NCT05861336

GEM+Nab-Paclitaxel Plus Losartan Followed by Stereotactic Radiotherapy for Locally Advanced Pancreatic Cancer

Phase II Study of Gemcitabine Plus Nab-Paclitaxel in Combination With Losartan Followed by Stereotactic Radiotherapy for Locally Advanced Pancreatic Cancer: OVERPASS Trial

• Status: Withdrawn
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 0 (actual)
• Sponsor: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

Single-arm, prospective, phase II study to evaluate safety and activity of an induction therapy with Gemcitabine (GEM) and nab-paclitaxel plus Losartan followed by Stereotactic Radiotherapy (SBRT) in patients affected by Locally Advanced Pancreatic Cancer (LAPC).

Detailed description

Pancreatic cancer (PC) is a malignant disease presenting high mortality rates, with a 5-year survival of about 11%, partly because of its known resistance to Chemotherapy (CHT) and Radiotherapy (RT). Radiation therapy in locally advanced and borderline resectable pancreatic cancer improves only local control as demonstrated by 5 studies published from 1980 to 2011 and confirmed by the more recent LAP-07 trial, which investigated conventional RT after induction CHT with the same results. Losartan was administered because it indirectly affects tumor microenvironment mechanisms of chemo- and radioresistance. PC cells, through transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF) and Angiotensin II activating signaling pathways lead to tumor microenvironment (TME) cells activation, like pancreatic stellate cells, which play a key role in chemoresistance. Angiotensin system and TGF-β increase and maintain the extracellular matrix, which acts as a barrier against drugs. Murphy et al. showed that Losartan administration during chemotherapy resulted in an effective decrease in plasma levels of TGF-β. Their unexpected successful results suggest that targeting not only tumor but also TME might be a novel treatment paradigm. The purpose of this study is to prospectively evaluate the safety and activity, in terms of resectability rate, of GEM-nab-paclitaxel chemotherapy with concurrent Losartan followed by SBRT in patients with LAPC. Secondary endpoints are margin-negative resection rate (R0), progression-free survival (PFS), overall survival (OS), blood biomarkers response, safety and quality of life. A Carbohydrate antigen-19.9 (CA19.9) reduction ≥15% from baseline to the end of induction therapy and Carcinoma embryonic antigen (CEA) are tested as a reliable prognostic factor.

Conditions

• Pancreatic Cancer

Interventions

Type	Name	Description
DRUG	Losartan	Losartan will be administered at the dose of 25 mg PO qd starting on Cycle 1 Day 1. If this dose will be tolerated during week 1, escalation to 50 mg PO qd at Cycle 1 Day 8
DRUG	Gemcitabine	Gemcitabine 1000 mg/m2 on days 1, 8 and 15 every 28 days
DRUG	Nab paclitaxel	nab-paclitaxel 125 mg/m2 on days 1, 8, and 15
RADIATION	Stereotactic Body Radiation Therapy	7 consecutive fractions for a total dose of 35-42 Gy

Timeline

• Start date: 2023-06-14
• Primary completion: 2024-12-23
• Completion: 2024-12-23
• First posted: 2023-05-16
• Last updated: 2024-12-27

Locations

2 sites across 1 country: Italy