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

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.

Study Overview

• Status: Terminated
• Conditions: HIV Infection; Hematopoietic and Lymphoid Cell Neoplasm; Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Acute Erythroid Leukemia; Acute Megakaryoblastic Leukemia; Non-Hodgkin Lymphoma; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Anemia
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Radiation: Total-Body Irradiation; Drug: Thiotepa; Procedure: Umbilical Cord Blood Transplantation; Biological: Dilanubicel

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Cleveland, Ohio, United States, 44128
      • Cleveland Cord Blood Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Regimen A (fludarabine, cyclophosphamide, TBI, dilanubcel); 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: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Drug: Fludarabine; Given IV; Other Names: Fluradosa; 2-Fluorovidarabine; 9-Beta-D-arabinofuranosyl-2-fluoroadenine; 118218; 2-Fluoro-9-beta-arabinofuranosyladenine; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; TOTAL BODY IRRADIATION; Procedure: Umbilical Cord Blood Transplantation; Undergo UCBT; Other Names: Cord Blood Transplantation; UCB transplantation; Biological: Dilanubicel; Given IV; Other Names: NLA101; Allogeneic UCB-derived Hematopoietic Stem and Progenitor Cells NLA101; Allogeneic Umbilical Cord Blood-derived HSPCs NLA101
Experimental: Regimen B (anticancer drugs, TBI, dilanubicel); 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: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Drug: Fludarabine; Given IV; Other Names: Fluradosa; 2-Fluorovidarabine; 9-Beta-D-arabinofuranosyl-2-fluoroadenine; 118218; 2-Fluoro-9-beta-arabinofuranosyladenine; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; TOTAL BODY IRRADIATION; Drug: Thiotepa; Given IV; Other Names: Tepadina; STEPA; TESPA; Tespamin; TSPA; Tespamine; Thio-Tepa; Thiofosfamide; Thiofozil; Thiophosphamide; Thiophosphoramide; Thiotef; Tifosyl; Triethylenethiophosphoramide; WR 45312; Triethylene thiophosphoramide; Procedure: Umbilical Cord Blood Transplantation; Undergo UCBT; Other Names: Cord Blood Transplantation; UCB transplantation; Biological: Dilanubicel; Given IV; Other Names: NLA101; Allogeneic UCB-derived Hematopoietic Stem and Progenitor Cells NLA101; Allogeneic Umbilical Cord Blood-derived HSPCs NLA101

What is the study measuring?

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 36. This outcome was originally intended to be assessed for per the aforementioned definitions, but was only able to be assessed through 35 days post-transplant.	Up to day 35 post-transplant

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
Median Number of Days Post-Transplant to Neutrophil Recovery Occurred	Neutrophil recovery is defined as the first day of 2 consecutive days of absolute neutrophil count >= 500 after the first post-cord blood transplant nadir. This outcome was originally intended to be assessed for up to 45 days post-transplant, but was only able to be assessed through 35 days post-transplant.	Up to Day 35 post-transplant
Platelet Engraftment	Will be defined as the first day of a platelet count > 20,000/ul with subsequent transfusions for 7 days. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.	35 days post-transplant
Incidence of Severe (Grades III-IV) Acute Graft Versus Host Disease (GVHD)	Will be defined by the 2014 National Institutes of Health (NIH) criteria. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.	35 days post-transplant
Incidence of Chronic GVHD	Will be defined by the 2014 NIH criteria. This outcome was originally intended to be assessed for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.	35 days post-transplant
Incidence of Non-relapse Mortality	Will be defined as death without a prior relapse. This outcome was originally intended to be assessed for up to 180 days post-transplant, but was only able to be assessed through 35 days post-transplant.	35 days post-transplant
Human Immunodeficiency Virus (HIV) Plasma Viral Load	Assess CCR5Δ32 cord blood stem cell engraftment and its effect on biomarkers of HIV-1 infection, including plasma viral load and replication-competent reservoirs, as well as in gut and other sites (if tissue samples are available). This outcome was originally intended to be assessed weekly for up to 2 years post-transplant, but was only able to be assessed through 35 days post-transplant.	Baseline and weekly to 35 days 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	Count of participants with HIV rebound, measured by 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

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Filippo Milano, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2022
• Primary Completion (Actual): November 11, 2022
• Study Completion (Actual): November 30, 2022

Study Registration Dates

• First Submitted: September 6, 2019
• First Submitted That Met QC Criteria: September 6, 2019
• First Posted (Actual): September 10, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 11, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Disease; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Precancerous Conditions; Bone Marrow Diseases; Anemia; Leukemia, Lymphoid; Myeloproliferative Disorders; Leukemia, Myeloid, Acute; Syndrome; Leukemia; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Preleukemia; Myelodysplastic Syndromes; Anemia, Refractory, with Excess of Blasts; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Anemia, Refractory; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Thiotepa; Vidarabine
• Other Study ID Numbers: RG1004070; NCI-2019-05729 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); R34HL142322 (U.S. NIH Grant/Contract); 10304 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No