A Reduced-Intensity Conditioning Regimen (Cyclophosphamide, Pentostatin, Anti-thymocyte Globulin) Followed by Haploidentical Hematopoietic Stem Cell Transplant for the Treatment of Patients With Refractory or Recurrent Severe Aplastic Anemia

NCT05757310 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: 23139NCI-2022-10251P30CA033572
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial evaluates the safety and feasibility of using a reduced-intensity regimen of cyclophosphamide, pentostatin, and anti-thymocyte globulin prior to a CD4+ T-cell depleted haploidentical hematopoietic cell transplant (haploHCT) for the treatment of patients with severe aplastic anemia that does not respond to treatment (refractory) or that has come back (recurrent). Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid. It may also lower the body's immune response. Pentostatin blocks a protein needed for cell growth. Anti-thymocyte globulin is an immunosuppressive drug can destroy immune cells known as T-cells. HaploHCT transfers blood-forming stem cells from a healthy partially-matched donor to a patient. Administering a regimen of cyclophosphamide, pentostatin, and anti-thymocyte globulin before haploHCT may help make room for the new, healthy cells and may reduce the risk of graft versus host disease.

Conditions

Recurrent Severe Aplastic Anemia; Refractory Severe Aplastic Anemia

Outcome Measures

Primary Outcomes (3)

• Incidence of adverse events

  Toxicity will be graded according to the National Cancer Institute's-Common Terminology Criteria for Adverse Events version 5.0. Graft versus host disease (GVHD) specific toxicities will be defined per 1994 Keystone Consensus Criteria. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study regimen and reversibility or outcome. This will include infectious disease related complications and autoimmune disease related complications. Cumulative incidence curves will be used for time to event variables with competing risks events such as acute GVHD or chronic GVHD. Point estimates and 90% confidence intervals will be used.

  From day -22 to day +100 or occurrence of unacceptable toxicity, whichever occurs first

• Ability to meet CD4+ T-cell depleted product release requirements (feasibility)

  The feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product will be assessed by the ability to meet product release requirements. Product release requirements include the following: (1) CD34+ cells: Post-processing CD34+ cell target of 7.5-13.0 x 106 cells/kg of recipient body weight; (2) CD4+ T-cell depletion: \>= 97% of CD4+ T-cells in the the hematopoietic cell product for manufacturing; (3) Sterility (e.g. endotoxin and gram staining). Descriptive statistics will be used to characterize feasibility.

  Up to 3 years

• Ability to meet minimum required cell dose (feasibility)

  The feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product will be assessed by the ability to meet minimum required cell doses. This outcome will be evaluated using the following: (1) CD34+ collected (per day of apheresis); (2) CD34+ recovery: % CD34+ cells recovered from the CD34+ cell number in the product being manufactured (pre-CD4+ T cell depletion); (3) Cell dose: pooled and back up product; (4) Cell dose adequate given recipient's body weight plus the required pre-processed back-up set aside (yes/no); (5) Number (median, range) of apheresis; (6) % CD4+ T-cell depletion; (7) reason for not meeting product release requirements. Descriptive statistics will be used to characterize feasibility.

  Up to 3 years

Secondary Outcomes (14)

• Incidence of adverse events of grade 3 or higher

  Up to 3 years

• Incidence of infection

  Up to 3 years

• Time to neutrophil recovery

  From the date of CD4+ T-cell-depleted product infusion to the first of three consecutive days of absolute neutrophil count (ANC) >= 500/mm^3 and ANC >= 1000/mm^3, assessed up to 3 years

• Time to platelet recovery

  Time to the first day of the first of three consecutive laboratory values when the platelet count is >= 20,000/mm^3 and 100,000/mm^3 without a platelet transfusion in the previous seven, assessed up to 3 years

• Marrow failure

  Up to 28 days post transplant for primary graft failure or after initial engraftment for secondary graft failure, assessed up to 3 years

Study Arms (1)

Treatment (conditioning, haploHCT)

EXPERIMENTAL

Patients receive cyclophosphamide PO and IV, pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.

Biological: Anti-Thymocyte Globulin; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspirate; Procedure: Bone Marrow Biopsy; Drug: Cyclophosphamide; Procedure: Haploidentical Hematopoietic Cell Transplantation; Drug: Pentostatin; Other: Questionnaire Administration

Interventions

Haploidentical Hematopoietic Cell Transplantation PROCEDURE

Undergo CD4+ T-cell depleted haploHCT

Also known as: Haploidentical Stem Cell Transplantation, HLA-Haploidentical Hematopoietic Cell Transplantation, Stem Cell Transplantation, Haploidentical

Treatment (conditioning, haploHCT)

Questionnaire Administration OTHER

Ancillary studies

Treatment (conditioning, haploHCT)

Anti-Thymocyte Globulin BIOLOGICAL

Given IV

Also known as: Antithymocyte Globulin, Antithymocyte Serum, ATG, ATS

Treatment (conditioning, haploHCT)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (conditioning, haploHCT)

Bone Marrow Aspirate PROCEDURE

Undergo bone marrow aspirate

Also known as: Human Bone Marrow Aspirate

Treatment (conditioning, haploHCT)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy

Also known as: Biopsy of Bone Marrow, Biopsy, Bone Marrow

Treatment (conditioning, haploHCT)

Cyclophosphamide DRUG

Given PO and IV

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Treatment (conditioning, haploHCT)

Pentostatin DRUG

Given IV

Also known as: (R)-3-(2-Deoxy-.beta.-D-erythro-pentofuranosyl)-3,6,7, 8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol, 2'-Deoxycoformycin, CI-825, Co-Vidarabine, Covidarabine, DCF, Deoxycoformycin, Nipent, PD-81565, Pentostatine

Treatment (conditioning, haploHCT)

Eligibility Criteria

• Age: Up to 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• RECIPIENT: Documented informed consent of the participant.
• RECIPIENT: Age: \>= 40 years but =\< 75 years of age at time of enrollment.
• RECIPIENT: Failed at least one trial of immunosuppressive therapy (IST) by being refractory (persistence of severe cytopenia and fulfillment of SAA disease criteria at least 3 months after initial IST) or having relapsed (initial improvement of cytopenia after first-line IST but then a later return to fulfillment of SAA disease criteria when IST is decreased or ceased). IST could have included anti-thymocyte globulin (ATG) based regimens, calcineuPririn inhibitors and/or other higher dose therapy directed at the treatment of primary SAA.
• RECIPIENT: Karnofsky performance score \>= 60%.
• RECIPIENT: Confirmed diagnosis of severe aplastic anemia as:
• Bone marrow cellularity \< 25% or marrow cellularity \< 50% but with \< 30% residual hematopoietic cells;
• Two out of three of the following (in peripheral blood):
• Neutrophils \< 0.5 x 10\^9/L;
• Platelets \< 20 x 10\^9/L;
• Reticulocyte count \< 20 x 10\^9/L (\< 60 x 10\^9/L using an automated analysis).
• RECIPIENT: No suitable fully matched related sibling donor (6/6 match for human leukocyte antigen \[HLA\]-A and B at intermediate or high resolution and DRbetaA1 at high resolution using deoxyribonucleic acid \[DNA\]-based typing) available.
• RECIPIENT: Available relative of the patient who is a haploidentical match, including biological parents, siblings or half siblings, children, uncles/aunts, first cousins, etc. Eligible haploidentical donors will have 2-4 mismatches if HLA-A, -B, -C, and -DRB1 typing is used; 2-5 mismatches if HLA-A, -B, -C, -DRB1, and -DQB1 typing is used; and 2-6 mismatches if HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 typing is used. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must demonstrate that they are a full haplotype match by being identical at a minimum of one allele (at high resolution DNA-based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1 if 8 allele typing is used; HLA-A, -B, -C, -DRB1, and -DQB1 if 10 allele typing is used; and HLA-A, -B, -C, -DRB1-, DQB1, and -DPB1 is 12 allele typing is used by the local center.
• RECIPIENT: Patient and/or legal guardian must sign informed consent for the hematopoietic stem cell transplantation (HSCT).
• RECIPIENT: The haplo donor and/or legal guardian must be able to sign informed consent documents.
• RECIPIENT: The potential haplo donor must be willing and able to donate bone marrow.

You may not qualify if:

• RECIPIENT: Inherited and acquired (non-aplastic anemia) bone marrow failure syndromes such as Fanconi anemia must be ruled out according to center standards.
• RECIPIENT: Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on marrow examination (e.g. Monosomy 7).
• RECIPIENT: Any somatic mutations (including TERT, TERC, DKC1, NOP10) other than PIG-A (PNH) or BCOR mutation.
• RECIPIENT: Diagnosis of myelodysplastic syndrome (MDS).
• RECIPIENT: Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as a positive cross-match test of any titer by complement-dependent cytotoxicity or flow cytometric testing or the presence of anti-donor HLA antibody to the high expression loci HLA-A, B, C, DRB1, or DPB1 with mean fluorescence intensity \[MFI\] \> 1000 by solid phase immunoassay).
• RECIPIENT: Prior allogeneic stem cell transplant.
• RECIPIENT: Prior solid organ transplant.
• RECIPIENT: Known life-threatening reaction (i.e., anaphylaxis) to Thymoglobulin (registered trademark) that would prohibit use for the patient as this study requires use of the Thymoglobulin (registered trademark) preparation of ATG.
• RECIPIENT: Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment.
• RECIPIENT: Seropositive for the human immunodeficiency virus (HIV).
• RECIPIENT: Active hepatitis B or C determined by a detectable viral load of HBV or HCV.
• RECIPIENT: Female patients who are pregnant (per institutional practice) or breast-feeding.
• RECIPIENT: Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent \> 5 years previously will be allowed. Cancer treated with curative intent =\< 5 years previously will not be allowed unless approved by the protocol chairs and/or protocol officer.
• RECIPIENT: Alemtuzumab or ATG within 2 weeks of enrollment.
• RECIPIENT: Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures.

Sponsors & Collaborators

• National Cancer Institute (NCI): collaborator
• City of Hope Medical Center: lead

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

RECRUITING

MeSH Terms

Conditions

Anemia, Aplastic

Interventions

Antilymphocyte Serum; Specimen Handling; Biopsy; Cyclophosphamide; Stem Cell Transplantation; Pentostatin

Condition Hierarchy (Ancestors)

Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Coformycin; Formycins; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Ryotaro Nakamura

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 10, 2023
• First Posted: March 7, 2023
• Study Start: November 15, 2024
• Primary Completion (Estimated): June 18, 2027
• Study Completion (Estimated): June 18, 2027
• Last Updated: January 5, 2026

Record last verified: 2025-12

Locations

US (1)