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Gemcitabine

Capecitabine

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Pancreatin

Vandetanib 100mg/day plus Gemcitabine plus CapecitabineDose

Vandetanib 300mg/day plus Gemcitabine plus CapectiabineDose

Vandetanib

Clinical Sciences & Operations

The purpose of this study is to define th Maximum Tolerated Dose (MTD) and the recommended dose (RD) of ZD6474 in combination with a fixed standard dose of gemcitabine and capecitabine

Dose Escalation Study With Zactima and Chemotherapy in Metastatic Pancreas Carcinoma

Dose Escalation Study of the Combination of ZD6474, Gemcitabine and Capecitabine in Locally Advanced Unresectable or Metastatic Pancreatic Adenocarcinoma

Sanofi

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Anti-Arrhythmia Agents

Antihypertensive Agents

Vasoconstrictor Agents

Losartan

Angiotensin II

Giapreza

Angiotensinogen

Angiotensin II Type 1 Receptor Blockers

Angiotensin Receptor Antagonists

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

Losartan Potassium

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

Peposertib

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients in Phase I undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive M3814 PO QD for 14 days in the absence of disease progression or unacceptable toxicity.Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study.

Patients in Phase II undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive M3814 PO QD for 14 days in the absence of disease progression or unacceptable toxicity.Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study.

Patients in Phase II undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive placebo PO QD for 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo CT and MRI during screening and on study.

Biopsy

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Placebo Administration

Site Public Contact

Vincent Chung

Farshid Dayyani

Edward J. Kim

Sarah L. Davis

Michael J. Pishvaian

Anup K. Kasi Loknath Kumar

Mohammed N. Al Hallak

Kathryn C. Hourdequin

Chaoyuan Kuang

Christos Fountzilas

Paul E. Oberstein

Karyn A. Goodman

Allyson J. Ocean

Michael McCormack

Emma C. Fields

Sarah L Davis

This phase I/II trial studies the safety, side effects and best dose of M3814 and to see how well it works when given together with radiation therapy in treating patients with pancreatic cancer that cannot be removed by surgery and has not spread to other parts of the body (localized). M3814 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 M3814 and hypofractionated radiation therapy together may be safe, tolerable and more effective than radiation therapy alone in treating patients with localized pancreatic cancer.

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of M3814 (peposertib) in combination with hypofractionated radiotherapy in patients receiving treatment for locally advanced pancreatic adenocarcinoma (LAPC). (Phase I) II. To determine the difference in progression free survival (PFS) between patients with LAPC treated with hypofractionated radiotherapy in combination with M3814 (peposertib) as compared to patients treated with hypofractionated radiotherapy alone. (Phase II)

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. (Phase I) II. To evaluate plasma pharmacokinetic (PK) profiles of M3814 (peposertib) in patients receiving hypofractionated radiotherapy. (Phase I) III. To compare the 2-year overall survival (OS) rate of patients treated with hypofractionated radiotherapy plus M3814 (peposertib) to that of those treated with hypofractionated radiotherapy alone. (Phase II) IV. To compare the objective response rate (ORR) by imaging of patients treated with hypofractionated radiotherapy plus M3814 (peposertib) to that of those treated with hypofractionated radiotherapy alone. (Phase II) V. To compare the disease control rate in patients treated with hypofractionated radiotherapy plus M3814 (peposertib) as compared to those patients treated with hypofractionated radiotherapy alone. (Phase II) VI. To explore gene signature patterns in baseline patient tumor tissues that may suggest response to the combination of M3814 (peposertib) and radiotherapy, as identified on whole exome sequencing and ribonucleic acid (RNA) sequencing (seq). (Phase II)

EXPLORATORY OBJECTIVE:

I. To explore changes in gene signature induced by M3814 (peposertib) and hypofractionated radiotherapy treatment as identified in analysis of cell-free deoxyribonucleic acid (DNA) from the peripheral blood. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of M3814 followed by a phase II study.

PHASE I: Patients undergo hypofractionated radiation therapy for 5 fractions every other day (QOD) over 2 weeks and receive M3814 orally (PO) once daily (QD) for 14 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 groups.

GROUP I: Patients undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive M3814 PO QD for 14 days in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients undergo hypofractionated radiation therapy for 5 fractions QOD over 2 weeks and receive placebo PO QD for 14 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection and tissue biopsy on study. Patients also undergo computed tomography (CT) and magnetic resonance imaging (MRI) during screening and on study.

After completion of study treatment, patients are followed up at 30, 60, and 90 days, and then every 3 months for up to 2 years.

Testing the Addition of a New Anti-cancer Drug, M3814 (Peposertib), to Radiation Therapy for Localized Pancreatic Cancer

A Phase 1/Randomized Phase 2 Study of M3814 (Peposertib) in Combination With Hypofractionated Radiotherapy for the Treatment of Locally Advanced Pancreatic Adenocarcinoma

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Results of cell-free DNA analysis will be compared pre- and post-treatment and reported descriptively.

The 95% confidence intervals will be provided.

Will be analyzed using a log-rank test to test for differences between the treatment groups in survival experience. The proportion of patients who survive through 2 years (i.e. the 2-year OS rate) will be compared between arms using Kaplan-Meier estimates.

Defined as the rate of patient survival at 2 years following completion of study treatment (based on Kaplan-Meier method).

Defined as the rate of complete or partial response by imaging following study treatment as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Will be summarized and compared between arms.

Defined as rate of stable disease, complete or partial response by imaging as assessed by RECIST v1.1. Will be summarized and compared between arms.

M3814 concentration time data will be analyzed non-compartmentally and reported descriptively.

Defined according to whole exome sequencing and ribonucleic acid sequencing, with a focus on deoxyribonucleic acid (DNA) damage repair signatures. Will be reported descriptively.

will be a monotherapy light dose escalation with single dose of Padeliporfin at light laser doses of 200, 400 and 600 mW/cm for 10 minutes.

Part A will proceed with light dose escalation and will continue until the maximum tolerated light dose (MTD) and/or recommended phase 2 dose (RP2D) is defined.

will be a dose expansion part at MTD/RP2D dose level identified in Part A to further assess the safety, tolerability, and treatment effect of the MTD and/ or RP2D

The laser light fiber with inflatable balloon to dam SMA blood flow during light illumination will be placed by an Interventional Radiologist in the SMA via a transfemoral artery approach. The balloon will be inflated to impede blood flow for total of 10 minutes during light illumination

Padeliporfin Vascular Targeted Photodynamic (VTP) therapy

Nadine Abi-Jaoudeh, MD

This is a prospective, multicenter, non-randomized, open label light dose escalation phase I trial to evaluate the safety and preliminary efficacy of Padeliporfin vascular targeted photodynamic therapy (VTP) applied via endovascular fiber placement within a dilatation catheter, through the superior mesenteric artery (SMA) in patients with stage III, locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC). The investigators will evaluate safety and preliminary efficacy of Padeliporfin VTP administered endovascularly using light dose escalation.

This is a prospective, multicenter, non-randomized, open label light dose escalation phase I trial to evaluate the safety and preliminary efficacy of Padeliporfin vascular targeted photodynamic therapy (VTP) applied via endovascular fiber placement within a dilatation catheter, through the superior mesenteric artery (SMA) in patients with stage III, locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC) with SMA solid tumor encasement \>180°. The investigators will evaluate safety and preliminary efficacy of Padeliporfin VTP administered endovascularly using light dose escalation.

Study Intervention: Patients enrolled in the study will undergo endovascular VTP, using Padeliporfin (WST-11) activated via endovascular fiber placement through the SMA, with intravenous administration of Padeliporfin at a fixed dose of 4 mg/kg of padeliporfin di-potassium, followed by total of 10 min illumination at 753 nm.

For light dose escalation (Part A), a 3+3 dose-escalation schema will be used. In a subsequent expansion phase (Part B), the optimal light dose as per light dose escalation, will be used in an additional cohort of patients to further evaluate preliminary efficacy.

Part B recruitment will be opened upon completion of Part A light dose escalation.

Padeliporfin VTP Treatment for Unresectable Pancreatic Adenocarcinoma

A Multicenter Open-label Phase 1 Trial to Evaluate Safety and Preliminary Efficacy of Endovascularly Applied Vascular Targeted Photodynamic Therapy (VTP) for Patients With Locally Advanced Unresectable Pancreatic Ductal Adenocarcinoma

Rate of resectability and downstaging will be evaluated by determining the percentage of patients who were initially deemed to have unresectable LA PDAC and following Padeliporfin VTP treatment, were subsequently deemed to have borderline resectable or resectable disease

Safety of endovascularly applied Padeliporfin VTP ablation will be assessed using the CTCAE version 5.0. All adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) for being included in analyses.

MTD is defined as the dose level associated with \<33% of DLT-evaluable patients experiencing a DLT. If the MTD is reached, the RP2D will be defined as MTD. If the MTD is not reached, the RP2D will be selected based on integrated evaluation of safety and clinical benefit for all dose levels tested.

Rate of resectability and downstaging (as per NCCN Clinical Practice Guidelines V1, May 4, 2023)

Impact Biotech Ltd

This is a single arm study in which all subjects will receive NEAAR medical food.

Standardized non-essential amino acid restricted medical food.

NEAAR Medical Food

Faeth Therapeutics

Brianna Loughran

Heather Lion

Investigative Site

Hoag Clinical Research

Backup

Sarah Ginn

Ethan Trull

Telice Terro

Andrew Hendifar, MD

This is a single arm study evaluating the tolerability and markers of pancreatic cancer with a specially designed medical food restricted in specific amino acids for the dietary management of subjects with locally advanced and unresectable or metastatic pancreatic adenocarcinoma. Subjects who are eligible to receive two FDA approved first line drug therapies, gemcitabine and nab-paclitaxel (gem+nabP), routinely prescribed in combination for pancreatic cancer may be included in this study.

Medical Food for the Dietary Management of Advanced/Metastatic Pancreatic Cancer

Prospective, Single Arm Medical Food Study to Evaluate a Standardized Nonessential Amino Acid Restriction (NEAAR) Medical Food for the Dietary Management of Advanced/Metastatic Pancreatic Cancer

The primary endpoint is the rate of the most common Grade 3 and 4 adverse event (AE) related to the NEAAR medical food.

Complete response and partial response using RECIST 1.1

Absolute and relative change from baseline of disease biomarkers

Duration from radiographic documentation of disease to radiographic documentation of progression or death from any cause

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Dose Escalation Study With Zactima and Chemotherapy in Metastatic Pancreas Carcinoma	NCT00681798	Pancreatic Canc...	Vandetanib	18 Years -	Sanofi
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
Testing the Addition of a New Anti-cancer Drug, M3814 (Peposertib), to Radiation Therapy for Localized Pancreatic Cancer	NCT04172532	Locally Advance... Locally Advance... Stage II Pancre... Stage III Pancr... Unresectable Pa...	Biopsy Biospecimen Col... Computed Tomogr... Hypofractionate... Magnetic Resona... Peposertib Placebo Adminis...	18 Years -	National Cancer Institute (NCI)
Padeliporfin VTP Treatment for Unresectable Pancreatic Adenocarcinoma	NCT05919238	Locally Advance...	Padeliporfin Va...	18 Years -	Impact Biotech Ltd
Medical Food for the Dietary Management of Advanced/Metastatic Pancreatic Cancer	NCT05078775	Metastatic Panc... Locally Advance...	NEAAR Medical F...	18 Years -	Faeth Therapeutics
Padeliporfin VTP Treatment for Unresectable Pancreatic Adenocarcinoma	NCT05919238	Locally Advance...	Padeliporfin Va...	18 Years -	Impact Biotech Ltd

Spots Global Cancer Trial Database for locally advanced unresectable pancreatic adenocarcinoma