1162 - Safety and Tolerability of Dose-Escalated, Hypofractionated Radiation Therapy in Combination with Losartan for Locally Advanced Pancreatic Cancer, a Phase I Prospective Clinical Trial
Presenter(s)
S. Lloyd1, R. Tao2, J. Fenlon3, J. D. Gruhl1, C. Nevala-Plagemann1, G. W. Gilcrease1, V. Florou1, C. G. Kinsey1, C. Scaife4, D. B. Evans5, M. S. Baker1, C. Gamblin1, and I. Garrido-Laguna1; 1University of Utah, Huntsman Cancer Hospital, Salt Lake City, UT, 2Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, 3Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 4University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, 5Department of Surgery, Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI
Purpose/Objective(s): Improved treatment options are needed for locally advanced pancreatic ductal adenocarcinoma. We conducted a Phase I prospective clinical trial for safety evaluation of dose-escalated, hypofractionated radiation therapy in combination with TGF-beta inhibitor, losartan to increase oxygen delivery and free radical formation during radiation therapy (RT).
Materials/Methods: Patients received at least one cycle of FOLFIRINOX or Gemcitabine-based chemotherapy prior to enrollment. No patients had resectable disease at study entry. All patients received 37.5 Gy in 15 fractions and a simultaneous integrated boost (SIB) to the portion of the target not overlapping with surrounding organs at risk (OAR). The SIB prescription dose was the highest dose achievable while meeting protocol-defined dose constraints to surrounding OARs, up to 67.5 Gy in 15 fractions. Losartan was given for 14 days prior to RT, during RT, and for an additional 28 days. The primary objective was to test the incidence of dose limiting toxicity defined as relevant grade 3 GI adverse events during treatment and in the subsequent 3 months. By pre-defined statistical design, a rate of 12% of DLTs would be acceptable and a rate of 30% would be unacceptable. As such, 5 DLTs out of 20 planned patients would be unacceptable. Secondary outcomes included adverse events, progression-free survival (PFS), overall survival (OS), and patient reported outcomes as measured by the MD Anderson Symptom Inventory - GI (MDASI-GI).
Results: Twenty-one patients were enrolled (20 evaluable for primary endpoint) and treated with RT and losartan with a median age of 62. Most patients (18/21, 86%) had T4 tumors. 18/21 patients received a boost dose of 60 to 67.5 Gy in 15 fractions (BED10 of 84-97.9 Gy) and 3/21 received lower boost doses. Three patients (14%) with T4 tumors, underwent a successful Whipple resection after RT. 1/20 (5%) evaluable patients experienced a DLT (gastric outlet obstruction). Grade 3+ AEs not meeting the criteria for a DLT occurred in 3/21(14%) patients. The most common AEs were nausea (71%), fatigue (52%), vomiting (48%), abdominal pain (43%), diarrhea (24%), constipation (19%), weight loss (19%), anorexia (14%), and dehydration (10%). One patient had grade 2 hypotension and stopped losartan. Median PFS was 3.94 months (95% CI: 2.3-NA). Median OS was 13.5 months (95% CI: 8.5-16.3). Mean MDASI-GI part 1 (symptom severity) scores at study entry, end of RT, 1 month and 3 months were 3, 2, 2, and 1.6.
Conclusion: Dose-escalated, hypofractionated RT in combination with losartan is safe and tolerable in locally advanced pancreatic cancer. Importantly, 3 (14%) patients with locally advanced disease were able to undergo successful surgery. However, there was no strong signal for improved cancer outcomes in this phase I safety study. Patient reported symptom severity improved from study entry to 3 months post treatment.