BIBW 2992 as add-on to Gem/Cis in Advanced Biliary Tract Cancer

Study Overview
=================
Brief Summary
-----------------
An open-label, uncontrolled, multicenter phase I/Ib trial to investigate safety and efficacy of BIBW 2992 added to the standard therapy of Gemcitabine/Cisplatin in chemo-naïve patients with advanced and/or metastatic adenocarcinoma of the biliary tract

Detailed Description
-----------------
The primary objective is safety and toxicity, including maximum tolerated dose, of BIBW 2992 when given as add-on therapy to Gem/Cis.

Official Title
-----------------
Open-label, Uncontrolled, Multicenter Phase I/Ib Trial to Investigate Safety and Efficacy of BIBW 2992 and Standard Gemcitabine/Cisplatin in Chemo-naïve Patients With Advanced Biliary Tract Adenocarcinoma

Conditions
-----------------
Metastatic Disease

Intervention / Treatment
-----------------
* Drug: BIBW 2992


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female patients aged ≥ 18 years Signed and dated written informed consent, Histologically confirmed adenocarcinoma of the gallbladder or intrahepatic bile ducts or extrahepatic bile ducts (metastasized) or histologically proven hepatic metastases of an earlier resected and histologically proven biliary tract cancer or a Klatskin tumour (hilar cholangiocarcinoma) with pain and biliary obstruction controlled adequate biliary drainage, no uncontrolled infection ECOG Performance Status of 0-1 LFTs: bilirubin (total) ≤ 1.5 x ULN, ALT/ AST/ alkaline phosphatase ≤ 3 2.5 x ULN (≤ 5 x ULN if liver metastases are present) No prior systemic treatment i) previous adjuvant chemotherapy is allowed (completed ≥ 6 months if containing Gemcitabine or platinum salts); ii) previous irradiation (external radiotherapy, brachytherapy, chemoembolization) and PDT are allowed, provided that there is still at least one unidimensionally measurable target lesion in an untreated area Resolution of all side effects of prior surgical procedures to CTCAE grade ≤ 1 (except for the laboratory values specified below) At least 4 weeks from any major surgery (at first dose of study drug) Life expectancy of at least 12 weeks. Cardiac left ventricular function with resting ejection fraction (LVEF) ≥ 50% Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to start of therapy: Haemoglobin > 10.0 g/dl (=6.2 mmol/l), blood transfusion is allowed Absolute neutrophil count (ANC) > 1,500/mm3 (=1.5x 109/L) Platelet count ≥ 100,000/μl (=100x 109/L) Total bilirubin ≤ 1.5 times the upper limit of normal ALT and AST ≤ 2.5 x institutional upper limit of normal (in case of liver metastases: ALT and AST ≤ 5 x institutional upper limit of normal) Prothrombin rate > 60% or INR < 1.5 Main exclusion criteria Large surgery (except diagnostic biopsy) or smaller surgical procedures, external radiotherapy, brachytherapy, or PDT within 30 days prior to start of treatment. Other tumor type than adenocarcinoma (e.g. leiomyosarcoma, lymphoma) or a second cancer except in patients with squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix which has been effectively treated. History of acute cardiac disease: congestive heart failure > NYHA class 2; active CAD (MI more than 6 months prior to study entry is allowed); Patients on immunosuppressant therapy or with known HIV infection Active clinically serious infections (> grade 2 NCI-CTC version 3.0) History of organ allograft Pregnant or breast-feeding patients. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study Gastrointestinal (GI) tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease History of pre-existing interstitial lung disease (ILD) Patients with untreated or symptomatic brain metastases. Persistent Grade 2 or greater neurotoxicity / neuropathy from any cause

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: For Part A of the study a standard 3+3 design was used. The recruitment was carried out in cohorts. Subjects were not allowed to participate in both cohorts. If the maximum tolerated dose was found there should be additional patients recruited to confirm the maximum tolerated dose (part B)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose level 1 (Part A)<br>30 mg BIBW 2992, Gemcitabin (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.) | Drug: BIBW 2992<br>* once daily per os<br>* Other names: Gemcitabine and Cisplatin;|
| Experimental: Dose level -1 (Part A)<br>30 mg BIBW 2992, Gemcitabin (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.) | Drug: BIBW 2992<br>* once daily per os<br>* Other names: Gemcitabine and Cisplatin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | In part A the maximum tolerated dose (MTD) of BIBW 2992 administered continuously to the standard therapy of Gemcitabine / Cisplatin (Gem/Cis) (administered together on day 1 and 8 of a three-week cycle) will be evaluated in a 2 step dose escalation. Safety and toxicity will be evaluated as described and considered primary for part B of the study. | Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progress (TTP) | Median time to progress (according to RECIST 1.1 criteria) including the 95% confidence intervals were determined using Kaplan-Meier estimates. Time from start of treatment to first documentation of objective tumour progression. Deaths were censored at the time of death. | Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period. | 
| Overall Survival (OS) | Median overall survival time including the 95% confidence interval were determined using Kaplan-Meier estimates. | Time from start of treatment to death due to any cause. Time to last observation will be used if a patient has not died and OS for the patient will be considered censored. Estimated time period: up to 76 weeks | 
| Objective Response Rate | Response was assessed by means of RECIST 1.1 criteria for target lesions, non-target lesions and the appearance of new lesions. Objective response was defined as the CR, PR or SD at end of treatment | Treatment period: up to eight cycles (maximum 8 months). | 
| Tumor Control Rate | Tumor control rate is defined as the best tumour response (confirmed partial or complete response, stable disease) that is achieved until end of treatment according to Recist 1.1. | Treatment period: up to eight cycles (maximum 8 months). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metastatic biliary tract cancer