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
  Purpose

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.


Condition Intervention Phase
Neuroblastoma
Drug: Protracted Oral Etoposide
Drug: Adriamycin and Cyclophosphamide
Drug: IV Cisplatin and IV Bolus Etoposide
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: PEPI: Protracted Etoposide in a Phase II Upfront Window for Induction Therapy for High Risk Neuroblastoma

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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


Enrollment: 13
Study Start Date: March 2007
Estimated Study Completion Date: March 2015
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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.
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: Adriamycin and Cyclophosphamide
Induction chemotherapy will consist of 5 cycles given 21 days apart. Cycle 3 and 5 will be adriamycin and cyclophosphamide
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

  Show Detailed Description

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00578864

Locations
United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
Texas Children's Hospital
Investigators
Principal Investigator: Peter Zage, MD Baylor College of Medicine
  More Information

No publications provided

Responsible Party: Peter Zage, Principal investigator, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT00578864     History of Changes
Obsolete Identifiers: NCT00600132
Other Study ID Numbers: H20255, PEPI
Study First Received: December 19, 2007
Results First Received: October 5, 2012
Last Updated: March 5, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Baylor College of Medicine:
Neuroblastoma
Etoposide
Cisplatin
Adriamycin
Cyclophosphamide
Cytoxan

Additional relevant MeSH terms:
Neuroblastoma
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
Etoposide phosphate
Cisplatin
Cyclophosphamide
Doxorubicin
Etoposide
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Antibiotics, Antineoplastic
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on July 23, 2014