Study Using a Drug-device Combination Product to Determine Safety, Tolerability and Antitumor Activity for Patients With Advanced, Non-small Cell Lung Cancer

This is an open label, multi-center Phase 1/2 study of NHT102, 5-Azacytidine Mircronised, Dry Powder Formulation Delivered by a Novel Inhalation Delivery System (device constituent product \[DCP\]). The study will enroll patients with advanced NSCLC limited to the lung and thoracic region. The study consists of three sequential parts:

Part 1 (Dose Escalation): Approximately five dose levels of NHT102 will be evaluated using a standard 3+3 design to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Patients receive NHT102 once daily on Days 1-5 and Days 15-19 of each 28 day cycle. A Safety Review Committee (SRC) will review safety data after each cohort completes the DLT evaluation period.

Part 2 (Dose Optimization): At least two dose levels selected from Part 1 will be evaluated using Simon's two stage design. Each dose level will enroll up to 25 evaluable patients to assess anti-tumor activity, safety, pharmacokinetics (PK), pharmacodynamics, and exploratory biomarkers.

Part 3 (Dose Expansion): The recommended Phase 2 dose (RP2D) selected from Part 2 will be further evaluated to characterize safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity.

Patients will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, or study termination. Follow up includes safety assessment at 30 days after end of treatment and 6 month survival follow up.

• NHT102 (Drug), also known as 5-AZA, 5-Azacytidine dry powder, NHT102-5-AZA, Azacitidine: NHT102 is an investigational drug product, 5-Azacytidine dry powder for oral inhalation. NHT102 is administered once daily via inhalation using a novel investigational inhalation delivery system. Dosing occurs on Days 1-5 and Days 15-19 of each 28-day cycle. Multiple dose levels (7 mg to 42 mg target lung dose per treatment day) are evaluated in Part 1, selected dose levels in Part 2, and the recommended Phase 2 dose (RP2D) in Part 3.
• DryNeb (Device), also known as Clinical Benchtop DryNeb, Novel Inhalation Delivery System: The DryNeb is a novel investigational inhalation delivery system that delivers micronized dry powder to the lungs.

Primary outcomes

• Incidence and Severity of Adverse Events (AEs) [From first dose through 30 days after the last dose.]: Treatment emergent adverse events, serious adverse events, and clinically significant laboratory or vital sign abnormalities assessed using CTCAE v6.0 (Part I).
• Incidence of dose-limiting toxicities (DLT)-Part I [28-day DLT evaluation period (Cycle 1)]: Number of participants experiencing DLTs during the DLT evaluation period, defined per protocol.
• Overall Response Rate (ORR)-Parts 2 and 3. [From first dose until first documented disease progression, date of death or patient withdrawal from the study for any reason, assessed up to six months.]: Proportion of participants achieving complete or partial response per RECIST v1.1.
• Progression Free Survival (PFS)-Parts 2 and 3. [From first dose until first documented disease progression, date of death or patient withdrawal from the study for any reason, assessed up to six months.]: Time from first dose to disease progression or death.
• Overall Survival (OS)-Parts 2 and 3. [From first dose until first documented disease progression, date of death or patient withdrawal from the study for any reason, assessed up to six months.]: Time from first dose to death.
• Duration of Response (DOR)-Parts 2 and 3. [From first documented response to date of first documented disease progression, date of death or patient withdrawal from the study for any reason, assessed up to six months.]: Time from first observation of response to progression or death.

Secondary outcomes

• Pharmacokinetic Parameters of NHT102-Parts 1, 2, and 3. [At the end of Cycle 1. (Each cycle is 28 days)]: To determine the PK parameter for the peak plasma concentration (Cmax).
• Incidence and Severity of Adverse Events (AEs)-Parts 2 and 3. [From first dose through 30 days after the last dose.]: TEAEs, SAEs, and clinically significant abnormalities assessed using CTCAE v6.0.
• Percent Change in DNA Methylation-Parts 2 and 3. [Baseline to post-treatment (estimated to be minimum of 7 months)]: Percent change in global DNA methylation in tumor and/or bronchial epithelium compared with pre treatment.
• PK parameters of NHT102. Parts 1, 2, and 3. [At the end of Cycle 1. (Each cycle is 28 days)]: Area under the curve (AUC) plasma concentration versus time curve.
• PK Parameters of NHT102. Parts 1, 2, and 3. [At the end of cycle 1. (Each cycle is 28 days)]: Time to maximum plasma concentration (Tmax)
• PK parameters of NHT102. Parts 1, 2 and 3. [At the end of Cycle 1. (Each Cycle is 28 days)]: Estimated time to reduce the plasma concentration by exactly one half (T1/2)

Other outcomes

• Percent Change in DNA Methylation - Part I. [Baseline (Day 1) to post-treatment. (Estimated minimum of 7 months)]: Percent change in global DNA methylation in tumor and/or bronchial epithelium compared with pre-treatment.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age ≥18 years
* Able to provide informed consent
* Able to perform acceptable and reproducible spirometry per ATS criteria
* Able to perform inhalation maneuver
* Histologically or cytologically confirmed NSCLC (squamous, adenocarcinoma, or large cell undifferentiated)
* Stage I-III NSCLC per AJCC 9th edition with recurrent or persistent thoracic confined disease
* Prior therapy with curative intent completed
* Actionable genomic alterations must have been treated or offered appropriate targeted therapy
* Not eligible for additional curative therapy
* At least one measurable lung lesion per RECIST v1.1 (measurable extra-pulmonary thoracic lesions do not qualify unless a measurable lung lesion is also present)
* ECOG performance status ≤2
* Life expectancy ≥12 weeks
* Adequate hematologic, renal, hepatic, and cardiovascular function
* Washout from prior therapy ≥30 days or ≥5 half lives
* Adequate pulmonary reserve: FEV1 ≥50% predicted, FEV1/FVC ≥45%, and DLCO ≥50% predicted
* No growth factor support, transfusions, or albumin within 14 days prior to first dose
* Resolution of adverse effects of prior therapy to Grade ≤1 (except fatigue, alopecia, and peripheral neuropathy)
* Contraception requirements for WOCBP and fertile men
* Agreement to refrain from smoking or inhaled substances during treatment

Exclusion Criteria:

* Systemic metastases beyond the lung, thoracic lymph nodes, or mediastinum region
* Anticancer therapy within 30 days or 5 half-lives, or current immunomodulator requirement
* Hypersensitivity to study drug or device components
* Concurrent anticancer therapy or immunomodulators
* Systemic or inhaled corticosteroids (exceptions apply)
* Active smokers within past 6 months
* Severe airway disease (criteria defined)
* Radiation therapy within 6 months
* Contraindication to study procedures
* Other malignancies except specified low risk types
* Major surgery within 4 weeks
* Clinically significant cardiovascular disease
* Uncontrolled medical conditions
* Active infection requiring IV therapy
* Live vaccine within 2 weeks of Cycle 1 Day 1
* Bleeding disorder unrelated to cancer
* Pregnancy or breastfeeding