N2007-02:Bevacizumab,Cyclophosphamide,& Zoledronic Acid in Patients W/ Recurrent or Refractory High-Risk Neuroblastoma

Study Description

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Brief Summary:

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Zoledronic acid may stop the growth of tumor cells in bone. Giving bevacizumab together with cyclophosphamide and zoledronic acid may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects of giving bevacizumab together with cyclophosphamide and zoledronic acid in treating patients with recurrent or refractory high-risk neuroblastoma.

Condition or disease	Intervention/treatment	Phase
Neuroblastoma	Drug: Bevacizumab; Drug: cyclophosphamide; Drug: zoledronic acid	Phase 1

Detailed Description:

OBJECTIVES:

Primary

• To determine the toxicities and feasibility of bolus and metronomic cyclophosphamide when given in combination with zoledronic acid with and without bevacizumab in patients with recurrent or refractory high-risk neuroblastoma.

Secondary

• To preliminarily evaluate the antitumor activity of this regimen in these patients within the confines of a pilot study.

OUTLINE: This is a multicenter study.

Patients receive cyclophosphamide IV over 1 hour and zoledronic acid IV over 15 minutes on day 0 and oral cyclophosphamide once daily on days 1-27 in course 1. In course 2 and all subsequent courses, patients receive bevacizumab IV over 30-90 minutes on days 0 and 14, cyclophosphamide IV over 1 hour and zoledronic acid IV over 15 minutes on day 1, and oral cyclophosphamide once daily on days 0 and 2-27. Treatment repeats every 28 days for up to 2 years* in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients may receive up to 13 doses of zoledronic acid.

After completion of study treatment, patients are followed periodically.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	36 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I Study of Bevacizumab With Bolus and Metronomic Cyclophosphamide and Zoledronic Acid in Children With Recurrent or Refractory Neuroblastoma
Study Start Date :	December 2009
Actual Primary Completion Date :	April 2014
Estimated Study Completion Date :	November 2018

Arms and Interventions

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Arm

Intervention/treatment

Treatment; Bevacizumab: Every course will be 28 days. Bevacizumab 10 mg/kg/dose , will be administered intravenously every 14 days beginning on day 0 of the second course. Cyclophosphamide will be administered as an intravenous (IV) bolus according to the protocol assigned dose level followed by daily oral dosing (25mg/m2/day) without interruption (unless toxicity supervenes). Zoledronic acid will be administered on day 0 of course 1 and day 1 of course 2 and all subsequent courses in a dose of 4mg/m2 (max 4 mg per dose). On days when zoledronic acid (ZA) and cyclophosphamide (CTX) are given together, CTX should be given first.

Drug: Bevacizumab; Every course will be 28 days. Bevacizumab 10 mg/kg/dose , will be administered intravenously every 14 days beginning on day 0 of the second course.; Other Names: Avastin; BV Drug: cyclophosphamide; Cyclophosphamide will be administered as an intravenous (IV) bolus according to the protocol assigned dose level followed by daily oral dosing (25mg/m2/day) without interruption (unless toxicity supervenes).; Other Names: Cytoxan; CTX Drug: zoledronic acid; Administered on day 0 of course 1 and day 1 of course 2 and all subsequent courses in a dose of 4mg/m2 (max 4 mg per dose). On days when zoledronic acid (ZA) and cyclophosphamide (CTX) are given together, CTX should be given first.; Other Names: Zometa; ZA

Outcome Measures

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Primary Outcome Measures :

1. Determination of toxicities and feasibility of the combination of bolus plus metronomic cyclophosphamide and zoledronic acid with and without bevacizumab when given to children with refractory or recurrent high risk neuroblastoma. [ Time Frame: Study entry, day 14 of course 1, prior to course 2, day 14 of course 2. ]
   Any dose limiting toxicity (DLT) as defined in section 9.2 of protocol.

Secondary Outcome Measures :

1. Evaluation of response within the confines of a phase I study. [ Time Frame: Before study treatment, prior to courses 3 and 6 and then after every 3rd subsequent course. ]
   Eligible patients are assessed for response after receiving 2 courses OR if they terminate treatment for reasons of toxicity OR if they progress prior to completion of 2 courses of therapy.
2. Analysis of Circulating Endothelial Cells, Circulating Factors, Gene expression and Bone Metabolism Studies. [ Time Frame: Will be measured a total of 4 times, prior to start of course and then at day 14 of courses 1 and 2 only. ]
   Biologic studies will be done to analyse circulating endothelial cells(CEC), circulating precursor cells (CEP)and assessment of markers of bone metabolism.

Eligibility Criteria

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Ages Eligible for Study:	up to 30 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Patients must be no more 30 years of age when enrolled on study.
• Patients must have relapsed neuroblastoma, refractory neuroblastoma that had less than a partial response to standard treatment or persistent neuroblastoma that had at least a partial response to standard treatment.
• Patients who have at least a partial response to standard treatment who still have neuroblastoma that can be seen on CT/MRI or MIBG scans must have a surgical biopsy done of the tumor to confirm that it is neuroblastoma. Patients with relapsed or refractory neuroblastoma do not need to have a biopsy done to enter on study.
• Patients must have adequate heart, kidney, liver blood clotting and bone marrow function. Patients who have bone marrow disease must meet the bone marrow function criteria to enter the study.
• Patients must have recovered from all prior chemotherapy and surgical procedures

Exclusion Criteria:

• They are known to be sensitive to Bevacizumab.
• They have a history of very high blood pressure which required intensive intervention
• They are pregnant or breastfeeding
• Neuroblastoma is present in the brain on a CT or MRI scan done at study entry. Patients with neuroblastoma found in the bones of the skull are eligible if there is no tumor mass associated with them pressing on the brain.
• They have a history non healing wounds

Contacts and Locations

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Locations

United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027-0700
Lucile Packard Children's Hospital at Stanford University Medical Center
Palo Alto, California, United States, 94304
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94143
United States, Georgia
Children's Healthcare of Atlanta
Atlanta, Georgia, United States, 30322
United States, Illinois
University of Chicago Comer Children's Hospital
Chicago, Illinois, United States, 60637
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Michigan
C.S Mott Children's Hospital
Ann Arbor, Michigan, United States, 48109
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229-3039
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
United States, Texas
Cook Children's Medical Center - Fort Worth
Fort Worth, Texas, United States, 76104
Texas Children's Cancer Center
Houston, Texas, United States, 77030-2399
United States, Washington
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States, 98105
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
CHU Sainte Justine
Montreal, Quebec, Canada, H3T 1C5

Sponsors and Collaborators

New Approaches to Neuroblastoma Therapy Consortium

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Julia L. Glade-Bender, MD	Herbert Irving Comprehensive Cancer Center

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

N07-02 Information on NANT.org 

Responsible Party:	New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier:	NCT00885326 History of Changes
Other Study ID Numbers:	CDR0000638257; P01CA081403 ( U.S. NIH Grant/Contract )
First Posted:	April 21, 2009
Last Update Posted:	April 11, 2018
Last Verified:	April 2018

Keywords provided by New Approaches to Neuroblastoma Therapy Consortium:

recurrent neuroblastoma

Additional relevant MeSH terms:

Neuroblastoma; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Bevacizumab; Cyclophosphamide; Zoledronic acid; Diphosphonates	Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Myeloablative Agonists; Bone Density Conservation Agents