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

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.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with histologically or cytologically confirmed pancreatic carcinoma
2. Clinical stage I-III, according to tumor, nodes and metastases (TNM) 8th ed.
3. Locally advanced disease, as defined per National Comprehensive Cancer Network (NCCN) Guidelines version 1.2022 (Appendix D)
4. Baseline systolic blood pressure (SBP) ≥ 100 mmHg (baseline SBP will be documented during the enrolment visit in a resting, seated position at least five minutes apart; SBP will be established as the average of the two readings; if SBP is borderline it may be measured in the other arm);
5. Age \>18 years and ≤75 years.
6. Life expectancy greater than 12 weeks.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
8. Presence of at least one measurable lesion in agreement to RECIST 1.1 criteria
9. Patients must have normal organ and marrow function as defined below:
10. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence, prior to study entry and continuing throughout the study period and for 6 months after final study drug administration. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
11. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Clinical stage IV, according to TNM 8th ed.
2. Patients who have previously received chemotherapy or radiotherapy for pancreatic cancer.
3. Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to any agent used in the study.
5. Serious concomitant systemic disorders incompatible with the study (at discretion of the investigator);
6. Patient already treated on other Losartan dosages than those prescribed by protocol or treated on other Angiotensin II Receptor Blockers (ARB) therapy for hypertension or renal protection (with diabetes) at the time of enrolment;
7. Baseline hypotension, defined as systolic BP lower than 100 mmHg on two readings obtained on two separated days prior to study enrolment.
8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.