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

Overseen By David S Schrump, M.D.

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

60 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Surgery to remove the tumors is the standard treatment for people diagnosed with early stages of NSCLC. Despite complete removal of these tumors, many recur (happen again). An FDA-approved drug combination to treat early-stage NSCLC prior to the surgery is durvalumab plus standard chemotherapy. The FDA approved infusion drug azacytidine \[AZA\] is used to treat several diseases because it can rapidly kill dividing cells (including cancer cells) but it is not approved for NSCLC. An inhaled (aerosolized) form of AZA is also not approved for NSCLC. However, researchers want to know if an inhaled version of AZA can help improve treatment of people with NSCLC because inhaled AZA goes directly into the lungs with limited absorption into the bloodstream. 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 be removed by surgery. Eligibility: Adults aged 18 and older with operable early-stage NSCLC. Participants will be required to also enroll in NIH protocol 06C0014 which allows for pre- and post-treatment biopsies and bloodwork to be obtained for additional research studies. Design: Participants will be screened. They will have a physical exam with blood tests. Their medical records will be reviewed. They will have imaging scans and tests of their heart and lung functions. Participants will be required to have a tissue sample (biopsy) taken of their tumor prior to receiving study drug and again during surgery after Cycle 3; airway tissue biopsies and collection of collect bronchial (lung) fluid may also be done. Participants will receive the study treatment for 3 cycles. Each cycle is 21 days. They will need to come to the NIH Clinical Center (CC) on days 1-4 of Cycles 1-3. AZA will be given as a drug mist that can be inhaled (like the type of mist in an asthma inhaler) using a nebulizer at the NIH Clinical Center (CC) for 3 days in a row (consecutive days) during the first week of each cycle. The participant will inhale the AZA drug mist for 20 to 30 minutes each time. Participants will also receive durvalumab and a specific 2-drug assigned chemotherapy by intravenous (IV) infusion on day 4 of each cycle. Participants will have a follow-up visit 2 weeks after their last dose of study drugs. Then they will have planned surgery to remove the tumors. Participants will have additional follow-up visits at the NIH CC about 1 and 3 months after the surgery, and then for every 3 months for up to 3 years. ...

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.

What data supports the effectiveness of the drug combination Azacytidine, Carboplatin, and Durvalumab for treating non-small cell lung cancer?

Research shows that Durvalumab, when used after chemoradiotherapy, significantly improves survival in patients with stage III non-small cell lung cancer. Additionally, Durvalumab combined with other chemotherapy drugs has shown improved survival in small-cell lung cancer, suggesting potential benefits in similar settings. ^{1 2 3 4 5}

Is the combination of Azacytidine, Chemotherapy, and Durvalumab safe for humans?

Durvalumab has been studied in combination with chemotherapy for lung cancer, and while it can cause side effects like pneumonitis (lung inflammation) and other immune-related issues, it is generally considered safe for use in humans. The safety of Azacytidine in combination with chemotherapy and Durvalumab specifically for non-small cell lung cancer has not been directly addressed in the provided studies. ^{3 6 7 8 9}

What makes the Azacytidine + Chemotherapy + Durvalumab treatment unique for non-small cell lung cancer?

This treatment is unique because it combines azacytidine, a drug that can modify gene expression, with chemotherapy and durvalumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells. This combination aims to enhance the effectiveness of the immune response against non-small cell lung cancer, potentially improving outcomes compared to standard treatments. ^{2 6 10 11 12}

Research Team

David S Schrump, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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]

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 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]

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 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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

De-escalating adjuvant durvalumab treatment duration in stage III non-small cell lung cancer. [2023]

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

Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. [2022]

3. England 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. [2022]

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

Uptake of Adjuvant Durvalumab After Definitive Concurrent Chemoradiotherapy for Stage III Nonsmall-cell Lung Cancer. [2023]

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

Durvalumab Immunotherapy: Nursing Management of Immune-Related Adverse Events During the Journey of Patients With Stage III Non-Small Cell Lung Cancer. [2021]

6. Ireland 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. [2021]

7. Ireland 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. [2022]

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

Efficacy and safety of consolidation durvalumab after chemoradiation therapy for stage III non-small-cell lung cancer: a systematic review, meta-analysis, and meta-regression of real-world studies. [2023]

9. Ireland 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. [2022]

10. China pubmed.ncbi.nlm.nih.gov

Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer. [2022]

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

Mocetinostat in Combination With Durvalumab for Patients With Advanced NSCLC: Results From a Phase I/II Study. [2023]

12. United States 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. [2022]