178 - A Dose Escalation Study of Papaverine As a Selective Hypoxic Radiosensitizer for Lung Stereotactic Body Radiation Therapy (SBRT) In the Treatment of Early-Stage Non-Small Cell Lung Cancer (NSCLC) and Other Malignancies
Presenter(s)
J. M. Brownstein1, T. M. Williams2, M. Welliver3, N. Sebastian4, S. J. Ma5, K. E. Haglund6, A. J. Sim7, M. Benej8, I. Papandreou8, K. Qing2, E. E. Graves9, and N. Denko3; 1Ohio State University Comprehensive Cancer Center, Columbus, OH, 2Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, 3Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 4Emory Proton Therapy Center, Atlanta, OH, 5The Ohio State University, Columbus, OH, 6Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, Columbus, OH, 7H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL, 8Ohio State University, Columbus, OH, 9Department of Radiation Oncology, Stanford University, Palo Alto, CA
Purpose/Objective(s):
SBRT has emerged as a safe and effective treatment for patients with peripheral early-stage NSCLC and limited lung metastases. However, large dose-per-fraction radiotherapy is particularly susceptible to hypoxic radiation resistance, potentially leading to local recurrence. Papaverine (PPV) is a benzylisoquinoline alkaloid that was historically prescribed for its phosphodiesterase (PE)/vasodilatory effects to treat acute ischemic events. In addition to its PDE activity, PPV functions as a mitochondrial inhibitor, temporarily reducing mitochondrial oxidative phosphorylation. PPV reduces oxygen consumption in tumors, which increases oxygen tension and has been shown to selectively radiosensitize tumors in mice. We now report the results of a phase I dose escalation study of PPV combined with SBRT for early-stage NSCLC and lung metastases.Materials/Methods:
Eligible patients with early-stage NSCLC or limited lung metastases who were candidates for SBRT (50 Gy in 4 or 5 fractions) were enrolled on an IRB-approved dose escalation protocol. This trial employed a Bayesian optimal interval (BOIN) design to find the maximum tolerated dose (MTD) of PPV, targeting a dose-limiting toxicity (DLT) rate of 0.25 when given in conjunction with SBRT. Based on the BOIN design, patients were planned to receive PPV at 3 dose levels (DL), either 0.5 mg/kg (DL -1), 1 mg/kg (DL 1) or 2mg/kg (DL 2) via IV infusions 30-90 minutes prior to each of their 4-5 radiation treatments. Patients had the option to participate in additional correlative MRI study.Results:
Between 6/2019 and 10/2025, 19 patients accrued to the trial and 18 completed study treatment. Of those, 2 were treated at DL -1, 10 were treated at DL 1, and 6 were treated at DL 2. The MTD was determined to be DL 2, which had a DLT rate posterior estimate of 0.17 (95% CI 0.01 to 0.53). Among the 18 study patients, 7 had early-stage NSCLC, 2 had metastatic NSCLC, and 9 had lung metastases from other histologies; one patient completed MRI correlative study. With a median follow up of 33.4 months, the 2-year control rate for local recurrence, regional recurrence and distant recurrence was 100%, 94% and 82%, respectively. For early-stage NSCLC patients, the 2-year progression free survival and overall survival were 83% and 83%, respectively. One patient at DL 1 and one patient at DL 2 encountered DLTs, namely G3 hypoxia/lung infection, and G3 fatigue, respectively (no G4+ toxicity).Conclusion:
We have successfully completed a dose escalation study of PPV with SBRT for patients with early-stage NSCLC and lung metastases. We determined an MTD and recommended phase 2 dose of 2 mg/kg (DL 2). Compared to historical controls of lung SBRT, PPV appears to have yielded better-than-predicted efficacy, with 2 year local control of 100%. More work is needed to better understand how to safely and effectively incorporate PPV as a selective hypoxic radiosensitizer.