Neoplasms

Symptoms and General Pathology

All Conditions

Rare Diseases

Neoplasm Metastasis

Pheochromocytoma

Paraganglioma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Paragangliomas 1

Neuroendocrine Tumor

Neuroepithelioma

Anti-Dyskinesia Agents

All Drugs and Chemicals

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Dermatologic Agents

Amino Acids

Carbidopa

Prednisolone

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Tretinoin

3-Iodobenzylguanidine

alpha-Methyltyrosine

Enzyme Inhibitors

Radiopharmaceuticals

Tyrosine

[131]I-MIBG

6-[18F]Fluorodopamine

[123]I-MIBG

This study will evaluate the effectiveness of 131MIBG in treating malignant pheochromocytoma and whether sensitization medications improve the response to treatment. Pheochromocytoma is a rare type of tumor that usually occurs in the adrenal glands. The tumor cells release chemicals like adrenaline that can cause large increases in blood pressure and pulse rate, with serious health consequences. Tumor in the adrenal glands usually can be removed surgically, but if the pheochromocytoma is malignant-i.e., has spread to many sites in the body-or is located in places where surgery is difficult or impossible, no satisfactory treatment is available. 131MIBG is a combination of an adrenaline-like chemical and a radioactive form of iodine. The 131MIBG attaches to the tumor cells and the high concentration of radioactive iodine kills them. Previous studies using 131MIBG to treat pheochromocytoma had a 36% response rate in terms of complete or partial improvement. This study will examine whether adding other sensitization medications to the 131MIBG treatment regimen will enhance its effectiveness in reducing the size and number of tumors.

Patients 18 years of age and older with malignant or inoperable pheochromocytoma may be eligible for this 18-month study. Candidates will be screened with various tests and procedures, which may include a medical history, physical examination, blood and urine tests, lung function studies, electrocardiogram, echocardiogram, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and bone scans and other scans using radioactive MIBG and octreotide.

Participants will be randomly assigned to one of two treatment groups: 1) 131MIBG plus sensitization medications, or 2) 131MIBG alone. All patients will be hospitalized 3 to 5 days for each 131MIBG treatment. The drug will be infused through a vein (intravenously, or I.V.) over 10 to 30 minutes. Patients will receive up to 3 treatments, separated by at least 3 months. All patients will also take potassium to protect the thyroid gland from radioactive iodine generated by the 131MIBG. The potassium is taken twice a day for 30 days, beginning the day before the 131MIBG treatment. Patients in the sensitization group will receive the following additional drugs for sensitization: methylprednisolone, intravenously a few minutes before 131MIBG treatment; Roaccutan, by mouth (capsules) twice a day for 6 weeks before treatment; Demser, by mouth 3 times a week for 1 week before treatment, and Carbidopa, by mouth every 6 hours for 4 days before treatment.

After each treatment, patients will have a clinical evaluation and periodic blood tests to check for adverse side effects of radiotherapy. Follow-up visits at NIH will be scheduled at 12 and 18 months after the first 131MIBG treatment for clinical, laboratory and imaging tests. Patients who had tumors in the lungs before treatment will have lung function tests 1, 3, and 6 months after each treatment. CT, MRI 131MIBG, and PET scanning will be done 1 week before each treatment.

Patients who have tumors that have grown by more than 25% and none that have shrunk by more than 50% or who have developed one or more new tumors while on 131MIBG treatment will be taken off the study.

Pheochromocytomas are tumors of chromaffin cells that synthesize catecholamines. This project tests the efficacy of radiotoxic treatment of malignant pheochromocytoma using (131)I-metaiodobenzylguanidine \[(131)I-MIBG\], and in particular, tests whether pre-treatment with enhancer pharmaceuticals increases the efficacy of experimental (131)I-MIBG treatment in reducing the size and number of tumors and the tumor burden.

131MIBG to Treat Malignant Pheochromocytoma

(131)I-Metaiodobenzylguanidine Treatment of Malignant Pheochromocytoma

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

James C. Reynolds, M.D./National Institute of Child Health and Human Development

Blood and Lymph Conditions

Leukemia

Leukemia, Myelomonocytic, Juvenile

Leukemia, Myelomonocytic, Acute

Leukemia, Myelomonocytic, Chronic

Hematologic Diseases

Leukemia, Myeloid

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Acute Graft Versus Host Disease

Chronic Graft Versus Host Disease

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Antirheumatic Agents

Cyclophosphamide

Melphalan

Busulfan

Antilymphocyte Serum

Mesna

Stem Cell Transplant

* Busulfan
* Cyclophosphamide
* Mesna
* Melphalan
* Anti-thymocyte Globulin (ATG)

Preparative Regimen

Margaret MacMillan, MD

The investigators hypothesize that long-term disease-free survival (DFS) in patients with JMML can be achieved with a treatment of busulfan (BU), cyclophosphamide (CY) and melphalan (L-PAM) followed by hematopoietic cell transplantation (HCT).

Prior to transplantation, subjects will receive BUSULFAN via the central venous line, six times a day for four days, CYCLOPHOSPHAMIDE via the central venous line once a day for two days, and MELPHALAN via the central venous line for one day. Busulfan, cyclophosphamide, and melphalan are given to destroy the subject's leukemia. As well, these drugs will destroy the subject's own immune system to help ensure the new bone marrow takes and grows after transplantation.

On the day of transplantation, bone marrow or umbilical cord blood from the donor will arrive to the bone marrow transplant unit and be transfused via venous line. These new cells will replace the subject's bone marrow.

Stem Cell Transplant for Juvenile Myelomonocytic Leukemia (JMML)

Hematopoietic Cell Transplantation in Children With Juvenile Myelomonocytic Leukemia

Masonic Cancer Center, University of Minnesota

Patients receiving study regimen.

Stem Cell Transplant: Transplantation on Day 0.

Preparative Regimen: - Busulfan

* Cyclophosphamide
* Mesna
* Melphalan
* Anti-thymocyte Globulin (ATG)

Intent-to-Treat

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Margaret MacMillan, MD

Determine Probability of Long-term Disease Free Survival in JMML

Combined Incidence of Neutrophil Engraftment, Graft-versus-host Disease (GVHD), Regimen-related Toxicity, and Relapse.

Overall Study

Recurrence

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neoplasms, Neuroepithelial

Neoplasms, Glandular and Epithelial

Anti-Infective Agents

Analgesics

Antibodies

Molgramostim

Sargramostim

Aldesleukin

Immunomodulating Agents

Immunoglobulins

Isotretinoin

Interleukin-2

Dinutuximab

Immunologic Factors

Analgesics, Non-Narcotic

Keratolytic Agents

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Standard IL-2 i.v. together with antibody ch14.18, GM-CSF and retinoic acid

IL-2 s.c. together with antibody ch14.18, GM-CSF and retinoic acid

17.5mg/m²d 10-20h i.v, d4-7 in cycles 1,3,5 and d8-11 in cycles 2,4.

antibody ch14.18

250µg/m²xd, d1-14 s.c. or i.v (2h) in cycles 1,3,5

GM-CSF

3.0 mio U/m²xd d1-4 continuous infusion i.v. and 4.5 mio U/m²xd d8-11 continuous infusion i.v. in cycles 2,4

IL-2 i.v.

0.06 mio U/m² i.v. test dosis for 30min. i.v. at least 2h before first subcutaneous (s.c.) application. 6 mio U/m²xd d1-5 and 8-12 s.c. in cycles 2,4

IL-2 s.c.

160mg/m²xd b.i.d.oral d 11-24 in cycles 1,3,5,6 and d15-28 in cycles 2,4

Retinoic acid

Frank Berthold, Prof. Dr.

Although the five year survival rate of children with high risk neuroblastoma have increased over the last three decades from 4 to 44 % (1), neuroblastoma is the second most frequent cause for cancer related death in childhood (11 %). Most patients show good initial response rates (complete (CR) and partial remission (PR) rate 95 %), but 55 % experience a largely treatment-resistant tumor progression.

Recently, a breakthrough with immunotherapy was reported by US investigators from the Children's Oncology Group (2) using the anti-ganglioside D2 (GD2) monoclonal antibody ch14.18 for tumor cell destruction and granulocyte macrophage-colony stimulating factor (GM-CSF) plus interleukin 2 (IL-2) for immunostimulation. This immune therapy resulted in an increase of 20 % Event free survival (EFS) at 2 year from randomization. However, this was associated with a high toxicity rate (pain, capillary leak syndrome).

The proposed trial compares the Childrens' Oncology Group (COG) "standard of care" arm (anti-GD2 + GM-CSF + IL-2 i.v. + retinoic acid oral) with an experimental arm (anti-GD2 + GM-CSF + IL-2 s.c. + retinoic acid oral) designed to reduce toxicity.

The potential benefit from this trial consists of the confirmation that the American trial design is feasible in an independent set of patients with different preceding therapy, at a different time point regarding to immune reconstitution after autologous stem cell transplantation (ASCT), the feasibility of a newly designed immunotherapy (which is hopefully less toxic) and the investigation of immune response parameters. This pilot study is the prerequisite for a consecutive randomized clinical trial comparing two immunotherapeutic approaches in a larger set of patients.

Neuroblastoma is the second most frequent solid tumour (7.6%) and the second cause of cancer related death (11%) in childhood. In particular the large high risk (HR) group has remained a challenge to Paediatric Oncologists. Although the 5 year survival rates of children with HR disease have increased over the last 3 decades from 4 to 44.4%, the vast majority of those children will finally succumb to disease \[1\]. Most patients show good initial responses to chemotherapy (CR + PR-rate 95 %), but a majority experiences a highly treatment resistant tumour progression (55%). Therefore new therapeutic modalities are urgently needed.

Recently, a randomized trial demonstrated that an immunotherapeutic concept using the anti-GD2 antibody ch14.18 together with interleukin 2, GM-CSF and retinoic acid improved the outcome of neuroblastoma patients which achieved CR or very good partial remission (VGPR) response to the preceding therapy. This treatment was associated with a high rate of toxic effects (neuropathic pain 52% of patients, capillary leak syndrome 23%). An earlier study using the antibody ch14.18 alone made comparable observations: pain despite of analgesia was seen in 33% of patients and severe capillary leak syndromes in 3 of 151 children. Differences of the reported frequencies are due to the different definitions of side effects.

The investigators therefore propose a randomized clinical trial comparing the COG immunotherapy concept with newly designed hopefully equally effective but less toxic concept. This modifies the application route of IL-2 from i.v. to s.c. and increases the IL-2 dose to 6.0 mio/m²xd (from 3.0 first week and 4.5 mio second week i.v.). Oral retinoic acid is used in both arms. The proposed randomized trial will answer the following questions:

(i) Confirmation of the feasibility to apply the COG immunotherapy as consolidation treatment after a different remission induction therapy in patients with recurrent and de novo high risk neuroblastoma (ii) Investigation of the feasibility to apply the new immunotherapy concept in patients with recurrent high risk neuroblastoma (iii) Comparison of the toxicity of both immunotherapy regimens with the aim to reduce grade 2 - 4 toxicities in the experimental arm.

(iv) Comparison of the immune response (antiidiotype antibodies, immune cell phenotypes, immune mediators, functional assays as antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) between treatment cycles (intraindividual), treatment arms (interindividual) and between recurrent and newly diagnosed patients (v) Comparison of pharmacokinetics of antibody ch14.18 in both arms (12.10.) (vi) Comparison of therapeutic efficacy by response evaluation at the end of the 25 week treatment (descriptive).

(vii) Comparison of patients´ QoL experienced in both immunotherapy regimens as indicated by parents rating in appropriate questionnaires.

NB2013-HR German (GPOH) / Dutch (DCOG) Trial

Randomized Phase 2 Trial Comparing Experimental Immunotherapy in Recurrent High Risk Neuroblastoma Patients With Standard Immunotherapy in Patients With Recurrent and Newly Diagnosed High Risk Neuroblastoma

Relevant grade 4 toxicities are defined as ascites, adult respiratory distress syndrome, capillary leak syndrome, cytokine release syndrome, dyspnea, hypotension, motor neuropathy, sensory neuropathy.

Key side effects are defined as capillary leak syndrome and cytokine release syndrome. Reduction is defined by at least 1 grade or score point or day less.

Neuralgia (with assessment of pain duration by days requiring morphine and maximum grade of pain scores during first 2 antibody cycles) will compared between both arms.

Maximum plasma concentration of the antibody assessed during the first 2 months of treatment.

University of Cologne

Prof. Dr.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
131MIBG to Treat Malignant Pheochromocytoma	NCT00028106	Pheochromocytom...	[131]I-MIBG 6-[18F]Fluorodo... [123]I-MIBG	18 Years - 70 Years	National Institutes of Health Clinical Center (CC)
Stem Cell Transplant for Juvenile Myelomonocytic Leukemia (JMML)	NCT00167219	Juvenile Myelom...	Stem Cell Trans... Preparative Reg...	- 18 Years	Masonic Cancer Center, University of Minnesota
NB2013-HR German (GPOH) / Dutch (DCOG) Trial	NCT02641782	Neuroblastoma	antibody ch14.1... GM-CSF IL-2 i.v. IL-2 s.c. Retinoic acid	18 Months - 25 Years	University of Cologne
131MIBG to Treat Malignant Pheochromocytoma	NCT00028106	Pheochromocytom...	[131]I-MIBG 6-[18F]Fluorodo... [123]I-MIBG	18 Years - 70 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for retinoic acid