- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05861336
GEM+Nab-Paclitaxel Plus Losartan Followed by Stereotactic Radiotherapy for Locally Advanced Pancreatic Cancer (OVERPASS)
Phase II Study of Gemcitabine Plus Nab-Paclitaxel in Combination With Losartan Followed by Stereotactic Radiotherapy for Locally Advanced Pancreatic Cancer: OVERPASS Trial
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Oriana Nanni
- Phone Number: +390543739266
- Email: oriana.nanni@irst.emr.it
Study Contact Backup
- Name: Bernadette Vertogen
- Phone Number: +390544286058
- Email: bernadette.vertogen@irst.emr.it
Study Locations
-
-
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Ravenna, Italy, 48121
- Recruiting
- UO Oncologia, AUSL della Romagna
-
Contact:
- Stefano Tamberi, MD
- Email: stefano.tamberi@auslromagna.it
-
Principal Investigator:
- Stefano Tamberi, MD
-
-
Forlì
-
Meldola, Forlì, Italy, 47014
- Recruiting
- U.O. Radioterapia IRCCS IRST
-
Contact:
- Antonino Romeo, MD
- Phone Number: +390543739170
- Email: antonino.romeo@irst.emr.it
-
Principal Investigator:
- Antonino Romeo, MD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Patients with histologically or cytologically confirmed pancreatic carcinoma
- Clinical stage I-III, according to tumor, nodes and metastases (TNM) 8th ed.
- Locally advanced disease, as defined per National Comprehensive Cancer Network (NCCN) Guidelines version 1.2022 (Appendix D)
- 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);
- Age >18 years and ≤75 years.
- Life expectancy greater than 12 weeks.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Presence of at least one measurable lesion in agreement to RECIST 1.1 criteria
- Patients must have normal organ and marrow function as defined below:
- 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.
- Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
- Clinical stage IV, according to TNM 8th ed.
- Patients who have previously received chemotherapy or radiotherapy for pancreatic cancer.
- Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to any agent used in the study.
- Serious concomitant systemic disorders incompatible with the study (at discretion of the investigator);
- 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;
- Baseline hypotension, defined as systolic BP lower than 100 mmHg on two readings obtained on two separated days prior to study enrolment.
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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 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
7 consecutive fractions for a total dose of 35-42 Gy
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of participants discontinuing study treatment due to treatment related grade≥3 non-hematological adverse event [Toxicity]
Time Frame: 40 months
|
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. |
40 months
|
Number of participants discontinuing study treatment due to treatment related grade≥3 adverse event [Toxicity]
Time Frame: 40 months
|
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. |
40 months
|
Resectability rate
Time Frame: 40 months
|
Rate of patients undergoing surgery on total patient population.
Resectability will be determined by Multidisciplinary team according
|
40 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
margin-negative resection rate (R0)
Time Frame: 80 months
|
Rate of negative margin resection determined by final pathology of the surgical specimen
|
80 months
|
progression-free survival (PFS)
Time Frame: 80 months
|
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
|
80 months
|
overall survival (OS)
Time Frame: 80 months
|
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
|
80 months
|
biomarker blood response
Time Frame: 80 months
|
A CA19.9 reduction ≥15% from baseline to the end of induction therapy and CEA are tested as a reliable prognostic factor
|
80 months
|
Incidence of Treatment-Emergent Adverse Events [Toxicity]
Time Frame: 80 months
|
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. |
80 months
|
Quality of life questionnaire (QLQ)
Time Frame: 80 months
|
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'.
|
80 months
|
Collaborators and Investigators
Investigators
- Principal Investigator: Antonino Romeo, MD, Irccs Irst
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Neoplasms
- Neoplasms by Site
- Endocrine System Diseases
- Digestive System Neoplasms
- Endocrine Gland Neoplasms
- Pancreatic Diseases
- Pancreatic Neoplasms
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Antihypertensive Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Antineoplastic Agents, Phytogenic
- Angiotensin II Type 1 Receptor Blockers
- Angiotensin Receptor Antagonists
- Paclitaxel
- Losartan
- Gemcitabine
Other Study ID Numbers
- IRST157.04
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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