Cyclophosphamide, Topotecan, and Bevacizumab (CTB) in Patients With Relapsed/Refractory Ewing's Sarcoma and Neuroblastoma

NCT01492673 | Completed Phase 2 Results

• 1 other identifier: 11-183
• Study Type: interventional
• Target: 9
• Locations: 2 countries
• Sites: 7

Brief Summary

The purpose of this study is to find out what effects, good and/or bad treatment with a new combination of drugs, cyclophosphamide, topotecan, and bevacizumab has on the patient and their cancer. The medications, cyclophosphamide and topotecan, are standard drugs often used together for the treatment of cancer in children with either Ewing's sarcoma or neuroblastoma. Bevacizumab is an experimental drug called an antibody that targets a protein important in the growth of cancer cells called vascular endothelial growth factor (VEGF). VEGF is made by tumor and other surrounding cells to help make blood vessels needed for the growth and spread of cancer cells in the body. The way that bevacizumab works is to stop the cancer cells from making their own blood supply, causing the tumor to stop growing bigger or from spreading. In adult clinical trials, bevacizumab has shown promising anti-cancer activity in patients with cancer of the colon/rectum (colorectal) and breast. It has been approved by the Food and Drug Administration (FDA) for use in patients with colorectal cancer but not in cancers found in children. Bevacizumab has been tested in early clinical studies in children and has been shown to be safe. Other goals of this study will include research tests designed to test the following changes in the patient or their cancer: to see how the body handles and breaks down bevacizumab (pharmacokinetics), to look at changes in proteins in the blood that may affect the way the cancer responds to the combination (angiogenic profile, angiogenesis associated serum biomarkers), to look at changes in genes that may affect how the cancer responds to treatment with this combination of medications (metabolic signature), and to monitor the effects of changes in the way the body grows and develops before and after bevacizumab is given.

Conditions

Neuroblastoma; Sarcoma

Keywords

Ewing's sarcoma; BEVACIZUMAB (AVASTIN); CYCLOPHOSPHAMIDE (CYTOXAN); TOPOTECAN; 11-183; POETIC

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate

  as measured by objective response rate (CR/PR) after 2 cycles of treatment and duration of response. after 2 cycles of treatment and duration of response according to the Revised RECIST guideline (version 1.1) Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

  2 years

Secondary Outcomes (1)

• Number of Participants With Adverse Events

  2 years

Study Arms (1)

Cyclophosphamide, Topotecan, and Bevacizumab (CTB)

EXPERIMENTAL

This is a multi-center, open label phase II study evaluating the safety and efficacy of the novel combination of agents consisting of bevacizumab, cyclophosphamide, and topotecan.

Drug: Cyclophosphamide, Topotecan, and Bevacizumab

Interventions

Cyclophosphamide, Topotecan, and Bevacizumab DRUG

The treatment schedule for this study will consist of a 21-day cycle. Dose modification will only occur with administration of the investigational agent, bevacizumab. The schedule of administration is summarized as follows. Administration of bevacizumab will precede the administration of the cyclophosphamide and topotecan by 3 days (Day - 3) to allow for vascular stabilization prior to initiation of chemotherapy. The chemotherapy backbone will consist of cyclophosphamide and topotecan administered as follows: cyclophosphamide 250 mg/m2/day IV over 30 minutes ± 5 minutes on Days 0-4 followed by topotecan 0.75 mg/m2/day IV over 30 minutes ± 5 minutes on Day 0-4 of every cycle. The dosing of cyclophosphamide and topotecan will be fixed.

Cyclophosphamide, Topotecan, and Bevacizumab (CTB)

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients must have histologically confirmed relapsed/refractory Ewing's sarcoma or neuroblastoma.
• Patients must have measurable disease. Patients with a diagnosis of neuroblastoma with MIBG avid disease only are permitted to enroll on this study.
• Patients must be ≤ 21 years of age at time of diagnosis
• Life expectancy ≥ 3 months
• Lansky or Karnofsky performance ≥ 70%
• Written informed consent
• Organ and marrow function defined as follows:
• Hematologic function, as follows
• Absolute neutrophil count ≥ 1000/μL
• Platelets ≥ 100 x 109/L (without transfusion \< 14 days before enrollment) Hemoglobin ≥ 9 gm/dl
• Renal function, as follows:
• Serum creatinine ≤ ULN for age. Refer to Appendix H for normal values for serum creatinine in children.
• If serum creatinine above these values, the calculated creatinine clearance or radioisotope GFR must be ≥ 60 ml/min/1.73 m2
• Urinary protein \< 2+ (unless total quantitative protein is \< 500 mg protein/day as determined by 24 H urine collection) for pediatric patients please refer to the CTCAE V4.0 for values.
• Hepatic function, as follows:

You may not qualify if:

• Patients with centrally-located pulmonary or mediastinal primary tumors or metastases adjacent to or invading large blood vessels.
• Prior left chest wall irradiation or a cumulative anthracycline dose of greater or equal to 300 mg/m2, unless the ejection fraction or fraction shortening is within normal institutional limits, in which case the patient can be enrolled.
• Inability to comply with study and/or follow-up procedures
• Life expectancy of less than 3 months
• Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study
• Active second malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within last five years
• History of other malignancies, except for other solid tumors curatively treated with no evidence of disease for \> 3 years prior to enrollment.
• Known infection with human immunodeficiency virus (HIV).
• Uncontrolled hypertension (sBP \>150 mmHg and/or diastolic BP \> 100 mmHg, found on two consecutive measurements separated by a one week period of time despite adequate medical support).
• Prior history of hypertensive crisis or hypertensive encephalopathy.
• New York Heart Association (NYHA) Grade II or greater congestive heart failure
• History of myocardial infarction or unstable angina within 6 months prior to Day - 3.
• History of stroke or transient ischemic attack within 6 months prior to Day -3.
• Known CNS disease, except for treated brain metastases.
• Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day -3 will be excluded.

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Genentech, Inc.: collaborator
• Children's Mercy Hospital Kansas City: collaborator
• Penn State University: collaborator
• University of Colorado, Denver: collaborator
• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: collaborator
• Phoenix Children's Hospital Center for Cancer & Blood Disorders: collaborator
• Alberta Children's Hospital: collaborator
• MD Anderson Cancer Center Orlando: collaborator
• M.D. Anderson Cancer Center: collaborator

Study Sites (7)

Phoenix Children'S Hospital

Phoenix, Arizona, 85016, United States

Location

University of Colorado Health Sciences Center and The Children's Hospital

Denver, Colorado, 80045, United States

Location

MD Anderson Cancer Center Orlando at Arnold Palmer Hospital for Children

Orlando, Florida, 32806, United States

Location

Children's Mercy Hospital & Clinics

Kansas City, Missouri, 64108, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Pennsylvania State University College of Medicine

Hershey, Pennsylvania, 17110, United States

Location

Alberta Children'S Hospital

Calgary, Alberta, T2N 1N4, Canada

Location

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Neuroblastoma; Sarcoma; Sarcoma, Ewing

Interventions

Cyclophosphamide; Topotecan; Bevacizumab

Condition Hierarchy (Ancestors)

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; Neoplasms, Connective and Soft Tissue; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Camptothecin; Alkaloids; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Tanya Trippett, MD
• Organization: Memorial Sloan Kettering Cancer Center

trippet1@mskcc.org

212-639-8267

Study Officials

• Tanya Trippett, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2011
• First Posted: December 15, 2011
• Study Start: December 1, 2011
• Primary Completion: October 31, 2018
• Study Completion: October 31, 2018
• Last Updated: October 29, 2019
• Results First Posted: October 29, 2019

Record last verified: 2018-10

Locations

US (6); CA (1)