Losartan and Hypofractionated Rx After Chemo for Tx of Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer (SHAPER)

Study Overview
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Brief Summary
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This phase I trial studies the side effects of losartan and hypofractionated radiation therapy after chemotherapy in treating patients with pancreatic cancer that may or may not be removed by surgery (borderline resectable) or has spread from its original site of growth to nearby tissues or lymph nodes and is not amenable to surgical resection (locally advanced unresectable). Losartan may improve blood flow and allows for better tissue oxygenation. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Giving losartan and hypofractionated radiation therapy may work better in treating patients with pancreatic cancer compared to hypofractionated radiation therapy alone.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess the safety of losartan potassium (losartan) in combination with hypofractionated radiation treatment for patients with stable or locally progressive pancreatic ductal adenocarcinoma (PDAC) after induction chemotherapy. SECONDARY OBJECTIVES: I. To assess the safety of losartan in combination with HRT for patients with stable or locally progressive PDAC after induction chemotherapy. II. To assess the efficacy of losartan in combination with HRT for patients with stable or locally progressive PDAC after induction chemotherapy. III. To assess the rate of hypotensive adverse events grade >= 3. EXPLORATORY OBJECTIVE: I. To assess patient reported quality of life. OUTLINE: Beginning day 1, patients receive losartan potassium orally (PO) once daily (QD). Beginning day 14, patients also undergo hypofractionated radiation therapy over 15 fractions 5 days a week for up to 3 weeks. Patients continue to receive losartan potassium PO QD during radiation therapy and for 28 days after completion of radiation therapy. After completion of study treatment, patients are followed up at 28 and 84 days, every 3 months for 12 months, and then every 6 months for up to 36 months.

Official Title
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SHAPER: A Phase 1 Study of Losartan and Hypofractionated Radiation Therapy After Induction Chemotherapy for Borderline Resectable or Locally Advanced Pancreatic Cancer

Conditions
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Borderline Resectable Pancreatic Adenocarcinoma, Locally Advanced Pancreatic Ductal Adenocarcinoma, Locally Advanced Unresectable Pancreatic Adenocarcinoma, Stage II Pancreatic Cancer AJCC v8, Stage IIA Pancreatic Cancer AJCC v8, Stage IIB Pancreatic Cancer AJCC v8, Stage III Pancreatic Cancer AJCC v8

Intervention / Treatment
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* Radiation: Hypofractionated Radiation Therapy
* Drug: Losartan
* Drug: Losartan Potassium
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed pancreatic ductal adenocarcinoma Borderline resectable or locally advanced unresectable pancreas cancer as defined by the National Comprehensive Cancer Network (NCCN) and determined by a pancreatic surgeon prior to therapy. This can be confirmed by the surgeon?s documentation in the electronic medical record, by a treatment planning conference note, or by the signature of a pancreatic surgeon At least one infusion of FOLFIRINOX or gemcitabine based chemotherapy must have been attempted. No more than 6 months of chemotherapy. Each completed cycle of FOLFIRINOX will be counted as 0.5 months. Each completed cycle of gemcitabine based chemotherapy will be counted as 1 month. If a partial cycle of chemotherapy is given, that partial cycle will be counted proportional to the amount given. E.G. if one of three planned infusions of gemcitabine based chemotherapy is given, it will be counted as 1/3 month. Enrollment must occur within 90 days of Day 1 of the last infusion given of chemotherapy. Patients who have primary tumor or regional lymph node progression on chemotherapy or prior to enrollment are eligible if no distant metastases are identified on the screening imaging assessment. Eastern Cooperative Oncology Group (ECOG) performance status =< 1 Absolute neutrophil count (ANC) >= 1500/uL Platelets >= 100k/uL Total Bilirubin =< 2.0 mg/dL Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (ULN) Serum creatinine < 1.25 md/dL Serum potassium < 5.0 mmol/L Negative serum or urine pregnancy test at screening for women of childbearing potential Highly effective contraception for both male and female subjects throughout the study and for at least 12 months after last study treatment administration if the risk of conception exists Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) v5.0 from toxicities related to any prior treatments, unless AEs are clinically nonsignificant and/or stable on supportive therapy Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines Exclusion Criteria: Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen of this trial Distant metastases. Regional lymphatic disease is acceptable Prior radiation therapy or definitive resection for pancreatic cancer Uncontrolled gastric or duodenal ulcer disease within 28 days of registration Chronic cough, defined 30% of days over 3 months with active symptoms at enrollment or over 12 months with last active symptoms occurring 6 months prior to enrollment Symptomatic hypotension (blood pressure < 90 systolic or < 60 diastolic at screening vital sign assessment) that has the potential to interfere with the patient's safety or ability to complete protocol treatment, at the discretion of the treating investigator Patients taking > 50mg losartan QD who, at the discretion of the treating investigator, cannot be reduced to the protocol defined regimen. Patients taking an angiotensin II receptor blocker or an angiotensin-converting enzyme inhibitor who, at the discretion of the treating investigator, cannot be safely discontinued prior to Day 1 dosing. Patients taking direct renin-angiotensin system inhibitors including aliskiren (Rasilez). Prior allergy to an angiotensin II receptor blocker Concurrent use of direct renin inhibitor including aliskiren (Rasilez) Patients with known history of: Heart failure. Patients with heart failure, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. Patients with a prior history of treatment with cardiotoxic agents should be evaluated for heart failure prior to enrollment at the discretion of the treating investigator. Solitary kidney, renal artery stenosis, or chronic renal failure Human immunodeficiency virus (HIV)-infected patients who are not on effective anti-retroviral therapy or have a detectable viral load within 6 months of trial entry Patients with known evidence of chronic hepatitis B virus (HBV) infection and a detectable HBV viral load Patients with a history of hepatitis C virus (HCV) infection who have not been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Subject is currently enrolled on another investigational treatment study for pancreas cancer

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (losartan, hypofractionated radiation therapy)<br>Beginning on day 1, patients receive losartan potassium PO QD. Beginning day 14, patients also undergo hypofractionated radiation therapy over 15 fractions 5 days a week for up to 3 weeks. Patients continue to receive losartan potassium PO QD during radiation therapy and for 28 days after completion of radiation therapy. Patients may begin additional anti-cancer therapy per investigator discretion after the last dose of HRT. Losartan can be given concurrently with additional therapy and Losartan dosing can continue until 28 days after last dose of HRT, regardless of when additional therapy is started. | Radiation: Hypofractionated Radiation Therapy<br>* Undergo hypofractionated radiation therapy<br>* Other names: hypofractionation;Drug: Losartan<br>* Given PO<br>Drug: Losartan Potassium<br>* Given PO<br>* Other names: losartan;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 or higher gastrointestinal toxicity rate | Will be graded according to Common Terminology Criteria for Adverse Events version (v) 5.0. The proportion of subjects that experience this endpoint will be tabulated along with an exact 90% binomial confidence interval (Clopper-Pearson). | Up to 3 months (84 days) after completion of radiation therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events | Will be graded according to Common Terminology Criteria for Adverse Events version (v) 5.0. | Up to 3 months (84 days) after completion of radiation therapy | 
| Response rate (clinical and/or pathologic partial response [PR] and complete response [CR]) | Will be described using Response Evaluation Criteria in Solid Tumors v1.1. The proportion of subjects with a PR and CR will be reported along with exact binomial confidence intervals (Clopper-Pearson). | Up to 36 months post-treatment | 
| Progressive free survival (PFS) | Kaplan-Meier methods will be used to report PFS. | From the time of enrollment until disease progression or death (any cause), assessed up to 36 months post-treatment | 
| Overall survival (OS) | Kaplan-Meier methods will be used to report OS. | From the patient?s first dose of study drug to death due to any cause, assessed up to 36 months post-treatment | 
| Number patients that require a medical intervention or hospitalization due to hypotension | Will be analyzed descriptively. | Up to 36 months post-treatment |