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.

Phase 1

Conditions: Metastatic rhabdomyosarcoma, metastatic non rhabdomyosarcoma soft-tissue sarcoma, metastatic Ewing's sarcoma/soft-tissue primitive neuroectodermal tumors (PNET) in childhood and adolescent patients.
MedDRA version: 9.1 Level: LLT Classification code 10015562 Term: Ewing's sarcoma metastatic
MedDRA version: 9.1 Level: LLT Classification code 10015761 Term: Extra-osseous Ewing's sarcoma metastatic
MedDRA version: 9.1 Level: LLT Classification code 10015568 Term: Ewing's tumor metastatic
MedDRA version: 9.1 Level: LLT Classification code 10058253 Term: Ewing's tumour metastatic
MedDRA version: 9.1 Level: LLT Classification code 10035639 Term: PNET of bone metastatic
MedDRA version: 9.1 Level: LLT Classification code 10042864 Term: Synovial sarcoma metastatic
MedDRA version: 9.1 Level: LLT Classification code 10016635 Term: Fibrosarcoma metastatic
MedDRA version: 9.1 Level: LLT Classification code 10029274 Term: Neurofibrosarcoma metastatic
MedDRA version: 9.1 Level: LLT Classification code 10024629 Term: Liposarcoma metastatic

Registration Number: EUCTR2007-005017-19-FR

Lead Sponsor: F. Hoffmann-La Roche Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: Not specified

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 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 clinical

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

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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