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

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

NCT ID: NCT05861336

Condition: Pancreatic Cancer

Conditions: Official terms:
Pancreatic Neoplasms
Paclitaxel
Gemcitabine
Losartan

Study type: Interventional

Study phase: Phase 2

Overall status: Recruiting

Study design:

Allocation: N/A

Intervention model: Single Group Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Intervention:

Intervention type: Drug
Intervention name: Losartan
Description: 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
Arm group label: Chemotherapy+Losartan+Stereotactic Radiation

Intervention type: Drug
Intervention name: Gemcitabine
Description: Gemcitabine 1000 mg/m2 on days 1, 8 and 15 every 28 days
Arm group label: Chemotherapy+Losartan+Stereotactic Radiation

Intervention type: Drug
Intervention name: Nab paclitaxel
Description: nab-paclitaxel 125 mg/m2 on days 1, 8, and 15
Arm group label: Chemotherapy+Losartan+Stereotactic Radiation

Intervention type: Radiation
Intervention name: Stereotactic Body Radiation Therapy
Description: 7 consecutive fractions for a total dose of 35-42 Gy
Arm group label: Chemotherapy+Losartan+Stereotactic Radiation

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.

Criteria for 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.

Gender: All

Minimum age: 18 Years

Maximum age: 75 Years

Healthy volunteers: No

Locations:

Facility:
Name: U.O. Radioterapia IRCCS IRST

Address:
City: Meldola
Zip: 47014
Country: Italy

Status: Recruiting

Contact:
Last name: Antonino Romeo, MD

Phone: +390543739170
Email: antonino.romeo@irst.emr.it

Investigator:
Last name: Antonino Romeo, MD
Email: Principal Investigator

Facility:
Name: UO Oncologia, AUSL della Romagna

Address:
City: Ravenna
Zip: 48121
Country: Italy

Status: Recruiting

Contact:
Last name: Stefano Tamberi, MD
Email: stefano.tamberi@auslromagna.it

Investigator:
Last name: Stefano Tamberi, MD
Email: Principal Investigator

Start date: June 14, 2023

Completion date: August 2029

Lead sponsor:
Agency: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
Agency class: Other

Source: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT05861336