ABC06: Active Symptom Control Alone or With mFOLFOX Chemotherapy for Locally Advanced/ Metastatic Biliary Tract Cancers

Sponsor

The Christie NHS Foundation Trust (Other)

Overall Status

Completed

CT.gov ID

NCT01926236

Collaborator

Cancer Research UK (Other)

162

Enrollment

Locations

Arms

Duration (Months)

9.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether fit patients (with ECOG performance score of 0-1) with advanced biliary tract cancer (ABC) benefit from chemotherapy in the second-line setting (after prior therapy with cisplatin and gemcitabine) in terms of overall survival.

Condition or Disease	Intervention/Treatment	Phase
Biliary Tract Cancer Gallbladder Cancer Cholangiocarcinoma Ampullary Cancer	Other: Active Symptom Control Drug: L-folinic acid Drug: 5 FU Drug: Oxaliplatin	Phase 3

Detailed Description

Active chemotherapy drugs for the treatment of ABC include gemcitabine, fluoropyrimidines and platinum agents. The randomized NCRN phase III ABC-02 trial provided level A evidence supporting first-line combination cisplatin and gemcitabine (CisGem) chemotherapy in ABC. To date, there is no randomized data to support the use of second-line chemotherapy in ABC. In this setting only a small number of retrospective and prospective (phase II) studies employing multiple different chemotherapy schedules have been conducted (level C). Thus, active symptom control (ASC) is the current standard of care after development of resistance to first-line chemotherapy. Oxaliplatin has activity in several gastrointestinal tumours and has synergistic activity with a favourable toxicity profile when used in combination with 5-FU. Several studies using mFOLFOX for biliary tract tumours have provided promising efficacy data and acceptable toxicity.

The aim of this trial is to determine if patients with ABC benefit with respect to survival from the addition of mFOLFOX chemotherapy to ASC in the second-line setting after progression to first-line treatment with CisGem. This study will establish the standard of care for patients with ABC who have progressed on first line CisGem chemotherapy.

This is a randomised phase III, multi-centre, controlled, open-label trial of patients with advanced biliary tract cancer with evidence of disease progression after prior CisGem chemotherapy treatment. Eligible patients (ECOG 0-1, adequate haematological, renal and liver function, adequate biliary drainage, with no evidence of ongoing infection) will be randomized to receive either ASC ("standard" arm) or ASC with oxaliplatin/5-FU chemotherapy ("experimental" arm). The total number of participants planned is 162 (randomized 1:1). At randomisation the following factors will be controlled for: serum albumin level, platinum sensitivity (determined from first-line therapy) and locally advanced vs metastatic disease.

The primary end point is overall survival. Quality of life and economic evaluation will assess the impact on patients and relative cost effectiveness of the intervention. Archival paraffin-embedded tissue will be collected at baseline and prospective blood samples (whole blood, serum and plasma) will be collected for translational research.

Study Design

Study Type:

Interventional

Actual Enrollment :

162 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase III, Randomised, Multicentre Open-label Study of Active Symptom Control (ASC) Alone or ASC With Oxaliplatin/ 5F-U Chemotherapy for Patients With Locally Advanced/ Metastatic Biliary Tract Cancers Previously Treated With Cisplatin/ Gemcitabine Chemotherapy.

Study Start Date :

Feb 1, 2014

Actual Primary Completion Date :

Jan 5, 2018

Actual Study Completion Date :

Jan 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A: Active symptom control (ASC) Active Symptom Control	Other: Active Symptom Control Active Symptom Control: monthly clinical review and active symptom control as needed, including biliary drainage, antibiotics, analgesia, steroids, anti-emetics, other palliative treatment for symptom control, palliative radiotherapy, blood transfusion.
Experimental: Arm B: ASC with OxMdG chemotherapy Active Symptom Control with OxMdG chemo (Oxaliplatin, L-folinic acid & 5FU)	Other: Active Symptom Control Active Symptom Control: monthly clinical review and active symptom control as needed, including biliary drainage, antibiotics, analgesia, steroids, anti-emetics, other palliative treatment for symptom control, palliative radiotherapy, blood transfusion. Drug: L-folinic acid L-folinic acid 175mg (or folinic acid 350mg) q14d, up to 12 cycles Other Names: Folinic acid Drug: 5 FU 5 FU 400 mg/m2 (bolus), 2400 mg/m2 (infusion), q 14d, up to 12 cycles Other Names: Fluorouracil Drug: Oxaliplatin Oxaliplatin 85mg/m2, q 14d, up to 12 cycles Other Names: Eloxatin

Arm

Intervention/Treatment

Active Comparator: Arm A: Active symptom control (ASC)

Active Symptom Control

Other: Active Symptom Control

Active Symptom Control: monthly clinical review and active symptom control as needed, including biliary drainage, antibiotics, analgesia, steroids, anti-emetics, other palliative treatment for symptom control, palliative radiotherapy, blood transfusion.

Experimental: Arm B: ASC with OxMdG chemotherapy

Active Symptom Control with OxMdG chemo (Oxaliplatin, L-folinic acid & 5FU)

Other: Active Symptom Control

Drug: L-folinic acid

L-folinic acid 175mg (or folinic acid 350mg) q14d, up to 12 cycles

Other Names:

Folinic acid

Drug: 5 FU

5 FU 400 mg/m2 (bolus), 2400 mg/m2 (infusion), q 14d, up to 12 cycles

Other Names:

Fluorouracil

Drug: Oxaliplatin

Oxaliplatin 85mg/m2, q 14d, up to 12 cycles

Other Names:

Eloxatin

Outcome Measures

Primary Outcome Measures

Overall survival [Evaluated by monthly follow-up until 12 months after last patient included]

Secondary Outcome Measures

Progression-free survival [Evaluated by monthly follow-up until 12 months after last patient included]
Clinical progression assessed monthly, radiological progression assessed to RECIST criteria every 12 weeks for patients in the chemotherapy arm.
Response rate (chemotherapy arm only) [After 12 weeks of treatment]
Toxicity (frequency of adverse events and serious adverse events) [Evaluated monthly until 12 months after last patient included]
Events will be classified according to CTCAE V4.03
Quality of life [Evaluated every 3 months until 12 months after last patient included]
Assessed from patient completed questionnaire data: QLQ-C30 and QoL BiL
Costs of health and social care [Evaluated every 3 months until 12 months after last patient included]
Health status (Euroqol) [Evaluated every 3 months until 12 months after last patient included]
Quality adjusted life years (QALYs) [Evaluated every 3 months until 12 months after last patient included]
Estimated from Euroqol and survival using published utility tariffs

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically / cytologically verified, non-resectable or recurrent / metastatic cholangiocarcinoma, gallbladder or ampullary carcinoma.
Patients must have failed no more than one prior course of chemotherapy (gemcitabine and cisplatin) with clear evidence of disease progression.
ECOG performance status 0-1.
Age >=18 years and life expectancy >3 months.
Adequate renal function with serum urea and serum creatinine < 1.5 times upper limit of normal (ULN) and creatinine clearance >= 30ml/min
Adequate haematological function: Hb >= 100g/l, WBC >= 3.0 x 109/L, ANC >= 2 x 109/L, platelet count >= 100 x 10*9/L
Adequate liver function: total bilirubin < 60 μmol/L and ALP, along with AST and/or ALT ≤ 5 x ULN
Adequate biliary drainage, with no evidence of ongoing infection (patients on maintenance antibiotics are eligible when acute sepsis has resolved).
Women of child bearing age must have a negative pregnancy test prior to study entry and be using an adequate contraception method, which must be continued for 4 months after the study, unless child bearing potential has been terminated by surgery/radical radiotherapy
Men must be willing to use an adequate method of contraception during chemotherapy and until 6 months after chemotherapy
Patients must have given written informed consent
Patients must be randomised and those allocated chemotherapy must start treatment within 6 weeks of diagnosis of disease progression

Exclusion criteria:

Incomplete recovery from previous therapy or unresolved biliary tree obstruction (includes ongoing neuropathy of grade >1 from cisplatin)
Any evidence of severe or uncontrolled systemic diseases which, in the view of the investigator, makes it undesirable for the patient to participate in the trial
Evidence of significant clinical disorder or laboratory finding which, in the opinion of the investigator makes it undesirable for the patient to participate in the trial
Any patient with a medical or psychiatric condition that impairs their ability to give informed consent
Any other serious uncontrolled medical conditions
Clinical evidence of metastatic disease to brain
Any pregnant or lactating woman
Clinically significant cardiovascular disease. [i.e. active; or <12 months since e.g. cerebrovascular accident, myocardial infarction, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled hypertension].

**Hypertension grading of ≥ 3 is an exclusion criteria (CTCAE v4.03). However, patients who have controlled hypertension with medication and/or diet may be included at the investigator's discretion. (This should be noted in the medical history section of the CRF).

Patients must not have a history of other malignant diseases within the last 5 years (other than adequately treated non-melanotic skin cancer or in-situ carcinoma of the uterine cervix).

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Queen Elizabeth Hospital	Birmingham	United Kingdom
2	Bristol Haematology & Oncology Centre	Bristol	United Kingdom
3	North Cumbria University Hospitals	Carlisle	United Kingdom
4	Beatson West of Scotland Cancer Centre	Glasgow	United Kingdom	G12 0YN
5	Castle Hill Hospital	Hull	United Kingdom
6	St James' Hospital	Leeds	United Kingdom
7	Clatterbridge Cancer Centre	Liverpool	United Kingdom
8	Guy's and St Thomas' Hospital	London	United Kingdom
9	Hammersmith Hospital	London	United Kingdom
10	Royal Free Hospital	London	United Kingdom
11	University College London	London	United Kingdom
12	Maidstone Hospital	Maidstone	United Kingdom
13	The Christie NHS Foundation Trust	Manchester	United Kingdom
14	Nottingham City Hospital	Nottingham	United Kingdom
15	Churchill Hospital	Oxford	United Kingdom
16	Weston Park Hospital	Sheffield	United Kingdom
17	Southampton General Hospital	Southampton	United Kingdom