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

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

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

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