Phase I Trial of Concurrent Stereotactic Body Radiation Therapy and Nelfinavir for Locally Advanced Borderline or Unresectable Pancreatic Cancer-Final Results

Abstract

The HIV protease inhibitor nelfinavir (NFV) displays notable radiosensitizing effects. There have been no studies evaluating combined stereotactic body radiation therapy (SBRT) and NFV for borderline/unresectable pancreatic cancer. The primary objective of this phase I trial (NCT01068327) was to determine the maximum tolerated SBRT/NFV dose, and secondarily evaluate outcomes. Following initial imaging, pathologic confirmation, and staging laparoscopy, subjects initially received 3 3-week cycles of gemcitabine/leucovorin/fluorouracil; patients without radiologic progression received SBRT(5 fractions)/NFV. Dose escalation was as follows: 1) 25 Gy/625 mg BID × 3 wk; 2) 25 Gy/1250 mg BID × 3 wk; 3)30 Gy/1250 mg BID × 3 wk; 4) 35 Gy/1250 mg BID × 3 wk; 5) 35 Gy/1250 mg BID × 5wk; and 6) 40 Gy/1250 mg BID × 5 wk. Pancreaticoduodenectomy was performed thereafter if deemed resectable; if not, gemcitabine/leucovorin/fluorouracil was administered. Forty-six patients enrolled (10/2008-5/2013). Thirty-nine patients received SBRT/NFV on protocol; 16 (41%) experienced any grade ≥2 adverse event (AEs) during and 1 month after SBRT. There were 21, 11, and 2 instances of grades 2, 3, and 4 toxicities, respectively. Four instances of grade 3 events & both grade 4 events occurred in a single patient (started prior to SBRT/NFV) at the initial dose level. The final dose level was the maximum tolerated dose. Long-term follow up revealed that 5 patients had late gastrointestinal (GI) bleed (2, superior mesenteric artery pseudoaneurysm; 1, unknown; 1, negative esophagogastroduodenoscopy; 1, disease progression invading GI). The median overall survival was 14.4 months. Six (15%) patients experienced a local failure; the median local failure-free survival was not reached. Twenty-six had a distant failure as the first failure site (9, liver; 6, lung; 9, peritoneum). The median distant failure-free survival was 11 months, and the median all failure-free survival was 10 months. Twelve patients underwent pancreaticoduodenectomy; their median survival (19 months) was similar to those of unresected patients receiving 35-40 Gy (18 months) (p=0.924). As compared to those receiving 25-30 Gy (10 months), there was a trend towards higher survival in whom 35-40 Gy was delivered (p=0.083). Concurrent SBRT (40 Gy)/NFV (1250 mg BID) for locally-advanced pancreatic cancer is safe and yields encouraging outcomes; a phase II study is currently ongoing. A close attention to SBRT plan & delivery is warranted to decrease the risk of late GI bleed.