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).
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
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
Gemcitabine 1000 mg/m2 on days 1, 8 and 15 every 28 days
nab-paclitaxel 125 mg/m2 on days 1, 8, and 15
U.O. Radioterapia IRCCS IRST
Meldola, Forlì, Italy
UO Oncologia, AUSL della Romagna
Ravenna, Italy
Number of participants discontinuing study treatment due to treatment related grade≥3 non-hematological adverse event [Toxicity]
Toxicity-related discontinuation is defined as: for chemotherapy + losartan phase, discontinuation due to a treatment-related ≥grade3 non-hematological adverse event; Toxicity assessments will be done using the NCI Common Terminology Criteria for Adverse Events v 5.0.
Time frame: 40 months
Number of participants discontinuing study treatment due to treatment related grade≥3 adverse event [Toxicity]
Toxicity-related discontinuation is defined as: for SBRT phase, discontinuation due to a ≥grade3 Adverse Events (Enteritis, Gastritis, Malabsorption, Nausea) occurring for three consecutive days. Toxicity assessments will be done using the NCI Common Terminology Criteria for Adverse Events v 5.0.
Time frame: 40 months
Resectability rate
Rate of patients undergoing surgery on total patient population. Resectability will be determined by Multidisciplinary team according
Time frame: 40 months
margin-negative resection rate (R0)
Rate of negative margin resection determined by final pathology of the surgical specimen
Time frame: 80 months
progression-free survival (PFS)
Progression-free survival will be defined as the time from the start date of protocol therapy to first objective documentation of progressive disease (distant or local) or death due to any cause or last tumor evaluation
Time frame: 80 months
overall survival (OS)
Overall survival will be calculated as the time from the start date of protocol therapy to date of death due to any cause or last follow-up
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
7 consecutive fractions for a total dose of 35-42 Gy
Time frame: 80 months
biomarker blood response
A CA19.9 reduction ≥15% from baseline to the end of induction therapy and CEA are tested as a reliable prognostic factor
Time frame: 80 months
Incidence of Treatment-Emergent Adverse Events [Toxicity]
All patient will be evaluated for toxicity using the NCI Common Terminology Criteria for Adverse Events (CTCAE v 5.0). All patients will be evaluated for toxicity after each therapy session. Toxicity analyses will be performed on all patients who received at least one dose of study treatment. Frequency tables will be performed for all categorical variables. Continuous variables will be presented using the median and range.
Time frame: 80 months
Quality of life questionnaire (QLQ)
Quality of Life will be measured using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire that is a patient-reported outcome measure used to assess health-related quality of life in patients undergoing cancer therapy. The scale ranging from 1-4, where 1 is labeled 'Good quality of life,' and 4 is labeled 'Bad quality of life'.
Time frame: 80 months