Second Line Therapy in Advanced Biliary Tract Cancer (BIT-2)

A Randomized Phase II Trial of Second Line Therapy in Advanced Biliary Tract Cancer: Capecitabine or Capecitabine Plus Mitomycin C

The purpose of this study is to assess the therapeutic activity of capecitabine alone or in combination with mitomycin C as second-line therapy in patients with advanced/metastatic biliary adenocarcinoma in progression after gemcitabine and platinum compounds

Study Overview

• Status: Completed
• Conditions: Biliary Tract Cancer
• Intervention / Treatment: Drug: Capecitabine; Drug: capecitabine and mitomycin

Detailed Description

Biliary tract adenocarcinoma is an uncommon tumor with a poor prognosis and a median overall survival (OS) rarely exceeding 6 months. Less than 25% of patients are resectable at diagnosis and, even in this subset of patients, relapse rate is high. An improvement of OS and quality of life for patients receiving chemotherapy versus best supportive care was demonstrated in advanced disease. Recently, cisplatin and gemcitabine combination was identified as the new standard first-line chemotherapy, yielding a median progression free survival (PFS) and median OS of 8.5 and 11.7 months, respectively. Despite the outcome improvement, disease progression is a constant and approximately half of patients failing upfront treatment has a good performance status and are willing to undergo further treatment. No standard salvage chemotherapy regimen has been identified. Clinical trials are difficult to perform due to the rarity and heterogeneity of these tumors and to the lack of interest of the pharmaceutical industry. Fluoropyrimidines and mitomycin C have been considered the basis of palliative chemotherapy for a long time. The investigators decided to explore the activity, in terms of PFS, of capecitabine alone or combined with mitomycin C as second-line therapy in patients with pathological diagnosis of advanced biliary tract cancer and progressive disease after gemcitabine and cisplatin, by means of an open label randomized multicentric phase II trial.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Ancona, Italy
    • Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi - G Salesi
  • Bergamo, Italy
    • A.O. Ospedali Riuniti
  • Bologna, Italy
    • Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi
  • Candiolo (Torino), Italy, 10060
    • Fondazione Piemontese Per la Ricerca sul Cancro
  • Catania, Italy
    • Azienda Ospedaliera Di Rilievo Nazionale E Di Alta Specializzazione Garibaldi
  • Milan, Italy, 20132
    • Ospedale San Raffaele
  • Padova, Italy
    • Istituto Oncologico Veneto I.R.C.C.S.
  • Pisa, Italy
    • Azienda Ospedaliero-Universitaria Pisana
  • Potenza, Italy
    • Azienda Ospedaliera Regionale San Carlo
  • Roma, Italy
    • Istituto Nazionale dei Tumori Regina Elena
  • Saronno (VA), Italy
    • Ospedale Generale provinciale
  • Torino, Italy
    • Azienda Ospedaliera Universitaria San Giovanni Battista di Torino
  • Udine, Italy, 33100
    • Azienda Ospedaliero Universitaria Santa Maria della Misericordia
  • Verona, Italy
    • Azienda Ospedaliera Universitaria Integrata
  • Ancona
    • Fabriano, Ancona, Italy
      • ASUR zona territoriale N. 6 FABRIANO
  • Palermo
    • Cefalù, Palermo, Italy
      • Fondazione Istituto San Raffaele G. Giglio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed and dated IRB/IEC-approved Informed Consent.
2. Cytological or histological diagnosis of locally advanced or metastatic adenocarcinoma of the biliary tract (Ampulla of Vater, gallbladder, intra or extra-hepatic biliary ducts).
3. Disease progressing after first-line chemotherapy with gemcitabine and platinum analogs (only one prior systemic therapy allowed).
4. Age 18-75 years
5. Karnofsky Performance Status > 50%
6. Estimated life expectancy of at least 3 months.
7. Negative pregnancy test (if female in reproductive years).
8. Adequate bone marrow, liver and kidney function: leukocyte > 3500/mm3; absolute neutrophil count (ANC) > 1500/mm3; platelet count > 100000/mm3; hemoglobin > 10 g/dl; creatinine < 1.5 mg/dL; total bilirubin ≤ 1.5 x upper limit of normal range (ULN); SGOT e SGPT ≤ 2.5 ULN
9. At the time of start of treatment, at least 2 weeks must have elapsed since completion of prior chemotherapy, minor surgery and radiotherapy (provided that no more than 25% of bone marrow reserve has been irradiated).
10. Resolution of all acute toxic effects of any prior chemotherapy, surgery or radiotherapy to NCI CTC (Version 4.03) grade ≤ 1 for hematologic toxicities and ≤ 2 for non hematologic toxicities, with the exception of alopecia.
11. Able and willing to comply with scheduled visits, therapy plans, and laboratory tests required in this protocol.

Exclusion Criteria:

1. Previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-site of the cervix and basal or squamous cell carcinoma of the skin and of other neoplasm without evidence of disease at least from 5 years.
2. Known brain metastases.
3. Previous second-line or adjuvant treatment.
4. Concurrent treatment with other experimental drugs.
5. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, cardiac arrhythmia) ≤1 year prior to dosing.
6. Clinically significant disease including: Cerebral Vascular Accident; other serious underlying medical condition(s) which could impair the ability of the patient to participate in the study.
7. History of interstitial lung disease (eg, pneumonia or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan
8. Known positive tests for human immunodeficiency virus (HIV) infection, active hepatitis B or hepatitis C
9. Subject who is pregnant or breast feeding
10. Woman or man of child-bearing potential not consenting to use adequate contraceptive precautions ie. double barrier contraceptive methods (e.g., diaphragm plus condom), or abstinence during the course of the study and for 6 months after the last study drug administration for women, and 1 month for men
11. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: capecitabine; oral capecitabine 2000 mg/m2 day 1-14 in two divided doses taken with food	Drug: Capecitabine; oral capecitabine 2000 mg/m2 day 1-14 in two divided doses taken with food. Cycles will be repeated in both arms every 3 weeks till progression, unacceptable toxicity, medical decision or patient's refusal or for a maximum of 6 months
Experimental: capecitabine plus mitomycin; oral capecitabine 2000 mg/m2 day 1-14 in two divided doses taken with food plus bolus IV infusion Mitomycin 6 mg/m2 day 1	Drug: capecitabine and mitomycin; oral capecitabine 2000 mg/m2 day 1-14 in two divided doses taken with food plus bolus IV infusion mitomycin C 6 mg/m2 day 1. Cycles will be repeated in both arms every 3 weeks till progression, unacceptable toxicity, medical decision or patient's refusal or for a maximum of 6 months; Other Names: capecitabine; mitomycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	This is a multi-centre phase II, randomized study. Patients will be stratified based on disease site and stage. For the purpose of the study, PFS-6 rate will be considered the primary outcome measure. The maximum PFS-6 rate of low clinical interest is 15% and the minimum PFS-6 rate of interest is set to 35%. The target enrollment, using a type I error of 5% and a test power of 90%, will be estimated to be 26 patients per treatment arm. The regimen will be considered active if at least 8 out of first 26 evaluable patients are PFS-6.	6 month PFS

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	the time from the date of randomization to the date of death from any cause All patients will be followed for survival every 3 months up to 2 years after the end of treatment	median OS (up to 2 years)

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Collaborators: Regione Lombardia
• Investigators: Principal Investigator: stefano cereda, MD, Ospedale San Raffaele (Milan, Italy)

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: February 3, 2012
• First Submitted That Met QC Criteria: February 9, 2012
• First Posted (Estimate): February 10, 2012

Study Record Updates

• Last Update Posted (Estimate): February 25, 2016
• Last Update Submitted That Met QC Criteria: February 24, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: chemotherapy; biliary tract cancer; advanced disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Biliary Tract Diseases; Biliary Tract Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Alkylating Agents; Antibiotics, Antineoplastic; Capecitabine; Mitomycins; Mitomycin
• Other Study ID Numbers: 2011-002002-70