E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic rhabdomyosarcoma, metastatic non rhabdomyosarcoma soft-tissue sarcoma, metastatic Ewing's sarcoma/soft-tissue primitive neuroectodermal tumors (PNET) in childhood and adolescent patients. |
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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 | 10015562 |
E.1.2 | Term | Ewing's sarcoma metastatic |
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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 | 10015761 |
E.1.2 | Term | Extra-osseous Ewing's sarcoma metastatic |
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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 | 10015568 |
E.1.2 | Term | Ewing's tumor metastatic |
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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 | 10058253 |
E.1.2 | Term | Ewing's tumour metastatic |
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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 | 10035639 |
E.1.2 | Term | PNET of bone metastatic |
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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 | 10042864 |
E.1.2 | Term | Synovial sarcoma metastatic |
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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 | 10016635 |
E.1.2 | Term | Fibrosarcoma metastatic |
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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 | 10029274 |
E.1.2 | Term | Neurofibrosarcoma metastatic |
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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 | 10024629 |
E.1.2 | Term | Liposarcoma metastatic |
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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 | 10060651 |
E.1.2 | Term | Malignant hemangiopericytoma metastatic |
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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 | 10039026 |
E.1.2 | Term | Rhabdomyosarcoma previously untreated |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the feasibility and efficacy of the combination of bevacizumab with standard chemotherapy as compared with standard chemotherapy alone in childhood and adolescent patients with metastatic rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), or Ewing’s sarcoma (ES)/soft-tissue PNET, as assessed by: • Incidence rate of patients with dose discontinuation or dose modification/delay. • Event-free survival (EFS) (2nd stage only)
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E.2.2 | Secondary objectives of the trial |
To determine the safety, tolerability and efficacy of the combination of bevacizumab with standard chemotherapy as compared with standard chemotherapy alone in patients with metastatic rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS) or Ewing’s sarcoma(ES)/soft-tissue PNET, as assessed by: • Adverse event profile. • Response rate (according to RECIST). • Overall survival. • Duration of response.
To characterize: • The pharmacokinetic (PK) characteristics of bevacizumab when combined with standard chemotherapy in childhood and adolescent patients. • Serum biomarker and tumor marker changes.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 greater than or equal to 2 years and less than or equal to 17 years. 3. Newly diagnosed, histologically documented, patients with one of the following diseases: • Metastatic rhabdomyosarcoma (RMS) - Risk factors (at least two of the RMS specific risk factors are required for the 1st stage of the study): - Patients greater than or equal to 10 years of age. - 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. • Metastatic non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS). • Metastatic Ewing’s sarcoma (ES)/soft-tissue primitive neuroectodermal tumor (PNET) - Risk factors (at least one of these ES/PNET specific risk factors is required for the 1st stage of the study): - Bone metastases. - Bone marrow metastases. 4. Age-adapted performance status and life expectancy adequate for chemotherapy according to the protocol. 5. Adequate bone marrow function: • Absolute neutrophil count (ANC) greater than or equal to 1.0 x 1'000'000'000/L and WBC greater than or equal to 2.0 x 1'000'000'000/L. • Platelet count greater than or equal to 100 x 1'000'000'000/L (in case of bone marrow involvement greater than or equal to 75 x1'000'000'000/L). • Hb > 7.5 g/dL (75g/L - including after transfusion). 6. Adequate blood clotting: PT-INR less than or equal to 1.5 and aPTT less than or equal to 1.5 x upper limit of normal (ULN) within 7 days prior to treatment start. 7. Adequate liver function: • Serum (total) bilirubin less than or equal to 1.5 x ULN. • AST and ALT less than or equal to 2.5 x ULN in patients without liver metastases, less than or equal to 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 greater than or equal to 2+ of proteinuria on dipstick urinalysis should undergo a 24-hour urine collection; children and adolescents less than or equal to 12 years must have less than or equal to 500 mg of protein/24 hours and patients > 12 years must have less than or equal to 1 g of protein/24 hours. • No clinical evidence of nephrotic syndrome. 9. Adequate cardiac function (Shortening Fraction (SF) greater than or equal to 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).
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E.4 | Principal 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 exclude evidence of tumor that is fully contiguous with, surrounding, or 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 attack (TIAs), unstable angina, or severe cardiac arrhythmia; clinical evidence of arterial hypertension, specified as systolic and diastolic BP greater than or equal to 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 greater than or equal to 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 greater than or equal to 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 greater than or equal to 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. 13. Patients not able to comply with the protocol. 14. Patients not able to comply with the long-term follow-up at the investigational site.
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E.5 End points |
E.5.1 | Primary end point(s) |
Stage 1 The primary endpoint of the first stage of the study is the incidence rate of patients with dose discontinuation or dose modification/delay of any component of study treatment. Stage 2 The primary endpoint of the second stage of the study is an exploratory analysis of the event-free survival defined as time between randomization and insufficient therapeutic response or death due to any cause. Patients without an event will be censored at the last follow up for progression. Patients with no post baseline follow up for progression will be censored at the day of randomization.
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Phase I/II two stage adaptive design |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
Adaptive: after formal safety analysis of I stage, recruitment into II stage to max 150 pts |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
bevacizumab+Standard chemotherapy vs Standard chemotherapy |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 final (end of stage II) analysis will be performed approximately 19 months after the last patient has been 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 | 6 |
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 | 6 |