GEM+Nab-Paclitaxel Plus Losartan Followed by Stereotactic Radiotherapy for Locally Advanced Pancreatic Cancer
NCT ID: NCT05861336
Last Updated: 2024-12-27
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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WITHDRAWN
PHASE2
INTERVENTIONAL
2023-06-14
2024-12-23
Brief Summary
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Detailed Description
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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
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Chemotherapy+Losartan+Stereotactic Radiation
Chemotherapy will be administered for six cycles as per clinical practice (nab-paclitaxel and gemcitabine: nab-paclitaxel 125 mg/m2 on days 1, 8, and 15, Gemcitabine 1000 mg/m2 on days 1, 8 and 15 every 28 days) Losartan will be administered per os every day during induction chemotherapy and maintained until starting SBRT.
SBRT will be administered in 7 consecutive fractions for a total dose of 35-42 Gy if no progression will be observed after induction therapy.
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
Gemcitabine
Gemcitabine 1000 mg/m2 on days 1, 8 and 15 every 28 days
Nab paclitaxel
nab-paclitaxel 125 mg/m2 on days 1, 8, and 15
Stereotactic Body Radiation Therapy
7 consecutive fractions for a total dose of 35-42 Gy
Interventions
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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
Gemcitabine
Gemcitabine 1000 mg/m2 on days 1, 8 and 15 every 28 days
Nab paclitaxel
nab-paclitaxel 125 mg/m2 on days 1, 8, and 15
Stereotactic Body Radiation Therapy
7 consecutive fractions for a total dose of 35-42 Gy
Eligibility Criteria
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Inclusion Criteria
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
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.
18 Years
75 Years
ALL
No
Sponsors
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Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS
OTHER
Responsible Party
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Principal Investigators
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Antonino Romeo, MD
Role: PRINCIPAL_INVESTIGATOR
IRCCS IRST
Locations
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U.O. Radioterapia IRCCS IRST
Meldola, Forlì, Italy
UO Oncologia, AUSL della Romagna
Ravenna, , Italy
Countries
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Other Identifiers
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IRST157.04
Identifier Type: -
Identifier Source: org_study_id