A Study of Nal-IRI With 5-FU, Levofolinic Acid and Oxaliplatin in Patients With Resectable Pancreatic Cancer

A Phase II Study of Liposomial IrinoTecan (Nal-IRI) With 5-Fluorouracil, Levofolinic Acid and Oxaliplatin in Patients With Resectable Pancreatic Cancer "nITRo Trial

Rational:Pancreatic cancer is a systemic disease at the time of diagnosis, even among patients with apparent localized disease. Surgical resection is the only potentially curative therapy for pancreatic cancer, but in patients who undergo surgery and postoperative therapy, metastatic relapse remains common and no more than 20% of patients achieve 5-year survival.

Because of this aggressive biologic behavior, an increasing interest is growing about preoperative treatments in resectable pancreatic cancer.

The combination chemotherapeutic regimen with irinotecan + 5-fluorouracil (5-FU)/leucovorin (LV) + oxaliplatin (FOLFIRINOX) is an effective choice for first line treatment in patients affected by advanced pancreatic cancer, and in this setting it achieved a Disease Control Rate of 70.2 % (10). In this regard, FOLFIRINOX is currently explored as preoperative regimen in a number of clinical trials in resectable pancreatic cancer.

A critical challenge in this field remains the introduction in these combination treatments of the most novel and effective agents such as nalIRI, in order to obtain a more profound tumor shrinkage, to increase the rate of R0 resections, to allow an early treatment of occult micrometastatic disease, and eventually, to improve survival in patients with resectable pancreatic cancer.

This study proposal is designed to address this challenge. Preliminary results, collected during the Part 1 Dose Escalation of a current clinical trial performed in mPDAC, show that dose of nal-IRI: 60 mg/m2, Oxaliplatin: 60 mg/m2, 5-FU/LV: 2400/400 mg/m2 is safe.

This is a study to determine the proportion of patients affected by resectable pancreatic cancer who achieve R0 resection after a perioperative 6-cycle chemotherapy, 3 pre- and 3 post-surgery, in the absence of disease progression or unacceptable toxicity.

All patients in the program will be identified by a unique identifier number assigned sequentially.

Patients will receive a treatment scheme of nal-IRI, oxaliplatin, Levofolinic Acid and 5-fluorouracil (5 -FU) on Day 1 and Day 15 of each 28 day cycles.

C1D1 is a fixed day, C1D15 and Day 1 and Day 15 of all subsequent cycles should be performed with a window of ± 2 days.

Patients achieving stable disease or better will undergo pancreatectomy 4-8 weeks after completion of first 3 courses of treatment. Within 4-8 weeks following pancreatectomy, patients will receive an additional 3 cycles of nal-IRI, oxaliplatin, Levofolinic Acid and 5-fluorouracil (5 -FU) treatment in the absence of disease progression or unacceptable toxicity.

Tumor responses will be assessed after 3 cycles of preoperative treatment and after 3 cycles of postoperative treatment or sooner if the treating physician suspects disease progression based on clinical signs and symptoms. All treatment decisions will be based on the local radiologist and/or treating physician assessment of disease status.

Inclusion Criteria:

1. Able to understand and provide written informed consent.

2. ≥ 18 years of age.

3. Histologically or cytologically confirmed adenocarcinoma of exocrine pancreas.

4. Patients must have measurable disease in the pancreas, with no evidence of metastatic disease on imaging of the chest, abdomen and pelvis (contrast-enhanced CT or MRI abdomen with contrast instead of abdominal CT); PET scans alone will not be adequate alternatives.

5. The primary tumor must be surgically resectable, defined as:

   1. no involvement (abutment or encasement) of the major arteries (celiac, common hepatic and/or superior mesenteric artery);
   2. no involvement or <180° interface between tumor and vessel wall of the portal vein, superior mesenteric vein and/or portal vein/splenic vein confluence.

6. Adequate hepatic, renal and hematological function.

Exclusion Criteria:

1. Serum total bilirubin ≥2 x ULN (biliary drainage is allowed for biliary obstruction).
2. Severe renal impairment (CLcr ≤ 30 ml/min).
3. Inadequate bone marrow reserves as evidenced by:
4. ANC ≤ 1,500 cells/μl; or Platelet count ≤ 100,000 cells/μl; or Hemoglobin ≤ 9 g/dL
5. KPS < 60
6. Patients who received previous chemotherapy or radiotherapy for pancreatic disease.
7. Any clinically significant disorder impacting the risk-benefit balance negatively per physician's judgment.
8. Any clinically significant gastrointestinal disorder, including hepatic disorders, bleeding, inflammation, occlusion, or diarrhea > grade 2.
9. Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) in last 6 months.
10. NYHA Class III or IV congestive heart failure, ventricular