OCELOT Trial)

Recruiting at 9 trial locations

Overseen By Daniel Breadner, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mark Vincent

Must be taking: Osimertinib

Must not be taking: CYP3A4 inducers

Disqualifiers: Pregnancy, Uncontrolled diseases, Brain metastases, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether taking osimertinib, a targeted therapy for lung cancer, again after previous treatments can benefit people with advanced non-small cell lung cancer. Initially, patients received osimertinib, followed by a different chemotherapy. Researchers now aim to determine if returning to osimertinib will be effective. The trial targets patients with a specific mutation in their cancer called EGFR. It may suit those previously treated with osimertinib whose lung cancer has spread. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that osimertinib is generally well-tolerated by patients with non-small cell lung cancer (NSCLC). Most patients manage the treatment's side effects, which are considered manageable. This drug effectively treats lung cancer with specific genetic changes and has demonstrated promising safety results.

Studies indicate that the combination of platinum and pemetrexed is also safe for patients with advanced NSCLC. Patients have tolerated this chemotherapy mix well, and its safety is supported in various treatment settings.

Both treatments have a strong track record of safety for their approved uses. Although using osimertinib again after previous treatment is a new approach, existing safety data is encouraging. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about osimertinib for lung cancer because it targets a specific mutation in the EGFR gene, which is a common driver of cancer growth in certain lung cancer patients. Unlike traditional chemotherapy, which attacks rapidly dividing cells indiscriminately, osimertinib specifically inhibits the mutated protein, potentially offering a more precise treatment with fewer side effects. Additionally, the concept of an "osimertinib rechallenge" is unique, as it suggests that patients might benefit from reintroducing the drug after initial treatment, potentially overcoming resistance that often develops with targeted therapies. This approach could provide a new strategy for managing lung cancer after traditional therapies have been exhausted.

What evidence suggests that osimertinib rechallenge might be an effective treatment for advanced non-small cell lung cancer?

Research has shown that osimertinib effectively treats patients with advanced non-small cell lung cancer (NSCLC) who have specific changes in their Epidermal Growth Factor Receptor (EGFR). In everyday medical practice, lower doses of osimertinib have helped patients who did not respond to their initial treatment. In this trial, participants may receive osimertinib as a first-line treatment or as a rechallenge after other treatments. Additionally, combining osimertinib with chemotherapy has extended the time patients live without their cancer worsening. Osimertinib also effectively controls cancer that has spread to the brain. Studies have shown that the combination of platinum and pemetrexed, which participants in this trial may receive as a second-line treatment, is effective for patients with advanced NSCLC, providing good responses and survival benefits. This combination has been successfully used in patients who have already tried other treatments. ^{1 3 4 6 7}

Who Is on the Research Team?

Mark Vincent, MD

Principal Investigator

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

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Osimertinib
• Platinum + Pemetrexed

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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]

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 (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]

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]

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]

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 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]

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]

Citations

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Tagrisso plus chemotherapy demonstrated a median ... Over the past decade, Tagrisso has consistently delivered strong survival benefits and tolerable safety across all stages of non-small cell lung ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11304135/

Real-world efficacy of low dose osimertinib as second-line ... Treatment with low dose osimertinib demonstrated good efficacy and tolerability in EGFR-mutated advanced NSCLC patients who failed first-line treatment.

3. sciencedirect.com sciencedirect.com/science/article/pii/S246829422500036X

Real-world comparative outcomes of EGFR-TKIs for first- ... This study compared real-world clinical outcomes of 1L osimertinib versus 1st or 2nd generation EGFR-TKIs (1/2G-TKIs) in patients with EGFR+ mNSCLC.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2306434

Osimertinib with or without Chemotherapy in EGFR- ... First-line treatment with osimertinib–chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR- ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7098834/

Osimertinib for Patients With Non–Small-Cell Lung Cancer ... In two phase II studies of patients with T790M-positive NSCLC and CNS metastasis, osimertinib demonstrated a CNS ORR of 54% and a CNS disease control rate of 92 ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1525730425001299

Osimertinib as First-Line Treatment for Patients With ... This study supports the long-term efficacy of OSI, with PFS and OS comparable to those in the FLAURA trial in a Japanese real-world setting.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02496663

NCT02496663 | Osimertinib and Necitumumab in Treating ... Giving necitumumab with osimertinib may be safe, tolerable in treating patients with EGFR-mutant non-small cell lung cancer. Detailed Description. PRIMARY ...