Trial of Infusional FOLFIRINOX in First Line Treatment of Advanced Biliary Tract Cancers

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Brief Title

Trial of Infusional FOLFIRINOX in First Line Treatment of Advanced Biliary Tract Cancers

Official Title

Phase II Trial of Infusional 5 FLUOROURACIL, LEUCOVORIN, OXALIPLATIN AND IRINOTECAN (FOLFIRINOX) in First Line Treatment of Advanced Biliary Tract Cancers

Brief Summary

      This study is to evaluate the response rate and toxicity profile of infusional 5
      fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFIRINOX) in first-line treatment of
      advanced biliary tract cancers and also to assess progression free survival and overall
      survival of FOLFIRINOX in first line treatment of advanced biliary tract cancers
    

Detailed Description

      Biliary tract carcinomas (BTCs) are invasive adenocarcinomas that arise from the epithelial
      cells of the biliary tree, which comprises intrahepatic and extrahepatic bile ducts, and the
      gallbladder. Even though BTCs are considered as rare tumors, they represent about 30% of the
      total primary liver cancers with an incidence rate close to that of hepatocellular carcinoma.
      Approximately 1200 new cases in the United Kingdom and 9000 in the United States are
      diagnosed annually. The Saudi Cancer Registry reported 911 case of gall bladder cancer, 318
      intrahepatic cholangiocarcinoma and 574 extrahepatic cholangiocarcinoma between 1994 and
      2009. Unfortunately, only a minority of patients diagnosed with these aggressive tumors
      present at an early resectable stage, and disease recurrence rates are high despite
      curative-intent surgery

      The prognosis of patients with advanced biliary tract cancers is poor and median survival for
      those undergoing supportive care alone is short. Systemic chemotherapy is increasingly being
      applied in cases of advanced biliary tract cancers. A benefit for chemotherapy over best
      supportive care alone was suggested in a trial that randomly assigned 90 patients with
      advanced pancreatic or biliary cancer (37 with bile duct cancer) to fluorouracil (FU)-based
      systemic chemotherapy or best supportive care alone with median survival of 6 months for
      chemotherapy versus 2.5 months for best supportive care.

      Different drugs has demonstrated activity in BTCs, including fluoropyrimidines, gemcitabine,
      cisplatin, and oxaliplatin. A pooled analysis from Eckel et al. that evaluated 104 trials
      with 2810 patients, has established gemcitabine combined with platinum compounds as the
      provisional standard of chemotherapy in advanced biliary tract cancer.

      In a randomized phase two study of 51 patients, Kornek et al, established the efficacy of
      mitomycin in combination with gemcitabine or capecitabine in previously untreated patients
      with advanced biliary tract cancers. Mitomycin and capecitabine was associated with superior
      complete response rate (31% vs 20%), median progression free survival (5.3 months vs 4.2
      months), and overall survival (9.25 months and 6.7 months). The EORTC 40955 trial randomized
      patients with BTCs to high dose 5FU vs combination of 5-FU, Leucovorin and cisplatin. The
      results showed that cisplatin and fluorouracil was more active than high-dose fluorouracil in
      terms of overall response rates (19% and 7.1%, respectively) and overall survival (8 months
      and 5 months, respectively), but progression free surviva; was similar in both treatment arms
      (3.3 months).

      The randomized, controlled, phase three ABC-02 study, which enrolled 410 patients with
      locally advanced or metastatic cholangiocarcinoma, gallbladder cancer or ampullary cancer,
      demonstrated that the combination of gemcitabine and cisplatin improved overall and
      progression free survival by 30% over gemcitabine alone. Median overall survival was 11.7
      months vs 8.1 months (HR, 0.64; 95% confidence interval, 0.52-0.80; p˂.001), and progression
      free survival was 8 months (HR, 0.51; 95% confidence interval, 0.51-0.77; p˂.001), both in
      favor of the combination arm. Although the rate of neutropenia was higher in the group
      receiving gemcitabine and cisplatin, there was no significant difference in the rate of
      neutropenia-associated infections between the 2 arms. Okusaka et al also reported similar
      findings in a phase two randomized study of 84 patients with advanced biliary tract cancers.
      Based on these results, the combination of gemcitabine and cisplatin is considered to be the
      standard of care for first-line chemotherapy for patients with advanced or metastatic biliary
      tract cancers.

      Triple-drug chemotherapy regimens also have been shown to be effective in patients with
      advanced biliary tract cancers, albeit in a very small number of patients. The phase three
      trial that evaluated fluorouracil, leucovorin and etoposide versus fluorouracil cisplatin and
      epirubicin didn't show one regimen to be significantly superior with respect to overall
      survival (12 months vs. 9 months, respectively) in patients with advanced biliary tract
      cancers, although the trial was underpowered to detect such a difference.

      In a phase two trial, the combination panitumumab, a monoclonal anti-epidermal growth factor
      receptor antibody, with gemcitabine and irinotecan showed encouraging efficacy with good
      tolerability in patients with advanced cholangiocarcinoma, with 5-month progression free
      survival rate of 69%.The median progression free survival and overall survival were 9.7
      months and 12.9 months, respectively.

      Results from the randomized phase three PRODIGE trial evaluating the combination of
      5-Fluorouracil, Leucovorin, oxaliplatin and Irinotecan (FOLFIRINOX) versus gemcitabine alone
      in patients with metastatic pancreatic cancer and good performance status showed dramatic
      improvements in both median PFS (6.4 vs 3.3 months; P˂ .001) and median OS (11.1 months vs.
      6.8 months; P˂ .001). Because of these strong results the National comprehensive cancer
      network (NCCN) and many other societies added FOLFIRINOX as a preferred, category 1
      recommendation for first line treatment of good performance status patients with metastatic
      pancreatic cancer in 2011.

      There are, however, some concerns about the toxicity of FOLFIRINOX regimen. In the PRODIGE
      trial, some of the grade 3 and 4 toxicity rates that were significantly greater in the
      FOLFIRINOX group than in the gemcitabine group were 45.7% for neutropenia, 12.7% for
      diarrhea, and 9.1 % for thrombocytopenia and 9% for sensory neuropathy.

      Despite the high levels of toxicity, no toxic deaths have been reported. Furthermore, the
      PRODIGE trial determined that, despite this toxicity, fewer patients in the FOLFIRINOX group
      than in the gemcitabine group experienced a degradation in their quality of life at 6 months
      (31% vs. 66%,p ˂ .001). A more detailed analysis of the quality of life of patients in this
      trial has been published and shows that FOLFIRINOX maintained and even improved quality of
      life more than gemcitabine did.

      Based on the above data, the investigators designed this phase two study of the efficacy and
      toxicity of FOFIRINOX regimen in first line treatment for patients with advanced biliary
      tract cancers. If the investigators achieved encouraging results, this regimen should then be
      compared with the standard combination of gemcitabine and cisplatin in future phase three
      trials.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Response rate

Secondary Outcome

 progression free survival

Condition

Biliary Tract Cancer

Intervention

FOLFIRINOX

Study Arms / Comparison Groups

 Experimental single arm
Description:  Chemotherapy using the FOLFIRINOX regimen will be given every 2 weeks for a total of 12 cycles. FOLFIRINOX consist of:
Oxaliplatin-85 mg/m2 IV Day 1
Leucovorin-400 mg/m2 IV Day 1
Irinotecan-180 mg/m2 IV Day 1
Fluorouracil (FU)-400 mg/m2 IV bolus Day 1
Fluorouracil 2400 mg/m2 infused over 46 hours starting day 1

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Combination Product

Estimated Enrollment

32

Start Date

January 3, 2017

Completion Date

August 1, 2024

Primary Completion Date

August 1, 2024

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically confirmed locally advanced (irresectable) or metastatic biliary tract
             cancers.

          2. Measurable disease. Defined as tumor that have uni or bi dimensional measurement not
             less than 1.5 cm on any dimension.

          3. Age ≥ 18 years.

          4. Signed written informed consent before enrolment.

          5. No prior chemotherapy or anti-neoplastic therapy other than radiotherapy more than 4
             weeks prior to enrolment and to areas other than the measurable disease.

          6. Patients of either sex or child bearing age must be willing to use adequate
             contraceptive measures during the study and for 6 months after treatment.

          7. Life expectancy of 6 months or more.

          8. Eastern Cooperative Oncology Group performance status of 0-1.

          9. Adequate renal function: creatinine within normal institutional range.

         10. Adequate hepatic function: Total bilirubin within normal institutional limits, serum
             aspartate aminotransferase and alanine aminotransferase levels ≤2.5 times the
             institutional upper limit of normal or ≤ 5 times the institutional upper limit of
             normal of elevated because of liver involvement.

         11. Adequate hematological values: leukocyte count ≥3.0 x 109/L, an absolute neutrophil
             count ≥1.5 x 109/L, a platelet count ≥100 x 109/L.

        Exclusion Criteria:

          1. Known or suspected dihydropyrimidine deficiency.

          2. Presence of central nervous system metastasis.

          3. Previous malignancy within 5 years, except adequately treated non melanomatous skin
             cancer or in situ cervical cancer.

          4. Severe cardiovascular disease (congestive heart failure New York Heart Association
             class three or four, unstable angina pectoris, myocardial infarction or significant
             arrhythmias).

          5. Psychiatric or mental disorder, precluding understanding of the information of the
             trial related topics and giving valid informed consent.

          6. Active uncontrolled infection.

          7. Pregnant patients (confirmed by β-Human chorionic gonadotrophin test where
             appropriate).

          8. Serious underlying medical condition (in the judgement of the investigator) which
             could impair the ability of the patient to participate in the trial.

          9. Any psychological, familial, geographic or social circumstances which could impair the
             patient's ability to participate in the trial and comply with follow up.

         10. Treatment with other experimental drugs within 30 days of entry into the trial.

         11. Treatment with other anti-cancer therapy.

         12. Known hypersensitivity to any of the study drugs.

         13. Breast feeding

         14. Legal incapacity.

         15. Patients with a known diagnosis of HIV infection.
      

Gender

All

Ages

19 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Shouki Bazarbashi, 966505443546, [email protected]

Location Countries

Saudi Arabia

Location Countries

Saudi Arabia

Administrative Informations


NCT ID

NCT03291899

Organization ID

RAC 2161 099


Responsible Party

Principal Investigator

Study Sponsor

King Faisal Specialist Hospital & Research Center


Study Sponsor

Shouki Bazarbashi, Principal Investigator, King Faisal Specialist Hospital and Research cente


Verification Date

August 2021