Azacytidine + Chemotherapy + Durvalumab for Non-Small Cell Lung Cancer

Overseen By Deneise C Francis, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Systemic corticosteroids

Disqualifiers: Inoperable, T4 tumors, Autoimmune, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 9 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to treat early-stage non-small cell lung cancer (NSCLC) before surgery. Researchers are testing whether inhaling the drug azacytidine (AZA) can enhance the effects of standard chemotherapy (including carboplatin) and another drug, durvalumab. The goal is to determine the safest and most effective dose of inhaled AZA, which targets the lungs directly and may reduce side effects. Individuals with early-stage NSCLC that can be surgically removed may qualify for this study. Participants should be willing to undergo surgery after the trial treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you must stop taking your current medications. However, you cannot take systemic corticosteroids above certain levels or inhaled corticosteroids within 14 days before starting the study treatment. Herbal and natural remedies with immune-modulating effects should also be stopped 7 days before the study treatment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found that inhaled Azacitidine (AZA) mostly remained in the lungs and did not significantly enter the bloodstream, reducing the likelihood of side effects in other parts of the body. It was well-tolerated, with no major issues such as low blood cell counts, lung problems, liver damage, or kidney damage at certain doses.

Research on durvalumab, a drug already approved for other lung cancer treatments, has shown it to be generally safe. Some individuals experienced minor side effects like changes in thyroid or liver function, and a few had colitis (inflammation of the colon). However, these effects were manageable.

In this clinical trial, researchers are exploring the combination of inhaled AZA with durvalumab and chemotherapy to treat early-stage non-small cell lung cancer (NSCLC). Since AZA is still under investigation for NSCLC, its safety is being closely monitored. However, durvalumab's existing approval provides some reassurance about its safety in the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination for non-small cell lung cancer because it introduces aerosolized azacytidine, which is not typically used in this way. Unlike standard treatments such as traditional chemotherapy that rely on intravenous administration, this method delivers azacytidine directly to the lungs as an aerosol, potentially leading to more targeted action with fewer systemic side effects. Additionally, the inclusion of durvalumab, an immune checkpoint inhibitor, may enhance the body's immune response against cancer cells, offering a fresh approach compared to conventional chemotherapy alone. These innovations could lead to more effective and personalized treatment options for patients.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research has shown that durvalumab, one of the treatments in this trial, is effective for certain types of lung cancer. Studies have found that it can reduce the risk of cancer growth or spread by 48% in specific patients. Additionally, it helps patients live about 11 months longer without their cancer worsening compared to those who do not take it.

For azacytidine (AZA), another treatment option in this trial, early research suggests that inhaling AZA might benefit lung cancer patients by directly targeting cancer cells in the lungs. In animal studies, it stopped lung cancer growth and reactivated genes that help fight cancer. These findings suggest that inhaled AZA could be beneficial in treating non-small cell lung cancer. ^{1 3 4 5 6}

Who Is on the Research Team?

David S Schrump, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

This trial is for people with early-stage non-small cell lung cancer (NSCLC) who are able to undergo surgery. Participants should be fit for the standard platinum-based chemotherapy combined with durvalumab, an immunotherapy drug.

Inclusion Criteria

Participants must be co-enrolled in protocol 06C0014: Prospective Evaluation of Genetic and Epigenetic Alterations in Patients with Thoracic Malignancies.

I am willing to have surgery to remove my tumor after initial treatment.

I am willing and able to have a biopsy through methods like bronchoscopy.

Exclusion Criteria

My cancer has spread to nearby tissues or organs.

I have had pneumonitis or lung disease affecting the tissue and space around the air sacs of my lungs.

I have an autoimmune disease, but it's under control or fits the exceptions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive inhaled azacytidine, durvalumab, and platinum-based chemotherapy for 3 cycles, each cycle lasting 21 days

9 weeks

4 visits per cycle (in-person)

Surgery

Participants undergo surgery to remove tumors within 3 weeks after completing treatment

3 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with visits at 1 month, 3 months, and every 3 months for up to 3 years

Up to 3 years

Multiple visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Azacytidine
• Carboplatin
• Durvalumab

Trial Overview The study tests inhaled azacytidine (an epigenetic therapy) alongside usual chemo drugs and durvalumab before surgery. It's a phase I/II trial, meaning it's checking both safety and how well this combination works as a pre-surgery treatment.

How Is the Trial Designed?

Group I: 2/ Phase II Dose Expansion Experimental Treatment 7 Interventions

Histology specific SOC platinum-based chemotherapy with durvalumab plus RP2D of aerosolized azacytidine

Group II: 1/ Phase I Dose Escalation Experimental Treatment 7 Interventions

Histology specific SOC platinum-based chemotherapy with durvalumab plus escalating/de-escalating doses of aerosolized azacytidine

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 3 trial involving 713 patients with stage III unresectable non-small-cell lung cancer, durvalumab significantly improved overall survival compared to placebo, with a 24-month survival rate of 66.3% versus 55.6%.

Durvalumab also prolonged progression-free survival, with a median duration of 17.2 months compared to 5.6 months for placebo, and no new safety concerns were identified, indicating it is a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. Antonia, SJ., Villegas, A., Daniel, D., et al.[2022]

In a study of 421 patients with stage III nonsmall-cell lung cancer (NSCLC) who completed chemoradiation, 76.5% initiated adjuvant durvalumab, indicating a strong uptake of this treatment in real-world settings.

The initiation of adjuvant durvalumab increased significantly over time, from 66% to 92%, suggesting that it has been rapidly integrated into clinical practice, particularly among patients with better performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uptake of Adjuvant Durvalumab After Definitive Concurrent Chemoradiotherapy for Stage III Nonsmall-cell Lung Cancer. Bryant, AK., Yin, H., Schipper, MJ., et al.[2023]

In a study of 34 patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiotherapy followed by durvalumab, 26.5% experienced symptomatic pneumonitis, but this did not negatively affect their overall survival or progression-free survival.

The management of pneumonitis included steroid treatment, and 70% of patients were able to safely resume durvalumab after recovery, indicating that re-challenging with durvalumab is feasible even after pneumonitis occurs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer. Hassanzadeh, C., Sita, T., Savoor, R., et al.[2022]

In a study of 35 patients with unresectable stage III non-small cell lung cancer (NSCLC) and baseline grade 1 radiation pneumonitis, durvalumab showed promising safety and effectiveness, with a median progression-free survival of 11.4 months.

Despite some patients experiencing increased pneumonitis, including 31% with grade ≥2 pneumonitis, durvalumab treatment was generally well-tolerated, suggesting it can be a viable option for this patient population after chemoradiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective multicenter cohort study of durvalumab for patients with unresectable stage III non-small cell lung cancer and grade 1 radiation pneumonitis. Sugimoto, T., Fujimoto, D., Sato, Y., et al.[2022]

In the phase III PACIFIC trial, durvalumab treatment led to a low incidence of immune-mediated adverse events (imAEs), with any-grade immune-mediated pneumonitis occurring in 9.4% of patients and grade 3/4 imAEs in only 3.4%.

Despite the occurrence of imAEs being more common with durvalumab compared to placebo, these events were generally manageable with treatments like corticosteroids, indicating that the benefits of the PACIFIC regimen outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterizing immune-mediated adverse events with durvalumab in patients with unresectable stage III NSCLC: A post-hoc analysis of the PACIFIC trial. Naidoo, J., Vansteenkiste, JF., Faivre-Finn, C., et al.[2022]

In a study of 1006 patients with stage III non-small cell lung cancer (NSCLC), early discontinuation of adjuvant durvalumab therapy was common, primarily due to tumor progression and immune-related adverse events, highlighting the need for careful monitoring during treatment.

The analysis indicated that shorter durations of durvalumab (6 or 9 months) may provide similar progression-free survival compared to the full 12-month course, suggesting that optimizing treatment duration could balance efficacy and patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De-escalating adjuvant durvalumab treatment duration in stage III non-small cell lung cancer. Bryant, AK., Sankar, K., Zhao, L., et al.[2023]

In the phase III CASPIAN study, durvalumab combined with etoposide and either cisplatin or carboplatin significantly improved overall survival in patients with extensive-stage small-cell lung cancer, with a median overall survival of 12.9 months compared to 10.5 months for the control group.

After more than 3 years of follow-up, durvalumab plus etoposide showed a 36-month overall survival rate of 17.6%, indicating that this combination is a promising first-line treatment option for extensive-stage small-cell lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. Paz-Ares, L., Chen, Y., Reinmuth, N., et al.[2022]

The combination of mocetinostat (70 mg TIW) and durvalumab was generally well tolerated in patients with advanced non-small cell lung cancer (NSCLC), with an objective response rate (ORR) of 11.5% across all phase II cohorts, indicating some effectiveness in this challenging population.

Notably, the treatment showed a higher ORR of 23.1% in patients whose disease was refractory to prior checkpoint inhibitor therapies, suggesting that mocetinostat may help overcome resistance to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study. Johnson, ML., Strauss, J., Patel, MR., et al.[2023]

In the phase III CASPIAN study, the combination of durvalumab with etoposide and either cisplatin or carboplatin significantly improved overall survival in patients with extensive-stage small-cell lung cancer compared to etoposide plus platinum alone.

Patient-reported outcomes showed that the addition of durvalumab not only maintained quality of life but also delayed the worsening of key symptoms like appetite loss, cough, and fatigue, indicating a beneficial impact on patients' overall well-being.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study. Goldman, JW., Garassino, MC., Chen, Y., et al.[2021]

The AEGEAN trial is a phase III study involving approximately 800 patients with resectable, early-stage non-small-cell lung cancer (NSCLC) that aims to evaluate the effectiveness of durvalumab combined with chemotherapy before surgery and as a monotherapy after surgery.

This study will assess key outcomes such as pathological complete response and event-free survival, potentially improving treatment strategies for patients with Stage II-III NSCLC, where current survival rates remain low despite standard postoperative chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial. Heymach, JV., Mitsudomi, T., Harpole, D., et al.[2022]

Citations

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First-in-human study of inhaled Azacitidine in patients with ... Conclusions: Inhaled Azacitidine resulted in negligible plasma levels compared to the previously reported subcutaneous administration and was well-tolerated. ...

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Study Details | NCT06694454 | Neoadjuvant Inhaled ... Objective: To find the safest and most effective dose of inhaled AZA in participants with early-stage non-small cell lung cancer (NSCLC) that can still ...

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First-in-human study of inhaled Azacitidine in patients with ... Conclusions. Inhaled Azacitidine resulted in negligible plasma levels compared to the previously reported subcutaneous administration and was well-tolerated. ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8026712/

First-in-human study of inhaled Azacitidine in patients with ... Aerosolized Azacitidine has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in murine models.

5. jto.org jto.org/article/S1556-0864(21)00371-3/fulltext

P01.05 Pilot Study of Inhaled Azacitidine in Patients With ... Aerosolized 5-Azacitidine (5-Aza) has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in ...

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Toxicity and Pharmacokinetic Studies of Aerosolized ... No significant myelosuppression, pulmonary toxicity, hepatotoxicity, or nephrotoxicity were observed at a daily dose of 2.5 mg/m2 for 7 days. Reversible lung ...