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NeuroblastomaPhase 2NCT01492673

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

A Phase 2 study testing Cyclophosphamide, Topotecan, and Bevacizumab in people with Neuroblastoma and Sarcoma, run by Memorial Sloan Kettering Cancer Center at 7 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages Up to 21 years
Conditions the study is for
Neuroblastoma, Sarcoma
What is being tested?
Cyclophosphamide, Topotecan, and Bevacizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
7 sitesin 2 countries
Study dates
Dec 2011to 31 Oct 2018
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
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  • 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:
  • Total bilirubin ≤ 1.5x ULN
  • AST and ALT ≤ 2.5x ULN for institution or ≤ 5x ULN for institution if clearly attributable to liver metastases
  • Albumin ≥ 2.5 g/dl. Coagulation: INR ≤ 1.5x ULN.
  • Prior Treatment: Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiation therapy prior to entry on study. Patients must have had at least one prior treatment regimen. Patients may have received treatment previously with cyclophosphamide or topotecan but no prior bevacizumab.
  • Myelosuppressive chemotherapy: Two weeks must have elapsed since administration of previous chemotherapy.
  • Biologic agents: At least 2 weeks must have elapsed since the completion of therapy with a monoclonal antibody. Seven days must have elapsed since the last dose of retinoids
  • Radiation therapy: For all patients, ≥ 4 weeks must have elapsed for local XRT; ≥ 6 months must have elapsed if prior radiation to ≥ 50% of the pelvis or if substantial bone marrow irradiation. Patients with a history of prior radiation with field including the heart (e.g. mantle) will be excluded.
  • Stem cell transplant: Patients who have undergone prior stem cell transplantation will not be excluded from study entry. At least 3 months must have elapsed since autologous or allogeneic stem cell transplantation. Patients must have no evidence of active graft versus host disease.

Who cannot join

  • 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
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  • 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.
  • Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day -3.
  • History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day -3.
  • Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day -3 or anticipation of need for major surgical procedure during the course of the study. (A major procedure constitutes an invasive procedure which requires general anesthetic support, hospitalization, and supportive care such as laparotomy, laminectomy, etc.)
  • Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1. (Minor surgical procedures include minimally invasive procedures such as fine needle aspiration, core biopsy, etc requiring little if any supportive care excluding lumbar puncture and bone marrow aspiration/biopsy.)
  • History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day -3.
  • Serious, non-healing wound, active ulcer, or untreated bone fracture.
  • Thrombolytics or treatment doses of warfarin within 28 days of initiating treatment. Patients who require low dose warfarin for central venous catheter patency are allowed to enter if their dose is < 2 mg per day total AND their International Normalized Ratio (INR) is ≤ 1.5.
  • Patients requiring treatment doses of heparin for any reason. The use of heparin flushes for maintenance of central venous catheters is permitted
  • Patients requiring aspirin > 325 mg per day or non-steroidal anti-inflammatory medications known to inhibit platelet function. Patients taking cyclooxygenase-2 inhibitors (COX-2) inhibitors are allowed to enroll.
  • History or clinical evidence of deep venous thrombosis including pulmonary embolus within 6 months of treatment.
  • Patients with proteinuria > 1+ on urine dipstick or UPC ratio ≥ 1.0 at screening. If >1+ proteinuria is detected on surveillance, a 24-hour collection must be performed if eligibility is desired. Patients with a 24-hour urine protein content of ≤ 500 mg are eligible.
  • Known hypersensitivity to any component of bevacizumab.
  • Pregnancy (positive pregnancy test) or lactation. (An effective means of contraception (men and women) in subjects of child-bearing potential must be used.)

Trial locations and contacts

7 sites in 2 countries.

7 sites in 2 countries

United States6 sites

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

    Denver, Colorado, 80045

  • Pennsylvania State University College of Medicine

    Hershey, Pennsylvania, 17110

  • Children's Mercy Hospital & Clinics

    Kansas City, Missouri, 64108

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

  • MD Anderson Cancer Center Orlando at Arnold Palmer Hospital for Children

    Orlando, Florida, 32806

  • Phoenix Children'S Hospital

    Phoenix, Arizona, 85016

Other trials in United States

Canada1 site

  • Alberta Children'S Hospital

    Calgary, Alberta, T2N 1N4

Other trials in Canada

About this study

Official title: A Phase II Trial of Cyclophosphamide, Topotecan, and Bevacizumab (CTB) in Patients With Relapsed/Refractory Ewing's Sarcoma and Neuroblastoma

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.

Read more

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.

Being tested
Cyclophosphamide, Topotecan, and Bevacizumab
Keywords
Ewing's sarcoma, BEVACIZUMAB (AVASTIN), CYCLOPHOSPHAMIDE (CYTOXAN), TOPOTECAN, 11-183, POETIC
Medical subject headings
Neuroblastoma, Sarcoma, Sarcoma, Ewing

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Cyclophosphamide, Topotecan, and BevacizumabDrug

    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.

Study groups in NCT01492673
Study groupRoleWhat they receive
Cyclophosphamide, Topotecan, and Bevacizumab (CTB)ExperimentalThis 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.
Receives: Drug: Cyclophosphamide, Topotecan, and Bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 2 years

Secondary outcomes (1)

  1. Number of Participants With Adverse Events

    Safety will be assessed by physical examination, interim history, and laboratory assessments. Adverse events will be graded according to the NCI-CTCAE, version 4.0

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Dec 2011 (estimated)
  2. Study startDec 2011
  3. Primary completion31 Oct 2018
  4. Study completion31 Oct 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01492673
Sponsor's protocol ID
11-183
Status last verified
Oct 2018
First submitted
12 Dec 2011
Last updated
29 Oct 2019

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cyclophosphamide, Topotecan, and Bevacizumab in people with Neuroblastoma and Sarcoma, run by Memorial Sloan Kettering Cancer Center at 7 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Oct 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Objective Response Rate (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01492673.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Oct 2019.

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