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Neoadjuvant Inhaled Azacytidine With Platinum-Based Chemotherapy and Durvalumab (MEDI4736) - a Combined Epigenetic-Immunotherapy (AZA-AEGEAN) Regimen for Operable Early-Stage Non-Small Cell Lung Cancer (NSCLC)

ConditionsNon-small Cell Lung Cancer (NSCLC)Carcinoma, Non-Small Cell LungNon-Small Cell Lung CarcinomaNon Small Cell Lung CancerNon Small Cell Lung Carcinoma
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18-120
SponsorNational Cancer Institute (NCI)

About 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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Histologically or cytologically confirmed, resectable per standard of care stage IB-IIIA non-small cell lung cancer (NSCLC) irrespective of programmed death-ligand 1 (PD-L1) expression. Note: Confirmation is required by NCI Laboratory of Pathology (LP).

Willingness to undergo tumor resection surgery per standard of care (SOC) guidelines following induction therapy (platinum chemotherapy and durvalumab).

Participants must have disease that can be safely accessed via bronchoscopic, thoracoscopic, or percutaneous biopsy techniques, and be willing to undergo tumor biopsy before treatment.

No prior therapy for the NSCLC.

Disqualifiers

Medically inoperable because of clinical co-morbidities.

Participants with T4 tumors invading the diaphragm, mediastinum, carina, trachea, esophagus, heart, great vessels, recurrent laryngeal nerve, or vertebral body.

Participants who experienced serious immune adverse events that required discontinuation of immune checkpoint inhibitor therapy for a prior non-NSCLC malignancy.

History of known EGFR or ALK alterations in the tumor.

Trial design

Design model

Sequential

Treatments tested in this trial

  • azacytidine

    Drug

    Aerosolized azacytidine (AZA) via nebulizer on 3 consecutive days during the first week of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles. Azacytidine will be given at escalating doses in phase 1, and at the established RP2D in phase 2.

  • carboplatin

    Drug

    Carboplatin (intravenous/IV), area under the serum drug concentration-time curve (AUC)=5-6 mg/mL/min based on cancer histology administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.

  • paclitaxel

    Drug

    Paclitaxel (IV), 200 mg/m\^2, is administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.

  • durvalumab

    Drug

    Durvalumab (IV) administered as a flat dose of 1500 mg on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.

  • cisplatin

    Drug

    Cisplatin (IV), 75 mg/m\^2, administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.

  • gemcitabine

    Drug

    Gemcitabine (IV), 1,250 mg/m\^2, administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.

  • pemetrexed

    Drug

    Pemetrexed (IV), 500 mg/m\^2, administered on day 4 of every cycle (1 cycle=21 days), for a maximum (total) of 3 cycles.

Treatment groups

60 Participants
are divided into 2 treatment groups
Group A: 1/ Phase I Dose EscalationExperimental treatment 7 interventions
Group B: 2/ Phase II Dose ExpansionExperimental treatment 7 interventions

Trial outcomes

Primary outcomes

1

Phase I: To determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of neoadjuvant aerosolized AZA in participants with operable early-stage NSCLC treated with standard of care (SOC) platinum-based chemotherapy and du...

DLTs noted at each dose level will be reported.

Time frame
starts at initiation of study drug, though end of DLT period
2

Phase II: To determine the frequency of pathologic complete responses (pCR) in participants receiving aerosolized AZA, durvalumab, and SOC platinum-based chemotherapy as induction therapy for early-stage NSCLC

Pathologic complete responses (pCR) is defined as no viable cancer cells in samples collected on histopathologic assessment. Fraction of evaluable participants who experience a pCR will be determined and reported along with 80% and 95% two-sided confidence intervals.

Time frame
baseline (pre-treatment biopsy), and at the time of SOC surgery post-cycle 3

Secondary outcomes

1

To evaluate pharmacokinetics

Pharmacokinetic endpoints will be reported using descriptive statistics.

Time frame
All participants: Cycle 1, Day 1 or 2, and Cycle 3, Day 1 or 2. Participants with MTD treatment: Cycle 1, Day 1 or 2, and Cycle 2, Day 1 or 2, and Cycle 3, Day 1 or 2.
2

To evaluate safety of the combination of AZA and chemo-durvalumab in participants with operable early-stage NSCLC

Safety of the agents will be assessed by determining the grade of adverse events noted in each participant and reporting the fraction with Grade 3 and Grade 4 adverse events. Safety data will be presented in a summary. The safety data will consist of the reporting of all adverse events, and may also include reporting vital signs, physical examination data, and laboratory safety data.

Time frame
starts at initiation of study drug, through 64 days after the last study drug administration
3

To evaluate event-free survival (EFS)

Event-free survival (EFS) at three years post treatment will be determined as the duration of time from start of treatment to time of disease recurrence or appearance of new primary cancer, whichever occurs first as appropriate using the Kaplan-Meier method and reported along with a 95% confidence interval, separately for phase I and II. The median EFS will also be reported along with a 95% confidence interval.

Time frame
baseline, Day 64 (treatment evaluation), then post-surgical 1 month, 3 months, and every 3 months thereafter until disease progression, until up to 3 years from the treatment initiation
4

To evaluate objective response (complete response [CR] + partial response [PR]) and stable disease [SD] per RECIST 1.1

The objective response rate will be based on CR+PR and the disease stabilization rate (SD) and reported separately in phase I and II along with a 95% confidence interval for each.

Time frame
baseline, and at Day 64 (treatment evaluation)

Other outcomes

Sponsors and contacts

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National Cancer Institute (NCI)

Lead sponsor

Source ClinicalTrials.gov
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