Sonoporation and Chemotherapy for the Treatment of Pancreatic Cancer

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.

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