Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

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Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Analgesics

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Interleukin-2

Mesna

Epratuzumab

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antimetabolites

Analgesics, Non-Narcotic

Antineoplastic Agents, Immunological

Haploidentical donor-derived NK cell infusion, Epratuzumab 360 mg/m\^2 once a day by vein (IV) on Day -4, Day -1 and Days 3, 6, 10, 13 and 17, and low-dose interleukin-2 (IL-2) Subcutaneous injections three times a week for 9 doses on Days 0 to 21; Fludarabine 25 mg/m\^2 once a day IV on Day -6 through Day -2 over 30 minutes; Cyclophosphamide 60 mg/kg once a day IV on Days -5 and -4 over 2 hours. Mesna 12 mg/kg by vein 5 times per day on Days -5 and -4 over 15 minutes.

360 mg/m\^2 once a day by vein on Day -4, Day -1 and Days 3, 6, 10, 13 and 17.

25 mg/m\^2 once a day by vein on Day -6 through Day -2 over 30 minutes.

60 mg/kg once a day by vein on Days -5 and -4 over 2 hours.

12 mg/kg by vein 5 times per day on Days -5 and -4 over 15 minutes.

Transplant of Haploidentical NK cells by vein on Day 0.

Infusion of NK cells

Subcutaneous injections three times a week for 9 doses on Days 0 to 21.

Anna Franklin, MD

The goal of this clinical research study is to learn if transferring the donor's NK cells, in combination with an antibody called epratuzumab and low-dose interleukin (IL-2), into your body can be done safely. Researchers want to find out if the infused NK cells will survive after the infusion and if the NK cell infusion helps to destroy cancer cells in the recipient's body and possibly to help control the disease.

Primary Objectives:

· Evaluate the feasibility of collecting an adequate number of natural killer (NK) cells from a donor and evaluate the safety of a haploidentical donor-derived NK cell infusion, Epratuzumab, and low-dose interleukin-2 (IL-2).

Secondary Objectives:

* Quantification and persistence of the infused donor NK cell in vivo;
* Quantification and persistence of cytokine levels;
* Assessment of NK cell immunophenotype and function;
* Correlate above with anti-tumor effect.

Study Drugs:

Epratuzumab is designed to attach to certain proteins on the surface of ALL cells. This may cause the cancer cells to die.

Cyclophosphamide is designed to interfere with the multiplication of cancer cells, which may slow or stop their growth. This may cause the cancer cells to die.

Fludarabine is designed to make cancer cells less able to repair damaged DNA (the genetic material of cells). This may increase the likelihood of the cells dying.

IL-2 is designed to help NK cells live longer and work better.

Experimental Therapy:

NK cells are the cells in the body that fight disease and infection. NK cells may destroy tumor cells, particularly when the NK cells are "mismatched" for certain proteins, called human leukocyte antigens (HLA). Researchers think that this ability to destroy tumor cells can be predicted by learning the donor's and the recipient's HLA types to see if they are a mismatch, and by checking for other specialized proteins found on the surface of the donor's NK cells. These proteins are called killer immunoglobulin receptors (KIR).

The NK cells will be collected from the donor's blood and then processed in a lab at M. D. Anderson, where researchers will use a machine, called a CliniMACS device, to separate out the NK cells from the rest of the donor's collected white blood cells and treat them overnight with a drug called IL-2. This is done to make the NK cells stronger before they are given to the recipient. You will also receive IL-2 injections under your skin to try to help the NK cells survive longer and to possibly increase the number of NK cells in your body after the infusion.

Screening Tests:

Before you can start treatment on this study, you will have "screening tests" to help the doctor decide if you are eligible to take part in this study. The following tests and procedures will be performed:

* You will have a bone marrow biopsy and/or aspiration to check the status of the disease. To collect a bone marrow biopsy and/or aspirate, an area of the hip is numbed with an anesthetic, and a small amount of bone marrow and bone is withdrawn through a needle.
* You will have a spinal tap to check the status of the disease. A spinal tap (also called a lumbar puncture) is when a special needle is inserted into the lower back through the space between the bones to draw a sample of the fluid that surrounds the spinal cord.
* You will have a pulse oximetry test to measure your heart rate and the level of oxygen in the blood. To perform this test, a clothespin-shaped device will be placed on your finger for about 1 minute.
* Your medical history will be recorded.
* You will have a physical exam, including a measurement of your vital signs (blood pressure, heart rate, breathing rate, and temperature).
* Blood (about 4 tablespoons) will be drawn for routine tests. This blood will also be checked for infections such as the human immunodeficiency virus (HIV). You will be told the results of this test. If you have an infection, you may not be able to take part in this study.
* Blood (about 2 tablespoons) will be drawn to test for HLA and KIR. You and the donor will be told the results of this test.
* Females who are able to have children must have a negative blood pregnancy test. This test will be performed with the blood drawn for routine tests as described above. If there is not enough blood leftover for this test, additional blood (about 1 teaspoon) will be drawn.

These screening tests, except for the HLA and KIR-typing, would also need to be repeated before an additional leukapheresis procedure can be done as a part of this study, in order to see if you continue to be eligible to have another one performed.

Identifying an Eligible Donor:

Your relative will be tested to see if his or her KIR has a type of "mismatch" that researchers think will help the donor's NK cells target the cancer cells in your body. They must also share half of your HLA genes to be eligible to take part in this study.

The donor's blood will also be checked for infections, such as HIV, to protect against the possibility of transmitting an infection to you during the NK cell infusion.

To help track the NK cells after infusion, researchers prefer (but do not require) that if you are a female recipient, your donor is male and if you are a male recipient, your donor is female.

Epratuzumab Administration:

If you and the donor are found to be eligible to take part in this study, on Day -4 (4 days before the NK cell infusion) and Day -1 (1 day before the NK cell infusion), you will have an epratuzumab infusion. The length of time this infusion will take will be different for each patient. This will be done using an indwelling catheter (a tube that remains in a vein, such as tunneled in the arm or through the chest to continuously inject or drain a part of your body). If you already have an indwelling catheter in place, you will not need to have a new one placed. However, if a new catheter is needed, you will be asked to sign a separate informed consent form for its placement.

On Day -1 (1 day before the NK cell infusion) and on Days 3, 6, 10, 13, and 17, you will receive an epratuzumab infusion. This will take several hours.

Conditioning Phase:

This phase will start within 28 days after the screening tests. During this phase, you will receive chemotherapy with cyclophosphamide and fludarabine to weaken your immune system in order to help the infused NK cells survive. You will stay in the hospital from Day -6 until after the NK cell infusion or longer if the doctor thinks it is necessary.

On Day -6 through Day -2, you will receive fludarabine 1 time each day by vein, over about 30 minutes each time.

On Days -5 and -4, you will receive cyclophosphamide 1 time each day by vein, over about 2 hours each time.

On Days -5 and -4, you will receive mesna 5 times per day by vein, over about 15 minutes each time. Mesna is given to protect your bladder from side effects that may be caused by cyclophosphamide.

Cyclophosphamide, fludarabine, and mesna will all be infused through the same indwelling catheter.

Infusion of NK cells:

On Day 0, you will receive the NK cells by vein, preferably through an indwelling catheter. If you do not have an indwelling catheter, you may receive the infusion intravenously (IV -- by vein). The doctor will decide the amount of NK cells to be infused, which will affect how long the infusion lasts. Usually the infusion should last less than 1 hour.

To help prevent an allergic reaction to the infused NK cells (such as fever and chills), you will receive Benadryl (diphenhydramine) by vein, over 15-30 minutes, and Tylenol (acetaminophen) by mouth. You will also receive fluids by vein to help decrease the risk of kidney damage. If the study doctor thinks it is necessary, you may also receive a steroid to help prevent side effects.

If the doctor thinks that you are not eligible to receive the NK cell infusion on Day 0, you will be taken off study without receiving the donor's NK cells. The collected NK cells will be thrown away.

This study allows eligible recipients under the age of 2 years of age to participate. You and/or a caregiver will be trained how to give the IL-2 injections to yourself. This drug will be injected under the skin for 9 doses. You will take 3 doses per week over a 3-week period after receiving the NK cells.

Measuring NK Cell Survival Through Blood Test:

On Day 0 (before the NK cell infusion and again 2 hours later), and 1 time on each of the following days: Days 2, 7, 14, 21, and 28, blood (about 4 teaspoons each time) will be drawn and tested to see how long the NK cells survive in your body.

If the disease gets worse or the infused NK cells can no longer be seen, this blood draw schedule may be stopped early.

Follow-Up Visits:

You will have follow-up visits at least 3 times per week during the first 3 weeks, and then 1 time about 28 days after your NK cell infusion. Then, you will have additional follow-up visits at about Months 2 and 3. At these visits, the following tests and procedures will be performed:

* You will have any changes in your medical history recorded.
* You will have a physical exam, including a measurement of your vital signs.
* Blood (about 2 tablespoons) will be drawn for routine tests.

On Days 14 and 28, and during Months 2 and 3, you will have a bone marrow biopsy and/or aspiration.

Length of Study:

You will remain on active study for up to 3 months following your NK cell infusion that you agree to have performed.

This is an investigational study. Cyclophosphamide, fludarabine, mesna, and IL-2 are FDA approved and commercially available. Cyclophosphamide and fludarabine are approved for treating leukemia in adults. IL-2 is FDA-approved, but not for the treatment of leukemia.

Epratuzumab is not FDA approved or commercially available. It is only being used in research.

The use of the CliniMACS machine and infusing NK cells combined with epratuzumab in patients with ALL are only being done in research.

Up to 10 recipients and 10 donors will take part in this study. All will be enrolled at The University of Texas (UT) MD Anderson Cancer Center.

Haploidentical Natural Killer (NK) Cells With Epratuzumab for Relapsed Acute Lymphoblastic Leukemia (ALL)

Adoptive Transfer of Haploidentical NK Cells in Combination With Epratuzumab for the Treatment of Relapsed Acute Lymphoblastic Leukemia

TTP calculated as average time, in months, from baseline to participants disease progression or death, monitored for a minimum of 1 year

Number of surviving participants without disease progression or death for any reason at one year post treatment.

M.D. Anderson Cancer Center

Haploidentical donor-derived NK cell infusion, Epratuzumab 360 mg/m\^2 once a day by vein (IV) on Day -4, Day -1 and Days 3, 6, 10, 13 and 17, and low-dose interleukin-2 (IL-2) Subcutaneous injections three times a week for 9 doses on Days 0 to 21; Fludarabine 25 mg/m\^2 once a day IV on Day -6 through Day -2 over 30 minutes; Cyclophosphamide 60 mg/kg once a day IV on Days -5 and -4 over 2 hours.

Haploidentical NK Cells + Epratuzumab

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Anna Franklin, MD, Assistant Professor

Both participants had recurrent disease before single month assessment therefore no data was analyzed. Study was terminated early due to slow accrual.

Time to Progression (TTP)

Overall Survival (OS)

Overall Study

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Starting on day -6, 60mg/Kg cyclophosphamide by vein will be administrated. Day -5 to -1 fludarabine administrated by vein at 25 mg/m2. 24-48 hours after chemotherapy completion, NK cell infusion will be injected (day 0). On day 7 a second NK cell infusion will be administrated. First infusion consist of 5x10\^7/kg NK CD3-CD56+ NK cells. The second NK cell infusion will include up to 5x10\^8 CD3-CD56+ cells if no treatment related toxicity occurred. Subcutaneous IL-2 (1x10\^6 UI/m2) three times a week for two weeks will be administrated after first NK infusion.

cyclophosphamide

* First allogeneic haploidentical NK cell iv. infusion: 5x10e7/kg, NK CD3-CD56+ immunophenotype, 24-48h after chemotherapy
* Second allogeneic haploidentical NK cell iv. infusion: up to 5x10e8/kg, NK CD3-CD56+immunophenotype, 7 days after the first infusion.

NK cell infusion

1x10\^6 UI/m2 three times a week for two weeks from first NK infusion (day 0)

IL-2

Antonio Pérez Martínez, MD, PhD.

The main goal of this study is to evaluate the anti-relapse prophylactic activity of inoculating Natural Killer (NK) cells as consolidation therapy of acute myeloid leukemia in paediatric patients with cytologic remission. The patients included have intermediate risk of relapse and no indication for allogeneic hematopoietic stem cell transplantation.

After the standard induction and consolidation chemotherapy treatment, patients will receive five days of fludarabine to try to kill any minimal residual disease and prevent NK cell rejection. Two different NK cells infusions will be performed within one week (day 0 and 7). Interleukin 2 (IL-2) will be administrated to increase the cytotoxic activity of NK cells.

Hypothesis:

NK cells are the natural defence against cancer cells. Thus, supplementing compatible NK cells from a related donor might increase the probability to eliminate any residual chemotherapy resistant cell in Acute myelogenous leukemia patients.

Description:

NK cells will be donated from a compatible family member who has a certain genetic code in their blood, called HLA, which partly matches patient genetic code, reducing any potential rejection. Interleukin-2 is co administrated during NK cell treatment to improve effectiveness.

Methodology:

The day that patient receive first NK cell infusion is called day 0. The days before are called minus days (-D). Conversely, the days after NK cell infusion are called plus days (+D).

Study administration

* After standard chemotherapy treatment against acute myeloid leukemia (AML) and restoration of haematologic normal levels, patients will receive a 60mg/kg of cyclophosphamide (day -6) and five daily intravenous cycles 25 mg/m2 of the chemotherapic fludarabine every day (day -5, -4, -3, -2, -1).
* Day 0 will be settled from 24h to 48h after fludarabine treatment completion. NK cells will be intravenous administered twice (day 0 and day 7). The first dose of NK cells (day 0) will contain up to 5x10\^7 cells/kg with immunophenotype NK (CD3-CD56+). The second dose might be higher (up to 5x10\^8 cells/kg) in case of no treatment related toxicity after first NK injection. In any case, no more than 1x10\^6 cells/kg with an immunophenotype T (CD56-CD3+) will be administrated.
* From day 0, IL-2 1x10\^6 UI/m2 subcutaneous will be administrated three times a week during two weeks.

Study visits

Before and after the treatment a bone marrow aspirate will be analyzed in order to evaluate minimal residue disease (cytology, cytometry and/or molecular studies) at least one month after NK injection. objective response rate will be reevaluated at least once a year.

Before treatment starts:

* Birthday, gender and personal medical history will be recorded
* physical examination, including measurement of the vital signs (temperature, heart and breathing rate, etc...)
* Blood and urine test
* Bone marrow aspirate in order to evaluate the basal disease

On every visit

* Physical examination and vital signs will be recorded
* Adverse event form
* Other concomitant drugs

After NK treatment

* It will be 11 visits on days +30, +60, +90, +180, +270, +360, +480, +600, +720, +900, +1080 which included a blood and urine test and Lansky/karnofsky scale.
* Additionally on days +30, +360, +720 and +1080 a bone marrow aspirate will be performed to evaluate relapse.

Length of the study:

Up to 35 AML patients will be included in the study during a 32 months recruitment period with a patient follow-up of thirty-six months. The maximum length of the study will be six years.

NK Cells as Consolidation Therapy of Acute Myeloid Leukemia in Children/Adolescents

NK Cells Infusion as Consolidation Treatment of Acute Myeloid Leukemia in Children and Adolescents

Relapse-free rate according to the clinical guidelines. A bone narrow aspirate one month after NK cell infusion will be evaluated for cytomorphological criteria and minimal residue disease (cytometry or real time PCR). Relapse defined as myeloid blast bone marrow presence with the same diagnosis markers, new ones or mixed. From cytologic analysis 25% of blast or minimal residue disease by cytometry (0,01%) and/or molecular level (0,0001%) present at diagnosis with or without cytogenetic alterations.

Relapse-free rate according to the clinical guidelines. A bone narrow aspirate one month after NK cell infusion and at least once a year during the three-year follow-up will be evaluated for cytomorphological criteria and minimal residue disease (cytometry or real time PCR). Relapse defined as myeloid blast bone marrow presence with the same diagnosis markers, new ones or mixed. From cytologic analysis 25% of blast or minimal residue disease by cytometry (0,01%) and/or molecular level (0,0001%) present at diagnosis with or without cytogenetic alterations.

All adverse events (AE) will be monitorized. AE of special interest: administration issues, infections, immunological/allergic/toxic reactions and concomitant drug interactions. AE will be classified according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTC) v4.0 criteria or MedDRA classification (mild, moderate, severe or life threatening ).

Donor HLA phenotype will be determined by SS-PCR. The aim is identify KIR ligand mismatch between donor and recipient to achieve better response. Ideally we will choose KIR ligand mismatch recipient donor pair (http://www.ncbi.nlm.nih.gov/pubmed/26341478).

Patient HLA phenotype will be determined by SS-PCR. The aim is identify KIR ligand mismatch between donor and recipient to achieve better response. Ideally we will choose KIR ligand mismatch recipient donor pair (http://www.ncbi.nlm.nih.gov/pubmed/26341478).

The objective is to identify activating KIRs and B haplotype (cen B), by PCR. Ideally we will choose B haplotype donors (http://www.ncbi.nlm.nih.gov/pubmed/20581313)

Chimerism after NK cell infusion by PCR or flow cytometry: to correlate with NK survival and expansion and with clinical outcome (http://www.ncbi.nlm.nih.gov/pubmed/26772158).

Ligand expression of the activatory (MICA, MICB and ULBPs) or inhibitory (HLA-1) receptors of the NK cells will be determined by multiparametric flow cytometry in order to determine the main variables to predict treatment effectiveness and safety.

In vitro allogenic NK cytotoxic activity against leukemic blast will be performed by real time Eur-TDA fluorescence (Blomberg et al. J Immunol Methods 1986).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Haploidentical Natural Killer (NK) Cells With Epratuzumab for Relapsed Acute Lymphoblastic Leukemia (ALL)	NCT00941928	Leukemia Pediatric Cance...	Epratuzumab Fludarabine Cyclophosphamid... Mesna Infusion of NK ... Interleukin-2	-	M.D. Anderson Cancer Center
NK Cells as Consolidation Therapy of Acute Myeloid Leukemia in Children/Adolescents	NCT02763475	Acute Myeloid L... Leukemia Myeloid Leukemi...	cyclophosphamid... Fludarabine NK cell infusio... IL-2	- 21 Years	Instituto de Investigación Hospital Universitario La Paz

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