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

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04083170
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 10
• Locations: 5
• Arms: 2
• Anticipated Duration (Months): 39.3
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects of a cord blood transplant using OTS 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. OTS 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 OTS 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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Thiotepa; Radiation: Total-Body Irradiation; Procedure: Umbilical Cord Blood Transplantation; Other: Cellular Therapy	Phase 2

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 umbilical cord blood-derived hematopoietic CD34-positive progenitor cells 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 umbilical cord blood-derived hematopoietic CD34-positive progenitor cells 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 Design

• Study Type: Interventional
• Anticipated Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Anticipated Study Start Date: Sep 22, 2022
• Anticipated Primary Completion Date: Dec 31, 2023
• Anticipated Study Completion Date: Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regimen A (fludarabine, cyclophosphamide, TBI, OTS) 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 umbilical cord blood-derived hematopoietic CD34-positive progenitor cells IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity.	Drug: Fludarabine; Given IV; Other Names: 118218 2-Fluoro-9-beta-arabinofuranosyladenine 2-Fluorovidarabine 9-Beta-D-arabinofuranosyl-2-fluoroadenine Fluradosa ; Drug: Cyclophosphamide; Given IV; Other Names: Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan ; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: TBI TOTAL BODY IRRADIATION Whole Body Irradiation Whole-Body Irradiation ; Procedure: Umbilical Cord Blood Transplantation; Undergo UCBT; Other Names: Cord Blood Transplantation UCB transplantation ; Other: Cellular Therapy; Given OTS IV; Other Names: Cell Therapy
Experimental: Regimen B (fludarabine, cyclophosphamide, thiotepa, TBI, OTS) 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 umbilical cord blood-derived hematopoietic CD34-positive progenitor cells IV over 5-10 minutes in the absence of disease progression or unacceptable toxicity.	Drug: Fludarabine; Given IV; Other Names: 118218 2-Fluoro-9-beta-arabinofuranosyladenine 2-Fluorovidarabine 9-Beta-D-arabinofuranosyl-2-fluoroadenine Fluradosa ; Drug: Cyclophosphamide; Given IV; Other Names: Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan ; Drug: Thiotepa; Given IV; Other Names: STEPA Tepadina TESPA Tespamin Tespamine Thiofosfamide Thio-Tepa Thiofozil Thiophosphamide Thiophosphoramide Thiotef Tifosyl Triethylene thiophosphoramide Triethylenethiophosphoramide TSPA WR 45312 ; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: TBI TOTAL BODY IRRADIATION Whole Body Irradiation Whole-Body Irradiation ; Procedure: Umbilical Cord Blood Transplantation; Undergo UCBT; Other Names: Cord Blood Transplantation UCB transplantation ; Other: Cellular Therapy; Given OTS IV; Other Names: Cell Therapy

Outcome Measures

Primary Outcome Measures

1. Primary graft failure rejection [Up to day 45]

   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.

Secondary Outcome Measures

1. 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.

2. Neutrophil recovery [Up to 2 years]

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

3. Platelet engraftment [Up to 2 years]

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

4. Severe (grades III-IV) acute graft versus host disease (GVHD) [Up to 2 years]

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

5. Chronic GVHD [Up to 2 years]

   Will be defined by the 2014 NIH criteria.

6. Non-relapse mortality [Up to day 180]

   Will be defined as death without a prior relapse.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Francisco	San Francisco	California	United States	94143
2	Children's National Medical Center	Washington	District of Columbia	United States	20010
3	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
4	Case Western Reserve University	Cleveland	Ohio	United States	44106
5	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Filippo Milano, Fred Hutch/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT04083170
• Other Study ID Numbers: RG1004070; NCI-2019-05729; R34HL142322; 10304
• First Posted: Sep 10, 2019
• Last Update Posted: Aug 23, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Myelodysplastic Syndromes; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Syndrome; Vidarabine; Cyclophosphamide; Thiotepa; Fludarabine; Fludarabine phosphate

Study Results

No Results Posted as of Aug 23, 2022