Clinical trial NCT00578864
Conditions: Neuroblastoma
Keywords: Neuroblastoma Etoposide Cisplatin Adriamycin Cyclophosphamide Cytoxan
Sponsor: Baylor College of Medicine
Start date: 2007-03-01; Completion date: 2015-03-01
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:
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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Protracted Oral Etoposide intervention 2: Doxorubicin intervention 3: IV Bolus Etoposide intervention 4: Cisplatin intervention 5: Cyclophosphamide intervention 6: Mesna intervention 7: Hematopoietic Factor intervention 8: Primary tumor resection
Intervention descriptions: intervention 1: 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 intervention 2: 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 intervention 3: 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 intervention 4: Cycle 1, 2, and 4 intervention 5: Cycle 3 and 5 with doxorubicin intervention 6: Standard weight-based dosing with cyclophosphamide intervention 7: Standard weight-based dosing after cycle 3 and 5 and if needed for neutropenic recovery after cycles 1,2 and 4 intervention 8: Resection of primary tumor after cycle 3, 4, or 5 as clinically appropriate

Protocol documents: