Concurrent FOLFIRINOX Plus High Intensity Focused Ultrasound for Pancreatic Cancer

Therapeutic Efficacy and Safety of Concurrent FOLFIRINOX Plus HIFU for Locally Advanced/Borderline Resectable Pancreatic Cancer: A Prospective Single-center, Single-arm, Investigator-initiated, Open-labeled, Exploratory Clinical Trial

In patients diagnosed with locally advanced pancreatic cancer (LAPC)/borderline resectable pancreatic cancer (BRPC) and planned chemotherapy using FOLFIRINOX, high intensity focused ultrasound (HIFU)/FOLFIRINOX combined treatment is performed on patients who agree to this study. The combined treatment group is treated in parallel with FOLFIRINOX and HIFU for the first four cycles and then CT is taken for reaction evaluation immediately, 2 months, and 4 months after the four-cycle treatment. For the response assessment, the response rate using RECIST ver. 1.1 and operable rate are evaluated and compared with the results of already established FOLFIRINOX single treatment in the investigators' institute. Time-to-progress and overall survival are calculated.

Patients diagnosed with pancreatic cancer through biopsy and diagnosed with LAPC/BRPC through computed tomography (CT) or magnetic resonance imaging (MRI) are referred to this clinical trial. When the referred patients are voluntarily signed a written consent form after hearing sufficient explanations related to this study, the referred patients will be registered for this clinical trial if all criteria for selection/exception are met.

A management log will be prepared for all subjects who have signed a clinical trial agreement and are registered in the study. These management logs are used to assign sequential subject numbers to subjects registered in clinical trials, and subject numbers are assigned 'screening numbers' and 'registration numbers'.

The subjects will visit on the scheduled date to receive chemotherapy and HIFU combined therapy and will be treated in accordance with the following treatment procedures and protocols.

<Visit 1 to Visit 4: Combined Treatment, Cycle 1, Cycle 2, Cycle 3, Cycle 4 ± 14 Days>

The subjects will receive combined treatments with anticancer drugs (FOLFIRINOX) and HIFU (ALPIUS 900) over four cycles over eight weeks. Afterwards, CT for reaction evaluation is taken immediately after 4 cycles (i.e., 2 months after the onset of combined treatment). CT is taken at intervals of two months up to 6 months after the onset of combined treatment.

At the end of each combined treatment, the patient will be observed about adverse events including anticancer drug adverse events and skin change and can be back home or hospitalized for one to two days after collecting blood for blood tests according to doctor's opinion.

<Schedule and procedures for combined treatment>

Perform a total of four treatments every two weeks for eight weeks.

Combined treatment procedure

Subjects are hospitalized and given anti-cancer drugs for about 50 hours in accordance with the standard protocol for anti-cancer treatment. If the medication is canceled or postponed due to the condition of the subject, the HIFU procedure will be canceled or postponed.

After the start of chemotherapy, receive HIFU treatment within 48 hours (30 minutes to 1 hour) and go up to the inpatient ward to monitor for 1 to 2 hours. If adverse events caused by anticancer drugs have not been recovered within 24 hours of administration or adverse events have not been fully recovered from previous HIFU procedures, the HIFU procedure may be canceled or postponed under the judgment of the investigator.

When combined treatment (anti-cancer drug administration) is completed, the subject shall be hospitalized for one to two days or return home depending on the physical condition of the subject.

<Treatment protocol>

Anti-cancer drug administration (FOLFIRINOX one time regimen) Oxaliplatin 85 mg/m2 (Intravenous, IV) Irinotecan 180 mg/m2 (Intravenous, IV) Leucovorin(Folic acid) 400 mg/m2 (Intravenous, IV) 5-fluorouracil 400 mg/m2 (IV push) 5-fluorouracil 2400 mg/m2 (Intravenous, IV) It is administered at the following schedule every two weeks. Day 1 : Oxaliplatin, Irinotecan, Leucovorin, 5-FU (IV-push), 5-FU (IV infusion) Day 2-3 : 5-FU (IV infusion)

The administration of anticancer drugs (FOLFIRINOX therapy) is applied equally to each treatment group and according to the institution's standard procedure. The FOLFIRINOX dose and administration cycle (interval) can be adjusted by the researcher's judgment depending on the condition and progress of the subject. Anti-cancer drugs used in clinical trials are licensed medicines and are used within the scope of permission.

<HIFU treatment (one-time treatment)>

The HIFU procedure is in accordance with the HIFU parameter, and the details of the pre-procedure, procedure, and post-procedure care of the subjects are in accordance with the manufacturer's ALPIUS 900 User Manual.

HIFU parameter

Acoustic Intensity 2.0 kilowatt (kW)/cm2, Duty cycle 1%, Exposure time 3 sec/point, Pulse repetition frequency (PRF) 10 Hz

Immediately, 2 months, and 4 months after completion of the 4th cycle combined treatment, the subjects visit the hospital to conduct the efficacy and safety assessment. The dose-limiting toxicity (DLT) or adverse device effect (ADE) assessment will be evaluated on each planned visit.

Treatment after the end of combined treatment of HIFU/Anticancer drug Subsequent treatment of patients who have completed HIFU/anti-cancer combined treatment in the first 4 cycles is determined and performed according to findings of CT performed after 4 cycles of combined treatment, overall physical condition of patients, and standard care guidelines. The implementation of surgery, continuation of FOLFIRINOX chemotherapy, conversion to other anticancer drugs, and further radiation therapy can be considered as possible treatments. This assessment is conducted after 8 and 12 cycles of treatment if the treatment continues for FOLFIRINOX chemotherapy, and further treatment policies are determined in accordance with the standard care guidelines. If surgery is performed after 8 or 12 cycles, additional cancer or radiotherapy may be performed after surgery according to surgery and pathological findings, and it is required to be determined in accordance with the standard care guidelines.

Inclusion Criteria:

All of the following selection criteria must be met before participants can be registered for this clinical trial.

1. Adults over 19-85
2. Persons with a Karnofsky Performance Scale (KPS) of 70 percent or more;
3. A person diagnosed as a tubular adenocarcinoma through biopsy.
4. A person diagnosed with LAPC/BRPC by computed tomography (CT) or magnetic resonance imaging (MRI)
5. A person willing to voluntarily agree to a clinical trial and comply with the test plan

Exclusion Criteria:

The following exclusion criteria may not be registered in clinical trials.

1. The presence of a cystic lesion within pancreatic cancer to be treated with HIFU or at the pancreas adjacent to the pancreatic cancer.
2. The presence of a wide range of scar or surgical clips observed in the passage through the ultrasonic beam.
3. In case proper ultrasound images for HIFU procedures are not shown
4. A person who cannot lie down in a comfortable position.
5. A person who has difficulty communicating
6. A person who has experience in toxic or hypersensitive reactions to FOLFIRINOX anticancer drugs.
7. A person pregnant or breastfeeding
8. Pancreatic cancer patients who have previously been anti-cancer treatment
9. If severe side effects such as aortic rupture, duodenum perforation, gastrointestinal damage or intestinal necrosis are expected due to HIFU procedures.
10. Other cases where participation in this clinical trial is judged inappropriate by the investigator (specific reasons should be recorded in the case report form)