P1.01-05 Phase I Study of Inhaled 5-Azacytidine (5-Aza) in Patients (Pts) with Advanced Non-Small Cell Lung Cancer (NSCLC)

Our previous study in an endo-bronchial NSCLC murine model suggested that aerosolized 5-Aza could inhibit cancer growth, prolong survival, and induce re-expression of methylated tumor suppressor genes. This is the first in human phase I study of 5-Aza delivered by inhalation in pts with advanced NSCLC. Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0-1, and good pulmonary function. Pts were treated with inhaled 5-Aza daily, D1 to D5 and D15 to D19 of a28-day cycle. Initial dose escalation used an accelerated titration scheme, followed by a 3 + 3 dose escalation and de-escalation design. The starting dose was 15mg/m2 (derived from preclinical studies that showed it to be a safe and DNA demethylating dose), followed by 30 and 45 mg/m2. The primary objective was to determine the MTD and toxicity (especially pulmonary toxicity). Secondary objectives included PK, methylation profiles pre and post 5-Aza (bronchoscopy), efficacy (RECIST 1.1), PFS and OS. From 3/2015 to 12/2017, 8 pts were treated with 3 escalating doses of inhaled 5-Aza, including 2 at the highest level of 45mg/m2. Median follow up: 15m. Median age 70, 62.5% female, 62.5% blacks, all PS=1, 87.5% adenocarcinoma with 1 EGFR and 2 KRAS mutants, 62.5% active/former smoker, mean number of prior therapies: 3 lines. Mean treatment cycles: 3.4 (1-12). No treatment related adverse events were reported. No DLTs were observed. Preliminary PK study indicated no detectable 5-Aza in the blood. No objective response was observed, 37.5% (3/8) had stable disease (SD). Median PFS and OS were 2 m and 12 m respectively. One pt had SD >17 m and received a total of 2 cycles, whereas another KRAS-mutant pt had SD >29 m and received a total of 12 cycles. Inhaled 5-Aza was well-tolerated with no treatment-related toxicity. The administration of 5-Aza by inhalation was feasible for multiple cycles in pts with advanced NSCLC without any significant pulmonary toxicity. The methylation studies in bronchial epithelium are ongoing and will be presented. Our results suggest that inhaled 5-Aza may represent a novel and safe therapeutic strategy for patients with lung-confined malignant and/or premalignant lesions. Clinical trial information: NCT02009436. Supported by NIH CA154755