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

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

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

Study Overview

• Status: Terminated
• Conditions: Metastatic Disease
• Intervention / Treatment: Drug: BIBW 2992

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Mainz, Germany, 55131
    • I. Medizinische Klinik und Poliklinik der Universitätsmedizin

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 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).

Collaborators and Investigators

• Sponsor: Johannes Gutenberg University Mainz
• Investigators: Principal Investigator: Markus Moehler, Prof. Dr. med., University Medical Center of the Johannes Gutenberg-University Mainz

Publications and helpful links

General Publications

• Moehler M, Maderer A, Ehrlich A, Foerster F, Schad A, Nickolay T, Ruckes C, Weinmann A, Sivanathan V, Marquardt JU, Galle PR, Woerns M, Thomaidis T. Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program. BMC Cancer. 2019 Jan 11;19(1):55. doi: 10.1186/s12885-018-5223-7.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: August 17, 2012
• First Submitted That Met QC Criteria: August 31, 2012
• First Posted (Estimate): September 6, 2012

Study Record Updates

• Last Update Posted (Actual): September 6, 2019
• Last Update Submitted That Met QC Criteria: August 26, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: metastatic biliary tract cancer
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Gemcitabine; Cisplatin; Afatinib
• Other Study ID Numbers: BIBW 2992

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No