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

Sponsor

New Approaches to Neuroblastoma Therapy Consortium (Other)

Overall Status

Completed

CT.gov ID

NCT00885326

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

120

Duration (Months)

1.9

Patients Per Site

Patients Per Site Per Month

Study Details

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

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 :

Dec 1, 2009

Actual Primary Completion Date :

Apr 1, 2014

Actual Study Completion Date :

Dec 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Other: 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

Arm

Intervention/Treatment

Other: 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

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

Outcome Measures

Primary Outcome Measures

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. [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

Evaluation of response within the confines of a phase I study. [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.
Analysis of Circulating Endothelial Cells, Circulating Factors, Gene expression and Bone Metabolism Studies. [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

Criteria

Ages Eligible for Study:

N/A to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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