Open-label, multi-center, randomized, two stage adaptive design study of the combination of bevacizumab with standard chemotherapy in minor patients with metastatic rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma or Ewing?s sarcoma/soft-tissue primitive neuroectodermal tumors - BERNIE

Phase 1

Conditions: childhood and adolescent patients, with metastatic rhabdomyosarcoma (RMS), nonrhabdomyosarcoma soft-tissue sarcoma (NRSTS), or Ewing?s sarcoma(ES)/soft-tissue primitive neuroectodermal tumor (PNET)
MedDRA version: 9.1Level: LLTClassification code 10039026
MedDRA version: 9.1Level: LLTClassification code 10016635
MedDRA version: 9.1Level: LLTClassification code 10015562
MedDRA version: 9.1Level: LLTClassification code 10029274

Registration Number: EUCTR2007-005017-19-IT

Lead Sponsor: ROCHE

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 154

Inclusion Criteria

1. Written informed consent of patient/parent/legally acceptable representative (latest approved version by the Independent Ethics Committee [IEC]/Institutional Review Board [IRB]), obtained prior to any study-specific procedures. 2. Age prior to treatment start ≥ 2 years and ≤ 17 years. 3. Newly diagnosed, histologically documented, patients with one of the following diseases: Metastatic Rhabdomyosarcoma (RMS). Risk factors:Bone or bone marrow involvement (considered as 1 site). More than two different organs with metastatic disease. Unfavorable primary sites: extremities (including buttocks and shoulder) and trunk. At least two of the RMS specific risk factors are required for the 1st stage of the study. Metastatic non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS). Metastatic Ewing?s sarcoma (ES)/soft-tissue primitive neuroectodermal tumor (PNET) Risk factors: Bone metastases. Bone marrow metastases. At least one of these ES/PNET specific risk factors is required for the 1st stage of the study. 4. Age-adapted performance status and life expectancy adequate for chemotherapy according to the protocol. 5. Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1.0 x 109/L and WBC ≥ 2.0 x 109/L. Platelet count ≥ 100 x 109/L (in case of bone marrow involvement ≥ 75 x 109/L). Hb > 7.5 g/dL (75 g/L - including after transfusion). 6. Adequate blood clotting: PT-INR ≤ 1.5 and aPTT ≤ 1.5 x upper limit of normal (ULN) within 7 days prior to treatment start. 7. Adequate liver function: Serum (total) bilirubin ≤ 1.5 x ULN. AST and ALT ≤ 2.5 x ULN in patients without liver metastases, ≤ 5 x ULN in patients with liver metastases. 8. Adequate renal function: Serum creatinine < 1.5 x ULN for age; If serum creatinine is > 1.5 x ULN for age, the creatinine clearance (or radioisotope GFR) must be > 70 mL/min/1.73 m2. Urine dipstick < 2+ for proteinuria. Patients who have ≥ 2+ of proteinuria on dipstick urinalysis should undergo a 24 hour urine collection; children and adolescents ≤ 12 years must have ≤ 500 mg of protein/24 hours and patients > 12 years must have ≤ 1 g of protein/24 hours. No clinical evidence of nephrotic syndrome. 9. Adequate cardiac function (Shortening Fraction (SF) ≥ 28%) at screening, as determined by echocardiography; no evident and clinically significant symptoms of CHF (must be < class II of classification for heart failure (New York Heart Association (NYHA) or Ross scale).
Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Previous malignant tumors. 2. Prior systemic anti-tumor treatment. 3. Evidence of symptomatic spinal cord compression, CNS or brain metastases; patients must undergo a MRI or CT scan of the brain and/or spine in case of suspected brain metastatic disease. 4. Tumor invading major blood vessels (CT scan based evidence); the investigator or radiologist must excludeor extending into the lumen of a major blood vessel (e.g. pulmonary artery or superior vena cava). 5. Major surgical procedures or anticipation of the need for major surgery (other than the standard per protocol surgery) between screening and the first safety follow-up visit is considered incompatible with the use of bevacizumab; minor surgical procedures, including biopsy similar to and including central venous access device placement, within less than 7 days prior to randomization, or anticipated treatment start before the wound has healed. 6. Documentation of clinically evident non-healing wound (as determined by the investigator), peptic ulcer or bone fracture. 7. Current or recent (within 30 days prior to study start) treatment with another investigational drug or participation in another investigational study. 8. Increased risk of gastrointestinal, renal, bone marrow, or congenital bleeding disorders. 9. History or evidence of severe uncontrolled intercurrent illness at study entry, e.g. Uncontrolled seizures. Any bleeding or clotting diathesis, e.g. venous or arterial thromboembolic events (VTE, ATE), pulmonary embolism (PE). Any clinically significant (i.e. active) cardiovascular disease, e.g. cerebrovascular accidents (CVAs)/stroke, myocardial infarction (MI), transient ischemic attacks (TIAs), unstable angina, or severe cardiac arrhythmia; clinical evidence of arterial hypertension, specified as systolic and diastolic BP ≥ 95th percentile for age, gender and height (see Appendix 7). Any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or places the patient at unacceptable risk from treatment complications. General or peripheral neuropathy ≥ grade 2 which is not induced by the underlying malignant disease. Uncontrolled infection. 10. Known hypersensitivity to: Any component of study drugs or ingredients. Chinese hamster ovary products or other recombinant human or humanized antibodies. 11. Ongoing (for ≥ 10 days prior to the 1st dose of study treatment) antithrombotic treatment, i.e. with aspirin or other platelet inhibitors, anticoagulants including thrombolytic agents, unfractionated or low-molecular-weight heparins, or coumarin-derived anticoagulants; well-controlled anticoagulation is permitted as primary prophylaxis against thromboembolic events (TEs) and/or for maintenance of patency of a central access venous device (CVAD). 12. Pregnancy and/or lactation: a negative serum pregnancy test in all female patients aged ≥ 12 years (to be confirmed by urine test if serum test was performed more than 7 days prior to treatment start) must be obtained before treatment start;fertile patients with potential to bear or father a child must use an effective method of contraception. et al.....

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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