Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Syndrome

Lymphoma

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Hematologic Neoplasms

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Leukemia, Lymphocytic, Chronic, B-Cell

Graft vs Host Disease

Hodgkin Disease

Preleukemia

Myelodysplastic Syndromes

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Myeloid Leukemia

Acute Myeloid Leukemia

Lymphosarcoma

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Chronic Graft Versus Host Disease

Acute Non Lymphoblastic Leukemia

Chronic Lymphocytic Leukemia

Homologous Wasting Disease

Hodgkin Lymphoma

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Fludarabine

Fludarabine phosphate

Rituximab

Melphalan

Antineoplastic Agents, Immunological

Immunologic Factors

Antimetabolites

Immunosuppressive Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Fludarabine 30 mg/m\^2 intravenous (IV) for 4 Days + Melphalan 140 mg/m\^2 IV for 1 Day + Rituximab 375 mg/m\^2 IV once weekly + Cord Blood Transplantation + Stem Cell Transplantation Infusion

30 mg/m\^2 by vein for 4 Days (Day -10 through Day -7).

Umbilical Cord Blood

375 mg/m\^2 by vein once weekly (Days -7, -1, +7, +14) for 4 Weeks (if appropriate).

Peripheral Blood Stem Cell Infusion

Partow Kebriaei, MD

The goal of this clinical research study is to learn if giving umbilical cord blood along with standard stem cells after high-dose chemotherapy will improve the response to a stem cell transplant. The safety of this treatment will also be studied.

Cord blood is a source of blood-forming cells that can be used for transplantation. Cord blood cells are taken from the umbilical cords of women who have given birth, and who have volunteered to donate their umbilical cord. Researchers hope that using cord blood before a stem cell transplant will help to reduce the risk of graft-versus-host-disease (GVHD). GVHD occurs when donor cells attack the cells of the person receiving the transplant.

If you are found to be eligible to take part in this study, you will receive chemotherapy for 5 days. You will receive fludarabine over about 30 minutes through a needle in your vein on Days 1-4. You will receive melphalan through a needle in your vein over about 30 minutes on Day 5.

On Day 7, you will receive the cord blood cells through a needle in your vein over about 30 minutes.

On Day 12, you will receive blood stem cells through a needle in your vein over 30-60 minutes. The stem cells you receive will be from a stem cell donor whose human leukocyte antigen (HLA- proteins on cells) type matches yours.

If appropriate for the disease, you will also receive rituximab about once weekly for 4 weeks, beginning on the day you receive melphalan. Rituximab is given though a needle in your vein over 2-3 hours.

You will receive the drugs tacrolimus and methotrexate to lower the risk of GVHD. Tacrolimus will be given through a needle in your vein non-stop for 2 weeks, starting 12 hours after the stem cell transplant. After the first 2 weeks, you will continue to receive tacrolimus by mouth, for at least 3 months. You will receive methotrexate though a needle in your vein over 30 minutes, starting 1 day after the stem cell transplant, for a total of 3 doses over the first 6 days after the stem cell transplant.

You will receive the G-CSF (granulocyte-colony stimulating factor) to help you blood cell counts recover. G-CSF will be given as an injection under the skin, beginning 1 week after the stem cell transplant. You will continue to receive G-CSF once a day until your blood cell counts reach a certain high enough level.

You will need to stay in the hospital for about 4 weeks beginning on Day 1. While you are in the hospital, blood (about 2 teaspoons) will be drawn every day for routine tests.

After you leave the hospital, you will return to the hospital for visits 2-3 times a week for at least 100 days after the transplant. During these visits, you will have a physical exam and blood (about 2 teaspoons) will be drawn for routine tests.

You will be asked to come back to the clinic for follow-up visits at 3, 6, 9 and 12 months after your transplant for routine safety testing. This will include a physical exam, a bone marrow biopsy, and blood (about 2 teaspoons) will be drawn for routine testing.

You will be considered off-study after the 12-month follow-up visit.

This is an investigational study. The stem cell transplant, the umbilical cord transplant, and all drugs used on this study are FDA approved. The use of umbilical cord blood and stem cells together is investigational. Up to 30 patients will take part in this study. All will be enrolled at M. D. Anderson.

Cellular Therapy With Cord Blood Cells

Use of Umbilical Cord Blood Cell in the Preparative Regimen of Patients With Advanced Hematologic Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Engraftment defined as first of three (3) consecutive days with Absolute neutrophil count (ANC) equal to or more than 0.5 \* 10\^9/L; assessed from baseline to 100 days post-engraftment.

M.D. Anderson Cancer Center

Age Continuous

Sex: Female, Male

United States

Region of Enrollment

Dr. Partow Kebriaei

Fludarabine 30 mg/m\^2 given daily for four days. Melphalan 140 mg/m\^2 given for one day. Umbilical Cord Blood Unit given on one day.

Fludarabine + Melphalan + Umbilical Cord Blood Unit

Number of Participants With Engraftment

Overall Study

Recurrence

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Amino Acids

Etoposide

Carboplatin

Lenograstim

Etoposide phosphate

Mechlorethamine

3-Iodobenzylguanidine

Enzyme Inhibitors

Phenylalanine

This is a single arm study. The following description applies to all the patients who are enrolled in the study:

On Day -21, patients receive 131I-MIBG infusion.

On Day -7, Day -6, Day -5, patients receive Carboplatin, Etoposide, Melphalan.

On Day -4, patients receive Carboplatin, Etoposide.

On Day -3, Day -2, Day -1, patients rest.

On Day 0, patients receive peripheral blood stem cell infusion.

Dosing of Carboplatin, Etoposide and Melphalan is based upon whole body dosimetry (cGy) estimates.

Filgrastim 5 micrograms/kg/day S.C. or IV will be given daily beginning on Day 0.

Local radiation therapy is to be given to previously non-irradiated primary and metastatic sites of disease.

Filgrastim 5 micrograms/kg/day S.C. or IV will be given daily beginning on Day 0. The first dose should begin four hours after the stem cell infusion is completed. Filgrastim will continue daily until the ANC \>=1500/uL for three consecutive days.

Filgrastim

The carboplatin will be administered as a continuous IV infusion Day - 7 through Day - 4, with dosing based upon pretreatment GFR levels. The carboplatin should be diluted to a concentration of 0.3 mg/ml in D5W 0.45NS and infused concomitantly with etoposide through the same central venous catheter using a "Y" connector; a controlled rate infusion pump is used for each arm of the "Y".

The etoposide shall be administered day -7 through day -4 via continuous intravenous infusion over 96 hours. For patients with a corrected GFR \>= 100 ml/min/1.72 m\^2, a dose of 300 mg/m\^2/day (10 mg/kg/day if child is \< 12 kg) shall be given. For patients with a corrected GFR 60-99 ml/min/1.72 m\^2, the etoposide will be administered at a dose of 160 mg/m\^2/day (5.3 mg/kg/day). The etoposide will be diluted in D5W 0.45%NS at a concentration of \< 0.4 mg/ml. Etoposide should not be mixed with carboplatin, but administered using a Y-connector.

For patients in either the normal GFR strata (\>=100 ml/min/1.73 m\^2), or reduced GFR strata (60-99 ml/min/1.73m\^2), melphalan shall be administered at a dose of 60 mg/m\^2/day (2 mg/kg/day if child is \< 12 kg) on day -7, -6, and -5 of study. The melphalan should be infused at a rate of less than 10 mg/minute, and should complete within 1 hour of reconstitution each day. The melphalan should be diluted in 0.9% NaCl at a concentration \< 2 mg/ml. The total dosage of melphalan to be administered will be 180 mg/m\^2.

Stem cells or marrow will be infused on day 0 of study therapy. Where the DMSO concentration in the stem cell product would exceed accepted level for infusion within a 24 hour period, stem cell products may be infused over two days to meet this standard. For purged PBSC: A minimum of 2.0 x 10\^6 viable CD34+ cells/kg must be available. For unpurged PBSC, a minimum of 2.0 x 10\^6 viable CD34+ cells/kg must be available. Having a back-up of 2.0 x 10\^6 viable CD34+ cells/kg purged or unpurged PBSC is recommended but not required. For purged bone marrow, a minimum of 1.5 x10\^8 mononuclear cells/kg must be available.

Peripheral blood stem cell infusion

Therapeutic 131I MIBG will be synthesized by Draximage Canada.with specific activity between 15 and 25mCi/ml. Radiopurity will be initially determined by Draximage, prior to shipment to participating centers. Free radioiodide content must then be rechecked at the treating center prior to infusion using HPLC or Sep-Pac methodology.

131I-MIBG

Local irradiation is to be given to previously non-irradiated primary and metastatic sites of disease. Local irradiation should not start till the patient is medically stable, has an ANC \> 1000/uL, platelets \> 30,000 / uL, and is \> 42 days post transplant. Recommended radiation guidelines consist of 2160 cGy total, given over 12 days using a single 180 cGy fraction/day. Any delay in local radiation that would extend treatment beyond day +84 should be discussed with the study chair. Local radiation will be administered at a participating NANT member site.

Radiation therapy

Gregory Yanik, MD

Katherine K. Matthay, MD

John M. Maris, MD

RATIONALE: Radioactive drugs, such as iodine I 131 metaiodobenzylguanidine, may carry radiation directly to tumor cells and not harm normal cells. Drugs used in chemotherapy, such as carboplatin, etoposide, and melphalan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. An autologous peripheral stem cell or bone marrow transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. Giving iodine I 131 metaiodobenzylguanidine and combination chemotherapy with an autologous peripheral stem cell or bone marrow transplant may allow more chemotherapy to be given so that more tumor cells are killed. Giving radiation therapy after an autologous peripheral stem cell or bone marrow transplant may kill any remaining tumor cells.

PURPOSE: This phase II trial is studying how well giving iodine I 131 metaiodobenzylguanidine together with combination chemotherapy and radiation therapy works in treating patients who are undergoing an autologous peripheral stem cell or bone marrow transplant for relapsed or refractory neuroblastoma.

OBJECTIVES:

Primary

* Determine the response rate in patients with relapsed or refractory neuroblastoma treated with iodine I 131 metaiodobenzylguanidine (\^131I-MIBG) and combination chemotherapy comprising carboplatin, etoposide, and melphalan followed by autologous bone marrow or peripheral blood stem cell transplantation and radiotherapy.

Secondary

* Determine the hematopoietic and nonhematopoietic toxicity of this regimen in these patients.
* Determine the tumor self-absorbed radiation dose (TSARD) in patients with measurable soft tissue lesions treated with this regimen.
* Correlate the TSARD with tumor response in patients with measurable residual soft tissue disease treated with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to risk (poor-risk group \[mixed or no response to induction therapy or progression during or after induction therapy\] vs good-risk group \[partial response after 4 courses of induction therapy\]) and kidney function at study entry (glomerular filtration rate \[GFR\] ≥ 100 mL/min vs GFR 60-99 mL/min)

* Stem cell harvest: Patients undergo a peripheral blood stem cell harvest or bone marrow harvest provided they have an adequate number of cells available. At least 2 weeks later, patients proceed to iodine I 131 metaiodobenzylguanidine (\^131I-MIBG) and combination chemotherapy.
* 131I-MIBG and combination chemotherapy: Patients receive \^131I-MIBG IV over 2 hours on day -21, carboplatin IV continuously on days -7 to -4, etoposide IV continuously on days -7 to -4, and melphalan IV over 1 hour on days -7 to -5.
* Stem cell infusion and filgrastim (G-CSF): Three days after completion of chemotherapy, patients undergo transplantation of either stem cells or bone marrow on day 0. Patients also receive G-CSF subcutaneously or IV over 1 hour once daily beginning on day 0 and continuing until blood counts return to normal.
* Radiotherapy: Once blood counts return to normal, patients undergo radiotherapy to primary and metastatic sites that have not received previous irradiation over 12 days beginning after day 42.

After completion of study treatment, patients are followed for 2 years and then periodically thereafter.

PROJECTED ACCRUAL: Approximately 50 patients (40 low-risk patients and 8-10 high-risk patients) will be accrued for this study.

N2001-02: I-MIBG With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma

I-Metaiodobenzylguanidine (MIBG) With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma

Tumor response based on evaluation performed on day 60 or at the time of disease progression/recurrence or start of another treatment - whichever comes first. Such evaluations will include 123I-MIBG scan, CT/MRI, urine catecholamine measurement, and bone marrow analysis (for those with marrow disease at study entry).

EFS will be measured from start of treatment until progression, death or start of another treatment - whichever comes first. We report the estimated probability of EFS at 3 years.

• Engraftment toxicity: delayed engraftment and/or failure to engraft defined as:

* neutrophils (ANC) \< 500/μL by day 28 post transplant, or
* platelets \< 20,000 /μL by day 56 post transplant, or
* if additional stem cells are required to be infused for any medical reason prior to initial engraftment of neutrophils or platelets.

Dose limiting veno-occlusive disease (VOD) defined as:

* the presence of hepatomegaly with right upper quadrant tenderness and an elevation of total bilirubin \> grade 1, PLUS
* the presence of grade 3 abnormalities of any ONE of the following: total bilirubin, hypoalbuminemia, weight gain, or hypoxia without other attribution

National Cancer Institute (NCI)

Children's Hospital Los Angeles

NANT Operations Center

Poor risk patients are those who experienced a Minor response (MR) or No Response (NR) to induction therapy or progressive disease (PD) during or following induction.

Poor Risk Patients

Good risk patients are those who experienced a Partial Response (PR) following 4 cycles of induction.

Good Risk Patients

Total

Age (in years) at time of treatment start.

Age, Continuous

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Normal GFR

Low GFR

Pre-therapy glomerular filtration rate:

Normal GFR: \>= 100 ml/min/1.73 m2 \& Low GFR: 60-99 ml/min/1.73 m2

GFR Status

Number of patients who signed the consent form and started treatment.

Araz Marachelian, MD, NANT Medical Director

One patient in the Poor Risk Cohort underwent surgery for resection (of his only measureable lesion) prior to post-treatment assessment and is not evaluable for response.

Response (Complete Response, Very Good Partial Response, and Partial Response) at 60-days Post Stem Cell Infusion

Estimated probability of 3-year progression free survival for all patients enrolled in each risk group.

Event-free Survival (EFS) at 3 Years

Engraftment DLT

Dose Limiting Veno-occlusive Disease (VOD) / Sinusoidal Obstruction Syndrome SOS

Anti-Infective Agents

Mycophenolic Acid

Tacrolimus

Thymoglobulin

Antilymphocyte Serum

Total Lymphoid Irradiation (2 times) at 80 cGy daily for five days + Thymoglobulin 1.5 mg/kg intravenous 5 days + Rituximab 375 mg/m\^2 intravenous on 4 different days + Blood stem cell transplant (BSCT)

80 cGy daily on days -11 to -7 and -4 to 0.

Total Lymphoid Irradiation

375 mg/m\^2 by vein on days -13, -6, 1, \& 8. Only those patients whose tumors express CD20 will receive Rituximab.

Chitra M. Hosing, MD

Primary Objective:

1. To determine whether the primary endpoint: the composite success rate, defined as the proportion of patients who are alive at day 100; and are without grade 3-4 Graft versus Host Disease (GVHD); and are without grade 4 toxicity (unrelated to infection); and have engrafted, is likely to be at least 40%.

Secondary Objectives:

1. To determine the cumulative incidence of chronic graft versus host disease.
2. To determine the overall and disease free survival.

The combination of drugs used for this study will help to weaken your immune system, which may help to allow the donor's blood stem cells to engraft (grow) in your body.

Anti-thymocyte globulin (also called ATG or thymoglobulin) is designed to help reduce the risk of transplant rejection and to help prevent graft versus host disease.

Rituximab is designed to attach to lymphoma cells, which may cause them to die.

If you are found to be eligible to take part in this study, you will be admitted to the hospital 12 days before the blood stem cell transplant (BSCT), in order to start the pre-transplant treatments and testing. You will have blood (about 1 tablespoon) drawn for routine tests every day while you are in the hospital (before and after the transplant). After the transplant, this blood will be used to check the status of the transplant and watch for any side effects.

You will receive radiation therapy (total lymphoid irradiation) for a total of 10 days before the planned transplant. Radiation therapy will not be given on the weekends. The last radiation treatment will be on the morning of the day you receive your stem cell transplant.

For a total of 5 days after admission to the hospital, you will also receive ATG. ATG will be given through a catheter (plastic tube) that is placed into the large chest vein. The catheter (called a central venous catheter) will stay in place throughout treatment.

You will receive certain drugs as premedication to try to prevent an allergic reaction to the ATG. These may include drugs like acetaminophen (Tylenol), diphenhydramine (Benadryl), and/or steroids which may include solumedrol or prednisone. Tylenol is given by mouth, and Benadryl and steroids are given either by vein (over 10-15 minutes) or by mouth.

The combination of ATG and radiation will weaken your immune system. A weakened immune system may help to allow your body to "accept" donor cells, and it may decrease the chance of your body rejecting the cells.

If your diagnostic biopsy showed that a certain protein was found on your tumor cells, you may also receive rituximab therapy. If you are eligible for rituximab treatment, you will receive the drug once a week for 4 weeks. You will receive rituximab through the central venous catheter or through a vein over 6-8 hours. The first dose will be given on an outpatient basis at 13 days before the stem cell transplant. The next 3 doses may be given in the hospital or on an outpatient basis. You will receive rituximab 6 days before the transplant, and then 1 and 8 days after the transplant. Tylenol and steroids will be given before the rituximab to try to prevent an allergic reaction.

You will be given tacrolimus to try to prevent graft versus host disease (when the donor's immune cells react against the recipient's body, attacking the recipient's cells and tissues). You will receive tacrolimus either through the central venous catheter (over 24 hours each time) or by mouth starting 3 days before the stem cell transplant. You will continue receiving tacrolimus as long as your doctor feels it is necessary, which could be anywhere from about 3 months to several years. This will depend on factors such as whether or not you have graft versus host disease, how many donor cells are in your blood, and the status of your disease.

Cellcept (MMF) will also be given to try to prevent graft versus host disease, starting 1 day after the transplant and continuing through Days 28-42 after the transplant. The MMF will be given twice a day through the central venous catheter over 2 hours, or by mouth.

After the pre-transplant treatments and testing are finished, you will have the blood stem cell transplant. Blood stem cells from a donor will be infused over about 1 hour through your central venous catheter. This can be done while you are in the hospital or on an outpatient basis at M. D. Anderson. Steroids and Benadryl will be given through the catheter before the stem cell transplant to try to prevent an allergic reaction. The catheter will be removed once you no longer need to be given fluids, blood products, and other treatments through the catheter for graft versus host disease. This may take anywhere from 3 months after the transplant to several years.

You will have additional blood (about 2 tablespoons) drawn, bone marrow aspirations and biopsies, chest CT scans, and/or chest x-rays performed as needed to check the effects of the transplant. You will have transfusions of blood and platelets as needed, and you will have to sign a separate consent document for these transfusions.

Blood (about 1 tablespoon each time) will also be drawn at least 2-3 times a week for at least 100 days after the transplant, or longer if the study doctor feels it is necessary.

Treatment will be given in the hospital or an outpatient basis at M. D. Anderson. You may need to stay in the hospital for 3-4 weeks. You will be taken off the study if your disease gets worse.

This is an investigational study. The FDA has approved the drugs used in this study. Their use together in this study is investigational. Up to 40 patients will take part in this study. All will be enrolled at M. D. Anderson Cancer Center.

Thymoglobulin and Total Lymphoid Irradiation for Hematologic Malignancies

Total Lymphoid Irradiation, Thymoglobulin, and Rituximab for Allogeneic Transplantation in Lymphoid Malignancies

Defined as the proportions of the patients who are alive at day 100, are without Grade 3-4 Graft Graft-versus-host disease (GVHD), without Grade 4 toxicity (unrelated to infection) and have engrafted. Toxicity grades according to Common Toxicity Criteria (CTC) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Genzyme, a Sanofi Company

Radiation + Chemotherapy + BSCT

Early termination due to financial support.

Chitra M. Hosing, MD/Associate Professor

Engraftment

Acute GvHD

alive at 100 days

Analysis was per protocol. One participant was inevaluable.

Composite Success Rate

Vorinostat

Histone Deacetylase Inhibitors

Radiopharmaceuticals

Patients on study will receive vorinostat orally once daily on days 1 to 14. The starting dose level is 180 mg/M2. The maximum dose is 400 mg. Patients will receive 131- I Metaiodobenzylguanidine on day 3, 1hr after vorinostat dosing. Patients will initially receive 8 mCi/kg 131-I MIBG with 180 mg/m2/dose vorinostat. The dose of 131-I MIBG will be escalated in subsequent cohorts to 15 mCi/kg and then to 18 mCi/kg. Peripheral Blood Stem Cell Infusion is planned for 2 weeks after MIBG infusion (day 17). The dose for Purged PBSC is a minimum of 2 x 106 viable CD34+ cells/kg and for Unpurged PBSC: a minimum of 2 x 106 viable CD34+ cells/kg. Stem cells must be infused over 15-30 minutes and within 1.5 hours of thawing. Patients will receive filgrastim following hematopoietic stem cell infusion according to institutional guidelines.

Patients on study will receive vorinostat orally once daily on days 1 to 14 of treatment.This is a single course treatment. The study has a planned dose escalation schedule, the starting dose level is 180 mg/M2.The maximum absolute dose of vorinostat is 400 mg.

Patients will receive 131-I MIBG on day 3 , one hour after vorinostat dosing.Patients will initially receive 8 mCi/kg 131-I MIBG with 180 mg/m2/dose vorinostat. The dose of 131-I MIBG will be escalated in subsequent cohorts to 15 mCi/kg and then to 18 mCi/kg.If the starting dose exceeds the maximum tolerated dose, patients will be treated with a lowering of vorinostat dose initially (150 mg/m2/day . Dose level -1). If this combination still exceeds the maximum tolerated dose, then a dose level using reduced dose 131-I MIBG will be studied (6 mCi/kg. Dose level -2).

131- I Metaiodobenzylguanidine

Stem cell infusion is planned for 2 weeks after MIBG infusion (day 17). However, stem cells may be infused on day 18 or day 19 to avoid weekend or holiday stem cell infusions.The dose for Purged PBSC is a minimum of 2 x 106 viable CD34+ cells/kg and for Unpurged PBSC: a minimum of 2 x 106 viable CD34+ cells/kg must be available. Stem cells must be infused over 15-30 minutes and within 1.5 hours of thawing.Stem cells will be infused following institutional guidelines for prophylaxis of hypersensitivity reactions and monitoring.

All patients will receive filgrastim following hematopoietic stem cell infusion according to institutional guidelines (section 4.2.3 of protocol).

Steven DuBois, MD

RATIONALE: Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radioactive drugs, such as iobenguane I 131, may carry radiation directly to tumor cells and not harm normal cells. Giving vorinostat together with iobenguane I 131 may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of giving vorinostat together with iobenguane I 131 in treating patients with resistant or relapsed neuroblastoma.

OBJECTIVES:

Primary

* To determine the maximum tolerated dose of vorinostat in combination with iobenguane I 131 in patients with resistant or relapsed neuroblastoma.
* To define the toxicities of vorinostat in combination with therapeutic doses of iobenguane I 131 in these patients.

Secondary

* To describe, within the context of a phase I study, the response rate in patients treated with vorinostat and iobenguane I 131.
* To describe histone acetylation levels and norepinephrine transporter mRNA levels in peripheral blood mononuclear cells after treatment with different doses of vorinostat.

OUTLINE: This is a multicenter study.

Patients receive oral vorinostat once daily on days 1-14 and iobenguane I 131 IV over 1½-2 hours on day 3. Patients undergo autologous peripheral blood stem cell transplantation on day 17.

Blood samples may be collected periodically for correlative biological studies.

After completion of study treatment, patients are followed up periodically.

N2007-03: Vorinostat and 131-I MIBG in Treating Patients With Resistant or Relapsed Neuroblastoma

Vorinostat With 131-I MIBG Therapy for Resistant/Relapsed Neuroblastoma: A Phase I Study IND# 105,744

All toxicities observed will be summarized in terms of type (organ affected or laboratory determination), severity (by NCI CTCAE) and attribution. Tables will be created to summarize these toxicities and side effects by dose level and by course.

Eligible patients with measurable or evaluable disease who receive 131-I MIBG are evaluable for response even if they fail to complete the course of therapy because of disease progression. Responses will be described for all patients registered on the study even if there are major protocol deviations .

Collection of samples for correlative biology is optional and not required for study entry. Although these studies are not mandated, all institutions are strongly urged to submit specimens for all consenting patients.

New Approaches to Neuroblastoma Therapy Consortium

Buthionine Sulfoximine

Protective Agents

Radiation-Protective Agents

Dose fixed at a bolus of 3 gm/M2 given over 30 minutes followed by a continuous infusion of 1 gm/M2/hour for 72 hours (total 72.5 hours).Total daily infusion dose (minus the initial bolus)will be 24 gm/m2/day.

buthionine sulfoximine

The dose level of melphalan will be assigned at study entry onto protocol. There will be 6 dose levels ranging from 20mg/m2/day x 2 days (dose level 1a) to 62.5 mg/m2/day x 2 days (dose level 6a). The starting dose level will be 1a, with a decrease to level 0a (15mg/m2/day x2 days) if there is unacceptable toxicity.

melphalan

Stem cells will be infused intravenously on day 0 , 24 hours after BSO continuous infusion is completed.Infused within 1.5 hours of thawing via a central venous catheter over 15-30 minutes.

5 microgram/kg/day , subcutaneous or intravenous, given daily beginning day 0. First dose to begin 4 hours after completion of stem cell infusion and then to continue till ANC \>/= 1500 mm3 for three consecutive days.

Samuel Volchenboum, MD

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with bone marrow or peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.

PURPOSE: Phase I trial to study the effectiveness of melphalan and buthionine sulfoximine followed by bone marrow or peripheral stem cell transplantation in treating children who have resistant or recurrent neuroblastoma.

OBJECTIVES:

* Determine the maximum tolerated dose of melphalan when combined with buthionine sulfoximine and followed by autologous bone marrow or peripheral blood stem cell support in children with resistant or recurrent high-risk neuroblastoma.
* Assess the toxic effects of this regimen in these patients.
* Determine the pharmacokinetics of this regimen in these patients.
* Determine the response rate of patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of melphalan.

Patients receive buthionine sulfoximine IV as a bolus over 30 minutes followed by a 72-hour continuous infusion beginning on day -4; melphalan IV over 15 minutes on days -3 and -2; autologous peripheral blood stem cells or bone marrow IV over 15-30 minutes on day 0; and filgrastim (G-CSF) subcutaneously or IV once daily beginning on day 0 and continuing until blood counts recover.

Cohorts of 3-6 patients receive escalating doses of melphalan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed at 84 days and then 2 months later if there is a complete and/or partial response. Patients who continue therapy on other protocols are followed before starting the new therapy. All patients are followed for life for any delayed toxic effects to protocol therapy and secondary malignancies.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study within 2-3 years.

N99-02: Melphalan and Buthionine Sulfoximine

Modulation of Intensive Melphalan (L-PAM) by Buthionine Sulfoximine (BSO) Autologous Stem Cell Support for Resistant or Recurrent High-Risk Neuroblastoma (IND 69-112)

Collection of blood samples for PK studies is optional and not required for study entry.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cellular Therapy With Cord Blood Cells	NCT00427557	Multiple Myelom... Leukemia Lymphoma	Fludarabine Melphalan Umbilical Cord ... Rituximab Peripheral Bloo...	- 80 Years	M.D. Anderson Cancer Center
Cellular Therapy With Cord Blood Cells	NCT00427557	Multiple Myelom... Leukemia Lymphoma	Fludarabine Melphalan Umbilical Cord ... Rituximab Peripheral Bloo...	- 80 Years	M.D. Anderson Cancer Center
N2001-02: I-MIBG With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma	NCT00253435	Neuroblastoma	Filgrastim Carboplatin Etoposide Melphalan Peripheral bloo... 131I-MIBG Radiation thera...	1 Year - 29 Years	Children's Hospital Los Angeles
N2001-02: I-MIBG With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma	NCT00253435	Neuroblastoma	Filgrastim Carboplatin Etoposide Melphalan Peripheral bloo... 131I-MIBG Radiation thera...	1 Year - 29 Years	Children's Hospital Los Angeles
Thymoglobulin and Total Lymphoid Irradiation for Hematologic Malignancies	NCT00476229	Lymphoma Leukemia	Thymoglobulin Total Lymphoid ... Peripheral Bloo... Rituximab	- 70 Years	M.D. Anderson Cancer Center
Thymoglobulin and Total Lymphoid Irradiation for Hematologic Malignancies	NCT00476229	Lymphoma Leukemia	Thymoglobulin Total Lymphoid ... Peripheral Bloo... Rituximab	- 70 Years	M.D. Anderson Cancer Center
N2007-03: Vorinostat and 131-I MIBG in Treating Patients With Resistant or Relapsed Neuroblastoma	NCT01019850	Neuroblastoma	Vorinostat 131- I Metaiodo... Peripheral Bloo... Filgrastim	2 Years - 30 Years	New Approaches to Neuroblastoma Therapy Consortium
N2007-03: Vorinostat and 131-I MIBG in Treating Patients With Resistant or Relapsed Neuroblastoma	NCT01019850	Neuroblastoma	Vorinostat 131- I Metaiodo... Peripheral Bloo... Filgrastim	2 Years - 30 Years	New Approaches to Neuroblastoma Therapy Consortium
N99-02: Melphalan and Buthionine Sulfoximine	NCT00005835	Neuroblastoma	buthionine sulf... melphalan Peripheral bloo... Filgrastim	- 30 Years	New Approaches to Neuroblastoma Therapy Consortium
Thymoglobulin and Total Lymphoid Irradiation for Hematologic Malignancies	NCT00476229	Lymphoma Leukemia	Thymoglobulin Total Lymphoid ... Peripheral Bloo... Rituximab	- 70 Years	M.D. Anderson Cancer Center
N99-02: Melphalan and Buthionine Sulfoximine	NCT00005835	Neuroblastoma	buthionine sulf... melphalan Peripheral bloo... Filgrastim	- 30 Years	New Approaches to Neuroblastoma Therapy Consortium

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