A Phase 1 Trial Investigating the Addition of Papaverine to Stereotactic Body Radiotherapy (SBRT) for Hypoxic Radiosensitization of Lung Tumors.

Abstract

IntroductionTumor hypoxia has been recognized as a barrier to effective radiotherapy. Preclinical work identified the FDA approved smooth muscle relaxant papaverine (PPV) as having an "off target" activity as a mitochondrial inhibitor that reduces hypoxia and radiosensitizes model tumors.MethodsWe conducted an IRB-approved phase 1 clinical trial to evaluate safety and feasibility of adding PPV to stereotactic body radiation therapy (SBRT) for tumors of the lung. Eligible patients with early-stage non-small cell lung cancer (NSCLC) or limited lung metastases who were candidates for SBRT (50 Gy in 4 or 5 fractions) were enrolled. Based on a Bayesian Optimal Interval (BOIN) design, patients were allocated to receive PPV 30-90 minutes prior to each SBRT fraction at 3 dose levels (DL): 0.5 mg/kg (DL-1), 1 mg/kg (DL1), or 2mg/kg (DL2).ResultsNineteen patients enrolled and 18 completed study treatment and were evaluable, with a median follow up of 33.4 months. Among 18 evaluable patients, 7 had early-stage NSCLC, 2 had metastatic NSCLC, and 8 had lung metastases from other histologies. The maximum tolerated dose (MTD) was determined to be DL2, which had a dose limiting toxicity (DLT) rate posterior estimate of 0.17 (95% CI 0.01 to 0.53). The 2-year controls rates for local, regional and distant control were 100%, 94% and 82%, respectively.ConclusionsWe demonstrate the feasibility and safety of PPV as a hypoxic radiosensitizer for SBRT. The MTD for this patient population is at least 2 mg/kg of PPV. Encouraging clinical results indicate that further investigation of PPV's utility as a tumor-selective radiosensitizer is warranted.