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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Acute Erythroid Leukemia, Acute Lymphoblastic Leukemia, Acute Megakaryoblastic Leukemia, Acute Myeloid Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Hematopoietic and Lymphoid Cell Neoplasm, HIV Infection, Myelodysplastic Syndrome, Myelodysplastic Syndrome With Excess Blasts, Non-Hodgkin Lymphoma, Refractory Anemia

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Thiotepa
* Radiation: Total-Body Irradiation
* Procedure: Umbilical Cord Blood Transplantation
* Biological: Dilanubicel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: >= 6 months to =< 65 years Treatment with combination antiretroviral therapy (cART) for at least 1 month before enrollment Viral load < 5000 copies/ml plasma on cART Disease criteria Acute myeloid leukemia High risk in first complete remission (CR1), >= 2 cycles to obtain complete remission (CR), erythroblastic or megakaryocytic leukemia; >= in second complete remission (CR2) All patients must be in CR as defined by hematologic recovery and < 5% blasts by morphology within the bone marrow and a cellularity of >= 15% Patients for whom adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible. Specimen for morphologic assessment, including possible repeat procedures will be obtained (as possible). These patients must be discussed with the lead principal investigator, Filippo Milano prior to enrollment Acute lymphoblastic leukemia High risk CR1 (for example, but not limited to: t(9;22), t(1;19), t(4;11) or other mixed-lineage leukemia [MLL] rearrangements, hypodiploid); greater than 1 cycle to obtain CR; >= CR2 All patients must be in CR as defined by hematologic recovery and < 5% blasts by morphology within the bone marrow and a cellularity of >= 15% Patients in which adequate marrow/biopsy specimens cannot be obtained to determine remission status by morphologic assessment, but have fulfilled criteria of remission by flow cytometry, recovery of peripheral blood counts with no circulating blasts, and/or normal cytogenetics (if applicable) may still be eligible. Specimen for morphologic assessment, including possible repeat procedures will be obtained (as possible). These patients must be discussed with the lead principal investigator, Filippo Milano prior to enrollment Chronic myelogenous leukemia excluding refractory blast crisis. To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate (Int)-2 or high risk (i.e., refractory anemia with excess blasts [RAEB], refractory anemia with excess blasts in transformation [RAEBt]) or refractory anemia with severe pancytopenia or high-risk cytogenetics. Blasts must be < 10% by a representative bone marrow aspirate morphology Other hematologic malignancy such as non-Hodgkin lymphomas. Fred Hutch site: These patients must be presented at Patient Care Conference (PCC) prior to enrollment, given potential competing eligibility on auto-transplant protocols. Participating centers: These patients must be discussed with the lead principal investigator, Filippo Milano prior to enrollment Karnofsky (>= 16 years old) >= 70% Lansky (< 16 years old) >= 50% Adults: Calculated creatinine clearance must be > 60 mL and serum creatinine =< 2 mg/dL Children (< 18 years old): Calculated creatinine clearance must be > 60 mL/min Total serum bilirubin must be < 3 mg/dL Transaminases must be < 3 x the upper limit of normal Diffusion capacity of the lung for carbon monoxide (DLCO) corrected > 50% normal or for pediatric patients in whom DLCO cannot be measured has adequate pulmonary function Left ventricular ejection fraction > 45% OR Shortening fraction > 26% Ability to understand and the willingness to sign a written informed consent document (adult subject or parent/legal guardian of minor subject) Exclusion Criteria: Uncontrolled viral or bacterial infection at the time of study enrollment Active or recent (prior 6 month) invasive fungal infection without infectious disease (ID) consult and approval Pregnant or breastfeeding Prior myeloablative transplant within the last 6 months Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation Central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy. Diagnostic lumbar puncture to be performed

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A (fludarabine, cyclophosphamide, TBI, dilanubcel)<br>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. | Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Mitoxan;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: SCT_TBI;Procedure: Umbilical Cord Blood Transplantation<br>* Undergo UCBT<br>* Other names: UCB transplantation;Biological: Dilanubicel<br>* Given IV<br>* Other names: NLA101;|
| Experimental: Regimen B (anticancer drugs, TBI, dilanubicel)<br>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. | Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Mitoxan;Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Radiation: Total-Body Irradiation<br>* Undergo TBI<br>* Other names: SCT_TBI;Procedure: Umbilical Cord Blood Transplantation<br>* Undergo UCBT<br>* Other names: UCB transplantation;Biological: Dilanubicel<br>* Given IV<br>* Other names: NLA101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary graft failure rejection | 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. | Up to day 45 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of infusion toxicities | Defined as Common Terminology Criteria for Adverse Events version 5.0 grade >= 3 events. | Within the first 24 hours after infusion | 
| Neutrophil recovery | Will be defined as the first day of 2 consecutive days of absolute neutrophil count >= 500 after the first post-cord blood transplant nadir. | Up to 2 years | 
| Platelet engraftment | Will be defined as the first day of a platelet count > 20,000/ul with subsequent transfusions for 7 days. | Up to 2 years | 
| Severe (grades III-IV) acute graft versus host disease (GVHD) | Will be defined by the 2014 National Institutes of Health (NIH) criteria. | Up to 2 years | 
| Chronic GVHD | Will be defined by the 2014 NIH criteria. | Up to 2 years | 
| Non-relapse mortality | Will be defined as death without a prior relapse. | Up to day 180 | 
| Human immunodeficiency virus (HIV) plasma viral load |  | Pre and post-transplant | 
| Immune homeostasis | Concentration of immunity cells per microliters after transplant | Up to 2 years | 
| Immune reconstitution | Concentration of immunity cells per microliters after transplant | Up to 2 years | 
| Change in HIV-1 induced inflammatory immune responses | HIV viral load by PCR (copies per milliliter; mL) | Up to 2 years | 
| HIV rebound following antiretroviral therapy (ART) cessation | HIV viral load by PCR (copies per milliliter; mL) | Up to 2 years | 
| Viral kinetics following ART cessation | HIV viral load by PCR (copies per milliliter; mL) | Up to 2 years |