E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cáncer colorrectal metastásico, no resecable, con KRAS no mutado y sin tratamiento previo.
Previously Untreated, KRAS Wild-Type, Unresectable, Metastatic Colorectal 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 | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
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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 estimate the treatment effect on progression-free survival (PFS) of panitumumab relative to bevacizumab in combination with mFOLFOX6 chemotherapy as first-line therapy for mCRC in subjects with tumors expressing wildtype KRAS. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate overall survival (OS), objective response (OR), duration of response (DOR), time to progression (TTP), time to response, resectability, safety and tolerability of panitumumab relative to bevacizumab in combination with mFOLFOX6 chemotherapy as first-line therapy for mCRC in subjects with tumors expressing wild-type KRAS. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
4.1.1 Disease related Histologically or cytologically-confirmed adenocarcinoma of the colon or rectum in subjects with unresectable metastatic disease At least 1 uni-dimensionally measurable lesion of at least 20mm per modified RECIST guidelines (see Appendix E) using conventional techniques (CT scan or MRI) or spiral CT scan. Lesion must not be chosen from a previously irradiated field, unless there has been documented disease progression in that field after irradiation and prior to randomization. All sites of disease must be evaluated ? 28 days prior to randomization Wild-type KRAS tumor status confirmed by central laboratory assessment of paraffin-embedded tumor tissue from the primary tumor or metastasis Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Appendix D) 4.1.2 Demographic Man or woman 18 years of age or older at the time the informed consent is obtained 4.1.3 Laboratory To be performed ? 7 days prior to randomization, unless otherwise specified: Hematologic function within the following limits: ? Absolute neutrophil count (ANC) ? 1.5 x 109/L ? Platelet count ? 100 x 109/L (without platelet transfusion ? 14 days prior to randomization) ? Hemoglobin (Hgb) ? 9.0 g/dL Renal function within the following limits: ? Creatinine clearance (GFR) ? 50 mL/min calculated by the Cockcroft- Gault method as follows: o Male creatinine clearance = (140 ? age in years) x (weight in Kg) / (serum creatinine in mg/dL x 72) o Female creatinine clearance = (140 ? age) x (weight in Kg) x 0.85 / (serum creatinine in mg/dL x 72) ? Urinary protein ? 30 mg by urinalysis or ? 1+ by dipstick or urine protein creatinine (UPC) ratio ? 0.5 by urinalysis (unless excretion of < 1000 mg of protein per day as determined by 24-hour urine collection). Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm. UPC ratio is calculated using one of the following formula: [urine protein]/[urine creatinine] - if both urine protein and creatinine are reported in mg/dL. [(urine protein) x0.088]/[urine creatinine] - if urine creatinine is reported in mmol/L. Hepatic function within the following limits: ? Total bilirubin ? 1.5 x ULN ? Alkaline phosphatase ? 2.5 x ULN (if liver metastases, ? 5 x ULN) ? Aspartate aminotransferase (AST) ? 2.5 x ULN (if liver metastases, ? 5 x ULN) ? Alanine aminotransferase (ALT) ? 2.5 x ULN (if liver metastases, ? 5 x ULN) Metabolic function within the following limits: ? Magnesium ? lower limit of normal Coagulation function within the following limits: ? Partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) ? 1.0 x ULN and international normalized ratio (INR) < 1.5 Negative pregnancy test ? 3 days prior to randomization (for woman of childbearing potential only) |
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E.4 | Principal exclusion criteria |
4.2.1 Disease Related History of prior or concurrent central nervous system (CNS) metastases History of other malignancy, except: ? Malignancy treated with curative intent and with no known active disease present for ? 3 years prior to randomization and felt to be at low risk for recurrence by the treating physician ? Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease ? Adequately treated cervical carcinoma in situ without evidence of disease ? Prostatic intraepithelial neoplasia without evidence of prostate cancer 4.2.2 Cancer Therapy Prior chemotherapy or other systemic anticancer therapy for the treatment of metastatic colorectal carcinoma including but not limited to bevacizumab and anti-EGFr therapy (eg cetuximab, panitumumab, erlotinib, gefitinib, lapatinib) Prior adjuvant chemotherapy (including oxaliplatin therapy) for the treatment of colorectal cancer ? 52 weeks prior to randomization with the following exceptions: ? Subjects may have received prior fluoropyrimidine therapy if administered solely for the purpose of radiosensitization Radiotherapy ? 14 days prior to randomization. Subjects must have recovered from all radiotherapy-related toxicities. Unresolved toxicities from prior anti-cancer therapy that, in the opinion of the investigator, excludes subject from participation 4.2.3 Other Medications Any anticoagulation therapy within 7 days prior to randomization except the use of low-dose warfarin [< 2 mg daily] or low molecular weight heparin or heparin flushes for prophylaxis against central venous catheter thrombosis which is allowed Chronic daily treatment with aspirin (> 325 mg/day) or non-steroidal anti-inflammatory agents known to inhibit platelet function. Treatment with dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and/or cilostazol (Pletal) is also not allowed Infection requiring a course of systemic anti-infectives that was completed ? 14 days before randomization (exception can be made at the judgment of the investigator for oral treatment of an uncomplicated urinary tract infection [UTI]) 4.2.4 General Significant cardiovascular risk: ? Myocardial infarction, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, percutaneous transluminal coronary angioplasty/stent, ongoing arrhythmias requiring medication or unstable angina ? 24 weeks prior to randomization ? Uncontrolled blood pressure defined as > 150 mm Hg systole or > 90 mm Hg diastole. Anti-hypertensive medications are allowed if hypertension is stably controlled at the time of randomization. ? Previous history of any CNS cerebrovascular ischemia or hemorrhage ? Pulmonary embolism, deep vein thrombosis, or other significant venous event ?8 weeks before randomization Significant bleeding risk: ? Major surgical procedure, open biopsy, or significant traumatic injury ? 28 days before randomization or not yet recovered from prior major surgery ? Anticipation of need for major elective surgical procedures during the course of the study ? Minor surgery ?14 days prior to randomization or not yet recovered from prior minor surgery ? Core biopsy or other minor procedure ? 7 days prior to randomization (with the exception of insertion of a vascular access device) ? Pre-existing bleeding diathesis and coagulopathy ? Serious or non-healing wounds, skin ulcers, or unhealed bone fractures ? Gastroduodenal ulcer(s) determined by endoscopy to be active or uncontrolled gastrointestinal ulcer ? 28 days before randomization History of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline CT scan Active inflammatory bowel disease or other bowel disease causing chronic diarrhea (defined as ? CTC grade 2, [CTCAE version 3.0]) Peripheral sensory neuropathy (? CTC grade 2 [CTCAE version 3.0] Any co-morbid disease or condition that could increase the risk of toxicity (such as clinically significant ascites) Subjects known to be human immunodeficiency virus (HIV) positive or known to have chronic or active hepatitis B or C infection Subject is currently enrolled in, or ? 30 days has passed since subject completed another investigational device or drug study(s), or subject is receiving other investigational agent(s) Woman of child-bearing potential is evidently pregnant (eg, positive HCG test) or is breast feeding Men and women of childbearing potential who do not consent to use adequate contraception during the course of the study and 24 weeks after the last dose of protocol specified therapy. Adequate contraceptive precautions includes double barrier contraceptive methods (eg, diaphragm and condom) or abstinence For further exclusion criteria see protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS): time from randomization date to date of radiologic disease progression per modified RECIST criteria or death. For subjects not meeting criteria for progression and alive at the analysis data cutoff date, PFS will be censored at their last evaluable disease assessment date. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | No |
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 | 14 |
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 | No |
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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approximately 36 months from the last subject randomized. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |