E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage IV Non-Small Cell Lung Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 primary objective of this study is to compare the overall survival (OS) of ramucirumab DP administered in combination with docetaxel versus docetaxel with placebo as therapy for patients with Stage IV non-small cell lung cancer (NSCLC) who have had disease progression during or after 1 prior first-line platinum-based chemotherapy with or without maintenance therapy for advanced/metastatic
disease. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to compare ramucirumab DP administered in combination with docetaxel versus docetaxel with placebo for:
Safety and toxicity profile
Progression-free survival (PFS)
Objective response rate (ORR)
Disease control rate (DCR)
Patient-reported outcomes (using Lung Cancer Symptom Scale [LCSS] and EuroQol EQ-5D) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Disease progression during or after one prior first-line platinum-based chemotherapy with or without maintenance therapy
- Prior bevacizumab as first-line and/or maintenance therapy is allowed
- Signed informed consent
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Histologically or cytologically confirmed non small cell lung cancer (NSCLC)
- Stage IV NSCLC disease
- Patients have measurable or nonmeasurable disease
- Adequate organ function, defined as: Total bilirubin less than or equal to Upper Limit of Normal (ULN), Aspartate Aminotransferase (AST) and Alanine Aminotransaminase (ALT) less than or equal to 2.5 x ULN, or less than or equal to 5 x ULN if the transaminase elevation is due to liver metastases; Serum creatinine less than or equal to 1.5 x ULN or calculated creatinine clearance greater than or equal to 50 ml/min (per the Cockcroft-Gault formula or equivalent and/or 24-hour urine collection)Absolute Neutrophil Count (ANC) greater than or equal to 1.5 x 103/µL, hemoglobin greater than or equal to 10.0 g/dl, and platelets greater than or equal to 100 x 103/µL; Adequate coagulation function as defined by International Normalized Ratio (INR) less than or equal to 1.5, prothrombin time and partial thromboplastin time less than or equal to 1.5 x ULN; The patient does not have:
o cirrhosis at a level of Child-Pugh B (or worse) or
o cirrhosis (any degree) and a history of hepatic encephalopathy or
clinically meaningful ascites resulting from cirrhosis. Clinically
meaningful ascites is defined as ascites resulting from cirrhosis and
requiring ongoing treatment with diuretics and/or paracentesis.
- Urinary protein is less than or equal to 1+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates proteinuria greater than or equal to 2+, a 24-hour urine must be collected and must demonstrate less than 1000 mg of protein
- Patients of reproductive potential (both sexes) must agree to use reliable method of birth control (hormonal or barrier methods) during the study period and at least 12 weeks after the last dose of study therapy
- Life expectancy of greater than or equal to 3 months
- Prior radiation therapy is allowed if: In the case of chest radiotherapy at least 28 days have elapsed from the completion of radiation treatment prior to randomization; In the case of focal or palliative radiation treatment at least 7 days have elapsed from last radiation treatment prior to randomization (and provided that 25% or less of total bone marrow had been irradiated); In the case of Central Nervous System (CNS) radiation at least 14 days have elapsed from the completion of radiation treatment prior to randomization |
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E.4 | Principal exclusion criteria |
- Disease progression on more than 1 prior chemotherapy regimens
- Patients whose only prior treatment was a tyrosine kinase inhibitor
- The patient's tumor wholly or partially contains small cell lung cancer
- Major surgery within 28 days prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization. Postoperative bleeding complications or wound complications from a surgical procedure performed in the last 2 months
- Concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, chemoembolization, or targeted therapy
- Last dose of bevacizumab must be at least 21 days from start of study treatment
- Last dose of cytotoxic chemotherapy must be at least 14 days from start of study treatment
- The patient has untreated CNS metastases. Patients with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation ending at least 2 weeks prior to randomization, or after surgical resection performed at least 28 days prior to randomization. No evidence of Grade greater than or equal to 1 CNS hemorrhage based on pretreatment Magnetic Resonance Imaging (MRI) or intravenous (IV) contrast CT scan
- Radiologically documented evidence of major blood vessel invasion or encasement by cancer
- Radiographic evidence of intratumor cavitation
- History of uncontrolled hereditary or acquired thrombotic disorder
- Chronic therapy with nonsteroidal anti-inflammatory drug (NSAIDs) or other antiplatelet agents; Aspirin use at doses up to 325 mg/day is permitted
- History of gross hemoptysis (defined as bright red blood or greater than or equal to 1/2 teaspoon) within 2 months prior to study entry
- Clinically relevant congestive heart failure (New York Heart Association [NYHA II-IV]) or symptomatic or poorly controlled cardiac arrhythmia
- Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization
- Uncontrolled arterial hypertension greater than or equal to 150 / greater than or equal to 90 mm Hg despite standard medical management
- Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to randomization
- Significant bleeding disorders, vasculitis, or Grade 3/4 gastrointestinal bleeding within 3 months prior to study entry
- Gastrointestinal (GI) perforation and/or fistulae within 6 months prior to randomization
- Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection Crohn's disease, ulcerative colitis, or chronic diarrhea
- Peripheral neuropathy greater than or equal to Grade 2 (NCI-CTCAE v 4.02)
- Serious illness or medical condition(s) including, but not limited to: Human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness; Active or uncontrolled clinically serious infection; Severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration
- Known allergy or hypersensitivity reaction to any of the treatment components
- The patient is pregnant or breastfeeding
- Patient is currently enrolled in or discontinued within 28 days prior to randomization from a clinical trial involving an investigational product or nonapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
- Prior therapy with docetaxel |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline to date of death from any cause |
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E.5.2 | Secondary end point(s) |
Progression free survival
Proportion of patients achieving an objective response (objective response rate)
Proportion of patients achieving disease control (Disease Control Rate)
Maximum Improvement on Lung Cancer Sympton Scale
Change from baseline up to 30 day follow up visit on EuroQol score
Cmax and Cmin of Ramucirumab
Incidence of anti Ramucirumab antibodies |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS: Baseline to measured progressive disease or date of death from any cause
ORR: Baseline to measured progressive disease
DCR: Baseline to measured progressive disease
Maximum Improvement on Lung Cancer Sympton Scale: Baseline through 30 day follow up visit
EuroQol score: Baseline, 30 day follow up visit
Cmax and Cmin of Ramucirumab: Baseline, prior to infusion of Cycle 3 and 5, and 30 days following last infusion
Incidence of anti Ramucirumab antibodies: Baseline, prior to infusion of Cycle 3 and 5, and 30 days following last infusion |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 68 |
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 | No |
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 |
Argentina |
Austria |
Canada |
France |
Germany |
Greece |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Netherlands |
Norway |
Poland |
Romania |
Russian Federation |
Spain |
Sweden |
Switzerland |
Taiwan |
Turkey |
United Kingdom |
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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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- A sufficient number of events (at least 869 events) have been observed for final analysis of the primary endpoint
AND
- The last patient has discontinued study treatment and completed the 30-day follow-up visit. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |