Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Rare Diseases

Recurrence

Breast Neoplasms

Breast Neoplasms, Male

Breast Diseases

Skin Diseases

Breast Cancer, Male

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Analgesics

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Interleukin-2

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Analgesics, Non-Narcotic

All patients with advanced metastatic breast cancer treated with natural killer cells after receiving fludarabine, cyclosphosphamide and total body irradiation.

administered intravenously 25 mg/m\^2 times 5 doses

administered intravenously 60 mg/kg days times 2 doses.

Total body irradiation

Infused cell dose is within the range of 1.5-8.0 x 10\^7/kg. Cell counts are based on total cells infused after the activation culture and washing determined on the morning of infusion.

Natural killer cell infusion

administered subcutaneously (10 MU) 3 times per week for 6 doses

Jeffrey Miller, MD

Sarah Cooley, MD

RATIONALE: Giving chemotherapy before a donor natural killer (NK) cell infusion helps stop the growth of tumor cells. It also helps stop the patient's immune system from rejecting the donor's cells. Giving NK cells from a related donor may kill the tumor cells.

PURPOSE: This study furthers the research of previous studies (MT2003-01 and MT2004-25) which were to determine a specific preparatory regimen (cyclophosphamide and fludarabine) could create an environment in which infused NK cells can grow and effectively treat patients with relapsed AML. This study will test the previous regimen in patients with breast cancer.

We believe that administration of related allogeneic (donor) natural killer cells along with IL-2, rather than autologous natural killer cells will provide the most effective anticancer therapy in this setting, and wish to test this approach. To do this, we will select a related donor who is partially HLA-matched with the study subject, to increase the likelihood that donor natural killer cells will kill the subject's cancer cells. We will also give chemotherapy drugs to increase the subject's tolerance for the donor natural killer cells. We will test the use of donor natural killer (NK) cell infusions. The immune system has a special way that it sees and identifies cancer cells or foreign agents (like viruses). The subject's own NK cells may not attack their cancer because NK cells see the tumor cells as "self" (a coating on the cell surface identifies a cell as "self" or "non-self"). We have reason to believe that NK cells may not kill cancer cells because NK cells have special receptors that "turn them off" when they encounter cancer cells (by seeing them as "self"). We may be able to get around this problem by using donor NK cells. Finally, subjects will receive a dose of subcutaneous IL-2 3 times a week (for 2 weeks) which has been proven safe in our previous studies to stimulate the natural killer cells.

Allogeneic Natural Killer (NK) Cells in Patients With Advanced Metastatic Breast Cancer

Allogeneic Natural Killer Cells in Patients With Advanced Metastatic Breast Cancer

Successful Natural Killer (NK) cell expansion is defined as detection of an absolute circulating donor-derived NK cell count of \>100 cells/ul of whole blood 14 days after infusion with \<5% donor T and B cells in mononuclear population (in metastatic breast cancer patients).

Defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria:

* Complete Response (CR: Disappearance of all target lesions
* Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions
* Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD
* Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions of appearance of one or more new lesions

of clinical benefit (CB; stable disease for greater than 6 months.

Number of patients who died within 100 days and after 100 days of natural killer (NK) treatment with or without total body irradiation.

Calculated median number of days of survival (patients alive days after treatment).

Masonic Cancer Center, University of Minnesota

Patients receiving natural killer cell infusion, fludarabine and cyclosphosphamide preparatory regimen, and with or without total body irradiation for treatment of metastatic breast cancer.

NK Cells With or Without Total Body Irradiation

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Number of Patients Who Had Expansion of Natural Killer Cells

Stable Disease

Progressive Disease

Number of Patients by Disease Response

Died within 100 days

Died after 100 days

Number of Patients Who Died While on Study

Overall Median Number of Days Patients Alive After Treatment

Overall Study

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Disease Attributes

Lymphosarcoma

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Childhood Acute Lymphoblastic Leukemia

Anti-Inflammatory Agents

Anti-Infective Agents

Antiemetics

Gastrointestinal Agents

Dermatologic Agents

Reproductive Control Agents

Micronutrients

Hematinics

Vitamins

Etoposide

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Cytarabine

Mitoxantrone

Dexamethasone

Aldesleukin

Methotrexate

Rituximab

Vincristine

Dexamethasone acetate

BB 1101

Pegaspargase

Etoposide phosphate

Mercaptopurine

Vinblastine

Asparaginase

Clofarabine

Teniposide

Hydrocortisone-17-butyrate

Antineoplastic Agents, Immunological

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Antimetabolites

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Antiviral Agents

Tubulin Modulators

Antimitotic Agents

Anti-HIV Agents

Anti-Retroviral Agents

Folinic Acid

Folate

Vitamin B9

Interventions: dexamethasone, vincristine sulfate, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, teniposide, vinblastine, natural killer cell infusion, laboratory biomarker analysis, therapeutic hydrocortisone

Cells for infusion are prepared using the CliniMACS System.

Interventions: dexamethasone, vincristine, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, natural killer cell infusion, allogeneic hematopoietic stem cell transplantation, laboratory biomarker analysis, therapeutic hydrocortisone

Cells for infusion are prepared using the CliniMACS System.

dexamethasone

vincristine sulfate

rituximab

clofarabine

cyclophosphamide

etoposide

aldesleukin

pegaspargase

methotrexate

mercaptopurine

cytarabine

mitoxantrone

teniposide

vinblastine

undergo allogeneic natural killer cell infusion

natural killer cell infusion

laboratory biomarker analysis

therapeutic hydrocortisone

allogeneic hematopoietic stem cell transplantation

The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.

CliniMACS

Sima Jeha, MD

The overall objective of this protocol is to improve the cure rate of relapsed precursor B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma.

This phase II trial is studying risk-directed therapy for B-lymphoblastic leukemia or lymphoma in first relapse. Standard risk (SR) and high risk (HR) participants will receive different therapy. Treatment will consist of chemotherapy for SR participants, and chemotherapy followed by hematopoietic stem cell transplant (HSCT) for HR in first relapse. Induction therapy consists of three blocks of chemotherapy. The first block is a novel immunotherapy regimen that includes chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells. SR participants will continue to receive chemotherapy for a total duration of approximately 2 years. HR participants will be candidates for HSCT and will proceed to transplant once a suitable donor is found and their minimal residual disease (MRD) is negative.

Primary objective

* To estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL and lymphoblastic lymphoma treated with risk-directed therapy.

Secondary objectives

* To determine minimal residual disease (MRD) levels at the end of remission induction therapy for participants with relapsed precursor B-cell ALL and compare the results with those in protocol ALLR17
* To estimate levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of remission induction therapy for relapsed precursor B-cell ALL.

STUDY DESCRIPTION:

The general treatment plan will consist of chemotherapy for standard-risk participants and chemotherapy followed by HSCT for high risk participants in first relapse of B-precursor ALL or lymphoblastic lymphoma. Remission induction for all participants consists of three blocks of therapy, wherein the first block is a novel immunotherapy regimen that includes cytotoxic chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells. Standard-risk patients will continue to receive chemotherapy for a total duration of approximately 2 years. High-risk patients will be candidates for HSCT and will proceed to transplant once a suitable donor is found and the patient achieves negative MRD.

Participants will be assigned to the standard arm if they experience late relapse (\> or = 6 months after completion of frontline therapy) AND maximum residual disease (MRD) is \<0.01% at the end of Block II of remission induction therapy. Provisional standard risk participants (i.e., late relapse) will be re-assigned to high risk if MRD is \> or = 0.01% at the end of Block II. Participants with lymphoma must be in complete remission at the end of Block III.

High risk participants will meet one of the following criteria:

* Early relapse (on therapy or \<6 months after completion of frontline therapy), OR
* Any relapse after hematopoietic stem cell transplant, OR
* MRD \> or = 0.01% at the end of Block II of remission induction therapy, OR
* Re-emergence of MRD at any time after attaining negative MRD on this clinical trial.

Natural killer (NK) cell collection: Donors who meet eligibility criteria will undergo apheresis once. The cells obtained will be purified for CD56+ cells utilizing the CliniMACS selection system. The NK cell product will undergo quality control testing following standard operating procedures of the St. Jude Human Applications Laboratory.

OUTLINE (STANDARD RISK):

REMISSION INDUCTION:

BLOCK I: Patients receive dexamethasone orally (PO) or intravenously (IV) thrice daily (TID) on days 1-8 and 21-28; vincristine sulfate IV on days 1, 21, 28, and 35; rituximab IV on days 4, 13, 20, and 27; clofarabine, cyclophosphamide, and etoposide IV on days 6-10; aldesleukin subcutaneously (SC) once every other day (QOD) on days 11-19; and pegaspargase IV on days 21 and 35. Patients also undergo natural killer (NK) cell infusion on day 12. Patients may receive triple intrathecal therapy comprising methotrexate, therapeutic hydrocortisone, and cytarabine on days 1, 5, 8, 11, 21, and 28. Patients continue on to Block II after count recovery.

BLOCK II: Patients receive methotrexate IV over 24 hours on days 1 and 8 and mercaptopurine PO on days 1-21. Patients also receive triple intrathecal therapy on day 1. High-risk patients with negative MRD continue on to transplantation. All patients with positive MRD continue on to Block III after count recovery.

BLOCK III: Patients receive cytarabine IV over 2 hours twice daily (BID) on days 1-4 and mitoxantrone hydrochloride IV over 1 hour on days 3-5. Patients also receive triple intrathecal therapy on day 7.

INTERIM CONTINUATION (for patients unable to tolerate dose intensive chemotherapy): Patients receive etoposide and cyclophosphamide IV on day 1, methotrexate IV on day 8, mercaptopurine PO on days 8-14, teniposide and cytarabine IV on day 15, dexamethasone PO TID on days 22-26, and vinblastine IV on day 22.

RE-INDUCTION THERAPY: Patients receive clofarabine, cyclophosphamide, and etoposide IV on days 1-5; dexamethasone PO on days 1-6; and pegaspargase on days 6 and 20 and vincristine sulfate IV on days 6, 13, and 20. Patients may also receive triple intrathecal therapy on days 1 and 15. Patients continue on to continuation treatment after count recovery.

CONTINUATION TREATMENT: Patients receive methotrexate IV over 2 hours on day 1 and mercaptopurine PO on days 1-7 of weeks 1, 2, 5, and 6; teniposide and cytarabine IV on day 1 of weeks 3 and 7; vincristine sulfate IV on day 1 of week 4; dexamethasone PO TID on days 1-5 of weeks 4 and 8; and vinblastine IV on day 1 of week 8. Treatment repeats every 8 weeks for up to 10 courses in the absence of disease progression or unacceptable toxicity. Patients may also receive triple intrathecal therapy on day 1 of week 1 of all courses and day 1 of week 5, courses 1-5.

Due to the unavailability of the drug Teniposide (VM-26), etoposide (VP-16) will be substituted for the remaining doses for patients currently on this study. The protocol Section 5.1.3 allows this substitution.

OUTLINE: GROUP 2 (high risk defined as participants not meeting the standard risk criteria noted above):

Patients receive Remission Induction (Blocks I, II, and III) treatment as described above for Group 1. Patients then undergo allogeneic hematopoietic stem cell transplantation (HSCT) as soon as they have negative MRD. Patients with negative MRD may continue chemotherapy until a suitable donor is found.

After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 1 year, and then yearly for up to 10 years.

Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma

A Phase II Study of Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma

Estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.

Estimate the 3-year event-free survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.

To determine minimal residual disease (MRD) levels at the end of remission induction therapy for participants with relapsed precursor B-cell ALL and compare the results with those in protocol ALLR17 (NCT00186875).

To estimate mean levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.

To estimate median levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block I of remission induction therapy for relapsed precursor B-cell ALL.

Cookies for Kids' Cancer

Assisi Foundation

St. Jude Children's Research Hospital

1. Late relapse (≥ 6 months after completion of frontline therapy) AND
2. MRD \< 0.01% at the end of Block II of remission induction therapy.

Provisional standard risk participants (i.e., late relapse) will be re-assigned to High risk if MRD ≥ 0.01% at the end of Block II.

Participants with lymphoma must be in complete remission at the end of Block III.

STANDARD RISK

1. Early relapse (on therapy or \< 6 months after completion of frontline therapy), OR
2. Any relapse after hematopoietic stem cell transplant, OR
3. MRD ≥ 0.01% at the end of Block II of remission induction therapy, OR
4. Re-emergence of MRD at any time after attaining negative MRD on ALLR18

HIGH RISK

All patients who received the protocol-specified therapy.

All Patients Enrolled on the Study

Total

1 to 9 years

>=10 years

Age, Customized

Black

White

Other

Race/Ethnicity, Customized

3-year Overall Survival Rate of Patients With Relapsed ALL

3-year Event-free Survival Rates in Patients With Relapsed ALL

All patients who had MRD data at the end of Remission Induction

ALLR18

ALLR17

On ALLR18, a total of 42 patients enrolled. Of them, 24 patients had MRD data at the end of Remission Induction. On ALLR17, a total of 40 patients enrolled. Of them, 32 patients had MRD data at the end of Remission Induction

Proportion of Participants With Positive Minimal Residual Disease

At Baseline

At Block I

Of the 42 patients enrolled, 34 patients had At Baseline data; 42 patients had data At Block I

Mean of CD20 Expression Levels

At Block 1

Median CD20 Expression Levels

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

Mesna

Fludarabine 25 mg/m\^2 intravenous (IV) Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2. Cyclophosphamide 60 mg/kg IV Daily Over 2 Hours On Days -5 and -4. Natural Killer Cell Infusion on Day 0. Mesna 12 mg/kg By Vein, Over about 15 minutes, 5 Times Per Day on Days -5 and -4. Interleukin-2 subcutaneously three times weekly for 9 total doses following NK Cell Infusion.

25 mg/m\^2 By Vein Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2.

60 mg/kg By Vein Daily Over 2 Hours On Days -5 and -4

Natural Killer Cell Infusion

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Allogeneic Natural Killer (NK) Cells in Patients With Advanced Metastatic Breast Cancer	NCT00376805	Breast Cancer	Fludarabine Cyclophosphamid... Total body irra... Natural killer ... Interleukin-2	18 Years -	Masonic Cancer Center, University of Minnesota
Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma	NCT01700946	Recurrent B-Cel... Recurrent Child...	dexamethasone vincristine sul... rituximab clofarabine cyclophosphamid... etoposide aldesleukin pegaspargase methotrexate mercaptopurine cytarabine mitoxantrone teniposide vinblastine natural killer ... laboratory biom... therapeutic hyd... allogeneic hema... CliniMACS	- 21 Years	St. Jude Children's Research Hospital
Haploidentical Natural Killer (NK) Cells in Patients With Relapsed or Refractory Neuroblastoma	NCT00698009	Neuroblastoma	Fludarabine Cyclophosphamid... Natural Killer ... Mesna Interleukin-2	-	M.D. Anderson Cancer Center
Natural Killer (NK) Cell Transplantation for AML	NCT00187096	Acute Myeloid L...	Cyclophosphamid... Natural Killer ... CliniMACS Syste...	- 21 Years	St. Jude Children's Research Hospital
Therapy for Children With Advanced Stage Neuroblastoma	NCT01857934	Neuroblastoma	cyclophosphamid... topotecan hu14.18K322A peripheral bloo... surgical resect... cisplatin etoposide doxorubicin vincristine busulfan melphalan peripheral bloo... natural killer ... radiation thera... GM-CSF G-CSF mesna levetiracetam interleukin-2 Isotretinoin CliniMACS	- 18 Years	St. Jude Children's Research Hospital
Natural Killer (NK) Cell Transplantation for AML	NCT00187096	Acute Myeloid L...	Cyclophosphamid... Natural Killer ... CliniMACS Syste...	- 21 Years	St. Jude Children's Research Hospital
Allogeneic Natural Killer (NK) Cells in Patients With Advanced Metastatic Breast Cancer	NCT00376805	Breast Cancer	Fludarabine Cyclophosphamid... Total body irra... Natural killer ... Interleukin-2	18 Years -	Masonic Cancer Center, University of Minnesota
Therapy for Children With Advanced Stage Neuroblastoma	NCT01857934	Neuroblastoma	cyclophosphamid... topotecan hu14.18K322A peripheral bloo... surgical resect... cisplatin etoposide doxorubicin vincristine busulfan melphalan peripheral bloo... natural killer ... radiation thera... GM-CSF G-CSF mesna levetiracetam interleukin-2 Isotretinoin CliniMACS	- 18 Years	St. Jude Children's Research Hospital

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