Clinical trial NCT00449033: A Phase III Randomized, Double-blind, Placebo Controlled Trial Comparing the Efficacy of Gemcitabine, Cisplatin and Sorafenib to Gemcitabine, Cisplatin and Placebo in First-Line Treatment of Patients With Stage IIIb With Effusion and Stage IV Non-Small Cell Lung Cancer (NSCLC)
Official title: A Phase III Randomized, Double-blind, Placebo Controlled Trial Comparing the Efficacy of Gemcitabine, Cisplatin and Sorafenib to Gemcitabine, Cisplatin and Placebo in First-Line Treatment of Patients With Stage IIIb With Effusion and Stage IV Non-Small Cell Lung Cancer (NSCLC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Non-Small Cell Lung Cancer (NSCLC)
Cancer
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2007-03-19
Enrollment: 904
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Evaluation of gemcitabine and cisplatin in combination with either sorafenib or placebo for the treatment of patients with advanced Non-Small Cell Lung Cancer (NSCLC)

Detailed description: During follow-up, it was determined that there was one additional patient on placebo that was still receiving treatment as of 06 APR 2010 and therefore 10 patients' data are reported in the current CSR addendum, 6 in the sorafenib + GC group and 4 in the placebo + GC group, and as before all in the ITT (non-squamous) population.

Eligibility criteria: Inclusion Criteria:

* Age \> 18 years old
* Stage IIIB (with cytologically confirmed malignant pleural or pericardial effusion) or Stage IV histological or cytological confirmation of NSCLC of non-squamous cell carcinoma subtype. (thoracentesis or pericardiocentesis is not necessary if a biopsy of the original tumor is available to confirm diagnosis of NSCLC).
* Patients with at least one measurable lesion. Lesions must be measured by CT-scan or MRI (Magnetic resonance imaging) according to Response Evaluation Criteria in Solid Tumors (RECIST, see Appendix 10.3)
* Life expectancy of at least 12 weeks
* Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to start of first dose:
* Hemoglobin \>/= 9.0 g/dl (\>/= 5.6 mmol/l)
* Absolute neutrophil count (ANC) \>/= 1,500/mm3
* Platelet count \>/= 100,000/µl
* Total bilirubin \</= 1.5 x upper limit of normal
* Alanine transaminase (ALT) and Aspartate transaminase (AST) \</= 2.5 x upper limit of normal (\</= 5 x upper limit of normal for patients with liver involvement of their cancer)
* Alkaline Phosphatase \</= 4 x upper limit of normal
* PT-INR (Prothrombin Time - International Normalized Ratio) (international normalized ratio of PT) /PTT (Partial Thromboplastin Time) \< 1.5 x upper limit of normal
* Serum Creatinine \</= 1.5 times the upper limit of normal and Serum Creatinine Clearance \>/= 70ml/min
* Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to performing any study specific procedures.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

Exclusion Criteria:

* Excluded medical conditions:

  * Cardiac disease: Congestive heart failure \> class II NYHA (New York Heart Association). Patients must not have unstable angina (anginal symptoms at rest) or active coronary artery disease (CAD), or myocardial infarction within the past 6 months
  * Cardiac arrhythmias requiring anti-arrhythmic therapy
  * Uncontrolled hypertension defined as systolic blood pressure \> 150 mmHg or diastolic pressure \> 90 mmHg, despite optimal medical management.
  * History of HIV (Human immunodeficiency virus) infection or chronic hepatitis B or C
  * Active clinically serious infections (\> grade 2 NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0)
  * Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
  * Known brain metastasis. Patients with neurological symptoms should undergo a CT scan/MRI of the brain to exclude brain metastasis.
  * History of organ allograft
  * Patients with evidence or history of bleeding diathesis or coagulopathy
  * Patients undergoing renal dialysis
  * Cancer other than NSCLC within 5 years prior to start of study treatment EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, or superficial bladder tumors \[Ta (Noninvasive tumor), Tis (Carcinoma in situ) \& T1 (Tumor invades lamina propria)\]
  * Uncontrolled hypertension defined as systolic blood pressure \> 150 mmHg or diastolic pressure \> 90 mmHg, despite optimal medical management.
  * Thrombotic or embolic events such as cerebrovascular accident including transient ischemic attacks within the past 6 months
  * Pulmonary hemorrhage/bleeding event \> Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 within 4 weeks of first dose of study drug
  * Any other hemorrhage/bleeding event \> CTCAE Grade 3 within 4 weeks of first dose of study drug
  * Serious, non-healing wound, ulcer, or bone fracture
  * Uncorrected dehydration
  * Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate birth control measures during the course of the trial. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate.
  * Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
  * Known or suspected allergy to the investigational agent or any agent given in association with this trial
  * Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
  * Patients unable to swallow oral medications
  * Any malabsorption condition
  * Patients with a hearing impairment (FOR GERMANY ONLY)
  * NSCLC patients with squamous cell carcinoma diagnosis documented either by cytology or biopsy.
* Excluded therapies and medications, previous and concomitant:

  * Any prior systemic anticancer therapy including cytotoxic therapy, targeted agents, experimental therapy, adjuvant, or neo-adjuvant therapy for NSCLC
  * Concomitant use of nephrotoxic drugs, ototoxic drugs, anticonvulsant, anti-gout treatment
  * Radiotherapy during study or within 3 weeks of start of study drug. (Palliative radiotherapy will be allowed as described in the Prior and Concomitant Therapy section)
  * Radiotherapy during study or within 4 weeks of start of study drug. (Palliative radiotherapy will be allowed as described in the Prior and Concomitant Therapy section) (FOR FRANCE ONLY)
  * Major surgery, open biopsy or significant traumatic injury within 4 weeks of first dose of study drug (bronchoscopy is allowed)
  * Granulocyte colony stimulating factor (GCSF) or Granulocyte macrophage colony stimulating factor (GMCSF), within 3 weeks of study entry (these growth factors may be used during the study thereafter).

Primary outcomes:
measure: Overall Survival (OS) in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months or date of death of any cause whichever came first
Secondary outcomes:
measure: OS in the ITT (Both Squamous and Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months or date of death of any cause whichever came first
measure: OS in the ITT (Squamous) Population
timeFrame: from randomization of the first patient until 38 months or date of death of any cause whichever came first
measure: Progression-free Survival (PFS) in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks
measure: Time to Progression (TTP) in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks
measure: Percentage of Participants With Different Tumor Response in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks
measure: Disease Control (DC) in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks
measure: Duration of Response in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks
measure: Duration of Stable Disease (SD) in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks
measure: Time to Response (TTR) in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months or date of death of any cause whichever came first
measure: Functional Assessment of Cancer Treatment-Lung (FACT-L) Scores in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months
measure: Lung Cancer Subscale (LCS) Scores in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient to 38 months later or death whatever occurs first.
measure: Time to Symptomatic Deterioration (TSD) in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient to 38 months later or death whatever occurs first
measure: Euro Quality of Life - 5D (EQ-5D) Index Scores in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months later or death whatever occurs first
measure: EQ-5D Visual Analog Scale (VAS) Scores in the ITT (Non-squamous) Population
timeFrame: from randomization of the first patient until 38 months later or death whatever occurs first
Other outcomes:
Locations:
city: Innsbruck
country: Austria
city: Linz
country: Austria
city: Wien
country: Austria
city: Wien
country: Austria
city: Brasschaat
country: Belgium
city: Bruxelles - Brussel
country: Belgium
city: Edegem
country: Belgium
city: Leuven
country: Belgium
city: Liege
country: Belgium
city: Namur
country: Belgium
city: Salvador
country: Brazil
state: Bahia
city: Salvador
country: Brazil
state: Bahia
city: Salvador
country: Brazil
state: Bahia
city: Brasília
country: Brazil
state: Distrito Federal
city: Goiania
country: Brazil
state: Goiás
city: Goiânia
country: Brazil
state: Goiás
city: Belo Horizonte
country: Brazil
state: Minas Gerais
city: Porto Alegre
country: Brazil
state: Rio Grande do Sul
city: Porto Alegre
country: Brazil
state: Rio Grande do Sul
city: Jaú
country: Brazil
state: Sao Paulo
city: Santo Andre
country: Brazil
state: Sao Paulo
city: Santo André
country: Brazil
state: Sao Paulo
city: Sorocaba
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: Rio de Janeiro
country: Brazil
city: Montreal
country: Canada
state: Quebec
city: Guangzhou
country: China
state: Guangdong
city: Wuhan
country: China
state: Hubei
city: Nanjing
country: China
state: Jiangsu
city: Hangzhou
country: China
state: Zhejiang
city: Hangzhou
country: China
state: Zhejiang
city: Beijing
country: China
city: Shanghai
country: China
city: Shanghai
country: China
city: Nicosia
country: Cyprus
city: HUS
country: Finland
city: Preitilä
country: Finland
city: Tampere
country: Finland
city: Bayonne
country: France
city: Grenoble
country: France
city: Grenoble
country: France
city: Hyeres
country: France
city: Le Mans Cedex 2
country: France
city: Marseille
country: France
city: Nantes
country: France
city: Nimes Cedex 2
country: France
city: Paris Cedex 15
country: France
city: Perpignan
country: France
city: Pierre Benite
country: France
city: Strasbourg
country: France
city: Tours
country: France
city: Heidelberg
country: Germany
state: Baden-Württemberg
city: Karlsruhe
country: Germany
state: Baden-Württemberg
city: Löwenstein
country: Germany
state: Baden-Württemberg
city: Gauting
country: Germany
state: Bayern
city: Frankfurt
country: Germany
state: Hessen
city: Hofheim
country: Germany
state: Hessen
city: Essen
country: Germany
state: Nordrhein-Westfalen
city: Köln
country: Germany
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
state: Sachsen
city: Großhansdorf
country: Germany
state: Schleswig-Holstein
city: Bad Berka
country: Germany
state: Thüringen
city: Hamburg
country: Germany
city: Heraklion
country: Greece
state: Creta
city: Athens
country: Greece
city: Budapest
country: Hungary
city: Budapest
country: Hungary
city: Deszk
country: Hungary
city: Matrahaza
country: Hungary
city: Szekesfehervar
country: Hungary
city: Torokbalint
country: Hungary
city: Ashkelon
country: Israel
city: Holon
country: Israel
city: Kfar Saba
country: Israel
city: Rehovot
country: Israel
city: Tel Hashomer
country: Israel
city: Rozzano
country: Italy
state: Milano
city: Monza
country: Italy
state: Monza-Brianza
city: Aviano
country: Italy
state: Pordenone
city: Bologna
country: Italy
city: Catania
country: Italy
city: Firenze
country: Italy
city: Livorno
country: Italy
city: Milano
country: Italy
city: Roma
country: Italy
city: Sassari
country: Italy
city: Venezia
country: Italy
city: Verona
country: Italy
city: México
country: Mexico
state: Distrito Federal
city: Guadalajara
country: Mexico
state: Jalisco
city: Monterrey
country: Mexico
state: Nuevo Leon
city: Den Bosch
country: Netherlands
city: Ede
country: Netherlands
city: Harderwijk
country: Netherlands
city: Heerlen
country: Netherlands
city: Nieuwegein
country: Netherlands
city: Terrassa
country: Spain
state: Barcelona
city: Cruces/Barakaldo
country: Spain
state: Bilbao
city: A Coruña
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Málaga
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
city: Valencia
country: Spain
city: Valencia
country: Spain
city: Basel
country: Switzerland
state: Basel-Stadt
city: Genéve
country: Switzerland
state: Genève
city: Bern
country: Switzerland
city: Cambridge
country: United Kingdom
state: Cambridgeshire
city: Aberdeen
country: United Kingdom
state: Grampian
city: Leicester
country: United Kingdom
state: Leicestershire
city: Sutton
country: United Kingdom
state: Surrey
city: Wolverhampton
country: United Kingdom
state: West Midlands
city: Birmingham
country: United Kingdom
city: London
country: United Kingdom
city: London
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S, Syrigos K, Le Marie E, Gottfried M, Vansteenkiste J, Alberola V, Strauss UP, Montegriffo E, Ong TJ, Santoro A; NSCLC [non-small-cell lung cancer] Research Experience Utilizing Sorafenib (NExUS) Investigators Study Group. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol. 2012 Sep 1;30(25):3084-92. doi: 10.1200/JCO.2011.39.7646. Epub 2012 Jul 30.