| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with metastatic androgen-independent prostate cancer |
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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 |
| To demonstrate the efficacy of aflibercept (Arm A) versus placebo (Arm B) in term of overall survival (OS) in patients treated with docetaxel / prednisone or prednisolone for metastatic androgen-independent prostate cancer (MAIPC). |
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| E.2.2 | Secondary objectives of the trial |
- To assess efficacy of aflibercept compared to placebo for:
. PSA response
. Pain response in patients with stable pain at baseline.
. Time to occurrence of any skeletal related events (SRE).
. Progression-free survival.
. Tumor response in patients with measurable disease (RECIST).
. PSA-Progression free survival (PSA-PFS).
. Pain-Progression free survival (Pain-PFS).
. Health-Related Quality of Life (HRQL).
- To evaluate safety in both treatment arms.
- To determine the pharmacokinetics of IV aflibercept, in this population.
- To determine the immunogenicity of IV aflibercept.
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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 EFC6546 study protocol version 2.0, dated 2007-03-23.
The objectives are the following:
- to assess the pharmacokinetics of aflibercept. Free and bound aflibercept will be measured. The ratio free/bound aflibercept will also estimated as an indicator of the presence of circulating endogenous VEGF.
- to determine immunogenicity of aflibercept.
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| E.3 | Principal inclusion criteria |
1. Histologically- or cytologically-confirmed prostate adenocarcinoma.
2. Metastatic disease.
3. Progressive disease while receiving hormonal therapy or after surgical castration documented by at least one of the following:
- Increase in measurable disease, and/or
- Appearance of new lesions, including those on bone scan (≥2 new lesions) consistent with progressive prostate cancer, and/or
- Rising PSA defined as 2 sequential increases above a previous lowest reference value. Each value must be obtained at least 1 week apart. A PSA value of at least 2 ng/ml is required at study entry.
4. Effective castration (serum testosterone levels ≤ 50 ng/dL) by orchiectomy and/or LHRH agonists with or without anti-androgens. If the patient has been treated with LHRH agonists (i.e., without orchiectomy), then this therapy should be continued. If patients were either started on complete androgen blockade, or had a PSA response (defined by any reduction in PSA sustained for at least 3 months) after adding an antiandrogen, prior anti-androgen therapy should be stopped before randomization: at least 6 weeks for bicalutamide and nilutamide, and at least 4 weeks for flutamide, megestrol acetate and any other hormonal therapy. |
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| E.4 | Principal exclusion criteria |
- Related to methodology:
1. Prior cytotoxic chemotherapy for prostate cancer, except estramustine and except adjuvant/neoadjuvant treatment completed > 3 years ago.
2. Less than 28 days elapsed from prior treatment with estramustine, radiotherapy, surgery to the time of randomization. Patients may be on biphosphonates prior to study entry.
3. Prior isotope therapy (e.g., strontium, samarium, etc.), or whole pelvic irradiation, or prior radiotherapy to > 30% of bone marrow. Prior radiotherapy < 30% of bone marrow that is less than 4 weeks since the completion of radiation therapy. Or if the patient has not recovered from side effects of radiotherapy.
4. Adverse event (excluding alopecia and those listed in the specific exclusion criteria) from any prior anticancer therapy of grade >1(National Cancer Institute Common Terminology Criteria [NCI CTCAE] v3.0) at the time of randomization.
5. Prior treatment with VEGF inhibitors or VEGF receptor inhibitors.
6. Less than 18 years.
7. Eastern Cooperative Oncology Group (ECOG) performance status > 2.
8. History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.
9. Prior malignancy. Adequately treated basal cell or squamous cell skin cancer are allowed, as well as any other cancer for which chemotherapy has been completed >5 years ago and from which the patient has been disease-free for > 5 years.
10. Participation in another clinical trial and any concurrent treatment with any investigational drug within 30 days prior to randomization.
11. Any of the following within 6 months prior to randomization: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure, cerebrovascular accident or transient ischemic attack.
12. Any of the following within 3 months prior to randomization: treatment-resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event.
13. Occurrence of deep vein thrombosis within 4 weeks prior to randomization.
14. Acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV disease requiring antiretroviral therapy.
15. Any severe acute or chronic medical condition which could impair the ability of the patient to participate to the study or interfere with interpretation of study results.
16. Absence of signed and dated Institutional Review Board (IRB)-approved patient informed consent form prior to enrollment into the study.
17. Patient with reproductive potential who do not agree to use accepted and effective method of contraception during the study treatment period and for at least 6 months after the completion of the study treatment. The definition of “effective method of contraception” will be based on the investigator’s judgment.
For patients enrolled in the United Kingdom, their partner (unless surgically sterile, post menopausal or for another reason have no chance of becoming pregnant) should use an effective mean of contraception described hereafter: oral contraceptives or intra uterine device.
- Related to aflibercept:
18. Urine protein-creatinine ratio (UPCR) > 1 on morning spot urinalysis or proteinuria > 500 mg/24 hours.
19. Serum Creatinine > 1.5 x ULN. If creatinine 1.0 - 1.5 x ULN, creatinine clearance will be calculated either according to Cockcroft-Gault formula for patients younger than 65 years or, according to a MDRD formula for patients ≥65 years . Creatinine clearance < 60 mL/min will exclude the patient
20. Uncontrolled hypertension, defined as blood pressure >150/100 mm Hg (NCI CTCAE v.3.0 grade ≥ 2), or systolic blood pressure >180 mm Hg if diastolic blood pressure <90 mm Hg, on at least 2 repeated determinations on separate days, within 3 months prior to randomization.
21. Patients on anticoagulants with unstable dose of warfarin and/or having an out-of-therapeutic range INR (>3), within 4 weeks prior to randomization.
22. Evidence of clinically significant bleeding diathesis or underlying coagulopathy (e.g. INR>1.5 without vitamin K antagonist therapy), non-healing wound.
Related to docetaxel regimen:
23. History of hypersensitivity to docetaxel, or polysorbate 80.
24. Inadequate organ and bone marrow function as evidenced by:
·Hemoglobin <10.0 g/dL
·Absolute neutrophil count < 1.5 x 109/L
·Platelet count < 100 x 109/L
·AST/SGOT and/or ALT/SGPT > 1.5 x ULN
·Total bilirubin > 1.0 x ULN
25. Contraindications to the use of corticosteroid treatment.
26. Symptomatic peripheral neuropathy grade > 2 (National Cancer Institute Common Terminology Criteria [NCI CTCAE] v3.0).
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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. |
|
| 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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 |
| Patient treated with Taxotere and prednisone/prednisolone |
|
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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