Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Syndrome

Lymphoma

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Hematologic Neoplasms

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Leukemia, Myelomonocytic, Juvenile

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Bone Marrow Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Lymphosarcoma

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Analgesics

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Immunomodulating Agents

Interleukin-2

Mesna

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Analgesics, Non-Narcotic

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Participants undergo haploidentical donor derived natural killer cell infusion (cells obtained from donors and selected using CliniMACS cell selection system) and chemotherapy (cyclophosphamide, fludarabine, interleukin-2, mesna).

Haploidentical donor derived natural killer cell infusion

Cyclophosphamide, Fludarabine, Interleukin-2, Mesna

Chemotherapy

Cell selection system based on magnetic-activated cell sorting

CliniMACS

David Shook, MD

Modern frontline therapy for patients with hematologic malignancies is based on intensive administration of multiple drugs. In patients with relapsed disease, response to the same drugs is generally poor, and dosages cannot be further increased without unacceptable toxicities. For most patients, particularly those who relapse while still receiving frontline therapy, the only therapeutic option is hematopoietic stem cell transplantation (SCT). For those who relapse after transplant, or who are not eligible for transplant because of persistent disease, there is no proven curative therapy.

There is mounting evidence that NK cells have powerful anti-leukemia activity. In patients undergoing allogeneic SCT, several studies have demonstrated NK-mediated anti-leukemic activity. NK cell infusions in patients with primary refractory or multiple-relapsed leukemia have been shown to be well tolerated and void of graft-versus-host disease (GVHD) effects. Myeloid leukemias are particularly sensitive to NK cells cytotoxicity, while B-lineage acute lymphoblastic leukemia (ALL) cells are often NK-resistant. We have developed a novel method to expand NK cells and enhance their cytotoxicity. Expanded and activated donor NK cells have shown powerful anti-leukemic activity against acute myeloid leukemia (AML) cells and T-lineage ALL cells in vitro and in animal models of leukemia.

The present study represents the translation of these laboratory findings into clinical application.We propose to determine the safety of infusing expanded NK cells in pediatric patients who have chemotherapy refractory or relapse hematologic malignancies including AML, T-lineage ALL, T-cell lymphoblastic lymphoma (T-LL), chronic myelogenous leukemia (CML), juvenile myelomonocytic leukemia (JMML),myelodysplastic syndrome (MDS), Ewing sarcoma family of tumors (ESFT) and rhabdomyosarcoma (RMS). The NK cells used for this study will be obtained from the patient's family member who will be a partial match to the patient's immune type (HLA type).

Secondary objectives include the evaluation of the in vivo lifespan and phenotype of the expanded NK cells and explore the efficacy of these donor NK cells in study participants with relapsed or refractory hematologic malignancies or sarcomas.

Pilot Study of Expanded, Donor Natural Killer Cell Infusions for Refractory Non-B Lineage Hematologic Malignancies and Solid Tumors

Pilot Study of Expanded, Activated Haploidentical Natural Killer Cell Infusions for Non-B Lineage Hematologic Malignancies and Solid Tumors

National Cancer Institute (NCI)

Assisi Foundation

St. Jude Children's Research Hospital

Heart and Blood Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Central Nervous System Depressants

Anesthetics

Melphalan

Busulfan

Thiotepa

Clofarabine

Antimetabolites

Hyperfractionated total body irradiation to a dose of 1375-1500 cGy (depending on age, stage of disease and requirement of general anesthesia) with lung shielding) Thiotepa (5 mg/kg/day x 2 or 10 mg/kg/day x 1) Cyclophosphamide (60 mg/kg/day x 2) (or fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated)

Busulfan (0.8 mg/kg every 6 hours x 10 or 12 doses), (depending on disease) with dose modified according to pharmacokinetics Melphalan (70mg/m2/day x 2 ) Fludarabine (25mg/m2/ day x 5)

Clofarabine (20mg/m2/ day x 5) (or, for children \<18 years of age, 30mg/m2/day x 5 if deemed suitable and with PI approval), Melphalan (70 mg/m2/day x 2) Thiotepa (5 mg/kg/day x 2 or 10mg/kg/day x1)

Melphalan (70 mg/m2/day x 2) Fludarabine (25mg/m2/ day x 5 ) Thiotepa (5 mg/kg/day x 2 or 10mg/kg/day x1)

total body irradiation

60 mg/ kg/day x 2 (or fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated).

0.8 mg/kg every 6 hours x 10 or 12 doses (depending on disease) with dose modified according to pharmacokinetics

20mg/m2/ day x 5 (or, for children \<18 years of age, 30mg/m2/day x 5 if deemed suitable and with PI approval)

(CliniMACS) T-cell depleted PBSC Transplant

Richard O'Reilly, MD

The purpose of this study is to find out the effects of using a system called CliniMACS to remove Tcells from blood stem cells. Removing T-cells may help stop a side effect called Graft-Versus-Host Disease (GVHD). Some studies have been done with CliniMACS, but the Food and Drug Administration (FDA) has not yet approved it.

HLA-Compatible Related or Unrelated Donors With CD34+ Enriched, T-cell Depleted Peripheral Blood Stem Cells Isolated by the CliniMACS System in the Treatment of Patients With Hematologic Malignancies

A Phase II Trial of Transplants From HLA-Compatible Related or Unrelated Donors With CD34+ Enriched, T-cell Depleted Peripheral Blood Stem Cells Isolated by the CliniMACS System in the Treatment of Patients With Hematologic Malignancies and Other Lethal Hematologic Disorders

Standard BMT-CTN and IBMTR systems clinical criteria as defined by Rowlings, et al will be used to establish and grade acute GvHD. Chronic GvHD will be diagnosed and graded according to the criteria of Sullivan (CIBMTR).

Memorial Sloan Kettering Cancer Center

Please note: participants were not censored from adverse event evaluation if they had a second or third transplant on protocol

Hyperfractionated total body irradiation to a dose of 1375-1500 cGy (depending on age, stage of disease and requirement of general anesthesia) with lung shielding) Thiotepa (5 mg/kg/day x 2 or 10 mg/kg/day x 1) Cyclophosphamide (60 mg/kg/day x 2) (or fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated)

total body irradiation: dose of 1375-1500 cGy

Thiotepa: 5 mg/kg/day x 2 or 10 mg/kg/day x 1

Cyclophosphamide: 60 mg/ kg/day x 2 (or fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated).

(CliniMACS) T-cell depleted PBSC Transplant

Total Body Irradiation, Thiotepa and Cyclophosphamide

Busulfan (0.8 mg/kg every 6 hours x 10 or 12 doses), (depending on disease) with dose modified according to pharmacokinetics Melphalan (70mg/m2/day x 2 ) Fludarabine (25mg/m2/ day x 5)

Busulfan: 0.8 mg/kg every 6 hours x 10 or 12 doses (depending on disease) with dose modified according to pharmacokinetics

Melphalan: 70mg/m2/day x 2

Fludarabine: 25mg/m2/ day x 5

(CliniMACS) T-cell depleted PBSC Transplant

Busulfan, Melphalan and Fludarabine

Clofarabine (20mg/m2/ day x 5) (or, for children \<18 years of age, 30mg/m2/day x 5 if deemed suitable and with PI approval), Melphalan (70 mg/m2/day x 2) Thiotepa (5 mg/kg/day x 2 or 10mg/kg/day x1)

Thiotepa: 5 mg/kg/day x 2 or 10 mg/kg/day x 1

Melphalan: 70mg/m2/day x 2

Clofarabine: 20mg/m2/ day x 5 (or, for children \<18 years of age, 30mg/m2/day x 5 if deemed suitable and with PI approval)

(CliniMACS) T-cell depleted PBSC Transplant

Clofarabine, Melphalan and Thiotepa

Melphalan (70 mg/m2/day x 2) Fludarabine (25mg/m2/ day x 5 ) Thiotepa (5 mg/kg/day x 2 or 10mg/kg/day x1)

Thiotepa: 5 mg/kg/day x 2 or 10 mg/kg/day x 1

Melphalan: 70mg/m2/day x 2

(CliniMACS) T-cell depleted PBSC Transplant

Melphalan, Fludarabine and Thiotepa

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Engrafted

Primary Graft Failure

Late graft failure

Not Evaluable Engraftment

Please note 13 participants were not evaluated in the data set as they received a second or third HCT on protocol.

The Incidence of Durable Hematopoietic Engraftment for T-cell Depleted Transplants Fractionated by the CliniMACS System Administered After Each of the Four Disease Targeted Cytoreduction Regimens.

aGVHD II-IV

cGVHD, Limited

cGVHD, Extensive

Number of Participants With Acute and Chronic GVHD Following T-cell Depleted, CD34+ Progenitor Cell Enriched Transplants Fractionated by the CliniMACS System.

Alive

Dead (not non-relapse mortality)

Dead (non-relapse mortality)

Incidence of Non-relapse Mortality (Transplant-related Mortality) Following Each Cytoreduction Regimen and a Transplant Fractionated by the CliniMACS System.

Survival

Disease Free Survival

2 patients received 2 separate transplants on each Arm A and C

Survival and Disease-free Survival (DFS)

Disease free survival

2 patients received 2 separate transplants on each Arm A and C. Please note 13 participants were not evaluated in the data set as they received a second or third HCT on protocol.

Proportion of Patients Receiving Optimal CD3+ (<1x10^5/kg) Cell Doses the Proportion of Patients Receiving CD3+ T-cell Doses > 1x10^5/kg.

Proportion of Patients Receiving Optimal CD34+ (> 5x10^6/kg) Cell Doses the Proportion Recurring Suboptimal Doses (< 2x10^6/kg) CD34+ Cells

Correlation of Doses of CD34+ Progenitors and CD3+ T Cells With Engraftment

Overall Study

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Nervous System Diseases

Wilms Tumor

Central Nervous System Neoplasms

Neuroblastoma

Nervous System Neoplasms

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Kidney Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Neoplastic Syndromes, Hereditary

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Genetic Diseases, Inborn

Wilms' Tumor

Neuroepithelioma

Stem Cell Transplantation

Transplant recipients will receive high dose Busulfan and Melphalan followed by autologous CD133+ antigen specific hematopoietic stem cell infusion. The autologous graft product will be selected using the investigational CliniMACS device.

Busulfan, Melphalan

Gregory Hale, M.D.

Studies have provided evidence that residual microscopic malignant cells in autologous bone marrow or blood stem cell grafts can contribute to posttransplant relapse. Researchers are currently exploring different methods in an attempt to purify or "purge" the stem cell product to minimize the risk of tumor contamination.

The CD133+ antigen is a protein contained on or "expressed" on numerous cells in the human body including specific hematopoietic progenitor (blood forming) cells. However, this antigen is not expressed on certain cancer cells including neuroblastoma. A technique using the investigational CliniMACS cell sorting device has been developed in an effort to filter out only those stem cells that express this CD133+ antigen in order to infuse a hematopoietic stem cell product with no tumor contamination potential.

The primary objective of this study is to establish safety of treating patients with a high dose chemotherapy regimen of Busulfan and Melphalan followed by autologous CD133+ hematopoietic stem cell support. Transplants recipients are expected to achieve engraftment as defined by an absolute neutrophil count of greater than or equal to 500/mm3 for three consecutive days by day 42-post infusion. Thus, safety of the treatment plan will be evaluated in terms of failure to engraft by this specific time period.

Secondary objectives for this protocol include the following:

* To describe CD133+ graft content post-selection and to describe the yield and purity of CD133+ content of the graft obtained.
* To describe the negative selection efficiency of this strategy by assessing the processed product for tumor specific markers, when applicable.
* To characterize the proliferation of clonal progeny of CD133+ cells.
* To characterize lymphocyte and hematopoietic reconstitution (including the kinetics of platelet engraftment) in these patients.
* To estimate one-year disease-free and overall survival in these transplant recipients.

Chemotherapy With CD133+ Select Autologous Hematopoietic Stem Cells for Children With Solid Tumors and Lymphomas

Busulfan and Melphalan With Autologous Hematopoietic Stem Cell Support With Positively-Selected CD133+ Hematopoietic Cells for Children With High Risk Solid Tumors and Lymphomas

University of Miami

Gregory Hale, MD / Principal Investigator

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pilot Study of Expanded, Donor Natural Killer Cell Infusions for Refractory Non-B Lineage Hematologic Malignancies and Solid Tumors	NCT00640796	Leukemia, Myelo... Leukemia, Lymph... Juvenile Myelom... T-cell Lymphobl... Myelodysplastic...	Haploidentical ... Chemotherapy CliniMACS	- 18 Years	St. Jude Children's Research Hospital
HLA-Compatible Related or Unrelated Donors With CD34+ Enriched, T-cell Depleted Peripheral Blood Stem Cells Isolated by the CliniMACS System in the Treatment of Patients With Hematologic Malignancies	NCT01119066	Acute Lymphobla... Acute Myelogeno... Myelodysplastic... Multiple Myelom...	total body irra... Thiotepa Cyclophosphamid... Busulfan Melphalan Fludarabine Clofarabine (CliniMACS) T-c...	- 69 Years	Memorial Sloan Kettering Cancer Center
Chemotherapy With CD133+ Select Autologous Hematopoietic Stem Cells for Children With Solid Tumors and Lymphomas	NCT00152126	Neuroblastoma Central Nervous... Lymphomas Wilms Tumor	Stem Cell Trans... Busulfan, Melph...	- 25 Years	St. Jude Children's Research Hospital
Pilot Study of Expanded, Donor Natural Killer Cell Infusions for Refractory Non-B Lineage Hematologic Malignancies and Solid Tumors	NCT00640796	Leukemia, Myelo... Leukemia, Lymph... Juvenile Myelom... T-cell Lymphobl... Myelodysplastic...	Haploidentical ... Chemotherapy CliniMACS	- 18 Years	St. Jude Children's Research Hospital

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