Sonoporation and Chemotherapy for the Treatment of Pancreatic Cancer

Optimizing Ultrasound Enhanced Delivery of Therapeutics

This phase I/II trial studies the effect of sonoporation in addition to standard of care chemotherapy in treating patients with pancreatic cancer. Sonoporation is a novel method that uses ultrasound and microbubbles to increase therapeutic effect by increasing uptake or enhance sensitization. Sonoporation together with chemotherapy may work better in treating patients with pancreatic cancer compared to chemotherapy alone.

Study Overview

• Status: Recruiting
• Conditions: Stage II Pancreatic Cancer AJCC v8; Stage III Pancreatic Cancer AJCC v8; Stage IV Pancreatic Cancer AJCC v8; Stage IIA Pancreatic Cancer AJCC v8; Stage IIB Pancreatic Cancer AJCC v8; Metastatic Pancreatic Ductal Adenocarcinoma; Locally Advanced Pancreatic Ductal Adenocarcinoma; Unresectable Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Other: Quality-of-Life Assessment; Procedure: Magnetic Resonance Imaging; Drug: Nab-paclitaxel; Drug: Gemcitabine Hydrochloride; Drug: Fluorouracil; Drug: Oxaliplatin; Drug: Leucovorin Calcium; Drug: Irinotecan Hydrochloride; Procedure: Contrast-Enhanced Ultrasound; Other: Perflubutane Microbubble; Procedure: Computed Tomography

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate the safety and therapeutic efficacy of sonoporation on pancreatic ductal adenocarcinoma (PDAC) standard of care (SoC) treatment based on local progression-free and overall survival with the main endpoint being an increase in median progression-free survival of subjects by 8.7 months in the sonoporation group relative to controls.

SECONDARY OBJECTIVES:

I. To evaluate the effect of sonoporation on the median time to treatment failure (TTF) (in percent).

II. To evaluate the effect of sonoporation on the number of chemotherapy cycles subjects can undergo.

III. To evaluate the effect of sonoporation on tumor volume measured by clinical diagnostic ultrasound.

IV. To evaluate the effect of sonoporation on tumor perfusion using contrast enhanced ultrasound (CEUS) - specifically harmonic imaging (HI) and subharmonic imaging (SHI).

V. To evaluate the effect of sonoporation on tumor interstitial fluid pressures using subharmonic aided pressure estimation (SHAPE).

VI. To evaluate the effect of sonoporation on tumor volume using clinical diagnostic computed tomography (CT).

VII. To evaluate the effect of sonoporation on tumor stiffness using clinical ultrasound shear wave elastography (SWE).

VIII. To evaluate the effect of sonoporation on serum CA 19-9 concentrations. IX. Clinical benefit response, which is a measure of clinical improvement based on analgesic consumption, Eastern Cooperative Oncology Group (ECOG) performance status, and weight change.

X. To evaluate the effect of sonoporation on patient quality of life.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive standard of care chemotherapy consisting of gemcitabine hydrochloride and nab-paclitaxel intravenously (IV) over 60 minutes on days 1, 8 and 15 OR fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin (FOLFIRINOX) IV on days 1 and 2. Treatments repeat every 28 days for up to 3 cycles for gemcitabine and nab-paclitaxel, and every 14 days for up to 7 cycles for FOLFIRINOX in the absence of disease progression or unacceptable toxicity. Patients also receive sonazoid IV over 20 minutes and undergo CEUS. Patients undergo computed tomography (CT) or positron emission tomography (PET)/CT or magnetic resonance imaging (MRI) during screening and as clinically indicated on study.

ARM II: Patients receive standard of care chemotherapy consisting of gemcitabine hydrochloride and nab-paclitaxel IV over 60 minutes on days 1, 8 and 15 OR FOLFIRINOX IV on days 1 and 2. Treatments repeat every 28 days for up to 3 cycles for gemcitabine and nab-paclitaxel, and every 14 days for up to 7 cycles for FOLFIRINOX in the absence of disease progression or unacceptable toxicity. Patients undergo CT or PET/CT or MRI during screening and as clinically indicated on study.

After completion of study treatment, patients are followed up every 3 months.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Flemming Forsberg, PhD; Phone Number: 215-955-4870; Email: Flemming.Forsberg@jefferson.edu

Study Locations

• Norway
  • Bergen, Norway, 5021
    • Recruiting
    • Haukeland University Hospital
    • Contact: Odd Gilja; Phone Number: 47 55972133; Email: Odd.Gilja@uib.no
• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Recruiting
      • Sidney Kimmel Cancer Center at Thomas Jefferson University
      • Contact: Flemming Forsberg, PhD; Phone Number: 215-955-4870; Email: Flemming.Forsberg@jefferson.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient must be >= 18 years old

• Patient has a new diagnosis of PDAC and is scheduled to undergo SoC chemotherapy

  • (International Classification of Diseases [ICD]-10 C25.0 Malignant neoplasm: Head of pancreas, C25.1: Malignant neoplasm: Body of pancreas, C25.2 Malignant neoplasm: Tail of pancreas, C25.3 Malignant neoplasm: Pancreatic duct and C25.9 Malignant neoplasm: Pancreas, unspecified). Any ICD-10 code in the C25 section (malignant neoplasm of pancreas) will be acceptable
  • Histologically verified, locally advanced (stage II/III) or metastatic (stage IV) adenocarcinoma of the pancreas
• The PDAC must be visible on grayscale ultrasound prior to injection of ultrasound contrast
• Must be ambulatory with an ECOG performance status between 0 and 2

• Female patients of child-bearing potential must have a negative urine pregnancy test and use (and agree to continue to use throughout the study) one of the following forms of contraception from the screening Visit until completion of the first study follow-up visit: hormonal (oral, implant or injection) begun > 15 days prior to the screening visit, barrier (e.g., condom, diaphragm with spermicide), intra-uterine device or vasectomized partner (6 months minimum). Male patients must also agree to practice throughout the study an approved method of birth control.

  * (Note: To be considered NOT of child-bearing potential, female patients must be postmenopausal [with amenorrhea for at least 2 years prior to study entry] or surgically sterile [bilateral tubal ligation at least 6 months prior to study entry, or of a hysterectomy and/or bilateral oophorectomy])

• Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to International Conference on Harmonization (ICH)/Good Clinical Practice (GCP), and national/local regulations

Exclusion Criteria:

• Patient participated in an investigational study within 7 days prior to study entry (or, if longer, within five half-lives of the last dose of any investigational drug
• Patient has severe chronic obstructive pulmonary disease, or pulmonary hypertension or unstable cardiopulmonary conditions

• Patients who are medically unstable. For example:

  • Patients on life support or in a critical care unit
  • Patients with unstable occlusive disease (e.g., crescendo angina)
  • Patients with clinically unstable cardiac arrhythmias, such as recurrent ventricular tachycardia
  • Patients with uncontrolled congestive heart failure (New York Heart Association [NYHA] class IV)
  • Patients with recent cerebral hemorrhage
  • Patients who have undergone surgery within 24 hours prior to the study sonographic examination
• Patient with a history of any psychiatric disorder or cognitive impairment that would interfere with participation in the study in the opinion of the investigator
• Patient requires dialysis or has severely impaired renal function, defined as a serum creatinine >= 1.5 x ULN or calculated creatinine clearance < 45 mL/min at the screening visit
• Patient has severe impairment of liver function, defined as a serum albumin level =< 25 g/L and/or a prothrombin time international normalized ratio (INR) > 2.3 (or activated partial thromboplastin time [APTT] > 6 seconds above the upper limit of normal), or a Child Pugh Score C at the screening visit
• Patients diagnosed with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV)
• Patients with a history of anaphylactic allergy to eggs or egg products, manifested by one or more of the following symptoms: generalized urticaria, difficulty in breathing, swelling of the mouth and throat, hypotension, or shock. (Subjects with non anaphylactic allergies to eggs or egg products may be enrolled in the study, but must be watched carefully for 1 hour following the administration of Sonazoid)
• Patients that are allergic to any other component of Sonazoid
• Any reason why, in the opinion of the investigator, the patient should not participate
• Patient is pregnant or is breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (sonazoid, ultrasound, chemotherapy); Patients receive standard of care chemotherapy consisting of gemcitabine hydrochloride and nab-paclitaxel IV over 60 minutes on days 1, 8 and 15 OR FOLFIRINOX IV on days 1 and 2. Treatments repeat every 28 days for up to 3 cycles for gemcitabine and nab-paclitaxel, and every 14 days for up to 7 cycles for FOLFIRINOX in the absence of disease progression or unacceptable toxicity. Patients also receive sonazoid IV over 20 minutes and undergo CEUS. Patients undergo CT or PET/CT or MRI during screening and as clinically indicated on study.	Other: Quality-of-Life Assessment; Ancillary studies; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Medical Imaging; Magnetic Resonance / Nuclear Magnetic Resonance; nuclear magnetic resonance imaging; Magnetic resonance imaging (procedure); Drug: Nab-paclitaxel; Given IV; Other Names: ABI-007; Abraxane; Albumin-bound Paclitaxel; ABI 007; Albumin-Stabilized Nanoparticle Paclitaxel; Nanoparticle Albumin-bound Paclitaxel; Paclitaxel Albumin; paclitaxel albumin-stabilized nanoparticle formulation; protein-bound paclitaxel; nanoparticle paclitaxel; Paclitaxel Protein-Bound; Paclitaxel Nanoparticle Albumin-bound; Drug: Gemcitabine Hydrochloride; Given IV; Other Names: Gemzar; dFdCyd; Difluorodeoxycytidine Hydrochloride; Gemcitabine HCI; LY-188011; LY188011; Hydrochloride; 1-(2-Oxo-4-amino-1; 122111-03-9; 2-dihydropyrimidin-1-yl)-2-deoxy-2; 2-difluororibose, hydrochloride; 2'Deoxy-2'; 2'-Difluorocytidine; Drug: Fluorouracil; Given IV; Other Names: 5-Fluracil; Fluracil; 5 Fluorouracil; 5 Fluorouracilum; 5 FU; 5-Fluoro-2,4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; 5FU; AccuSite; Carac; Fluoro Uracil; Fluouracil; Flurablastin; Fluril; Ribofluor; Ro 2-9757; 2,4-Dioxo-5-fluoropyrimidine; 5-Fluoro-2,4(1H,3H)-pyrimidinedione; 51-21-8; 5-FU, 5-Fu; fluorouraci; Fluracedy; Drug: Oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; Ai Heng; Aiheng; Diaminocyclohexane Oxalatoplatinum; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; 61825-94-3; oxalato (1R,2R-cyclohexanediamine)platinum(II); trans-l DACH oxalatoplatinum; trans-l diaminocyclohexane oxalatoplatinum; [(1R,-2R)-1,2-cyclohexanediamine-N,N'][oxalato (2--)-O,O']platinum; [SP-4-2-(1R-trans)]-(1,2,cyclohexanediamine-N; N')[ethanedioato(2--)-O; O']platinum; Drug: Leucovorin Calcium; Given IV; Other Names: Wellcovorin; citrovorum factor; folinic acid; Citrovorum; Adinepar; Calcifolin; Calcium (6S)-Folinate; Calcium Folinate; Calcium Leucovorin; Calfolex; Calinat; Cehafolin; Citofolin; Citrec; Cromatonbic Folinico; Dalisol; Disintox; Divical; Ecofol; Emovis; Flynoken A; Folaren; Folaxin; FOLI-cell; Foliben; Folidan; Folidar; Folinac; Folinate Calcium; Folinic Acid Calcium Salt Pentahydrate; Folinoral; Folinvit; Foliplus; Folix; Imo; Lederfolat; Lederfolin; Leucosar; leucovorin; Rescufolin; Rescuvolin; Tonofolin; 1492-18-8; 5-Formyl Tetrahydrofolate; 5-Formyl-5,6,7,8-tetrahydrofolic Acid; 5-Formyl-5,6,7,8-tetrahydropteroyl-L-glutamic Acid; Calcium N-(p-((((6RS)-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl)methyl)amino)benzoyl)-L-glutamate (1:1); N-[4-[[(2-Amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amnio]benzoyl]-L-glutamic Acid; Factor; Calcium Salt (1:1); N-[p-[[(2-Amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl)methyl]amino]benzoyl]glutamic Acid; Drug: Irinotecan Hydrochloride; Given IV; Other Names: Campto; Camptosar; U-101440E; CPT-11; Camptothecin 11; Camptothecin-11; CPT 11; Irinomedac; Irinotecan Hydrochloride Trihydrate; Irinotecan Monohydrochloride Trihydrate; 136572-09-3; Procedure: Contrast-Enhanced Ultrasound; Undergo CEUS; Other: Perflubutane Microbubble; Oxaliplatin; Procedure: Computed Tomography; Undergo CT or PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Tomography; tomography; CT SCAN; computerized axial tomography; Computerized axial tomography (procedure)
Active Comparator: Arm II (chemotherapy); Patients receive standard of care chemotherapy consisting of gemcitabine hydrochloride and nab-paclitaxel IV over 60 minutes on days 1, 8 and 15 OR FOLFIRINOX IV on days 1 and 2. Treatments repeat every 28 days for up to 3 cycles for gemcitabine and nab-paclitaxel, and every 14 days for up to 7 cycles for FOLFIRINOX in the absence of disease progression or unacceptable toxicity. Patients undergo CT or PET/CT or MRI during screening and as clinically indicated on study.	Other: Quality-of-Life Assessment; Ancillary studies; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Medical Imaging; Magnetic Resonance / Nuclear Magnetic Resonance; nuclear magnetic resonance imaging; Magnetic resonance imaging (procedure); Drug: Nab-paclitaxel; Given IV; Other Names: ABI-007; Abraxane; Albumin-bound Paclitaxel; ABI 007; Albumin-Stabilized Nanoparticle Paclitaxel; Nanoparticle Albumin-bound Paclitaxel; Paclitaxel Albumin; paclitaxel albumin-stabilized nanoparticle formulation; protein-bound paclitaxel; nanoparticle paclitaxel; Paclitaxel Protein-Bound; Paclitaxel Nanoparticle Albumin-bound; Drug: Gemcitabine Hydrochloride; Given IV; Other Names: Gemzar; dFdCyd; Difluorodeoxycytidine Hydrochloride; Gemcitabine HCI; LY-188011; LY188011; Hydrochloride; 1-(2-Oxo-4-amino-1; 122111-03-9; 2-dihydropyrimidin-1-yl)-2-deoxy-2; 2-difluororibose, hydrochloride; 2'Deoxy-2'; 2'-Difluorocytidine; Drug: Fluorouracil; Given IV; Other Names: 5-Fluracil; Fluracil; 5 Fluorouracil; 5 Fluorouracilum; 5 FU; 5-Fluoro-2,4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; 5FU; AccuSite; Carac; Fluoro Uracil; Fluouracil; Flurablastin; Fluril; Ribofluor; Ro 2-9757; 2,4-Dioxo-5-fluoropyrimidine; 5-Fluoro-2,4(1H,3H)-pyrimidinedione; 51-21-8; 5-FU, 5-Fu; fluorouraci; Fluracedy; Drug: Oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; Ai Heng; Aiheng; Diaminocyclohexane Oxalatoplatinum; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; 61825-94-3; oxalato (1R,2R-cyclohexanediamine)platinum(II); trans-l DACH oxalatoplatinum; trans-l diaminocyclohexane oxalatoplatinum; [(1R,-2R)-1,2-cyclohexanediamine-N,N'][oxalato (2--)-O,O']platinum; [SP-4-2-(1R-trans)]-(1,2,cyclohexanediamine-N; N')[ethanedioato(2--)-O; O']platinum; Drug: Leucovorin Calcium; Given IV; Other Names: Wellcovorin; citrovorum factor; folinic acid; Citrovorum; Adinepar; Calcifolin; Calcium (6S)-Folinate; Calcium Folinate; Calcium Leucovorin; Calfolex; Calinat; Cehafolin; Citofolin; Citrec; Cromatonbic Folinico; Dalisol; Disintox; Divical; Ecofol; Emovis; Flynoken A; Folaren; Folaxin; FOLI-cell; Foliben; Folidan; Folidar; Folinac; Folinate Calcium; Folinic Acid Calcium Salt Pentahydrate; Folinoral; Folinvit; Foliplus; Folix; Imo; Lederfolat; Lederfolin; Leucosar; leucovorin; Rescufolin; Rescuvolin; Tonofolin; 1492-18-8; 5-Formyl Tetrahydrofolate; 5-Formyl-5,6,7,8-tetrahydrofolic Acid; 5-Formyl-5,6,7,8-tetrahydropteroyl-L-glutamic Acid; Calcium N-(p-((((6RS)-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl)methyl)amino)benzoyl)-L-glutamate (1:1); N-[4-[[(2-Amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amnio]benzoyl]-L-glutamic Acid; Factor; Calcium Salt (1:1); N-[p-[[(2-Amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl)methyl]amino]benzoyl]glutamic Acid; Drug: Irinotecan Hydrochloride; Given IV; Other Names: Campto; Camptosar; U-101440E; CPT-11; Camptothecin 11; Camptothecin-11; CPT 11; Irinomedac; Irinotecan Hydrochloride Trihydrate; Irinotecan Monohydrochloride Trihydrate; 136572-09-3; Procedure: Computed Tomography; Undergo CT or PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Tomography; tomography; CT SCAN; computerized axial tomography; Computerized axial tomography (procedure)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Gehan-Breslow-Wilcoxon test and Log-rank (Mantel-Cox) test will be used to compare progression free survival (PSF) between the groups with and without sonoporation.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of chemotherapy cycles a subject can tolerate	Gehan-Breslow-Wilcoxon test and Log-rank (Mantel-Cox) test will be used to compare number of chemotherapy cycles between the groups with and without sonoporation.	Up to 3 years
Overall survival	Gehan-Breslow-Wilcoxon test and Log-rank (Mantel-Cox) test will be used to compare overall survival (PSF) between the groups with and without sonoporation.	Up to 3 years
Tumor volume changes	Relative changes will be measured with ultrasound, computed tomography and/or magnetic resonance imaging and will also be compared between the groups with and without sonoporation.	Up to 3 years
Contrast enhanced ultrasound data	Will provide perfusion and pressure estimates, which will be compared (individually and jointly) to subject outcomes in the groups with and without sonoporation as determined by the medical oncology team.	Up to 3 years
Tumor stiffness	Will be measured as shear wave velocity obtained by ultrasound shear wave elastography and will be compared between the groups with and without sonoporation.	Up to 3 years

Collaborators and Investigators

• Sponsor: Flemming Forsberg
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Flemming Forsberg, PhD, Thomas Jefferson University

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2021
• Primary Completion (Estimated): December 30, 2024
• Study Completion (Estimated): January 31, 2025

Study Registration Dates

• First Submitted: March 26, 2021
• First Submitted That Met QC Criteria: March 26, 2021
• First Posted (Actual): March 29, 2021

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Adenocarcinoma; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Hematinics; Paclitaxel; Fluorouracil; Oxaliplatin; Leucovorin; Irinotecan; Calcium; Levoleucovorin; Albumin-Bound Paclitaxel; Folic Acid; Calcium, Dietary; Camptothecin; Tetrahydrofolates; Formyltetrahydrofolates; Gemcitabine
• Other Study ID Numbers: 20F.1207; R01CA199646 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No