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

Phase 2

Terminated

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

• Registration Number: NCT04083170
• Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary

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

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 Timeline

• Study First Submitted: 2019-09-06
• Study First Submitted QC: 2019-09-06
• Study First Posted: 2019-09-10
• Study Start: 2022-10-06
• Primary Completion: 2022-11-11
• Study Completion: 2022-11-30
• Disposition First Submitted: 2023-10-27
• Results First Submitted: 2024-10-09
• Status Verified: 2024-12
• Results First Submitted QC: 2024-12-11
• Last Update Submitted: 2024-12-11
• Results First Posted: 2025-01-01
• Disposition First Posted: 2025-01-01
• Last Update Posted: 2025-01-01

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 1

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Regimen A (fludarabine, cyclophosphamide, TBI, dilanubcel)	Umbilical Cord Blood Transplantation	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.
Regimen A (fludarabine, cyclophosphamide, TBI, dilanubcel)	Dilanubicel	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.
Regimen A (fludarabine, cyclophosphamide, TBI, dilanubcel)	Total-Body Irradiation	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.
Regimen B (anticancer drugs, TBI, dilanubicel)	Total-Body Irradiation	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.
Regimen B (anticancer drugs, TBI, dilanubicel)	Umbilical Cord Blood Transplantation	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.
Regimen B (anticancer drugs, TBI, dilanubicel)	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.
Regimen A (fludarabine, cyclophosphamide, TBI, dilanubcel)	Fludarabine	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.
Regimen A (fludarabine, cyclophosphamide, TBI, dilanubcel)	Cyclophosphamide	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.
Regimen B (anticancer drugs, TBI, dilanubicel)	Fludarabine	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.
Regimen B (anticancer drugs, TBI, dilanubicel)	Cyclophosphamide	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.
Regimen B (anticancer drugs, TBI, dilanubicel)	Thiotepa	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.

Primary Outcome Measures

Name	Time	Method
Primary Graft Failure Rejection	Up to day 35 post-transplant	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.

Secondary Outcome Measures

Name	Time	Method
Incidence of Infusion Toxicities	Within the first 24 hours after infusion	Defined as Common Terminology Criteria for Adverse Events version 5.0 grade \>= 3 events.
Median Number of Days Post-Transplant to Neutrophil Recovery Occurred	Up to Day 35 post-transplant	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.
Platelet Engraftment	35 days post-transplant	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.
Incidence of Severe (Grades III-IV) Acute Graft Versus Host Disease (GVHD)	35 days post-transplant	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.
Incidence of Chronic GVHD	35 days post-transplant	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.
Incidence of Non-relapse Mortality	35 days post-transplant	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.
Human Immunodeficiency Virus (HIV) Plasma Viral Load	Baseline and weekly to 35 days post-transplant	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.
Immune Homeostasis	Up to 2 years	Concentration of immunity cells per microliters after transplant
Immune Reconstitution	Up to 2 years	Concentration of immunity cells per microliters after transplant
Change in HIV-1 Induced Inflammatory Immune Responses	Up to 2 years	HIV viral load by PCR (copies per milliliter; mL)
HIV Rebound Following Antiretroviral Therapy (ART) Cessation	Up to 2 years	Count of participants with HIV rebound, measured by HIV viral load by PCR (copies per milliliter; mL)
Viral Kinetics Following ART Cessation	Up to 2 years	HIV viral load by PCR (copies per milliliter; mL)

Trial Locations

Locations (5)

Fred Hutch/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States

Cleveland Cord Blood Center; 🇺🇸 Cleveland, Ohio, United States

University of California San Francisco; 🇺🇸 San Francisco, California, United States

Case Western Reserve University; 🇺🇸 Cleveland, Ohio, United States

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States