First-in-human study of inhaled Azacitidine in patients with advanced non-small cell lung cancer
Autor: | Roman Perez-Soler, Ni Fan, Simon D. Spivack, Balazs Halmos, Rasim Gucalp, Haiying Cheng, Bilal Piperdi, Amit Verma, Yiyu Zou, Tushar D. Bhagat, Chirag D. Shah, Mimi Y. Kim |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Cancer Research medicine.medical_specialty Lung Neoplasms Azacitidine Asymptomatic Gastroenterology Article Pulmonary function testing 03 medical and health sciences Mice 0302 clinical medicine Bronchoscopy Pharmacokinetics Internal medicine Carcinoma Non-Small-Cell Lung Medicine Animals Humans Lung cancer Adverse effect medicine.diagnostic_test business.industry DNA Methylation medicine.disease 030104 developmental biology Treatment Outcome Oncology Tolerability 030220 oncology & carcinogenesis medicine.symptom Neoplasm Recurrence Local business medicine.drug |
Zdroj: | Lung Cancer |
ISSN: | 1872-8332 |
Popis: | Background Aerosolized Azacitidine has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in murine models. We hypothesized that inhaled Azacitidine is safe and effective in reversing epigenetic changes in the bronchial epithelium secondary to chronic smoking. Patients and Methods We report the first in human study of inhaled Azacitidine. Azacitidine in aqueous solution was used to generate an aerosol suspension of 0.25–5 μm particle size. Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0–1, and adequate pulmonary function. Patients received inhaled Azacitidine daily on days 1–5 and 15–19 of 28-day cycles, at 3 escalating doses (15, 30 and 45 mg/m2 daily). The primary objective was to determine the feasibility and tolerability of this new therapeutic modality. The key secondary objectives included pharmacokinetics, methylation profiles and efficacy. Results From 3/2015 to 2/2018, eight patients received a median number of 2 (IQR = 1) cycles of inhaled Azacitidine. No clinically significant adverse events were observed, except one patient treated at the highest dose developed an asymptomatic grade 2 decreased DLCO which resolved spontaneously. One patient receiving 12 cycles of therapy had an objective and durable partial response, and two patients had stable disease. Plasma Azacitidine was only briefly detectable in patients treated at the higher doses. Moreover, in 2 of 3 participants who agreed and underwent pre- and post-treatment bronchoscopy, the global DNA methylation in the bronchial epithelium decreased by 24 % and 79 % post-therapy, respectively. The interval between last inhaled treatment and bronchoscopy was 3 days. Conclusions Inhaled Azacitidine resulted in negligible plasma levels compared to the previously reported subcutaneous administration and was well-tolerated. The results justify the continued development of inhaled Azacitidine at non-cytotoxic doses for patients with lung-confined malignant and/or premalignant lesions. |
Databáze: | OpenAIRE |
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