Bevacizumab in Treating Young Patients With Refractory Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This phase I trial is studying the side effects and best dose of bevacizumab in treating young patients with refractory solid tumors. Monoclonal antibodies, such as bevacizumab, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To estimate the maximum tolerable dose (MTD) of bevacizumab by dose escalation to a maximum of 15mg/kg, even if MTD is not reached, administered as an intravenous infusion, every 2 weeks to children with refractory solid tumors. II. To determine the dose-limiting toxicities (DLT) and other toxicities of bevacizumab given on this schedule. III. To characterize the pharmacokinetic behavior of bevacizumab in children with refractory cancer. SECONDARY OBJECTIVES: I. To preliminarily define the antitumor activity of bevacizumab within the confines of a phase I study. II. To assess the biologic activity of bevacizumab by measuring levels of total serum VEGF, and parallel angiogenic markers V-CAM-1, ICAM-1, bFGF, and TSP-1 at baseline and at time points post therapy. III. To explore the biologic effect of bevacizumab on circulating endothelial cells (CECs) and circulating endothelial cell precursors (CECPs). IV. To determine in archival tumor tissue the expression of VEGF by immunohistochemistry and/or real time PCR. OUTLINE: This is a dose-escalation, multicenter study. Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bevacizumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Official Title
-----------------
A Phase I Study of Bevacizumab in Refractory Solid Tumors

Conditions
-----------------
Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
-----------------
* Biological: bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed solid tumor at original diagnosis Measurable or evaluable* disease No known curative therapy exists No lymphomas or primary CNS tumors No history or clinical evidence of CNS metastasis by head CT scan Performance status - Karnofsky 50-100% (patients > 10 years of age) Performance status - Lansky 50-100% (patients ≤ 10 years of age) At least 8 weeks Patients without bone marrow involvement: Absolute neutrophil count ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 (transfusion independent) Hemoglobin ≥ 8.0 g/dL (RBC transfusion allowed) Patients with bone marrow metastases: Platelet count ≥ 75,000/mm^3 (transfusion independent) Granulocytopenia, anemia, and/or mild thrombocytopenia allowed No known bleeding diathesis or coagulopathy No known thrombophilic condition (e.g., protein S, protein C, or antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation, homocystinemia, or antiphospholipid antibody syndrome) PT or PTT ≤ 1.2 times upper limit of normal (ULN) ALT ≤ 5 times ULN Bilirubin ≤ 1.5 times ULN Albumin ≥ 2 g/dL Creatinine clearance or radioisotope glomerular filtrationrate ≥ 70 mL/min Creatinine based on age as follows: Creatinine ≤ 0.8 mg/dL (patients ≤ 5 years of age) Creatinine ≤ 1.0 mg/dL (patients 6 to 10 years of age) Creatinine ≤ 1.2 mg/dL (patients 11 to 15 years of age) Creatinine ≤ 1.5 mg/dL (patients > 15 years of age) No proteinuria 24-hour urine protein ≤ 500 mg No history of stroke No deep venous or arterial thrombosis within the past 3 months No uncontrolled hypertension Hypertension must be well-controlled with stable doses of medication for at least 2 weeks No history of myocardial infarction No severe or unstable angina No transient ischemic attack within the past 6 months No cerebrovascular accident within the past 6 months No other arterial thromboembolic event within the past 6 months No clinically significant or severe peripheral vascular disease No pulmonary embolism within the past 3 months Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 3 months after study participation No chronic non-healing wound, ulcer, or bone fracture No significant traumatic injury within the past 28 days No uncontrolled seizures No uncontrolled infection No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies Recovered from prior immunotherapy More than 1 week since prior growth factors At least 2 months since prior stem cell transplantation No evidence of active graft-vs-host disease At least 8 weeks since prior monoclonal antibody therapy At least 7 days since prior antineoplastic biologic agents No prior bevacizumab No concurrent prophylactic growth factors No other concurrent immunotherapy or biologic therapy More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) and recovered No concurrent chemotherapy Recovered from prior radiotherapy At least 4 months since prior craniospinal radiotherapy At least 4 months since prior radiotherapy to ≥ 50% of the pelvis At least 6 weeks since other prior substantial bone marrow radiotherapy At least 2 weeks since prior local palliative small-port radiotherapy No concurrent radiotherapy More than 28 days since prior major surgery At least 7 days since prior minor surgery (for limited purposes of tissue retrieval) and recovered At least 24 hours since prior placement of an indwelling IV catheter At least 1 week since prior full-dose anticoagulation therapy, including systemic thrombolytic agents, heparin, low-molecular weight heparin, and warfarin Local intralumenal anticoagulants (e.g., heparin or tissue plasminogen activator) allowed to maintain patency of preexisting, permanent, indwelling IV catheters or peripheral IV catheters for blood sampling More than 1 week since prior antipyretic and anti-inflammatory medications (except acetaminophen) No concurrent full-dose anticoagulation therapy No concurrent anti-inflammatory medication Concurrent acetaminophen allowed No other concurrent cancer therapy No other concurrent investigational agents

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose defined based on the dose-limiting toxicities graded according to Common Terminology Criteria for Adverse Events v3.0 |  | 28 days |