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Vitamin B9

mFOLFIRINOX REGIMEN: Oxaliplatin intravenously (IV) over 2 hrs, leucovorin calcium IV over 2 hrs, and irinotecan hydrochloride IV over 90 minutes on day 1. Also receive fluorouracil IV over 46 hrs starting on day 1. Repeats every 14 days for up to 4 cycles. Those with response and no disease progression may receive an additional 2 months.

GA REGIMEN: Those with disease progression or toxicity to mFOLFIRINOX switch to GA regimen comprising gemcitabine hydrochloride IV over 30-60 mins and nab-paclitaxel IV over 30-40 mins on days 1, 8, and 15. Repeats every 28 days for 2 cycles.

LOSARTAN: Cycle 1 day 1, start losartan potassium orally once daily until end of RT.

RT/SURGERY: Short-course RT for 10 fractions over 5 days weekly or long-course RT with 15-25 fractions over 5 days weekly along with oral capecitabine twice daily on Monday-Friday or fluorouracil IV over 5-7 days weekly until completion of RT. Patients then undergo surgery 1-4 weeks following RT

Irinotecan Hydrochloride

Leucovorin Calcium

Losartan Potassium

Radiation Therapy

Resection

Diagnostic Imaging

Biospecimen Collection

Charles D. Lopez

Charles D Lopez

This phase II trial evaluates whether early switching from modified fluorouracil/irinotecan/leucovorin/oxaliplatin (mFOLFIRINOX) chemotherapy regimen to a combination of gemcitabine and nab-paclitaxel (GA) before surgery is effective in treating patients with pancreatic cancer that can be surgically removed (resectable or borderline resectable), or that has spread to nearby tissue or lymph nodes and cannot be removed by surgery (locally-advanced unresectable). Chemotherapy drugs, such as fluorouracil, irinotecan, leucovorin, oxaliplatin, gemcitabine, and nab-paclitaxel work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. The study will also evaluate the drug losartan in combination with mFOLFIRINOX or GA.

PRIMARY OBJECTIVE:

I. To determine the rate of margin-negative (R0) resection in participants with resectable or borderline resectable pancreatic cancer (BRPC) following treatment using NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX alone, or switch to GA).

SECONDARY OBJECTIVES:

I. To determine the progression-free survival (PFS) of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA).

II. To determine the PFS for the subset of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy, plus preoperative radiation therapy (RT).

III. To determine the disease-free survival (DFS) of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA).

IV. To determine the DFS for the subset of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT.

V. To determine the overall survival (OS) of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy.

VI. To determine the OS for the subset of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT.

VII. To assess the surgical complications of resectable or BRPC participants that undergo surgical resection.

VIII. To assess 30-day post-operative mortality of participants with resectable or BRPC that undergo surgical resection.

IX. To assess safety of NeoOPTIMIZE adaptive therapy (all participants).

EXPLORATORY OBJECTIVES:

I. To monitor changes in CA19-9 levels (all participants). II. To determine the rate of margin-negative (R0) resection in patients with locally advanced pancreatic cancer (LAPC), following treatment using NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX alone, or switch to GA).

III. To determine the PFS of LAPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA).

IV. To determine the PFS for the subset of LAPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative radiation therapy (RT).

V. To determine the disease-free survival (DFS) of LAPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA).

VI. To determine the DFS for the subset of LAPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT.

VII. To determine the OS of LAPC participants that received NeoOPTIMIZE adaptive therapy.

VIII. To determine the OS for the subset of LAPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT.

IX. To assess the surgical complications of LAPC participants that undergo surgical resection.

X. To assess 30-day post-operative mortality of LAPC participants who undergo surgical resection.

OUTLINE:

mFOLFIRINOX REGIMEN: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 90 minutes on day 1. Patients also receive fluorouracil IV over 46 hours starting on day 1. Treatment with mFOLFIRINOX repeats every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo disease restaging (re-stage I). Patients with radiographic response and no disease progression receive mFOLFIRINOX for an additional 2 months (approximately 4 cycles). Patients then undergo second re-staging (re-stage II).

GA REGIMEN: After re-stage I, patients with disease progression or toxicity to mFOLFIRINOX (per assessment of the treating physician) switch to receive the GA regimen comprising gemcitabine hydrochloride IV over 30-60 minutes and nab-paclitaxel IV over 30-40 minutes on days 1, 8, and 15. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo second re-staging (re-stage II). Patients may be switched to GA regimen from FOLFIRINOX regimen prior to re-stage I (per assessment of the treating physician).

LOSARTAN: Starting cycle 1 day 1, patients also receive losartan potassium orally (PO) once daily (QD) until completion of RT in the absence of disease progression or unacceptable toxicity.

RT/SURGERY: Patients with no vascular tumor involvement at re-stage II, undergo surgery 1-4 after completion of chemotherapy. Patients with resolution of tumor contact with pancreatic vasculature at re-stage II, undergo short-course RT to receive a total of 10 fractions over 5 days weekly (Monday-Friday). Patients with tumor vessel involvement that is persistent at re-stage II, undergo long-course RT to receive a total of 15-25 fractions over 5 days weekly (Monday-Friday), and receive capecitabine PO twice daily (BID) on Monday-Friday or fluorouracil IV over 5-7 days weekly until completion of RT. Patients then undergo surgery 1-4 weeks after completion RT.

Patients undergo diagnostic imaging as clinically indicated throughout the trial. Patients also undergo blood sample collection throughout the trial.

After completion of study treatment, patients are followed up as clinically indicated and following institutional standards, and then every 3 months for 6 months, and then every 6 months for up to 2 years.

NeoOPTIMIZE: Early Switching of mFOLFIRINOX or Gemcitabine/Nab-Paclitaxel Before Surgery for the Treatment of Resectable, Borderline Resectable, or Locally-Advanced Unresectable Pancreatic Cancer

NeoOPTIMIZE: An Open-Label, Phase II Trial to Assess the Efficacy of Adaptive Switching of FOLFIRINOX or Gemcitabine/Nab-Paclitaxel as a Neoadjuvant Strategy for Patients With Resectable and Borderline Resectable/Locally Advanced Unresectable Pancreatic Cancer

Using the safety analysis set, the levels of CA19-9 will be descriptively reported (across all participants).

Will be estimated with exact 95% confidence interval.

Results will be qualitatively described when statistical measures are not feasible.

Assessed per the Clavien-Dindo classification system. Results will be qualitatively described when statistical measures are not feasible.

Using the surgery analysis set, the proportion of participants with R0 resection will be estimated with exact 95% confidence interval.

Using the efficacy analysis set, the estimated distribution of the PFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., gemcitabine/nab-paclitaxel \[GA\] or modified fluorouracil/irinotecan/leucovorin/oxaliplatin \[mFOLFIRINOX\] +/- radiation therapy \[RT\] \[i.e., short- or long-course, or both RT modalities combined\]) will be performed for PFS.

Using the efficacy analysis set, the estimated distribution of the PFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX +/- RT \[i.e., short- or long-course, or both RT modalities combined\]) will be performed for PFS.

Using the surgery analysis set, the estimated distribution of the DFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. Using the efficacy analysis set, the estimated distribution of the DFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX +/- RT \[i.e., short- or long-course, or both RT modalities combined\]) will be performed for DFS.

Using the efficacy analysis set, the estimated distribution of the DFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX +/- RT \[i.e., short- or long-course, or both RT modalities combined\]) will be performed for DFS.

Using the efficacy analysis set, the estimated distribution of the OS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. Using the efficacy analysis set, the estimated distribution of the OS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX +/- RT \[i.e., short- or long-course, or both RT modalities combined\]) will be performed for OS.

Using the efficacy analysis set, the estimated distribution of the OS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX\] +/- RT \[i.e., short- or long-course, or both RT modalities combined\]) will be performed for OS.

Peri- and post-operative complications occurring within 30 days following surgery will be categorized per the Clavien-Dindo classification system. Using the surgery analysis set, the proportion of participants with peri- and post-operative complications occurring within 30 days following surgery.

The proportion of 30-day post-operative mortality will be estimated and reported with two-sided exact 95% confidence intervals. If necessary, the proportion of 30-day post-operative mortality may be estimated from the Kaplan Meier product limit method.

The incidence of grade \>= 3 toxicities per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 will be determined using the safety analysis set. The exact 95% confidence interval will be reported with the point estimate of toxicity rate. Adverse events will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA version 21.1) preferred term and system organ class and a preferred term. The severity of the adverse events (AE) will be assessed by National Cancer Institute (NCI) CTCAE v 5.0 criteria. Descriptive statistics using the safety analysis set will be used to report on all on-study AEs, grade 3-4 AEs, treatment-related AEs, grade 3-4 treatment-related AEs, serious adverse events (SAEs), treatment-related SAEs, and AEs leading to discontinuation per CTCAE v 5.0. Grade 3-4 laboratory abnormalities will be summarized using worst grade NCI CTCAE v 5.0 criteria.

Oregon Health and Science University

OHSU Knight Cancer Institute

Principal Investigator

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

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.

Undergo hypofractionated radiation therapy

Hypofractionated Radiation Therapy

Quality-of-Life Assessment

Questionnaire Administration

Mitchell Shea

Shane Lloyd

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.

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.

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

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

Will be assessed using MD Anderson Symptom Inventory-Gastrointestinal (MDASI-GI).

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).

Will be graded according to Common Terminology Criteria for Adverse Events version (v) 5.0.

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).

Kaplan-Meier methods will be used to report PFS.

Kaplan-Meier methods will be used to report OS.

National Cancer Institute (NCI)

University of Utah

Heart and Blood Diseases

Hypertension

Vascular Diseases

Cardiotonic Agents

Anti-Infective Agents

Lisinopril

Ramipril

Angiotensin-Converting Enzyme Inhibitors

Benazepril

HIV Protease Inhibitors

Protease Inhibitors

Patients receive oral benazepril hydrochloride once daily on days 1-7.

Patients receive oral lisinopril once daily on days 1-7.

Patients receive oral ramipril twice daily on days 1-7.

Patients receive oral losartan potassium once daily on days 1-7.

lisinopril

losartan potassium

laboratory biomarker analysis

benazepril hydrochloride

ramipril

William Petty

RATIONALE: Benazepril hydrochloride, lisinopril, ramipril, and losartan potassium may help lower blood pressure.

PURPOSE: This phase II trial is studying how well benazepril hydrochloride, lisinopril, ramipril, or losartan potassium works in treating hypertension in patients with solid tumors.

PRIMARY OBJECTIVES:

I. To determine which drug has the greatest effect on Ang-(1-7) levels in cancer patients with hypertension.

SECONDARY OBJECTIVES:

I. To determine the effect of these drugs on levels of Ang II, VEGF, PlGF, and ACE in the same patients.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

* ARM I: Patients receive oral benazepril hydrochloride once daily on days 1-7.
* ARM II: Patients receive oral lisinopril once daily on days 1-7.
* ARM III: Patients receive oral ramipril twice daily on days 1-7.
* ARM IV: Patients receive oral losartan potassium once daily on days 1-7. In all arms, treatment continues in the absence of unacceptable toxicity.

Benazepril Hydrochloride, Lisinopril, Ramipril, or Losartan Potassium in Treating Hypertension in Patients With Solid Tumors

A Phase II Study of the Effect of ACE Inhibitors on Pro-Angiogenic Hormones in Cancer Patients With Hypertension

Wake Forest University Health Sciences

Patients receive oral benazepril hydrochloride once daily on days 1-7.

laboratory biomarker analysis: Correlative studies

benazepril hydrochloride: Given orally

Arm I

Patients receive oral lisinopril once daily on days 1-7.

lisinopril: Given orally

laboratory biomarker analysis: Correlative studies

Arm II

Patients receive oral ramipril twice daily on days 1-7.

laboratory biomarker analysis: Correlative studies

ramipril: Given orally

Arm III

Patients receive oral losartan potassium once daily on days 1-7.

losartan potassium: Given orally

laboratory biomarker analysis: Correlative studies

Arm IV

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

William J. Petty, MD

Changes in Ang1-7 Levels Among Patients After ACE-I/ARB Treatment Measured in Picogram/Milliliter

Data were not analyzed due to insufficient accrual to the study and lack of statistical power.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
NeoOPTIMIZE: Early Switching of mFOLFIRINOX or Gemcitabine/Nab-Paclitaxel Before Surgery for the Treatment of Resectable, Borderline Resectable, or Locally-Advanced Unresectable Pancreatic Cancer	NCT04539808	Pancreatic Aden... Stage 0 Pancrea... Stage I Pancrea... Stage III Pancr... Stage IV Pancre...	Capecitabine Fluorouracil Irinotecan Hydr... Leucovorin Calc... Losartan Potass... Oxaliplatin Radiation Thera... Resection Diagnostic Imag... Biospecimen Col...	18 Years -	OHSU Knight Cancer Institute
Losartan and Hypofractionated Rx After Chemo for Tx of Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer (SHAPER)	NCT04106856	Borderline Rese... Locally Advance... Locally Advance... Stage II Pancre... Stage IIA Pancr... Stage IIB Pancr... Stage III Pancr...	Hypofractionate... Losartan Losartan Potass... Quality-of-Life... Questionnaire A...	18 Years -	University of Utah
Benazepril Hydrochloride, Lisinopril, Ramipril, or Losartan Potassium in Treating Hypertension in Patients With Solid Tumors	NCT01234922	Hypertension Unspecified Adu...	lisinopril losartan potass... laboratory biom... benazepril hydr... ramipril	18 Years -	Wake Forest University Health Sciences

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