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

• ClinicalTrials.gov Identifier: NCT00885326
• Recruitment Status: Completed
• First Posted: April 21, 2009
• Last Update Posted: March 12, 2020
• Sponsor: New Approaches to Neuroblastoma Therapy Consortium
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): New Approaches to Neuroblastoma Therapy Consortium

Study Description

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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 29 participants
• Allocation: N/A
• 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
• Actual Study Completion Date: December 2019

Arms and Interventions

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

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

• 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

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

• Responsible Party: New Approaches to Neuroblastoma Therapy Consortium
• ClinicalTrials.gov Identifier: NCT00885326
• Other Study ID Numbers: CDR0000638257; P01CA081403 ( U.S. NIH Grant/Contract )
• First Posted: April 21, 2009
• Last Update Posted: March 12, 2020
• Last Verified: March 2020

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; Zoledronic Acid; Cyclophosphamide; Bevacizumab; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bone Density Conservation Agents