| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The patient population includes patients with Stage IIIB (with effusion) or Stage IV NSCLC of non-squamous cell carcinoma subtype, with ECOG performance status 0 or 1, for whom treatment with gemcitabine and cisplatin is considered medically acceptable. Patients must have measurable disease and must not have received prior systemic anticancer therapy. |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The objective of this phase III study is to compare the efficacy of sorafenib in combination with gemcitabine and cisplatin versus placebo with gemcitabine and cisplatin for first-line treatment of patients with stage IIIB (with effusion) or Stage IV NSCLC.
The primary efficacy objective is to compare overall survival (OS) in NSCLC patients with non-squamous cell carcinoma histology treated with gemcitabine, cisplatin and sorafenib to patients treated with gemcitabine, cisplatin and placebo.
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| E.2.2 | Secondary objectives of the trial |
Secondary eficacy objectives will include progression-free survival (PFS), tumour responses and patient reported outcomes (PRO).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age > or = 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 > or = 9.0 g/dl (> or = 5.6 mmol/l)
•Absolute neutrophil count (ANC)> or = 1,500/mm3
•Platelet count > or = 100,000/ul
•Total bilirubin ≤ 1.5 x upper limit of normal
•ALT and 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 (international normalized ratio of PT) /PTT ≤1.5 x upper limit of normal
•Serum Creatinine ≤ 1.5 times the upper limit of normal and Serum Creatine 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.
•ECOG Performance Status of 0 or 1
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| E.4 | Principal exclusion criteria |
•Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have unstable anigina (anginal symptoms at rest) or active coronary artery disease (CAD), or myocardial infarction within the past 6 months.
•Cardiac arrthythmias requiring anti-arrthythmic 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)]
•Thrombotic or embolic events such as cerebrovascular accident including transient ischemic attacks within the past 6 months
•Pulmonary hemorrhage/bleeding event >or = CTCAE Grade 2 within 4 weeks of first dose of study drug
•Any other hemorrhage/bleeding event > or = 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
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)
•Major surgery, open biopsy or significant traumatic injury within 4 weeks of first dose of study drug (bronchoscopy is allowed)
•Granuloctye 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).
•Therapeutic anticoagulation with vitamin K antagonists such as warfarin, or with heparins or heparinoids. Low dose warfarin (1 mg po qd) is permitted if the INR (International normalized ratio) is ≤ 1.5. Low-dose aspirin is permitted (≤ 100 mg daily).
•Investigational drug therapy outside of this trial during or within 4 weeks of study entry
•NSCLC patients with squamous cell carcinoma diagnosis documented either by cytology or biopsy.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy analisis will be based on patients with non-squamous cell histology for the primary as well as the secondary efficacy variables. The primary efficacy variable is overall survival (OS). One-sided alpha of 0.025 will be used for OS analysis.
Overall survival is defined as the time (days) from randomisation to death due to any cause. Patients alive at the time of analysis will be censored at their last contact date.
In addition to the final analysis of OS, which will be performed at the end of the study, two futility interim analyses of OS are planned during the study.These will be based on the projcted number of events in non-sqaumous cell carcinoma patients.
The first futility analysis of OS is planned to take place when approximately 182 deaths are observed (that is, after one third of the total number of events). The second futility analysis of OS is planned to take place when approximately 363 deaths are observed (that is, after two thirds of the total number of events). The futility analyses will be performed based on ruling out at 20% increase in OS. There is no planned early stopping for efficacy. The final efficacy analyses of OS will be performed when approximately 544 deaths in non-squamous cell carninoma patients occur. The final efficacy boundary will be calculated separately from the futility analyses, which will make the futility and final efficacy analyses independent of eachother, hence non-adherence to the futility does not inflate false-positive rate, alpha to over 0.025 (one-sided). Additionally, as no early stopping for efficacy is planned, the alpha level for the final OS analysis will remain at 1-sided 0.025. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 36 |
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