Clinical trial NCT03528785: A Study of Nal-IRI With 5-FU, Levofolinic Acid and Oxaliplatin in Patients With Resectable Pancreatic Cancer
Official title: A Phase II Study of Liposomial IrinoTecan (Nal-IRI) With 5-Fluorouracil, Levofolinic Acid and Oxaliplatin in Patients With Resectable Pancreatic Cancer "nITRo Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma
Keywords: Pancreatic Adenocarcinoma
Liposomial IrinoTecan
nal-IRI
Resectable pancreatic cancer
Lead sponsor: Centro Ricerche Cliniche di Verona
Sponsor class: OTHER
First posted: 2018-05-18
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of patients achieving R0 resection after preoperative nanoliposomal irinotecan (nal-IRI), Oxaliplatin, Leucovorin (LV), 5-FluoroUracil (5-FU)
timeFrame: 4-8 weeks after the completion of 3 courses of treatment
Secondary outcomes:
measure: To determine 2-year overall survival (OS)
timeFrame: 2 years
measure: determine disease-free survival (DFS)
timeFrame: through study completion, an average of 2 years
measure: estimate frequency and severity of adverse events associated with chemotherapy
timeFrame: through study completion, an average of 2 years
measure: determine overall response rate (ORR) following preoperative chemotherapy
timeFrame: through study completion, an average of 2 years
measure: estimate proportion of patients going to surgery for resection after preoperative chemotherapy
timeFrame: through study completion, an average of 2 years
measure: estimate pathologic response rate (pCR)
timeFrame: through study completion, an average of 2 years
measure: assess lymph node status
timeFrame: through study completion, an average of 2 years
measure: assess surgical mortality
timeFrame: through study completion, an average of 2 years
measure: assess surgical morbidity
timeFrame: through study completion, an average of 2 years
Other outcomes:
Locations:
city: Verona
country: Italy
facility: Centro Ricerche Cliniche
Study officials:
affiliation: centro ricerche cliniche
name: stefano milleri, Dr
role: STUDY_DIRECTOR
References:
citation: Simionato F, Zecchetto C, Merz V, Cavaliere A, Casalino S, Gaule M, D'Onofrio M, Malleo G, Landoni L, Esposito A, Marchegiani G, Casetti L, Tuveri M, Paiella S, Scopelliti F, Giardino A, Frigerio I, Regi P, Capelli P, Gobbo S, Gabbrielli A, Bernardoni L, Fedele V, Rossi I, Piazzola C, Giacomazzi S, Pasquato M, Gianfortone M, Milleri S, Milella M, Butturini G, Salvia R, Bassi C, Melisi D. A phase II study of liposomal irinotecan with 5-fluorouracil, leucovorin and oxaliplatin in patients with resectable pancreatic cancer: the nITRO trial. Ther Adv Med Oncol. 2020 Sep 4;12:1758835920947969. doi: 10.1177/1758835920947969. eCollection 2020.