Protracted Etoposide During Induction Therapy for High Risk Neuroblastoma

NCT00578864 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: H20255PEPI
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Neuroblastoma

Keywords

Neuroblastoma; Etoposide; Cisplatin; Adriamycin; Cyclophosphamide; Cytoxan

Outcome Measures

Primary Outcomes (2)

• 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.

  Partial response or better

  2 months

• 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.

  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 at least 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

  2 months

Secondary Outcomes (3)

• Overall Survival in Children With High Risk Neuroblastoma Treated on This Regimen.

  3 years

• Number of Patients Who Have Surgery After the Second Cycle of Induction Therapy

  2 months

• Event Free Survival in Children With High Risk Neuroblastoma Treated on This Regimen.

  3 years

Study Arms (2)

Protracted Oral Etoposide

EXPERIMENTAL

Protracted oral etoposide for cycles 1, 2 and 4 of induction. Etoposide will be given in combination with IV cisplatin (a standard of care agent). If a subject does not respond after cycle 2, cycle 4 will be bolus etoposide in combination with IV cisplatin. All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.

Drug: Protracted Oral Etoposide; Drug: Doxorubicin; Drug: Cisplatin; Drug: Cyclophosphamide; Drug: Mesna; Drug: Hematopoietic Factor; Procedure: Primary tumor resection

IV Bolus Etoposide

ACTIVE COMPARATOR

IV bolus etoposide in combination with IV cisplatin will be given for cycles 1,2, and 4 of induction chemotherapy for patients who are not eligible for the experimental arm (e.g.require emergent treatment) All patients will receive Adriamycin and cyclophosphamide for cycle 3 and 5 as a standard of care.

Drug: Doxorubicin; Drug: IV Bolus Etoposide; Drug: Cisplatin; Drug: Cyclophosphamide; Drug: Mesna; Drug: Hematopoietic Factor; Procedure: Primary tumor resection

Interventions

Protracted Oral Etoposide DRUG

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

Protracted Oral Etoposide

Doxorubicin DRUG

Given together with cyclophosphamide for cycle 3 and 5 of induction chemotherapy 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: Doxorubicin 37.5 mg/m2 (1.25 mg/kg if \< 12 kg) IV over 15 minutes

IV Bolus Etoposide; Protracted Oral Etoposide

IV Bolus Etoposide DRUG

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

IV Bolus Etoposide

Cisplatin DRUG

Cycle 1, 2, and 4

IV Bolus Etoposide; Protracted Oral Etoposide

Cyclophosphamide DRUG

Cycle 3 and 5 with doxorubicin

IV Bolus Etoposide; Protracted Oral Etoposide

Mesna DRUG

Standard weight-based dosing with cyclophosphamide

IV Bolus Etoposide; Protracted Oral Etoposide

Hematopoietic Factor DRUG

Standard weight-based dosing after cycle 3 and 5 and if needed for neutropenic recovery after cycles 1,2 and 4

IV Bolus Etoposide; Protracted Oral Etoposide

Primary tumor resection PROCEDURE

Resection of primary tumor after cycle 3, 4, or 5 as clinically appropriate

IV Bolus Etoposide; Protracted Oral Etoposide

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Patients who are pregnant or lactating are not eligible.
• 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.

Sponsors & Collaborators

• Baylor College of Medicine: lead

Study Sites (1)

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Neuroblastoma

Interventions

Doxorubicin; Cisplatin; Cyclophosphamide; Mesna

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

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids

Results Point of Contact

• Title: Peter Zage, MD
• Organization: BAYLOR

pezage@txch.org

832-824-4615

Study Officials

• Peter Zage, MD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: December 19, 2007
• First Posted: December 21, 2007
• Study Start: March 1, 2007
• Primary Completion: July 1, 2009
• Study Completion: March 1, 2015
• Last Updated: March 27, 2020
• Results First Posted: November 6, 2012

Record last verified: 2020-03

Locations

US (1)