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Randomized Phase II Trial of FOLFIRI3 vs. FOLFOX in Gemcitabine-refractory Advanced Pancreatic Cancer

Phase 2
18 Years
Not Enrolling
Metastatic Pancreatic Cancer

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Trial Information

Randomized Phase II Trial of FOLFIRI3 vs. FOLFOX in Gemcitabine-refractory Advanced Pancreatic Cancer

Given the poor response rate, usually less than 20% in gemcitabine-based doublet in the
first-line setting for advanced pancreatic cancer, an additional problem in the therapeutic
management of this common malignant disease constitutes the need for effective treatment
alternatives in patients failing gemcitabine-based chemotherapy. To date, few studies have
assessed second-line chemotherapy primarily due to the poor prognosis, and the limited life
expectancy in advanced pancreatic cancer after failure first-line chemotherapy, and there
has been no established second-line treatment for pancreatic cancer after failure to

1. Oxaliplatin combination with 5-FU (FOLFOX)

Oxaliplatin, diaminocyclohexane-platinum, is an alkylating agent inhibiting DNA
replication by forming adducts between two adjacent guanines or guanine and adenine
molecules. With regard to the inhibition of DNA synthesis, the adducts of oxaliplatin
appear to be more effective than cisplatin adducts. Synergism between oxaliplatin and
5-FU has been demonstrated in vitro, and in vivo. Combination of oxaliplatin and 5-FU
has proven effective as first- or second-line treatment for advanced colorectal cancer.
After being extensively developed as a treatment for colorectal cancer, the role for
oxaliplatin in upper gastrointestinal malignancies including pancreatic cancer is an
emerging area of investigation. In preclinical studies, oxaliplatin has cytotoxic
activity against pancreatic cancer cell lines. When used as single agent as first-line
treatment or as second-line treatment after failure to gemcitabine-based chemotherapy,
oxaliplatin has minimal activity against pancreatic cancer. However, when it is used
with 5-FU, it produced 10% objective response rate with a 21% of clinical benefit
response with minimal toxicities in chemotherapy-naïve patients. In phase II studies as
second-line treatment, oxaliplatin with 5-FU is well tolerated and produced a objective
response rate of 23.3% with additional 30.0% of patients achieving stable disease.
Furthermore, recently Oettle et al. reported that weekly infusional 5FU/LV with
oxaliplatin prolongs survival and improves quality of life in advanced pancreatic
cancer after gemcitabine failure compared with best supportive care alone.

2. Irinotecan combination with 5-FU (FOLFIRI.3)

Irinotecan has a strong growth-inhibiting effect on cultured pancreatic adenocarcinoma
cells. It is also highly active on pancreatic tumor cells in culture and in xenograft
models. Irinotecan monotherapy has been tested in patients with previously untreated
pancreatic cancer, yielding response rates of 9-27%. In vitro studies indicate that
synergism between irinotecan and 5-FU is sequence dependent, cytotoxicity is being stronger
when irinotecan is administered before 5-FU. Recently, French study group reported that
FOLFIRI.3 regimen, comprising of irinotecan D1 and D3 with 5-FU for 2 days from D2, has
promising activity in chemotherapy-naïve and pretreated patients with advanced pancreatic
cancer. The confirmed response rate was 37.5% with a median progression-free survival of 5.6
months. The study also suggested no cross-resistance between gemcitabine and FOLFIRI.3.

The investigators are to evaluate the efficacy and safety of FOLFOX or FOLFIRI.3 combination
chemotherapy as second-line salvage chemotherapy in patients with advanced pancreatic

Inclusion Criteria:

1. Pathologically proven pancreatic adenocarcinoma

2. Age 18 year or older

3. ECOG performance status of 2 or lower

4. Documented disease progression while receiving or within 6 months after discontinuing
gemcitabine-based first-line or adjuvant chemotherapy

5. Adequate bone marrow function A. WBCs > 4,000/µL, absolute neutrophil count
[ANC]>1,500/µL B. Hemoglobin >9.0 g/dL C. Platelets > 100,000/µL

6. Adequate kidney function (creatinine<1.5 mg/dL)

7. Adequate liver function (bilirubin<1.5 mg/dL [< 2.5 mg/dL for obstructive jaundice
with adequately decompressed bile duct obstruction], transaminases levels<3 times the
upper normal limit, and serum albumin of >2.5 mg/dL)

8. No serious other medical condition that would preclude treatment

Exclusion Criteria:

1. Other tumor type than adenocarcinoma

2. Evidence of GI bleeding or GI obstruction

3. Presence or history of CNS metastasis

4. Axial skeletal radiotherapy within 6 months

5. Neuropathy grade 2 or worse

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Time Frame:

Every 6 weeks

Safety Issue:


Principal Investigator

Jae-Lyun Lee, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Asan Medical Center


Korea: Food and Drug Administration

Study ID:




Start Date:

March 2007

Completion Date:

September 2009

Related Keywords:

  • Metastatic Pancreatic Cancer
  • pancreatic cancer
  • gemcitabine
  • oxaliplatin
  • irinotecan
  • fluorouracil
  • Failure to gemcitabine chemotherapy
  • Pancreatic Neoplasms