FOLFIRINOX for 2nd-line Treatment of BTC
FOLFIRINOX for 2nd-line Treatment of BTC
Biliary tract cancer (BTC) is rare in the West, but it is relatively high in Asia, including
 Korea. Currently used as the standard primary treatment in metastatic or locally advanced BTC
 is gemcitabine/platinum combination chemotherapy.There is no standard secondary chemotherapy
 recognized after the failure of the gemcitabine/platinum first line treatment. The
 investigators try to evaluate role of 5-FU, leucovorin, irinotecan, and oxaliplatin
 combination chemotherapy (FOLFIRINOX) for the patients who progressed after
 gemcitabine/cisplatin first line chemotherapy.
<Biliary tract cancer> Biliary tract cancer (BTC) is a common term for malignant tumors that
 occur in gallbladder and bile duct, the path in which bile is released. According to the
 anatomical location, biliary tract cancer is divided into intrahepatic cholangiocarcinoma and
 extrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma is classified as
 perihilar cholangiocarcinoma and distal cholangiocarcinoma. Biliary tract cancer is rare in
 the West, but it is relatively high in Asia, including Korea. Biliary tract cancer occurs
 annually in Korea, accounting for about 5,600 cases, 2.4 percent of the total cancer, and
 ranks sixth in deaths from cancer. Biliary tract cancer is a type of cancer that is difficult
 to treat because most patients are diagnosed with progressive diseases that cannot be
 operated. Only about a quarter of patients are diagnosed with surgical-ready conditions as a
 treatment where full surgical operation can be expected to complete, but the five-year
 survival rate for operation is poor at 8-44% due to a high recurrence after surgery.

 <Metastatic or relapsed biliary tract cancer treatment> Chemotherapy is the main treatment in
 BTC, which is relapsed or metastatic status. 5- Fluorouracil (5-FU)-based treatment has been
 shown to improve the survival period for pancreatic and bile cancer patients compared to the
 optimal supportive care (5-FU/leucovorin ± etoposide 6.0 vs. 2.5 months, p <0.01). Also,
 chemotherapy helped maintain the quality of life. The improvement in quality of life over a
 period of at least four months showed a significant difference compared to 10% in the group
 that received only optimal supportive care for 36% of the chemotherapy group. (p < 0.01).
 Currently used as the standard primary treatment in metastatic or locally advanced BTC is
 gemcitabine/platinum combination chemotherapy. In a large phase III study,
 Gemcitabine/cisplatin significantly improved the median value of the progressive free
 survival (PFS) period from 5.0 months to 8.0 months, and the overall survival (OS) period
 from 8.1 months to 11.7 months, compared to the gemcitabine alone. If Cisplatin is not
 available, oxaliplatin can be considered as a merger with gemcitabine. The
 Gemcitabine/oxaliplatin regimen reported in the phase II and phase III studies PFS was
 4.2-5.5 months, median for the OS period was 9.5-12.4 months.

 <Salvage treatment of biliary tract cancer> To date, there is no standard secondary
 chemotherapy recognized after the failure of the gemcitabine/platinum primary treatment.
 Since BTC usually occurs at an advanced age and shows a low frequency of occurrence in the
 West, there are practical limitations to conducting large-scale clinical research. So far,
 there is no large three-phase study proving the benefits of secondary chemotherapy after the
 failure of gemcitabine/platinum chemotherapy. Implementation of secondary chemotherapy in
 actual clinicians is known to vary from country to country, depending on the medical judgment
 of the responsible clinician. In a large-scale retrospective study by the Association des
 Gastro-Enterologies Oncology (AGEO) group in France, 32.5% of the patients were treated with
 second line therapy, and 75% of the patients were reported in Japan. A retrospective study
 and a two-phase study and systematic literature review suggest that there will be a benefit
 from the treatment if second line treatment is selected for patients whose general health is
 relatively well maintained. Results of single or combination therapy using drugs such as
 Irinotecan, oxaliplatin, 5-FU, S-1, and capecitabine were reported in phase II and
 retrospective studies, yielding an average of 3.2 months of PFS, 7.7% of mean response rate,
 and 7.2 months of OS.

 The 5-FU/leucovorin/irinotecan (FOLFIRI) therapy, along with the capecitabine/irinotecan
 therapy, is reported as the most commonly used secondary chemotherapy in the AGEO group in
 France. A treatment strategy for continuous use of FOLFIRI as a secondary treatment after the
 failure of Gemcitabine/oxaliplatin showed the median value for OS period of 21.9 months, and
 the median value for the PFS period. The PFS and OS due to the FOLFIRI was found to be 3.2
 months and 8.4 months, respectively. On the other hand, the FOLFOX therapy, which combines
 oxaliplatin with 5-FU, showed a response rate of 21.6 % when administered as a secondary
 treatment after the failure of gemcitabine/cisplatin, and a median PFS of 3.1 months. A phase
 III study is currently underway that compares the administration of FOLFOX as a secondary
 treatment with the optimum support. In Korea, there is a problem with the standard
 reimbursement for applying to drugs prescribed to cancer patients, and in particular, cancer
 drugs that can be used as secondary therapy in metastatic BTC patients are limited. There is
 a need to improve the prognosis of BTC patients by expanding the use of various drugs that
 have been proven through external clinical research.

 <5-FU, leucovorin, irinotecan, and oxaliplatin combination chemotherapy (FOLFIRINOX) regimen
 for other cancer of BTC> In a pre-clinical experiment, oxaliplatin and irinotecan have
 synergistic effects and are known to have relatively no overlap of toxic effects among, 5-FU,
 leucovorin, irinotecan, and oxaliplatin. The combination treatment of
 5-FU/leukovorin/irinotecan/oxaliplatin (FOLFIRINOX) had a high therapeutic effect on
 progressive pancreatic cancer and colon cancer. In a phase III study comparing FOLFIRINOX and
 gemcitabine as a first line treatment in metastatic pancreatic cancer, the objective response
 rate (32 vs. 9%), PFS (6.4 vs. 3.3 months) and OS (11.1 vs. 6.8 months) were significantly
 higher in FOLFIRINOX. On the other hand, treatment-related toxicities, with a grade 3/4 of
 neutropenia (46 vs. 21%), febrile neutropenia (5.4 vs. 1.2%), thrombocytopenia (9.1 vs.
 3.6%), sensory neuropathy (9 vs. 0%), vomiting (23 vs. 18%), and diarrhea (113 vs. 2%) were
 more common in FOLFIRINOX. In a phase III study comparing the
 5-FU/leukovorin/irinotecan/oxaliplatin(FORFOXRI) and the 5-FU/leukovorin/irinotecan(FORFIRI)
 as a first line treatment in metastatic colorectal cancer, the FORFOXRI group was objective
 response (66 vs. 41 %), the PFS (9.8 vs. 6.9 months) and the OS (2.6 vs. 16.7 months) showed
 significant improvements. In pancreatic cancer, FOLFIRINOX was a treatment that was limited
 in patients with good general condition due to its high level of toxicity, including
 neutropenia, but the dose-reduction proved to be applied not only as a primary treatment but
 also as a secondary treatment. In a phase II study of pancreatic cancer patients in China,
 there was a 29% of grade 3/4 neutropenia were reported due to the treatment of modified
 FOLFIRINOX using oxaliplatin 68 mg/m2, irinotecan 135 mg/m2, and 5-FU injection of 2,400
 mg/m2 for 46 hours, and there was no increase in mortality and febrile neutropenia. Other
 major grade 3 or higher toxicity levels showed improved safety profiles with thrombocytopenia
 (4.8%), anemia (8.1%), infection (4.8%), and elevated liver enzyme (14.5%).

 <Rationale of this trial>

 As a 2nd line treatment for metastatic BTC the assessment of modified FOLFIRINOX is supported
 by:

 -  The prognosis for metastatic BTC, which fails first line therapy, is poor and has no
 standardized treatment. Therefore, better treatment modalities are required to improve
 the survival of patients who no longer respond to first line treatment and to maintain
 the quality of life.

 -  Treatments that use irinotecan or oxaliplatin as secondary therapy for metastatic BTC
 have been shown in retrospective and phase II studies and are actually used in clinical
 practice of other countries.

 -  Oxaliplatin and irinotecan have synergistic effects and the FOLFIRINOX therapy, which
 uses both drugs together in 5-FU/leucovorin, has been shown to increase efficacy in
 pancreatic and colon cancer.

 -  The modified FOLFIRINOX, which was used with reduced dosage, indicates an acceptable
 toxic profile while maintaining its efficacy
Inclusion Criteria:

 1. Histologically confirmed BTC (cholangiocarcinoma or gall bladder (GB) cancer) , except
 ampulla of Vater cancer

 2. In the event that the progression of the gemcitabine/cisplatin is experienced during
 or after discontinuation of the first line treatment for metastatic, locally advanced
 or relapsed (it may be considered as a first line treatment that recurrence within six
 months of completion of the adjuvant or neo-adjuvant chemotherapy using
 gemcitabine/cisplatin)

 3. Patient (or legal representative) has completed an approved consent documents that he
 or she will participate in the test after receiving sufficient information about the
 clinical trial

 4. East clinical oncology group (ECOG) performance status 0-1

 5. One or more measurable lesions by RECIST v1.1.

 6. Appropriate organ functions; A. Liver: bilirubin ≤ 3 mg/dL, aspartate aminotransferase
 (AST) or alanine aminotransferase (ALT) ≤ 2.5 x ULN (in cases of liver metastasis, AST
 or ALT ≤ 5 x ULN) B. Kidney: An estimate of creatine clearance rate according to the
 Cockcroft-Gault formula (or local institution's standard method) > 30 mili-liter
 (mL)/min C. Hemoglobin ≥ 9 g/dL (transfusion allowed), absolute neutrophil count (ANC)
 ≥ 1500/μL, platelet count ≥ 75,000/μL.

 7. Expected life time over 3 months.

 8. Over 19 years old.

 9. In case of proper bile excretion function

 10. Have the will and ability to comply with the clinical trial plan during the study
 period, including treatment and scheduled visits and examination.

 11. For pre-menopausal women and for women less than one year after the onset of
 menopause, serum or urine pregnancy tests shall be confirmed negative during
 screening.

 12. For men and fertile women, the use of effective contraceptive methods should be agreed
 (effective contraception should be used for at least 30 days prior to the initial
 administration of a investigational drug, the trial period, and at least 90 days after
 the discontinuation of the test participation).

 Exclusion Criteria:

 1. ≥ 2 of prior chemotherapy for progressive BTC (except for adjuvant/neo-adjuvant
 chemotherapy with resting of more than six months)

 2. Symptomatic or untreated brain metastasis or spinal cord compression metastasis.

 3. Previous treatment using Irinotecan or oxaliplatin

 4. In case of major surgery within four weeks just before registration, excluding biopsy
 for diagnosis

 5. In case of chemotherapy or radiation therapy was received within three weeks prior to
 the administration of a test medication

 6. Grade 2 or higher peripheral neuropathy

 7. Grade 2 or higher toxicities caused by a previous cancer treatment based on NCI-CTCAE
 v 4.03 other than hair loss

 8. A person diagnosed with another malignant tumor within the last five years. Exceptions
 include basal or squamous cell carcinoma of the skin or intraepithelial neoplasia
 (bladder, uterine cervical, colorectal, breast)

 9. Pregnant or nursing woman

 10. If there is a severe or uncontrolled systemic disease, active infection, active
 bleeding tendency or organ transplantation history (including allo-hematopoietic stem
 cell transplantation)

 11. The following virus infection A. Known positive history for human immunodeficiency
 virus (Human Immunodeficiency virus, HIV) test or known acquired immunodeficiency
 syndrome (AIDS) B. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
 (positive Hepatitis B surface -Ag (+) or HCV RNA (+) if anti-HCV Ab screening test is
 positive)

 12. If there is a known alcohol or drug abuse

 13. In cases of clinically significant (i.e., active) cardiovascular disease: cerebral
 hemorrhage/brain infarction, myocardial infarction (pre-registration < 6 months),
 unstable angina, congestive heart failure (NYHA classification ≥2) or arrhythmia
 needed drug therapy.

 14. In case of a mental state in which it is impossible to understand and provide the
 consent.