Protracted Etoposide During Induction Therapy for High Risk Neuroblastoma (PEPI)
|First Received Date ICMJE||December 19, 2007|
|Last Updated Date||October 5, 2012|
|Start Date ICMJE||March 2007|
|Primary Completion Date||July 2009 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT00578864 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Protracted Etoposide During Induction Therapy for High Risk Neuroblastoma|
|Official Title ICMJE||PEPI: Protracted Etoposide in a Phase II Upfront Window for Induction Therapy for High Risk Neuroblastoma|
High-risk neuroblastoma is an aggressive childhood cancer that shows up as a lump or mass in the belly or around the spinal cord in the chest, neck, or pelvis. Often the tumor has spread around the body to the bones or to the soft center of the bone, called the bone marrow. High-risk neuroblastoma often responds to treatment at first, but it frequently comes back and may be even more difficult to treat. This study is being performed to try to increase the number of children who can be cured.
Chemotherapy (drug treatments for cancer) is usually given at high doses in short bursts (3 to 5 days) followed by a few weeks of rest and recovery. This burst and recovery is called a "cycle" and usually takes about 21 days. During the 2 weeks after the burst, the patient will usually have side effects, these are described in detail below. Some scientists and physicians have tried to give chemotherapy at lower doses for more days, called "metronomic" chemotherapy. This method of giving chemotherapy has been used to treat neuroblastoma that has failed more standard types of treatment (relapsed neuroblastoma) and has shown some promise for those patients. One of the reasons it may work is by killing the blood vessels that feed the tumor as well as killing tumor cells themselves (the way that burst chemotherapy works). We think that giving a burst of chemotherapy together with metronomic therapy may kill the tumor while decreasing the side effects that we have seen in the past . Treatment for high risk neuroblastoma usually occurs in 3 stages: induction, consolidation, and maintenance. During the induction phase, you will receive chemotherapy and possibly more surgery to get rid of most of your tumor cells. Most of the chemotherapy drugs during induction will be given in the standard burst method. One of the chemotherapy drugs, etoposide, will be given in lower, metronomic doses. The doctors will study how the tumors respond and the side effects patients have. After induction most childrens' tumors will have disappeared, also called remission. These children will receive the second stage of treatment called consolidation. During this stage, you will receive radiation treatments to your tumor and then higher doses of chemotherapy. Because of the side effects of the high doses of chemotherapy, we will collect and store some special blood cells (called hematopoietic stem cells) early in your treatment and keep them frozen. After the high doses of chemotherapy, these cells will be thawed and given to you into your vein. This will help protect you from some of the side effects. This is called hematopoietic stem cell transplant (HSCT). The final stage of treatment, called maintenance, consists of a drug that you take by mouth for 6 months. Surgery to remove large, or bulky, tumors is a standard part of treatment for high risk neuroblastoma. A few children can have their main tumor removed before chemotherapy, but most require the tumor to shrink first. Surgery has usually been scheduled for after 3 to 5 cycles of therapy, but no one really knows how quickly the tumors are ready to come out. Because chemotherapy has significant side effects that can change the risks of surgery, we will study how early surgeries to remove tumors can happen.
Neuroblastoma is the most common extracranial solid tumor of childhood. Approximately half of the children newly diagnosed with this tumor will have metastatic disease or histologically aggressive large tumors that are at "high risk" for treatment failure. Therapy for high risk neuroblastoma consists of intensive chemotherapy, surgery, radiation therapy, high dose therapy with autologous hematopoietic stem cell rescue (HDT/SCR), and biologic agents such as retinoids. Dose intensification has long been the focus of clinical research with development of maximum intensity induction regimens and multiple cycles of HDT/SCR. The majority of tumors will respond initially to this combination therapy, but relapse is common with a three-year event free survival of 30 to 40%. Additionally, the risk of acute and chronic toxicities from therapy is high and increases with intensification.
Review of risk factors for relapse or progressive disease suggests that response of tumors to induction chemotherapy is a predictor of poor outcomes with current treatment strategies. Novel approaches to induction therapy may be beneficial to the overall survival of children with HRNB; because the response rate to induction has historically been good, care must be taken when modifying the standard regimens. The trial that follows aims to address the initial tumor response by changing the dosing of etoposide, a known effective agent in both newly- diagnosed and salvage therapy, from bolus to protracted dosing. This dosing schedule may provide an anti- angiogenic effect as well as a cytotoxic anti-tumor effect. If this regimen proves equally effective as prior regimens it could serve as a backbone for the incorporation of other novel targeted agents. Additional research to improve understanding of neuroblastoma, the patients, and the impacts of therapy are also included for design of future clinical trials.
This study will evaluate the efficacy of protracted etoposide in combination with standard Cisplatin dosing. Although the most common schedule for children has historically been 50 mg/m2/day for 21 days, in this study the dose will be reduced to 14 days. A 14 day schedule will allow other chemotherapy to be given on a 21 day schedule while keeping the total cumulative dose of etoposide within the range of other prior effective regimens.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Study Arm (s)||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Estimated Completion Date||March 2014|
|Primary Completion Date||July 2009 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Pts can be enrolled but receive standard etoposide bolus dosing based on clinical conditions at diagnosis (need for emergency intervention because of renal, neurologic, or airway compromise). Pts who meet all other eligibility criteria may also choose to participate in the clinical trial w/o receiving the upfront window protracted dosing of etoposide; these children will receive standard etoposide bolus dosing.
Less than 18 yo at diagnosis
DIAGNOSIS Neuroblastoma or ganglioneuroblastoma verified by histology and/or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites.
Pts with newly diagnosed neuroblastoma and age 365 or more days with the following: * INSS Stage 2a/2b with MYCN amplification , AND unfavorable pathology * INSS Stage 3 with MYCN amplification AND/OR unfavorable pathology
Pts with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following: * Age more than 18 months (greater than 547 days) regardless of biologic features * Age 12 to 18 months (365-547 days) with any unfavorable biologic feature (MYCN amplification, unfavorable pathology and/or DNA index equal to 1) or any biologic feature that is indeterminant/unsatisfactory/unknown.
Pts with newly diagnosed neuroblastoma and age less than 365 days with INSS Stage 3, 4, 4S neuroblastoma with MYCN amplification (more than 10).
Pts 365 days or more initially diagnosed with INSS stage 1, 2, 4S who develop distant metastatic disease (meet criteria for INSS stage 4).
Pts may have had no prior systemic therapy except:
TIME FROM DIAGNOSIS Pts must be entered on this study - Within 3 weeks of diagnosis - After recovery from only 1 cycle of chemo on low/intermediate risk NB therapy, - Within 3 weeks of progression with widely metastatic tumor for INSS stage 1, 2, 4S if they received no prior chemotherapy.
LIVER FUNCTION Pts must have adequate liver function defined as
Pts of childbearing potential must practice an effective method of birth control while on study.
Patients who do not meet inclusion criteria.
Patients who are pregnant or lactating are not eligible.
EXCLUSION CRITERIA UPFRONT WINDOW Patients can be enrolled onto Stratum 1 but receive standard etoposide bolus dosing based on clinical conditions at diagnosis. Patients who meet all other eligibility criteria may also choose to participate in the clinical trial without receiving the upfront window protracted dosing of etoposide; these children will receive standard etoposide bolus dosing.
Patients whose tumor requires emergency intervention because of spinal cord compression, CNS compromise, or airway compromise.
Patients requiring dialysis.
If the patient and/or the patient's legally authorized guardian chose to participate in the clinical trial but chose to not participate in the phase II upfront window.
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00578864|
|Other Study ID Numbers ICMJE||H20255, PEPI|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Peter Zage, Baylor College of Medicine|
|Study Sponsor ICMJE||Baylor College of Medicine|
|Collaborators ICMJE||Texas Children's Hospital|
|Information Provided By||Baylor College of Medicine|
|Verification Date||October 2012|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP