E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Prostate 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 | 10062904 |
E.1.2 | Term | Hormone-refractory prostate cancer |
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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 | 10036909 |
E.1.2 | Term | Prostate 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 |
The primary objective of this phase II study in castration-resistant metastatic prostate cancer patients who have had orciectomy or are receiving an LHRH analogue is to demonstrate a prolonged progression-fee survival (PFS) in the group treated with sorafenib and bicalutamide in comparison to those treated with placebo and bicalutamide. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to compare treatment groups with respect to tumor response, disease control rate, time to PSA progression, PSA response rate and time to PSA response, time to next anti-tumor therapy, overall survival, patient reported outcomes (PRO), and further evaluation of the safety and toxicity profile of the combination treatment. Secondary objectives include also an evaluation of population pharmacokinetics and biomarkers, which may relate to sorafenib's pharmacological mechanism of action and to its antitumor activity. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Age ≥ 18 years. •Histological or cytological documentation of adenocarcinoma of the prostate •Asymptomatic or mildly symptomatic prostate cancer patients (non-opiate-requiring pain) •Progression of disease despite castrate levels of testosterone and adequate therapy with LHRH analogues or after orchiectomy, demonstrated by rising PSA in plasma on at least 2 consecutive measurements taken at least 7 days apart. The last measurement must be ≥2 ng/mL •Evaluable bone, lymph node (≥2 cm) or soft tissue metastases •Ongoing treatment with LHRH analogues unless patient had an orchiectomy •Serum plasma testosterone < 50 ng/dl at screening •ECOG Performance Status of 0 or 1 •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 14 days prior to the start of the study treatment [All laboratory assessments will be performed by a central laboratory (see separate laboratory manual for full details)]: •Hemoglobin ≥ 9.0 g/dl •Absolute neutrophil count (ANC) ≥1,500/mm3 •Platelet count ≥ 100,000/µl •Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) •ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer) •PT-INR/PT <1.5 x ULN. Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists. For patients on warfarin, close monitoring of at least weekly evaluations will be performed until INR is stable based on a measurement before the study treatment was started, as defined by the local standard of care. - Patients being anticoagulated for deep vein thrombosis and/or pulmonary embolus occurring within 12 months of the start of treatment are excluded from this trial. •Serum creatinine ≤ 1.5 x ULN •Men enrolled in this trial must use adequate barrier birth control measures while in the study and for 3 months after the completion of the study. •Signed informed consent must be obtained prior to any study specific procedures.
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E.4 | Principal exclusion criteria |
Excluded medical conditions:
•History of cardiac disease; •congestive heart failure >New York Heart Association (NYHA) class 2 •active coronary artery disease (myocardial infarction more than 6 months prior to start of study treatment is allowed) •cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) •uncontrolled hypertension (defined as blood pressure ≥ 160 mmHg systolic and/or ≥ 90 mmHg diastolic on medication) •History of HIV infection or chronic hepatitis B or C •Active clinically serious infections (> grade 2 National Cancer Institute - common terminology criteria for adverse event [NCI-CTCAE] version 3.0) •Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of start of study treatment and is clinically stable with respect to the tumor at the time of start of study treatment. Also, the patient must not be undergoing acute steroid therapy or taper therapy (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies). •Patients with seizure disorder requiring medication (such as steroids or anti-epileptics) •History of organ allograft •Patients with evidence or history of bleeding diathesis •Deep vein thrombosis and/or pulmonary embolus within 12 months of the start of study treatment •Delayed healing of wounds, ulcers or bone fractures •Patients with pre-existing thyroid abnormality whose thyroid function cannot be maintained within the normal range with medication •Patients undergoing renal dialysis •Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer that was curatively treated more than 3 years before the start of study treatment •Any condition that is unstable or could jeopardize the safety of the patient and his compliance in the study •Patients unable to swallow oral medications. This applies to patients with severe obstruction of upper gastrointestinal tract that requires gavage. •Known hypersensitivity to either NEXAVAR®, to the constituents of the placebo tablets used in this study or to the bicalutamide-containing drug •Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
Excluded therapies and medications, previous and concomitant:
•Antiandrogen therapy within the last 6 weeks prior to the start of study treatment •Prior sorafenib therapy •Any prior cytotoxic chemotherapy for advanced disease (patients that had received adjuvant or neoadjuvant chemotherapy are allowed to participate in the trial), or therapy with receptor tyrosine kinase inhibitors •Investigational drug therapy not included in this protocol during the study, or which is taken within 4 weeks or 5 half-lives before the start of the study treatment or inadequate recovery from any toxic effects of such therapies •Major surgery during the last 4 weeks prior to the start of study treatment •Autologous bone marrow transplant or stem cell rescue during the last 4 months prior to the start of study treatment •Use of biologic response modifiers, such as granylocyte colony-stimulating factor (G-CSF), within 3 weeks after the start of study treatment. (G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator. However, they may not be substituted for a required dose reduction.) Patients taking chronic erythropoietin are permitted in the study provided no dose adjustment is undertaken within 2 months prior to the start of study treatment or during the study. •There is no clinical information on the effect of CYP3A4 inducers on the pharmacokinetics of sorafenib, but substances that are inducers of CYP3A4 activity (e.g. rifampicin, St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) are expected to increase the metabolism of sorafenib and thus decrease sorafenib plasma concentrations. Also, there are no clinical data evaluating the effect of chronically co-administered CYP3A4 inducers on the efficacy of sorafenib. Since there is a possibility of decreased sorafenib efficacy due to decreased sorafenib concentrations upon chronic co-administration of CYP3A4 inducers, chronic co-administration of CYP3A4 inducers, should be avoided as much as possible.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable in this study is PFS. It will be measured from the date of randomization until the date of radiological or clinical relapse/progression (whichever is earlier), or until death (if death occurs before progression). Patients without tumor progression or death at the time of analysis will be censored at their last date of evaluation. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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) | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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 | 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 | 34 |
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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The end of study for regulatory purposes is defined as the date the last patient completes the end of treatment 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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |