Bevacizumab in Treating Young Patients With Refractory Solid Tumors

A Phase I Study of Bevacizumab in Refractory Solid Tumors

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.

Study Overview

• Status: Completed
• Conditions: Unspecified Childhood Solid Tumor, Protocol Specific
• Intervention / Treatment: Biological: bevacizumab

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Arcadia, California, United States, 91006-3776
      • COG Phase I Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; 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; Given IV; Other Names: Avastin; anti-VEGF humanized monoclonal antibody; anti-VEGF monoclonal antibody; rhuMAb VEGF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Julia Bender, COG Phase I Consortium

Study record dates

Study Major Dates

• Study Start: December 1, 2003
• Primary Completion (Actual): October 1, 2005

Study Registration Dates

• First Submitted: June 10, 2004
• First Submitted That Met QC Criteria: June 10, 2004
• First Posted (Estimate): June 11, 2004

Study Record Updates

• Last Update Posted (Estimate): June 5, 2013
• Last Update Submitted That Met QC Criteria: June 4, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibodies; Immunoglobulins; Bevacizumab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological
• Other Study ID Numbers: NCI-2012-01813; U01CA097452 (U.S. NIH Grant/Contract); ADVL0314; COG-ADVL0314; CDR0000367299; NCI-04-C-0148