StudienID: 458, Studienkennung: , UTRN:
A phase III trial program exploring the integration of bevacizumab, everolimus (RAD001), and<br />lapatinib into current neoadjuvant chemotherapy regimes for primary breast cancer.
To compare the pCR rates of neoadjuvant treatment of epirubicin / cyclophosphamidefollowed by docetaxel (EC-T) with or without bevacizumab (EC-T vs. ECB-TB) in patients withHer-2 negative primary breast cancer (Setting I).
To compare the pCR rates of neoadjuvant treatment with weekly paclitaxel with or withoutEverolimus (RAD001) (Pw vs. PwR) in patients with Her-2 negative primary breast cancershowing no sonographic response to 4 cycles of EC +/-B (Setting II).
To compare the pCR rates of neoadjuvant treatment with epirubicin / cyclophosphamidefollowed by docetaxel with either trastuzumab or lapatinib (ECH-TH vs. ECL-TL) in patientswith Her-2 positive primary breast cancer (Setting III).
Beginn der Einbringung
Ende der Einbringung
Aktuelle Pattientenzahl
Laufzeit in Monaten
Ein- Ausschlussalter
• Cyclophosphamid• Docetaxel• Epirubicin• Paclitaxel• Trastuzumab• - Everolimus- Lapatinib Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy.
1. Written informed consent for all study procedures including an additional core biopsy afterthe first four cycles of EC +/-B must be obtained and documented according to local regulatoryrequirements prior to beginning specific protocol procedures.
2. Complete baseline documentation must be sent to GBG Forschungs GmbH.
3. Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by corebiopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not allowed. In case ofbilateral cancer, the investigator has to decide prospectively which side will be evaluated forthe primary endpoint.
4. Tumor lesion in the breast with a palpable size of &#61619; 2 cm or a sonographical size of&#61619; 1 cm in maximum diameter. The lesion has to be measurable in two dimensions,preferably by sonography. In case of inflammatory disease, the extent of inflammation can beused as measurable lesion.
5. Patients should be in a stage of disease in which adjuvant chemotherapy would beconsidered. Therefore the following tumor stages are eligible * : - locally advanced tumors with cT3 or cT4 or - Estrogen (ER) and progesterone (PgR) receptor negative tumors or - ER or PgR positive tumors which are cN+ (for cT2) or pNSLN+ (for cT1).
* During the Run-In Phase only patients with cT4 or cT3 cN+ disease are eligible.
In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
6. Known HER-2/neu status detected on core biopsy. HER-2/neu positive is defined asHercepTest IHC 3+ or central FISH+.
7. Age &#61619; 18 years.
8. Karnofsky Performance status index &#61619; 80%.
9. Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF orshortening fraction) within 3 months prior to randomization. Results must be above the normallimit of the institution and above 55%.
10. Laboratory requirements:a) Hematology- Absolute neutrophil count (ANC) &#61619; 2.0 x 109 / L and- Platelets &#61619; 100 x 109 / L and- Hemoglobin &#61619; 10 g/dL (&#61619; 6.2 mmol/L)b) Hepatic function- Total bilirubin < 1x UNL and- ASAT (SGOT) and ALAT (SGPT) &#61603; 2.5x UNL and- Alkaline phosphatase &#61603; 5x UNL.
Patients with ASAT and / or ALAT > 1.5x UNL and associated with alkaline phosphatase >2.5x UNL are not eligible for the study.
c) Renal functionCreatinine &#61603; 175 µmol/L (2 mg/dL) < 1.5x UNL(or the calculated creatinine clearance should be &#61619; 60 mL/min).
d) ProteinuriaUrine dipstick for proteinuria < 2+. Patients discovered to have &#8805; 2+ proteinuria ondipstick urinalysis should undergo a 24-hour urine collection and must demonstrate &#8804; 1g of protein in 24 hours.
11. Paraffin tumor tissue block and two serum samples centrally made available (except whenthe patient does not agree to central biomaterial collection).
12. Negative pregnancy test (urine or serum) within 14 days prior to randomization for allwomen of childbearing potential.
13. Complete staging work-up within 3 months prior to randomization. All patients must havebilateral mammography, breast ultrasound (&#61603; 21 days), breast MRI (optional), chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan done. In case ofpositive bone scan, bone X-ray is mandatory. Other tests may be performed as clinicallyindicated.
14. Patients must be available and compliant for treatment and follow-up. Patients registeredon this trial must be treated and followed up at the participating or at a cooperating center.
1. Patients with low or moderate risk, who are only doubtful candidates for adjuvantchemotherapy and do not fulfil the inclusion criterion No. 5.
2. Evidence of distant metastasis.
3. Prior chemotherapy for any malignancy.
4. Prior radiation therapy for breast cancer.
5. Pregnant or lactating patients. Patients of childbearing potential must implement adequatenon-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices,sterilization) during study treatment.
6. Inadequate general condition (not fit for anthracycline-taxane based chemotherapy).
7. Previous malignant disease without being disease-free for less than 5 years (except CIS ofthe cervix and non-melanomatous skin cancer).
8. Known or suspected congestive heart failure (>NYHA I) and / or coronary heart disease,angina pectoris requiring antianginal medication, previous history of myocardial infarction,evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterialhypertension (i.e. BP >160 / 90 mm Hg under treatment with two antihypertensive drugs),rhythm abnormalities requiring permanent treatment, clinically significant valvular heartdisease.
9. Previous thromboembolic event.
10. Known hemorrhagic diathesis or coagulopathy with increased bleeding risk.
11. History of significant neurological or psychiatric disorders including psychotic disorders,dementia or seizures that would prohibit the understanding and giving of informed consent.
12. Pre-existing motor or sensory neuropathy of a severity &#61619; grade 2 by NCI criteria.
13. Currently active infection.
14. Active peptic ulcer, incomplete wound healing or unhealed bone fracture.
15. Disease significantly affecting gastrointestinal function, e.g. malabsorption syndrome,resection of the stomach or small bowel, ulcerative colitis.
16. History of abdominal fistula or any grade 4 non-gastrointestinal fistula, gastrointestinalperforation or intra-abdominal abscess within 6 months of enrolment.
17. Severe pulmonary condition / illness.
18. Unstable diabetes mellitus; Insulin-dependent type II diabetes mellitus.
19. Major surgery within the last 28 days or anticipation of the need for major surgery duringstudy treatment with bevacizumab. No minor surgeries including insertion of an indwellingcatheter within 24 h prior to chemotherapy.
20. Definite contraindications for the use of corticosteroids.
21. Known hypersensitivity reaction to one of the investigational compounds or incorporatedsubstances; or known dihydropyrimidine dehydrogenase deficiency.
22. Concurrent treatment with:a) chronic corticosteroids unless initiated > 6 months prior to study entry and at low dose(&#61603; 10 mg methylprednisolone or equivalent).
b) sex hormones. Prior treatment must be stopped before study entry.
c) virostatic agents like sorivudine or analogs like brivudine, concurrent treatment withaminoglycosides.
d) anticoagulants: heparin, warfarin as well as acetylic acid (e.g. Aspirin®) at a dose of > 325mg/day or clopidogrel at a dose of > 75 mg/day.
e) other experimental drugs or any other anti-cancer therapy.
f) drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A, e.g.
Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Ritonavir, Telithromycin,Erythromycin, Verapamil, Diltiazem within the last 5 days or the expected need for thesetreatments during study participation.
23. Participation in another clinical trial with any investigational, not marketed drug within 30days prior to study entry.
24. Male patients.
Randomization will be stratified by:- Participating center- ER/PR-status (ER or PgR pos. vs. ER and PgR neg.)- Extend of disease (T4 or N3 vs T1-3 and N0-2) Hauptziel(e)
• Gesamtüberlebensrate• Krankheitsfreie Überlebensrate• Nebenwirkungen• Andere• 1. To assess the toxicity of and compliance to all six treatments.
2. To determine the response rates of the breast tumor and axillary nodes by physicalexamination and imaging tests (sonography, mammography, or MRI) after treatment in allarms.
3. To determine the rates of pCR breast, pCR invasive, pCR invasive and nodes.
4. To determine the breast conservation rate after each treatment.
5. To determine the (loco-regional and distant) disease-free and overall survival after eachtreatment. In Her-2 positive disease, the cerebral disease-free survival will be determinedseparately.
6. To assess treatment efficacies in subgroups defined according to tumor stage (T2-3 vs.
T4), receptor status (ER and / or PgR positive vs. ER and PgR negative) and response bybest appropriate imaging method to the first four cycles of treatment (complete vs. partial vs.
no change).
7. To examine and compare pre-specified molecular markers such as Ki-67, phospho-mTOR,YB-1, COX-2, HuR, phospho-p70 S6K, p65 NF kappa B, PTEN, PI3-K, Akt, and a marker forstem cell like breast cancers (SOX-10) on core biopsy before and after end of chemotherapy.
Die Studie wird in folgenden Ländern durchgeführt Bundesland
• Nordrhein-Westfalen • Rheinland-Pfalz Studienleiter
Schleussnerstraße 4263263 Neu-Isenburg,Deutschland Studienkoordinator
1. Sponsor
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