Combination Therapy for Non-Small Cell Lung Cancer

Recruiting at 12 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: MedImmune LLC

Must not be taking: Immunosuppressants, Herbal supplements

Disqualifiers: Venous thrombosis, Myocardial infarction, Autoimmune disorders, others

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

Compensation: Varies

Number of Visits: Unknown

43 Participants Needed

Trial Summary

What is the purpose of this trial?

The objective of this study is to investigate the safety, tolerability, and antitumor activity of novel combination therapies administered in participants with advanced EGFRm NSCLC.

Will I have to stop taking my current medications?

The trial requires stopping certain medications before starting. You must stop taking any EGFR TKI (a type of cancer drug) 14 days before the trial and any other cancer treatments 21 days before. Herbal supplements and medications that affect liver enzymes (CYP3A4) must also be stopped for Arm A.

What data supports the effectiveness of the drug combination therapy for non-small cell lung cancer?

Osimertinib, a key component of the combination therapy, is effective for treating non-small cell lung cancer with specific EGFR mutations, as it has been shown to prolong survival and has received FDA approval for its use in these cases. ^{1 2 3 4 5}

Is the combination therapy for non-small cell lung cancer safe for humans?

Osimertinib (Tagrisso) has been studied for non-small cell lung cancer and is generally well tolerated, but it can cause side effects like diarrhea, rash, dry skin, and nail issues. Serious side effects occurred in about 28% of patients, and some stopped treatment due to these effects. Overall, it has a manageable safety profile with no new safety concerns identified. ^{1 6 7 8 9}

How is the drug combination therapy for non-small cell lung cancer unique?

This combination therapy is unique because it includes osimertinib, a third-generation drug specifically designed to target the EGFR T790M mutation, which is a common cause of resistance to earlier treatments. Osimertinib is known for its effectiveness and lower toxicity compared to other treatments, making it a promising option for patients with specific genetic mutations in their cancer. ^{1 3 5 10 11}

Research Team

MedImmune LLC

Principal Investigator

MedImmune LLC

Eligibility Criteria

This trial is for adults over 18 with advanced non-small cell lung cancer that has a specific mutation (EGFRm). Participants must have tried one EGFR inhibitor and can't be T790M positive. They should weigh at least 35 kg, be fairly active (ECOG of 0 or 1), and not have used certain medications recently. People with untreated brain metastases, recent heart issues, or autoimmune diseases in the last three years cannot join.

Inclusion Criteria

I weigh at least 35 kilograms.

My lung cancer is advanced or has spread, and tests show it has EGFR mutations.

I am fully active or can carry out light work.

Exclusion Criteria

I have had an autoimmune or inflammatory disorder in the last 3 years.

I have taken an EGFR inhibitor within the last 14 days.

I have had a blood clot in the last 3 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-escalation Treatment

Participants receive intravenous oleclumab and oral AZD4635 or osimertinib in a dose-escalation format to determine safety and tolerability

4 weeks

Bi-weekly visits for intravenous administration

Dose-expansion Treatment

Participants receive the recommended phase 2 dose (RP2D) of oleclumab and osimertinib until disease progression or unacceptable toxicity

Until disease progression or unacceptable toxicity

Bi-weekly visits for intravenous administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days after the last dose of study drug

Treatment Details

Interventions

• AZD4635
• MEDI9447
• Oleclumab
• Osimertinib

Trial Overview The study tests new combinations of drugs: Oleclumab with Osimertinib for those who've had one prior therapy, and Oleclumab with AZD4635 for those who've had two to four therapies. It aims to assess safety, tolerability, and how well these combos work against advanced EGFRm NSCLC.

Participant Groups

Group I: Oleclumab Dose 2 + Osimertinib Dose 1 Experimental Treatment 2 Interventions

In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD. In Part 2 (dose-expansion), participants (including participants dosed at the RP2D in Part 1) will receive IV oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD until documentation of disease progression, intolerable toxicity, or development of other reason for treatment discontinuation, whichever occurs first.

Group II: Oleclumab Dose 2 + AZD4635 Dose 2 Experimental Treatment 2 Interventions

In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral AZD4635 Dose 2 QD.

Group III: Oleclumab Dose 1 + Osimertinib Dose 1 Experimental Treatment 2 Interventions

In Part 1 (dose-escalation), participants will receive intravenous oleclumab (MEDI9447) Dose 1 every 2 weeks (Q2W) and oral osimertinib Dose 1 once daily (QD).

Group IV: Oleclumab Dose 1 + AZD4635 Dose 2 Experimental Treatment 2 Interventions

In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 2 QD.

Group V: Oleclumab Dose 1 + AZD4635 Dose 1 Experimental Treatment 2 Interventions

In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 1 QD.

Who Is Running the Clinical Trial?

MedImmune LLC

Lead Sponsor

Trials

348

Recruited

788,000+

Founded

1988

Headquarters

Gaithersburg, USA

Known For

Biologics research

Top Products

Synagis, FluMist

Dr. Reginald Seeto

MedImmune LLC

Chief Medical Officer since 2008

MD from University of Sydney, B.Sc. from University of Sydney

Peter Greenleaf

MedImmune LLC

Chief Executive Officer since 2006

MBA from St. Joseph’s University, B.S. from Western Connecticut State University

Findings from Research

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 (AZD9291) is effective in prolonging survival for non-small cell lung cancer patients with EGFR mutations, but resistance to the drug is a common issue, prompting the need to explore resistance mechanisms.

In this study, AZD9291-resistant NSCLC cell lines were established, revealing significant changes in circular RNA (circRNA) expression profiles, which may contribute to drug resistance and could serve as potential targets for future gene therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines. Chen, T., Luo, J., Gu, Y., 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]

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 is a third-generation EGFR tyrosine kinase inhibitor specifically designed to target the EGFR T790M mutation, which is a common cause of resistance to first-line EGFR TKIs in advanced non-small-cell lung cancer.

This review highlights the efficacy of osimertinib in clinical trials, demonstrating its ability to effectively treat patients with non-small-cell lung cancer harboring the T790M mutation while minimizing effects on normal EGFR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib making a breakthrough in lung cancer targeted therapy. Zhang, H.[2020]

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 study involving six patients with EGFR-mutated lung adenocarcinoma, the combination of osimertinib and ramucirumab was found to be generally safe, with only one case of dose-limiting toxicity (grade 3 appetite loss) and no other severe adverse events reported.

Five out of six patients showed a partial response to the treatment, with a median progression-free survival of 9.2 months for those with the EGFR T790M mutation, suggesting promising efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation. Akamatsu, H., Ozawa, Y., Oyanagi, J., et al.[2023]

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 study of 47 patients with advanced non-small cell lung cancer (NSCLC) who had EGFR mutations, those who received osimertinib immediately after nivolumab treatment experienced a significantly higher rate of severe liver toxicity (57.1%) compared to those treated with other drugs before osimertinib (5.0%).

The findings suggest that administering osimertinib right after immune checkpoint inhibitors like nivolumab may increase the risk of serious adverse events, particularly hepatotoxicity, highlighting the need for careful treatment sequencing in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe hepatotoxicity due to osimertinib after nivolumab therapy in patients with non-small cell lung cancer harboring EGFR mutation. Yamaguchi, O., Kaira, K., Kawasaki, T., et al.[2022]

The combination of osimertinib and platinum-based chemotherapy (OPP) demonstrated a high objective response rate of 90.9% in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer, indicating strong efficacy.

The treatment was well-tolerated, with no treatment-related deaths and an acceptable safety profile, as only 14.9% of patients discontinued due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study. Saito, R., Sugawara, S., Ko, R., et al.[2023]

References

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

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

2. Singapore pubmed.ncbi.nlm.nih.gov

Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines. [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. 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]

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

Osimertinib making a breakthrough in lung cancer targeted therapy. [2020]

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. Greece pubmed.ncbi.nlm.nih.gov

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation. [2023]

9. France pubmed.ncbi.nlm.nih.gov

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

10. Singapore pubmed.ncbi.nlm.nih.gov

Severe hepatotoxicity due to osimertinib after nivolumab therapy in patients with non-small cell lung cancer harboring EGFR mutation. [2022]

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

Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study. [2023]