Protracted Etoposide During Induction Therapy for High Risk Neuroblastoma (PEPI)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Texas Children's Hospital
Information provided by (Responsible Party):
Peter Zage, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT00578864
First received: December 19, 2007
Last updated: March 5, 2014
Last verified: March 2014

December 19, 2007
March 5, 2014
March 2007
July 2009   (final data collection date for primary outcome measure)
  • Response Rate Associated With Two Cycles of Cisplatin With Protracted Oral Etoposide When Administered as Up-front Window Therapy to Previously Untreated Children With High Risk Neuroblastoma Tumors. [ Time Frame: 2 months ] [ Designated as safety issue: No ]
  • Rate of Toxicities Associated With Cisplatin With Protracted Oral Etoposide When Administered as Up-front Window Therapy to Previously Untreated Children With High Risk Neuroblastoma. [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]

    If a patient experiences any one of the following toxicities, attributed to induction chemotherapy cycles 1, or 2, that patient will be counted as having a dose limiting toxicity. 13.2.1.1 Inability to achieve ANC > 750 by Day 35 from start of chemotherapy cycle 1 or 2 (unless documented tumor involvement of marrow) 13.2.1.2 Inability to achieve platelet count > 75,000 by Day 35 from start of chemotherapy cycle 1 or 2 (unless documented tumor involvement of marrow) 13.2.1.3 Any Grade 2 or greater toxicity non-hematopoietic/non-mucosal (mucositis/stomatitis) that is not reversible to Grade 1 or baseline by day 21 from start of chemotherapy cycle excluding

    • Hematopoietic toxicity
    • Mucositis/stomatitis
    • Anorexia, nausea, vomiting
    • Febrile neutropenia
  • To estimate the response rate associated with two cycles of cisplatin with protracted oral etoposide when administered as up-front window therapy to previously untreated children with high risk neuroblastoma tumors. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • - To describe the toxicities associated with cisplatin with protracted oral etoposide when administered as up-front window therapy to previously untreated children with high risk neuroblastoma. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00578864 on ClinicalTrials.gov Archive Site
  • Overall Survival in Children With High Risk Neuroblastoma Treated on This Regimen. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Percentage of Patients Who Have Surgery After the Second Cycle of Induction Therapy [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    the measure is the number of patients who have surgery after two cycles of induction
  • Event Free Survival in Children With High Risk Neuroblastoma Treated on This Regimen. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    The first of the two events (relapse or death) was chosen to represent disease free survival
  • Evaluate the induction response rates, patterns of treatment failure, event free survival and overall survival in children with high risk neuroblastoma treated on this regimen. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • - Evaluate the feasibility and toxicity of resection of primary tumors after two cycles of induction chemotherapy. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • - To describe the anti-angiogenic effects of cisplatin and protracted oral etoposide in previously untreated children with high risk neuroblastoma. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • Estimate the change in neuropsychological assessment battery in children greater than 2 years old at diagnosis and correlate these changes with toxicities of therapy. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • Provide a consistent treatment strategy as a platform for the study of biologic features of the tumor and patient. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Protracted Etoposide During Induction Therapy for High Risk Neuroblastoma
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.

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. 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, patients will receive chemotherapy and possibly more surgery to get rid of most of the 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, subjects will receive radiation treatments to the 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 treatment and keep them frozen. After the high doses of chemotherapy, these cells will be thawed and given to the subject. . This is called hematopoietic stem cell transplant (HSCT). The final stage of treatment, called maintenance, consists of a drug taken 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.

This study is being done to evaluate the outcomes of disease response and survival in children with high risk neuroblastoma treated on this regimen.

Induction Phase Overview The induction phase is approximately 15 weeks long. Chemotherapy is generally given every 3 weeks, each 3 week block is called a "cycle". During these 15 weeks we will treat subjects with chemotherapy 5 times using combinations of 4 different chemotherapy drugs. All IV chemotherapy drugs will be given in the hospital. During this 15 weeks doctors will try to collect special blood cells called hematopoietic stem cells. If the subject's tumor has not been removed completely you will have a surgery to take the rest of the tumor out as soon as possible once it has shrunk with the first two cycles of chemotherapy.

Induction Phase Chemotherapy During the first 2 cycles of chemotherapy all children will receive two drugs: cisplatin and etoposide. Cisplatin is given through an IV for everyone. If participating in the research treatment plan, etoposide by mouth mouth for 14 days. After the first two cycles we will repeat studies to see if the tumor has shrunk. Then all children will receive two other chemotherapy drugs called cyclophosphamide and adriamycin during the 3rd cycle. If the subject responded to the first two cycles, the 4th cycle will be IV cisplatin and oral etoposide again; if the subject did not respond to the first two cycles, the 4th cycle will be IV cisplatin with standard IV etoposide. The 5th cycle will again be adriamycin and cyclophosphamide.

If subjects choose not to participate in the research treatment plan, or are not eligible for the research treatment plan, cycle 1, 2, and 4 will be IV Cisplatin and IV Etoposide.

Here is the induction treatment:

Treatment #1, 2, and 4:

Cisplatin and etoposide: Cisplatin will be given once a day for 5 days through an IV. Etoposide will be given either by mouth once a day for 14 days (research treatment plan) or through an IV for 3 days (standard treatment plan).

Treatment #3 and 5: Cyclophosphamide and adriamycin: Cyclophosphamide and adriamycin are given daily for 2 days, both drugs are given through an IV. Cyclophosphamide may cause irritation of the bladder so another drug called mesna will be given several times after each dose to help prevent this.

After treatment #3 and #5 patients will receive a drug called G-CSF. It stimulates the body to make white blood cells (infection fighting cells) to help prevent infections that can happen because of chemotherapy. G-CSF is an injection that must be given daily.

Surgery: If the primary tumor was not removed before chemotherapy,subjects will undergo a second surgery after receiving chemotherapy. Tumor reevaluation is after cycle #2 and if it is resectable subjects will have surgery at that time. If this is not possible images of the tumor will be taken after cycle #3 and again after cycle #5. Surgery will occur as soon as the tumor is resectable

Stem Cell Harvest Stem cells are special cells that can make all the different types of blood cells. Usually they are found in the bone marrow, but after chemotherapy many more of them are in your blood stream. Between the third and fifth cycles of induction, stem cells will be collected from the blood using a procedure called apheresis. The central line or catheter is connected to a machine that draws some of the subjects blood out of one side of the catheter, filters out the stem cells, and returns the rest of the blood through the other side of the catheter. Each apheresis procedure takes about 4-6 hours. The procedure may need to be done several times to collect enough stem cells.

The consolidation phase takes approximately 15 weeks to complete and consists of radiation to the tumor followed by high doses of chemotherapy and hematopoietic stem cell transplant.

HERE IS THE TREATMENT PLAN:

Local Tumor Radiation:

Local radiation therapy is given daily for about 2 weeks. Radiation beams will be aimed at the sites of the tumor. Each child's treatment will be designed just for them. The doctor who gives radiation will discuss the therapy in detail. Some children require sedation for radiation therapy. Radiation therapy does not usually require admission to the hospital.

High Dose Chemotherapy and Hematopoietic Stem Cell Transplant Carboplatin, etoposide and melphalan: Carboplatin and etoposide are given daily for 4 days followed by melphalan for 3 days. Stem cells will be infused after chemotherapy.

After high dose therapy subjects will receive G-CSF to help stimulate the growth of white blood cells. Other drugs will be used during and after the chemotherapy to prevent or decrease side effects from this treatment. Until the stem cells restore safe levels of blood cells, subjects will need to be hospitalized. This treatment may require hospitalization for 3 to 4 weeks or longer.

Maintenance Phase Starting approximately 3 months following stem cell transplant subjects will receive six monthly treatments with 13-cis-retinoic acid. 13-cis retinoic acid is a drug closely related to vitamin A and has been shown to help stop the multiplication of any remaining neuroblastoma cells in the body. This drug will be taken 2 times a day by mouth for 14 days and then not take it for the following 14 days. This 28-day cycle will be repeated 6 times.

AFTER COMPLETING STUDY TREATMENT The consolidation phase of treatment for high risk neuroblastoma lasts about 4 months. The entire treatment will last about 12-14 months.

Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Neuroblastoma
  • Drug: Protracted Oral Etoposide

    IV Cisplatin and Oral Protracted Etoposide for induction

    Induction chemotherapy will consist of five cycles 21 days apart. Cycles 1, 2 and 4 will be IV cisplatin and etoposide. Patients on the phase II window will receive the first two cycles of chemo with IV cisplatin and oral protracted etoposide. If their tumor responds with a CR, VGPR or PR, it will be repeated during cycle 4. If their tumor does not respond cycle 4 will include bolus etoposide

    Cisplatin with Oral Protracted Etoposide for cycles 1, 2 and 4

    Day 1 - 5

    • Hour 0: Etoposide 50 mg/m2 po daily
    • Hours 1 to 7: Cisplatin 40 mg/m2

    Day 6 - 14

    • Etoposide 50 mg/m2 po once daily
  • Drug: Adriamycin and Cyclophosphamide

    Induction chemotherapy will consist of 5 cycles given 21 days apart. Cycle 3 and 5 will be adriamycin and cyclophosphamide.

    Day 1 and 2

    • Hours 0 to 6: Cyclophosphamide 2000 mg/m2 (67 mg/kg if < 12 kg) with Mesna 400 mg/m2 (13 mg/kg if < 12 kg) in D5½NS 600 mL/m2 IV over 6 hours to run at 100 mL/m2/hr
    • Hours 6 to 6.25: Adriamycin 37.5 mg/m2 (1.25 mg/kg if < 12 kg) IV over 15 minutes
  • Drug: IV Cisplatin and IV Bolus Etoposide

    Induction chemotherapy will consist of five cycles of chemotherapy given 21 days apart. The 1st, 2nd and 4th cycles will the IV Cisplatin and Etoposide. Patients ineligible to participate on the phase II window will receive IV bolus etoposide during cycles 1, 2 and 4.

    Cisplatin with Bolus IV Etoposide

    Day 1

    Hours 0 to 6: Cisplatin 40 mg/m2

    Days 2, 3, 4:

    Hours 0 to 1: Etoposide 200 mg/m2 Hours 1 to 7: Cisplatin 40 mg/m2

    Day 5:

    Hours 0 to 6: Cisplatin 40 mg/m2

  • Experimental: Protracted Oral Etoposide
    Protracted etoposide for cycles 1, 2 and 4 of induction. If a subject does not respond after cycle 2, cycle 4 will be bolus etoposide.
    Intervention: Drug: Protracted Oral Etoposide
  • Active Comparator: IV Cisplatin and IV Bolus Etoposide
    This arm is for patients whose tumor does not respond satisfactorily to the first two cycles of chemotherapy with IV cisplatin and oral protracted etoposide. Patients on this arm will receive cycle 4 etoposide given as a bolus IV dose.
    Intervention: Drug: IV Cisplatin and IV Bolus Etoposide
  • Experimental: Adriamycin and Cyclophosphamide
    Induction chemotherapy will consist of 5 cycles given 21 days apart. Cycle 3 and 5 will be adriamycin and cyclophosphamide
    Intervention: Drug: Adriamycin and Cyclophosphamide
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
13
March 2015
July 2009   (final data collection date for primary outcome measure)

Inclusion Criteria:

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:

  • Localized emergency radiation to sites of life threatening or function-threatening disease
  • No more than one cycle of chemotherapy according to the intergroup low or intermediate risk neuroblastoma studies prior to determination of MYCN amplification and histology.

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.

HEMATOPOIETIC FUNCTION

  • ANC 750/µL or more
  • Plt 75,000/µL or more
  • or bone marrow involvement with tumor.

LIVER FUNCTION Pts must have adequate liver function defined as

  • Direct Bilirubin 1.5 mg/dL or less
  • AST and ALT 5 x ULN or less

Pts of childbearing potential must practice an effective method of birth control while on study.

Exclusion Criteria:

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.

Both
Not Provided
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00578864
H20255, PEPI
Yes
Peter Zage, Baylor College of Medicine
Baylor College of Medicine
Texas Children's Hospital
Principal Investigator: Peter Zage, MD Baylor College of Medicine
Baylor College of Medicine
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP