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Gemcitabine and Sorafenib in Advanced Biliary Tract Cancer (GEMSO)

Primary Purpose

Adenocarcinoma

Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Gemcitabine
Placebo
Sorafenib
Sponsored by
PD Dr Markus Möhler
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adenocarcinoma focused on measuring advanced, metastatic, biliary, tract

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male and female patients aged 18 years and older
  • Signed and dated informed consent before the start of specific protocol procedures

  • Adenocarcinoma of the gallbladder or intrahepatic bile ducts or histologically proven hepatic metastases of an earlier resected and histologically proven biliary tract cancer

    • Not amenable to curative surgical resection
    • With at least one unidimensionally measurable target lesion in non-irradiated (or treated by photodynamic therapy, PDT) area (largest diameter ≥ 1 cm (spiral CT scan or MRI) or ≥ 2 cm (conventional CT scan)
    • With pain and biliary obstruction controlled
    • Cytologically or histologically confirmed

  • Note : in case of uncertain biliary tract origin (e.g., intrahepatic CCCs), inclusion is possible if

    • extensive search for primary tumor (thoracic and abdomino pelvic CT scan, colonoscopy, upper digestive endoscopy, serum PSA level for men or mammography for women, and FDG-PET if possible) is negative
    • histological examination is consistent with bile duct adenocarcinoma, with IHC positive for cytokeratin 7 and 19 and negative for cytokeratin 20 [Shimonishi, 2000].
    • No histological evidence of hepatocellular carcinoma (HCC)
    • No prior palliative (radio)-chemotherapy (gemcitabine or fluoropyrimidine-based chemotherapy)

  • Note:

    • previous adjuvant chemotherapy is allowed (completed since ≥ 6 months if containing gemcitabine or platinum salts);
    • previous irradiation (external radiotherapy, brachytherapy, chemoembolization) and PDT are allowed, provided that there is at least one unidimensionally measurable target lesion in untreated area
  • Resolution of all side effects of prior surgical procedures to grade ≤ 1 (except for the laboratory values specified below)
  • At least 4 weeks from any major surgery (at first dose of study drug)
  • ECOG Performance Status of 0-2

Exclusion Criteria:

  • Surgery (except diagnostic biopsy), 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. Patients curatively treated and disease free for at least 5 years will be discussed with the sponsor before inclusion
  • History of cardiac disease: congestive heart failure > NYHA class 2; active CAD (MI more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension
  • Any of the following within the 12 months prior to starting the study treatment,: coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, or pulmonary embolism
  • Ongoing cardiac dysrhythmias of grade ≥ 2, atrial fibrillation of any grade, or QTc interval > 450 msec for males or > 470 msec for females
  • Hypertension that cannot be controlled by medications ( > 150/100 mmHg despite optimal medical therapy)
  • History of HIV infection
  • Active clinically serious infections ( > grade 2 NCI-CTC version 3.0)
  • Known Central Nervous System tumors including metastatic brain disease
  • Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
  • History of organ allograft
  • Patients with evidence or history of bleeding diathesis
  • Active disseminated intravascular coagulation, or patients prone to thromboembolism
  • Patients undergoing renal dialysis
  • Pregnant or breast-feeding patients

Sites / Locations

  • Klinikum der Johannes Gutenberg-Universität Mainz, I. Med. Klinik
  • Universitätsklinikum Jena, Klinik für Innere Medizin, Innere Medizin II
  • Universitätsklinikum Hamburg-Eppendorf, I. Med. Klinik, Zentrum für Innere Medizin, Martinistr. 3
  • Klinikum Fulda gAG, Tumorklinik, Pacelliallee 4
  • Klinikum der Johann-Wolfgang Goethe-Universität, Innere Medizin I, Theodor-Stern-Kai 7
  • Universitätsklinikum des Saarlandes, Klinik für Innere Medizin II, Kirrberger Str., Gebäude 41
  • Klinikum der Universität München, Medizinische Klinik II, Marchioninistr. 15
  • Klinikum rechts der Isar, TU München, II. Medizinische Klinik und Poliklinik, Ismaningerstr. 22
  • II. Med. Klinik, Leopoldina-Krankenhaus der Stadt Schweinfurt, Gustav-Adolf-Str. 8
  • Klinikum Esslingen
  • Universitätsklinikum Halle, Innere Medizin I

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

1

2

Arm Description

Gemcitabine + Sorafenib

Gemcitabine + Placebo

Outcomes

Primary Outcome Measures

Progression-free Survival (PFS)
The primary endpoint is the progression-free survival (PFS) defined as the time from start of treatment to first documentation of objective tumor progression or to death due to any cause, whichever occurs first during treatment or follow-up period. For patients not known to have died as of the data cut-off date and who do not have objective progressive disease, PFS will be censored at the date of the last objective progression-free disease assessment. For patients who receive subsequent anticancer therapy (after discontinuation from the study drug) prior to objectively determined disease progression or death, PFS will be censored at the date of the last objective progression-free disease assessment prior to post-discontinuation anti-cancer therapy. Acceptable documentation of objective disease progression status consists of objective assessments using CT scan assessment method.

Secondary Outcome Measures

Overall Survival
Overall Survival (OS) is measured from start of treatment to death due to any cause until end of follow-up period. Time to last observation will be used if a patient has not died and OS for the patient will be considered censored at the date of the last observation.
Best Overall Response
Best Overall Response (BOR) is defined as the best tumor response (confirmed partial or complete response, stable disease) that is achieved during treatment or within 30 days after termination of active therapy that is confirmed according to the RECIST tumor response criteria. Best response is determined from the sequence of responses assessed. For complete response (CR) or partial response (PR), best response must be confirmed by a second assessment within 4 -6 weeks. Two objective status determinations of CR before progression are required for a best response of CR. Two determinations of PR or better before progression, but not qualifying for a CR, are required for a best response of PR. Best response of Stable Disease (SD) is defined as disease that does not meet the criteria of CR, PR or Progressive Disease (PD) and has been evaluated at least one time, at least 6 weeks after baseline assessment.
Time to Objective Response
Time to Objective Response (OR) is defined as the time from start of treatment to objective tumor response (CR or PR) is first documented according to the RECIST tumor response criteria during treatment or until 30 days after termination of active therapy. Response must subsequently be confirmed. For subjects failing to achieve an objective response and who did not progress during the trial, time to objective response will be censored at their last date of tumor evaluation.

Full Information

First Posted
April 15, 2008
Last Updated
September 18, 2013
Sponsor
PD Dr Markus Möhler
Collaborators
Johannes Gutenberg University Mainz, Interdisciplinary Center for Clinical Trials (IZKS)
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1. Study Identification

Unique Protocol Identification Number
NCT00661830
Brief Title
Gemcitabine and Sorafenib in Advanced Biliary Tract Cancer (GEMSO)
Official Title
A Randomized, Double-blind, Multicenter Phase II Trial With Gemcitabine Plus Sorafenib Versus Gemcitabine Plus Placebo in Patients With Chemo-naive Advanced or Metastatic Adenocarcinoma of the Biliary Tract
Study Type
Interventional

2. Study Status

Record Verification Date
September 2013
Overall Recruitment Status
Completed
Study Start Date
May 2008 (undefined)
Primary Completion Date
June 2010 (Actual)
Study Completion Date
June 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
PD Dr Markus Möhler
Collaborators
Johannes Gutenberg University Mainz, Interdisciplinary Center for Clinical Trials (IZKS)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This trial will be conducted to evaluate the efficacy, safety and tolerability of a combination of gemcitabine plus sorafenib in comparison of gemcitabine plus placebo as a first-line palliative therapy in chemo-naive advanced or metastatic CCC. There is strong scientific rationale for exploring the role of sorafenib in combination with gemcitabine in advanced CCC. Sorafenib is a novel signal transduction inhibitor that prevents tumor cell proliferation and angiogenesis through blockade of the Raf/MEK/ERK pathway at the level of Raf kinase and the receptor tyrosine kinases VEGF-R2, R3 and PDGFR-β. Mutations in these signaling pathways display by far the most common genetic alterations in CCC and overexpression correlates to poor prognosis. Furthermore, there is no evidence of a consistent or meaningful pharmacokinetic interaction between sorafenib and gemcitabine, suggesting that sorafenib can safely be combined with gemcitabine. Clinical results of a combination of sorafenib and gemcitabine in a phase I study in pancreatic cancer suggested a therapeutic effect, and the safety and efficacy results together with the knowledge of the molecular pathology of CCC provide a rationale for a randomized, placebo-controlled phase II trial consisting of gemcitabine plus sorafenib in advanced CCC.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adenocarcinoma
Keywords
advanced, metastatic, biliary, tract

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
103 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Gemcitabine + Sorafenib
Arm Title
2
Arm Type
Placebo Comparator
Arm Description
Gemcitabine + Placebo
Intervention Type
Drug
Intervention Name(s)
Gemcitabine
Intervention Description
Gemcitabine 1000 mg/m2 body surface i.v. first cycle at day 1, 8, 15, 22, 29, 36, 43. Next cycles at day 1, 8, 15.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Sorafenib
Intervention Description
Sorafenib 400 mg bid orally continuously
Primary Outcome Measure Information:
Title
Progression-free Survival (PFS)
Description
The primary endpoint is the progression-free survival (PFS) defined as the time from start of treatment to first documentation of objective tumor progression or to death due to any cause, whichever occurs first during treatment or follow-up period. For patients not known to have died as of the data cut-off date and who do not have objective progressive disease, PFS will be censored at the date of the last objective progression-free disease assessment. For patients who receive subsequent anticancer therapy (after discontinuation from the study drug) prior to objectively determined disease progression or death, PFS will be censored at the date of the last objective progression-free disease assessment prior to post-discontinuation anti-cancer therapy. Acceptable documentation of objective disease progression status consists of objective assessments using CT scan assessment method.
Time Frame
one year
Secondary Outcome Measure Information:
Title
Overall Survival
Description
Overall Survival (OS) is measured from start of treatment to death due to any cause until end of follow-up period. Time to last observation will be used if a patient has not died and OS for the patient will be considered censored at the date of the last observation.
Time Frame
one year
Title
Best Overall Response
Description
Best Overall Response (BOR) is defined as the best tumor response (confirmed partial or complete response, stable disease) that is achieved during treatment or within 30 days after termination of active therapy that is confirmed according to the RECIST tumor response criteria. Best response is determined from the sequence of responses assessed. For complete response (CR) or partial response (PR), best response must be confirmed by a second assessment within 4 -6 weeks. Two objective status determinations of CR before progression are required for a best response of CR. Two determinations of PR or better before progression, but not qualifying for a CR, are required for a best response of PR. Best response of Stable Disease (SD) is defined as disease that does not meet the criteria of CR, PR or Progressive Disease (PD) and has been evaluated at least one time, at least 6 weeks after baseline assessment.
Time Frame
one year
Title
Time to Objective Response
Description
Time to Objective Response (OR) is defined as the time from start of treatment to objective tumor response (CR or PR) is first documented according to the RECIST tumor response criteria during treatment or until 30 days after termination of active therapy. Response must subsequently be confirmed. For subjects failing to achieve an objective response and who did not progress during the trial, time to objective response will be censored at their last date of tumor evaluation.
Time Frame
one year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and female patients aged 18 years and older Signed and dated informed consent before the start of specific protocol procedures Adenocarcinoma of the gallbladder or intrahepatic bile ducts or histologically proven hepatic metastases of an earlier resected and histologically proven biliary tract cancer Not amenable to curative surgical resection With at least one unidimensionally measurable target lesion in non-irradiated (or treated by photodynamic therapy, PDT) area (largest diameter ≥ 1 cm (spiral CT scan or MRI) or ≥ 2 cm (conventional CT scan) With pain and biliary obstruction controlled Cytologically or histologically confirmed Note : in case of uncertain biliary tract origin (e.g., intrahepatic CCCs), inclusion is possible if extensive search for primary tumor (thoracic and abdomino pelvic CT scan, colonoscopy, upper digestive endoscopy, serum PSA level for men or mammography for women, and FDG-PET if possible) is negative histological examination is consistent with bile duct adenocarcinoma, with IHC positive for cytokeratin 7 and 19 and negative for cytokeratin 20 [Shimonishi, 2000]. No histological evidence of hepatocellular carcinoma (HCC) No prior palliative (radio)-chemotherapy (gemcitabine or fluoropyrimidine-based chemotherapy) Note: previous adjuvant chemotherapy is allowed (completed since ≥ 6 months if containing gemcitabine or platinum salts); previous irradiation (external radiotherapy, brachytherapy, chemoembolization) and PDT are allowed, provided that there is at least one unidimensionally measurable target lesion in untreated area Resolution of all side effects of prior surgical procedures to grade ≤ 1 (except for the laboratory values specified below) At least 4 weeks from any major surgery (at first dose of study drug) ECOG Performance Status of 0-2 Exclusion Criteria: Surgery (except diagnostic biopsy), 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. Patients curatively treated and disease free for at least 5 years will be discussed with the sponsor before inclusion History of cardiac disease: congestive heart failure > NYHA class 2; active CAD (MI more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension Any of the following within the 12 months prior to starting the study treatment,: coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, or pulmonary embolism Ongoing cardiac dysrhythmias of grade ≥ 2, atrial fibrillation of any grade, or QTc interval > 450 msec for males or > 470 msec for females Hypertension that cannot be controlled by medications ( > 150/100 mmHg despite optimal medical therapy) History of HIV infection Active clinically serious infections ( > grade 2 NCI-CTC version 3.0) Known Central Nervous System tumors including metastatic brain disease Patients with seizure disorder requiring medication (such as steroids or anti-epileptics) History of organ allograft Patients with evidence or history of bleeding diathesis Active disseminated intravascular coagulation, or patients prone to thromboembolism Patients undergoing renal dialysis Pregnant or breast-feeding patients
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Markus Moehler, MD
Organizational Affiliation
Johannes Gutenberg University Mainz, I. Med. Klinik
Official's Role
Principal Investigator
Facility Information:
Facility Name
Klinikum der Johannes Gutenberg-Universität Mainz, I. Med. Klinik
City
Mainz
State/Province
Rheinland-Pfalz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Universitätsklinikum Jena, Klinik für Innere Medizin, Innere Medizin II
City
D-07740 Jena
Country
Germany
Facility Name
Universitätsklinikum Hamburg-Eppendorf, I. Med. Klinik, Zentrum für Innere Medizin, Martinistr. 3
City
D-20248 Hamburg
Country
Germany
Facility Name
Klinikum Fulda gAG, Tumorklinik, Pacelliallee 4
City
D-36043 Fulda
Country
Germany
Facility Name
Klinikum der Johann-Wolfgang Goethe-Universität, Innere Medizin I, Theodor-Stern-Kai 7
City
D-60590 Frankfurt
Country
Germany
Facility Name
Universitätsklinikum des Saarlandes, Klinik für Innere Medizin II, Kirrberger Str., Gebäude 41
City
D-66421 Homburg/Saar
Country
Germany
Facility Name
Klinikum der Universität München, Medizinische Klinik II, Marchioninistr. 15
City
D-81377 München
Country
Germany
Facility Name
Klinikum rechts der Isar, TU München, II. Medizinische Klinik und Poliklinik, Ismaningerstr. 22
City
D-81675 München
Country
Germany
Facility Name
II. Med. Klinik, Leopoldina-Krankenhaus der Stadt Schweinfurt, Gustav-Adolf-Str. 8
City
D-97422 Schweinfurt
Country
Germany
Facility Name
Klinikum Esslingen
City
Esslingen
ZIP/Postal Code
73730
Country
Germany
Facility Name
Universitätsklinikum Halle, Innere Medizin I
City
Halle
ZIP/Postal Code
06120
Country
Germany

12. IPD Sharing Statement

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Gemcitabine and Sorafenib in Advanced Biliary Tract Cancer (GEMSO)

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