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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01679405
Recruitment Status : Terminated (No sufficient clinical or molecular signals for efficacy were observed.)
First Posted : September 6, 2012
Results First Posted : January 22, 2019
Last Update Posted : September 6, 2019
Information provided by (Responsible Party):
PD Dr Markus Möhler, Johannes Gutenberg University Mainz

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

Condition or disease Intervention/treatment Phase
Metastatic Disease Drug: BIBW 2992 Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
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
Study Start Date : August 2012
Actual Primary Completion Date : April 2016
Actual Study Completion Date : April 2016

Arm Intervention/treatment
Experimental: Dose level 1 (Part A)
30 mg BIBW 2992, Gemcitabin (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)
Drug: BIBW 2992
once daily per os
Other Name: Gemcitabine and Cisplatin

Experimental: Dose level -1 (Part A)
30 mg BIBW 2992, Gemcitabin (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)
Drug: BIBW 2992
once daily per os
Other Name: Gemcitabine and Cisplatin

Primary Outcome Measures :
  1. Number of Adverse Events [ Time Frame: Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period. ]

    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.

Secondary Outcome Measures :
  1. Time to Progress (TTP) [ Time Frame: Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period. ]
    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.

  2. Overall Survival (OS) [ Time Frame: 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 ]
    Median overall survival time including the 95% confidence interval were determined using Kaplan-Meier estimates.

  3. Objective Response Rate [ Time Frame: Treatment period: up to eight cycles (maximum 8 months). ]
    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

  4. Tumor Control Rate [ Time Frame: Treatment period: up to eight cycles (maximum 8 months). ]
    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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01679405

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I. Medizinische Klinik und Poliklinik der Universitätsmedizin
Mainz, Germany, 55131
Sponsors and Collaborators
Johannes Gutenberg University Mainz
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Principal Investigator: Markus Moehler, Prof. Dr. med. University Medical Center of the Johannes Gutenberg-University Mainz
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: PD Dr Markus Möhler, Principal Investigator, Johannes Gutenberg University Mainz Identifier: NCT01679405    
Other Study ID Numbers: BIBW 2992
First Posted: September 6, 2012    Key Record Dates
Results First Posted: January 22, 2019
Last Update Posted: September 6, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by PD Dr Markus Möhler, Johannes Gutenberg University Mainz:
metastatic biliary tract cancer
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplastic Processes
Pathologic Processes
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors