E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients Treated with Gemcitabine for Metastatic Pancreatic Cancer. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033605 |
E.1.2 | Term | Pancreatic cancer metastatic |
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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 |
To demonstrate improvement in overall survival (OS) with aflibercept by comparison to placebo in patients treated with gemcitabine as first line treatment for metastatic pancreatic cancer. |
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E.2.2 | Secondary objectives of the trial |
- To compare in the two treatment arms (by sequential order of statistical analysis): • Progression Free Survival (PFS), • Clinical Benefit assessed by Time to symptoms worsening (TTSW) and improvement in tumor related symptoms, • Overall Response Rate (ORR) in patients with measurable disease at study entry (as per RECIST criteria). - To assess the overall safety in the two treatment arms. - To assess immunogenicity of aflibercept. - To perform population pharmacokinetics in all patients randomized in selected centres. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There are 2 sub-studies, i.e. pharmacokinetics and immunogenicity sub-studies, which are part of the EFC10547 study protocol. The objectives are the following: • To assess the pharmacokinetics of intravenous (IV) aflibercept. Free and bound aflibercept will be measured. The ratio free aflibercept/bound aflibercept will be also estimated as an indicator of the presence of circulating endogenous VEGF. • To determine immunogenicity of IV aflibercept |
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E.3 | Principal inclusion criteria |
- Cytologically or histologically confirmed evidence of epithelial cancer (adenocarcinoma) of the exocrine pancreas. - Metastatic disease. Patients with measurable and with non-measurable disease (as per RECIST criteria) are eligible. - No prior chemotherapy for pancreatic disease. Prior irradiation or chemoradiotherapy with 5-fluorouracil, in which 5-FU was used as a radio-sensitizing agent, is allowed if the treatment-free interval is of at least 3 months. |
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E.4 | Principal exclusion criteria |
- Related to the methodology : • Chemotherapy or other systemic therapy for pancreatic cancer. • Less than 42 days elapsed from prior major surgery (28 days from other prior surgery) to the time of randomization. Less than 28 days elapsed from prior radiation therapy. • Prior treatment with anti-VEGF or VEGF-Receptor-inhibitors. • Age < 18 years. • ECOG performance status (PS) of 3-4. • History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. • History of another neoplasm. Adequately treated basal cell or squamous cell skin cancers, carcinoma in situ of the cervix, or any other cancer from which the patient has been disease free for > 5 years are allowed. • Participation in other clinical trial and any concurrent treatment with any investigational drug within 30 days prior to randomization. • Any of the following events within the 3 months prior to randomization: treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, grade 3 or 4 gastrointestinal bleeding/hemorrhage, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event. • Any of the following events within the 6 months prior to randomization: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft surgery, NYHA class III or IV congestive heart failure, stroke or transient ischemic attack. • Occurrence of deep vein thrombosis within 4 weeks prior to randomization. • Known human immunodeficiency virus (HIV) infection requiring antiretroviral treatment or acquired immunodeficiency-syndrome (AIDS)-related illness. • Other severe acute or chronic medical condition, which could impair the ability of the patient to participate to the study or to interfere with interpretation of study results. • Absence of signed and dated Institutional Review Board (IRB)-/Independent Ethical Committee (IEC)-approved patient informed consent form prior to enrollment into the study. • Pregnant or breast-feeding woman. Positive serum or urine pregnancy test for women of reproductive potential prior to randomization. • Patient with reproductive potential (male, female) who do not agree to use accepted and effective method of contraception during the study treatment period and for at least 3 months after the completion of the study treatment. The definition of “effective method of contraception” will be based on the investigator’s judgment.
- Related to aflibercept • Urine Protein-Creatinine Ratio (UPCR) > 1 on morning spot urinalysis or proteinuria > 500 mg/24h. • Serum Creatinine > 1.5 x upper limit of normal (ULN). If creatinine 1.0 - 1.5 x ULN, creatinine clearance, calculated according to Cockcroft-Gault formula < 60 mL/min will exclude the patient. • Uncontrolled hypertension defined as blood pressure > 150/100 mmHg (≥ grade 2 according to NCI CTCAE v. 3.0), or systolic blood pressure >180 mmHg if diastolic blood pressure < 90 mmHg, on at least 2 repeated determination on separate days within 3 months prior to study enrollment. • Patients on anticoagulants therapy with unstable dose of warfarin and/or having an out-of-therapeutic range INR (>3) within the 4 weeks prior to randomization. • Evidence of clinically significant bleeding diathesis, non-healing wound or underlying coagulopathy (e.g. INR>1.5 without vitamin K antagonist therapy…).
- Related to Gemcitabine • Absolute neutrophil counts (ANC) < 1,500/mm3, platelets < 100,000/mm3, hemoglobin < 9.0 g/dL, • Total bilirubin > 1.5 x ULN, transaminases (SGOT/SGPT) > 2.5 x ULN (unless liver metastasis are present, 5 x ULN in that case), AP > 3 x ULN (unless liver metastasis are present, 5 x ULN in that case). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Survival (OS), defined as the time interval from the date of randomization to the date of death due to any cause. |
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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 | Yes |
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
determine immunogenicity of aflibercept (AVE0005) |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
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) | 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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Patients are treated with gemcitabine |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 64 |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |