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Serine

Patients receive fludarabine phosphate IV over 1 hour and busulfan IV over 3 hours on days -13 to -10. Patients then receive allogeneic CD56-positive CD3-negative natural killer cells IV over 1 hour on day -8. Patients also receive aldesleukin SC QD on days -8 to -4. Patients then undergo allogeneic PBSC transplant on day 0.

Allogeneic CD56-positive CD3-negative Natural Killer Cells

Allogeneic Hematopoietic Stem Cell Transplantation

Fludarabine Phosphate

Laboratory Biomarker Analysis

Peripheral Blood Stem Cell Transplantation

Pharmacological Study

Richard E Champlin

This phase I/II trial studies the side effects and best dose of donor natural killer cells when given together with donor stem cell transplant and to see how well they work in treating patients with myeloid malignancies that are likely to come back or spread. Giving chemotherapy, such as busulfan and fludarabine phosphate, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells and natural killer cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

PRIMARY OBJECTIVES:

I. Assess the safety of infusing ex vivo expanded natural killer (NK) cells in patients receiving busulfan-fludarabine phosphate (fludarabine) with an allogeneic human leukocyte antigen (HLA) matched hematopoietic transplantation for myeloid malignancies. Two sources of NK cells could be studied, depending on what donor source is available: cells from the HLA matched related donor or cells from an unrelated cord blood unit.

II. For each source of NK cells: the maximum tolerated cell dose; the phenotype and function of the ex vivo expanded NK cells and their survival in vivo; the rate of engraftment, graft-vs.-host disease (GVHD), immune reconstitution, relapse rates and survival for patients receiving this regimen will be determined.

OUTLINE: This is a phase I, dose-escalation study of NK cells followed by a phase II study.

Patients receive fludarabine phosphate intravenously (IV) over 1 hour and busulfan IV over 3 hours on days -13 to -10. Patients then receive allogeneic CD56-positive CD3-negative natural killer cells IV over 1 hour on day -8. Patients also receive aldesleukin subcutaneously (SC) once daily (QD) on days -8 to -4. Patients then undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0.

Donor Natural Killer Cells and Donor Stem Cell Transplant in Treating Patients With High Risk Myeloid Malignancies

NK Cells With HLA Compatible Hematopoietic Transplantation for High Risk Myeloid Malignancies

Participants that experienced DLT related to the NK Cells post transplant at different dose levels.

Participants that survived between day of transplant and day of death on different dose levels.

Number of participants that had grade 3 toxicities up to day 42.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Donor participants only signed the consents and were not part of the results and Adverse events were not collected.

Allogeneic stem cell transplant for patients with high risk myeloid malignancies conditioned with Fludarabine and Busulfan in combination with ex vivo expanded NK cells from 3 different NK cell sources : KIR mismatched haplo donors, KIR mismatched cord blood donors or HLA matched related donors.

Phase I: NK Cell Dose Level 1_10^6

Phase I: NK Cell Dose Level 2_10^7

Phase I: NK Cell Dose Level 3_ 3x10^7

Allogeneic stem cell transplant for patients with high risk myeloid malignancies conditioned with Fludarabine and Busulfan in combination with phase I/II escalation ex vivo expanded NK cells from 3 different NK cell sources : KIR mismatched haplo donors, KIR mismatched cord blood donors or HLA matched related donors.

Phase I: NK Cell Dose Level 4_ 10^8

Phase II: NK Cell Dose Level 3_3x10^7

Allogeneic stem cell transplant for patients with high risk myeloid malignancies conditioned with Fludarabine and Busulfan in combination with phase I/II escalation ex vivo expanded NK cells from 3 different NK cell sources : KIR mismatched haplo donors, KIR mismatched cord blood

Phase II: NK Cell Dose Level 4_ 10^8

Donors: KIR mismatched haplo donors, KIR mismatched cord blood donors or HLA matched related donors.

Donors

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

United States

Region of Enrollment

Richard Champlin, MD / Stem Cell Transplantation Department

Group A: NK cells from KIR mismatched haplo donors

Group B: NK cells from KIR mismatched cord blood donors

Group C: NK cells from matched related donors

Twenty one donor participants were not included in outcome analysis.

Number of Participants Who Experienced Dose-limiting Toxicities (DLT)

Overall Survival

Number of Participants With Grade 3 Toxicities

Overall Study

Infections

Immune System Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Communicable Diseases

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Anemia

Lymphoma

Hematologic Neoplasms

Acquired Immunodeficiency Syndrome

HIV Infections

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Anemia, Refractory

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Lymphosarcoma

Myelodysplastic Syndrome With Excess Blasts

Antirheumatic Agents

Cyclophosphamide

Thiotepa

Vidarabine

Patients receive fludarabine IV over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 to -6, and undergo TBI BID on days -4 to -1. Patients then undergo umbilical cord blood transplant on day 0. Between 4-24 hours after transplant completion, patients receive dilanubicel IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity.

Patients receive fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 4 hours on days -5 to -4, and undergo TBI QD on days -2 to -1. Patients then undergo umbilical cord blood transplant on day 0. Between 4-24 hours after transplant completion, patients receive dilanubicel IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity.

Total-Body Irradiation

Umbilical Cord Blood Transplantation

Dilanubicel

Filippo Milano

Timothy Henrich

Blachy Saldana

Kirsten Boughan

Marcie Finney

Mary Laughlin

This phase II trial studies the side effects of a cord blood transplant using dilanubicel and to see how well it works in treating patients with human immunodeficiency virus (HIV) positive hematologic (blood) cancers. After a cord blood transplant, the immune cells, including white blood cells, can take a while to recover, putting the patient at increased risk of infection. Dilanubicel consists of blood stem cells that help to produce mature blood cells, including immune cells. Drugs used in chemotherapy, such as fludarabine, cyclophosphamide, and thiotepa, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Total body irradiation is a type of whole-body radiation. Giving chemotherapy and total-body irradiation before a cord blood transplant with dilanubicel may help to kill any cancer cells that are in the body and make room in the patient's bone marrow for new stem cells to grow and reduce the risk of infection.

OUTLINE: Patients are assigned to 1 of 2 regimens.

REGIMEN A: Patients receive fludarabine intravenously (IV) over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 to -6, and undergo total body irradiation (TBI) twice daily (BID) on days -4 to -1. Patients then undergo umbilical cord blood transplant on day 0. Between 4-24 hours after transplant completion, patients receive dilanubicel IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity.

REGIMEN B: Patients receive fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 4 hours on days -5 to -4, and undergo TBI once daily (QD) on days -2 to -1. Patients then undergo umbilical cord blood transplant on day 0. Between 4-24 hours after transplant completion, patients receive dilanubicel IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28, 80, and 180 days, and then at 1 and 2 years.

Cord Blood Transplant With Dilanubicel for the Treatment of HIV Positive Hematologic Cancers

Infusion of Off-the-Shelf Ex Vivo Expanded Cryopreserved Progenitor Cells to Facilitate the Engraftment of a Single CCR5Δ32 Homozygous or Heterozygous Cord Blood Unit in Patients With HIV and Hematological Malignancies

Will be defined by no neutrophil recovery by day 45 (regardless of donor chimerism) or autologous recovery (neutrophil recovery but \< 10% donor chimerism in blood and bone marrow) by day 45.

Defined as Common Terminology Criteria for Adverse Events version 5.0 grade \>= 3 events.

Will be defined as the first day of 2 consecutive days of absolute neutrophil count \>= 500 after the first post-cord blood transplant nadir.

Will be defined as the first day of a platelet count \> 20,000/ul with subsequent transfusions for 7 days.

Will be defined by the 2014 National Institutes of Health (NIH) criteria.

Will be defined by the 2014 NIH criteria.

Will be defined as death without a prior relapse.

Concentration of immunity cells per microliters after transplant

HIV viral load by PCR (copies per milliliter; mL)

National Heart, Lung, and Blood Institute (NHLBI)

Fred Hutchinson Cancer Center

Azacitidine

Vorinostat

Enzyme Inhibitors

Histone Deacetylase Inhibitors

Patients receive azacitidine SC QD on days 1-7 and vorinostat PO 2-3 times daily on days 3-5, 3-9, or 3-16. Treatment repeats every 28 days for at least 4 courses in the absence of disease progression or unacceptable toxicity.

Lewis R Silverman

This phase I/II trial studies the side effects and best dose of vorinostat and azacitidine and to see how well they work in treating patients with myelodysplastic syndromes or acute myeloid leukemia. Vorinostat may stop the growth of cancer or abnormal cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer or abnormal cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving vorinostat together with azacitidine may kill more cancer or abnormal cells.

PRIMARY OBJECTIVES:

I. To evaluate the safety and toxicity of vorinostat in combination with azacitidine in patients with myelodysplastic syndromes (MDS) and some select patients with acute myeloid leukemia (AML) (step 1).

II. To identify doses of both vorinostat and azacitidine for safe combination of the 2 agents that can be administered in repetitive cycles over time for use in phase II studies.

III. To determine the response rate of patients treated with the combination of suberoylanilide hydroxamic acid (SAHA) (vorinostat) and azacitidine at the doses established as safe and effective in Step 1 in an expanded cohort of patients with MDS.

IV. To obtain preliminary data on the effects of treatment with the combination of vorinostat and Aza C (azacitidine) in patients with MDS on a series of biologic surrogate markers including: deoxyribonucleic acid (DNA) methylation of specific genes (e.g. p15); histone acetylation; hematopoietic progenitor growth and differentiation; the fate of the MDS clone and changes in gene expression by array profiling.

SECONDARY OBJECTIVES:

I. Determine effect of treatment with the combination on time to response, time to leukemic transformation and frequency of transformation to leukemia in patients with MDS during the phase II segment of the study.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive azacitidine subcutaneously (SC) once daily (QD) on days 1-7 and vorinostat orally (PO) 2-3 times daily on days 3-5, 3-9, or 3-16. Treatment repeats every 28 days for at least 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed monthly for 6 months and then every 2 months thereafter.

Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

A Phase 1/2 Study of Vorinostat [Suberoylanilide Hydroxamic Acid (SAHA)] in Combination With Azacitidine in Patients With the Myelodysplastic Syndrome (MDS)

Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.

Ninety-five percent confidence intervals will be estimated for the response proportion in all three treatment groups via binomial proportions.

The frequency of subjects experiencing toxicities will be tabulated. Toxicities will be assessed and graded according to CTCAE v. 5.0 terminology. Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.

Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Donor Natural Killer Cells and Donor Stem Cell Transplant in Treating Patients With High Risk Myeloid Malignancies	NCT01823198	Accelerated Pha... Acute Erythroid... Acute Megakaryo... Acute Myeloid L... Acute Myeloid L... Acute Myeloid L... Blast Phase Chr... Blasts Under 20... Blasts Under 20... Chronic Myelomo... High Risk Myelo... Myelodysplastic... Recurrent Chron... Therapy-Related... Therapy-Related...	Aldesleukin Allogeneic CD56... Allogeneic Hema... Busulfan Fludarabine Pho... Laboratory Biom... Peripheral Bloo... Pharmacological...	7 Years - 65 Years	M.D. Anderson Cancer Center
Cord Blood Transplant With Dilanubicel for the Treatment of HIV Positive Hematologic Cancers	NCT04083170	Acute Erythroid... Acute Lymphobla... Acute Megakaryo... Acute Myeloid L... Chronic Myeloge... Hematopoietic a... HIV Infection Myelodysplastic... Myelodysplastic... Non-Hodgkin Lym... Refractory Anem...	Fludarabine Cyclophosphamid... Thiotepa Total-Body Irra... Umbilical Cord ... Dilanubicel	6 Months - 65 Years	Fred Hutchinson Cancer Center
Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia	NCT00392353	Acute Erythroid... Acute Megakaryo... Acute Myeloid L... Chronic Myelomo... Myelodysplastic... Myelodysplastic... Myelodysplastic... Recurrent Adult... Refractory Anem...	Azacitidine Laboratory Biom... Pharmacological... Vorinostat	18 Years -	National Cancer Institute (NCI)
Cord Blood Transplant With Dilanubicel for the Treatment of HIV Positive Hematologic Cancers	NCT04083170	Acute Erythroid... Acute Lymphobla... Acute Megakaryo... Acute Myeloid L... Chronic Myeloge... Hematopoietic a... HIV Infection Myelodysplastic... Myelodysplastic... Non-Hodgkin Lym... Refractory Anem...	Fludarabine Cyclophosphamid... Thiotepa Total-Body Irra... Umbilical Cord ... Dilanubicel	6 Months - 65 Years	Fred Hutchinson Cancer Center
Cord Blood Transplant With Dilanubicel for the Treatment of HIV Positive Hematologic Cancers	NCT04083170	Acute Erythroid... Acute Lymphobla... Acute Megakaryo... Acute Myeloid L... Chronic Myeloge... Hematopoietic a... HIV Infection Myelodysplastic... Myelodysplastic... Non-Hodgkin Lym... Refractory Anem...	Fludarabine Cyclophosphamid... Thiotepa Total-Body Irra... Umbilical Cord ... Dilanubicel	6 Months - 65 Years	Fred Hutchinson Cancer Center

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