Osimertinib + Necitumumab for Lung Cancer

Recruiting at 16 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must be taking: Osimertinib

Must not be taking: CYP3A4 inducers

Disqualifiers: Interstitial lung disease, Active malignancies, others

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

Compensation: Varies

Number of Visits: 2

Duration: 21 days per cycle

138 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking any previous EGFR-TKI medications at least 7 days before joining, except for those on osimertinib in certain cohorts who can continue. Additionally, you must avoid medications or supplements that strongly affect CYP3A4 enzymes.

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

Osimertinib has been shown to be effective in treating non-small cell lung cancer (NSCLC) with specific genetic mutations, improving disease-free survival in early-stage cases and showing excellent activity in metastatic cases. It is generally well tolerated and has a manageable safety profile. ^{1 2 3 4 5}

What safety information is available for the combination of Osimertinib and Necitumumab in humans?

Osimertinib has been studied in patients with lung cancer, and common side effects include diarrhea, rash, dry skin, and nail problems. Serious side effects occurred in 28% of patients, and 5.6% stopped treatment due to these effects. ^{1 6 7 8 9}

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

The combination of Osimertinib and Necitumumab is unique because Osimertinib is a third-generation drug that specifically targets mutations in the EGFR gene, which are common in certain lung cancers, and is known for its effectiveness and lower toxicity compared to other treatments. This combination may offer a novel approach by potentially enhancing the effectiveness of treatment through dual targeting of cancer pathways. ^{1 3 4 10 11}

What is the purpose of this trial?

This phase I trial studies the safety, side effects and best dose of necitumumab when given together with osimertinib in treating patients with EGFR-mutant non-small cell lung cancer that is stage IV or has come back after a period of improvement (recurrent) and who have progressed on a previous EGFR tyrosine kinase inhibitor. Immunotherapy with monoclonal antibodies, such as necitumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving necitumumab with osimertinib may be safe, tolerable in treating patients with EGFR-mutant non-small cell lung cancer.

Research Team

Jonathan W. Riess

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Eligibility Criteria

This trial is for adults over 18 with stage IV or recurrent non-small cell lung cancer (NSCLC) that has specific EGFR mutations and worsened after previous treatments. Participants must be able to swallow pills, have a life expectancy of more than 3 months, good organ function, and agree to use contraception. It's not for those with certain heart issues, uncontrolled illnesses, recent major surgery, interstitial lung disease history, pregnant/breastfeeding women, or HIV-positive patients on antiretrovirals.

Inclusion Criteria

You meet certain requirements for the dose escalation and expansion groups A, B, C, D, and E.

You have a specific amount of disease that can be measured using a standard method called RECIST 1.1.

You are expected to live for at least 3 more months.

Exclusion Criteria

I do not have any unmanaged ongoing illnesses.

I have a heart condition related to abnormal heart rhythms.

My heart's pumping ability is below normal.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive osimertinib orally once daily and necitumumab intravenously on days 1 and 8, with cycles repeating every 21 days in the absence of disease progression or unacceptable toxicity.

21 days per cycle

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up visits at 4 weeks, 8 weeks, every 12 weeks for 1 year, and annually thereafter.

Up to 1 year

Multiple visits (in-person)

Treatment Details

Interventions

• Necitumumab
• Osimertinib

Trial Overview The trial tests the combination of two drugs: Necitumumab (an immunotherapy drug) and Osimertinib (a drug blocking enzymes needed by cancer cells). The goal is to see if this combo is better at treating NSCLC compared to current methods. Patients will also undergo various scans and provide biospecimens to assess treatment effects.

Participant Groups

Group I: Treatment (osimertinib, necitumumab) Experimental Treatment 7 Interventions

Patients receive osimertinib PO QD on days 1-21 and necitumumab IV over 60 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and CT scan, MRI and blood sample collection throughout the study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

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]

In a study of 46 treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer, alternating therapy with osimertinib and afatinib resulted in a median progression-free survival of 21.3 months, indicating promising efficacy despite not meeting the primary endpoint of 12-month progression-free survival probability.

The treatment was generally well-tolerated, with common side effects including diarrhea (73.9%) and rash (63.0%), and only a few cases of serious pneumonitis, suggesting a manageable safety profile for this alternating therapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L). Hayashi, H., Yonesaka, K., Nakamura, A., 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]

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 (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]

In a phase 2 study involving 122 patients with advanced nonsquamous NSCLC and EGFR-sensitizing mutations, the combination of osimertinib and bevacizumab did not significantly improve progression-free survival (PFS) compared to osimertinib alone, with median PFS of 22.1 months versus 20.2 months, respectively.

The study reported a higher incidence of grade 3 or worse adverse events in the combination therapy group (56%) compared to the monotherapy group (48%), indicating that while the combination did not enhance efficacy, it may increase the risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study. Kenmotsu, H., Wakuda, K., Mori, K., et al.[2023]

Osimertinib, a treatment for metastatic EGFRm T790M non-small-cell lung cancer, has been analyzed using newly developed and validated LC-MC/MS methods across various biological matrices, including plasma, urine, and cerebrospinal fluid.

The assays demonstrated high selectivity, accuracy, and robustness, successfully analyzing over 20,000 clinical samples, which supports the effective clinical development of osimertinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of osimertinib in human plasma, urine and cerebrospinal fluid. Mitchell, R., Bailey, C., Ewles, M., et al.[2022]

In a phase 2 study involving 210 patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), osimertinib demonstrated significant efficacy, with 70% of patients achieving an objective response, including 3% with complete responses.

Osimertinib was found to have manageable side effects, although serious adverse events occurred in 25% of patients, with interstitial lung disease being the only fatal event possibly related to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Goss, G., Tsai, CM., Shepherd, FA., 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]

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. Ireland pubmed.ncbi.nlm.nih.gov

Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L). [2022]

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

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC. [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. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: Outcome of Osimertinib Treatment in Lung Adenocarcinoma Patients With Acquired KRAS Mutations. [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. Greece pubmed.ncbi.nlm.nih.gov

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

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

Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Determination of osimertinib in human plasma, urine and cerebrospinal fluid. [2022]

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

Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. [2022]

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

Osimertinib: First Global Approval. [2022]