Surgical Resection of Synchronous Pulmonary or Hepatic Oligometastatic Pancreatic Ductal Adenocarcinoma

Surgical Resection of Synchronous Pulmonary or Hepatic Oligometastatic Pancreatic Ductal Adenocarcinoma (PHOLIPANC): A Phase II Single Arm Trial

Surgical Resection of Synchronous Pulmonary or Hepatic Oligometastatic Pancreatic Ductal Adenocarcinoma (PHOLIPANC). This is an interventional, open-label, non-randomised, single-arm phase II clinical trial.

Eligible patients with hepatic or pulmonary oligometastatic adenocarcinoma of the pancreas must have received neoadjuvant FOLFIRINOX chemotherapy in cycles of 14 days, or other clinically indicated alternative. FOLFIRINOX is not a study treatment.

In this clinical trial the investigators will enroll subjects with hepatic or pulmonary oligometastatic pancreatic ductal adenocarcinoma and perform a synchronous surgical resection. In patients with progressive disease during or after the first four cycles of neoadjuvant chemotherapy, those patients will not be eligible for study enrollment. Patients with tumor response or stable disease after the first 4-cycles but a non-resectable primary tumor according to the evaluation of an interdisciplinary tumor board must receive 4 more cycles of neoadjuvant chemotherapy before being evaluated for eligibility for the Study Entry Screening. Patients with hepatic metastasis with tumor response or stable disease and a resectable primary tumor after the first 4 cycles can undergo explorative laparotomy and synchronous resection of the tumor and hepatic metastases, if feasible. In patients who undergo exploratory laparotomy and are deemed to have unresectable disease by the surgeon, the patients may receive 4 more cycles of neoadjuvant chemotherapy 2-4 week after surgery, before the patient will be re-evaluated for the eligibility for the Study Entry Screening. Patients with pulmonary metastasis with tumor response or stable disease and a resectable primary tumor after the first 4 cycles can undergo resection of the primary tumor followed by resection of pulmonary metastases or vice versa, if feasible.

All eligible patients with hepatic metastasis will undergo exploratory laparotomy surgery and synchronous resection of the tumor and hepatic metastases, if feasible according to the surgeon, 2-6 weeks after the last neoadjuvant chemotherapy treatment. All eligible patients with pulmonary metastasis will undergo resection of the primary tumor followed by resection of pulmonary metastases or vice versa, if feasible.

1. Inclusion Criteria at the Pre-Screening Enrollment

   • Histologically confirmed diagnosis of treatment-naïve limited hepatic or pulmonary metastatic adenocarcinoma of the pancreas Meet the definition of limited hepatic or pulmonary metastasis according to CT/MRI that is done prior to the starting of any anticancer treatment. Either CT scan of chest, abdomen, and pelvis with intravenous contrast or a combination of MRI of abdomen and pelvis and CT scan of chest is acceptable radiographic imaging. CT/MRI can be done at an outside facility, but must be reviewed by a Johns Hopkins Medicine radiologist.
   • Measurable disease according to RECIST v1.1
   • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
   • Being a candidate for the chemotherapy with FOLFIRINOX or modified FOLFIRINOX
   • Patients ≥18 years at the time of signing the informed consent
   • Patient's written informed consent prior to any trial-specific procedure
   • Patient's legal capacity to consent to participation in the clinical trial

2. Exclusion Criteria at the Pre-Screening Enrollment

   • Acinar cell carcinoma and/or neuroendocrine carcinoma of the pancreas
   • Symptomatic clinically significant ascites
   • Evidence of any distant metastases other than limited hepatic or pulmonary metastasis as defined in inclusion criterion 1.
   • Evidence of simultaneous pulmonary and hepatic metastases
   • Any tumor-specific pretreatment of the adenocarcinoma of the pancreas (including but not limited to surgery, radiation therapy, chemotherapy or ablative procedures). Currently being on FOLFIRINOX or modified FOLFIRINOX (mFOLFIRINOX) is allowed, unless more than 2 treatments of FOLFIRINOX or mFOLFIRINOX has been given.
   • Any malignancies other than adenocarcinoma of the pancreas in the 2 years before the start of the clinical trial except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, breast cancer, prostate cancer or superficial bladder tumors (Ta, Tis and T1)
   • Known HIV seropositivity
   • Known active or chronic Hepatitis B or Hepatitis C infection
   • Any other severe concomitant disease or disorder, which could influence patient's ability to participate in the clinical trial and his/her safety during the trial or interfere with interpretation of results, e.g., severe hepatic, renal, pulmonary, cardiovascular, metabolic or psychiatric disorders

3.2 Eligibility Criteria for Study Entry Enrollment at the Pre-Surgery phase 3.2.1 Inclusion Criteria for study continuation at the Pre-Surgery phase

• ECOG performance status 0-1
• Received FOLFIRINOX, modified FOLFIRINOX or the further modified forms including FOLFIRI, FOLFOX, 5FU or capecitabine. Liposomal irinotecan is permitted. Switching to gemcitabine/nal-paclitaxel due to intolerability of FOLFIRINOX is also permitted.
• Radiographical evidence of disease response or stable disease with CA19-9 decrease > 20% from the baseline or CA19-9 that is not detectable
• Patients ≥18 years at the time of signing the informed consent
• Patient's written informed consent prior to any trial-specific procedure
• Patient's legal capacity to consent to participation in the clinical trial

3.2.2 Exclusion Criteria for Study Entry Enrollment at the Pre-surgery phase

• Symptomatic clinically significant ascites
• Evidence of any distant metastases other than limited hepatic or pulmonary metastasis as defined in inclusion criterion 1.
• Evidence of simultaneous pulmonary and hepatic metastases
• Any malignancies other than adenocarcinoma of the pancreas in the 2 years before the start of the clinical trial except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, breast cancer, prostate cancer or superficial bladder tumors (Ta, Tis and T1)
• Pregnant or breast-feeding female
• Radiographic evidence of severe portal hypertension
• Liver cirrhosis ≥ Child Pugh B
• Known HIV seropositivity
• Active or chronic Hepatitis B or Hepatitis C infection
• Clinically significant cardiovascular or vascular disease or disorder ≤6 months before enrolment into the clinical trial (e.g., myocardial infarction, unstable angina pectoris, chronic heart failure New York Heart Association (NYHA) ≥ Grade 2, uncontrolled arrhythmia, cerebral infarction)
• Any other severe concomitant disease or disorder, which could influence patient's ability to participate in the clinical trial and his/her safety during the trial or interfere with interpretation of results, e.g., severe hepatic, renal, pulmonary, cardiovascular, metabolic or psychiatric disorders.
• Hepatic metastasis that are only amenable to ablation. However, if liver lesions are found intraoperatively and subsequently ablated and if the pancreatic surgery is distal pancreatectomy, the patients would still be considered evaluable. Ablation of liver lesions during the pancreatoduodenectomy is not allowed.
• Radiographical evidence of disease progression.