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Reduced Intensity Allogeneic HCT in Advanced Hematologic Malignancies w/T-Cell Depleted Graft

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ClinicalTrials.gov Identifier: NCT05088356
Recruitment Status : Recruiting
First Posted : October 21, 2021
Last Update Posted : October 29, 2021
Sponsor:
Collaborator:
Orca Biosystems, Inc.
Information provided by (Responsible Party):
Stanford University

Brief Summary:
Reduced intensity conditioning (RIC) has been increasingly adopted as a modality to allow preparative conditioning pre-transplant to be tolerated by older adults or those patients that are otherwise unfit for myeloablative conditioning. In this study Reduced intensity conditioning (RIC) conditioning is used and followed by match aploidentical donor peripheral blood stem cell transplantation.

Condition or disease Intervention/treatment Phase
Allogeneic Hematopoietic Cell Transplantation (HCT) Advanced Hematologic Malignancies Acute Leukemia Chronic Myelogenous Leukemia Myelodysplastic Syndromes Myeloproliferative Disorders Drug: Purified regulatory T-cells (Treg) plus CD34+ HSPC Drug: Fludarabine Drug: Melphalan Device: CliniMACS CD34 Reagent System Drug: Tacrolimus Drug: Cyclophosphamide Drug: Plerixafor Drug: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent Phase 1

Detailed Description:

The objectives for the study are listed below:

Primary Objectives

-Determine the safety, and feasibility of administration of several dose combinations of conventional T-cells (Tcon) and regulatory T-cells (Treg)

Secondary Objectives

  • To determine the GVHD-free relapse-free survival (GRFS) post-HCT
  • To determine the overall survival (OS) post-HCT
  • To measure the incidence and severity of acute and chronic GVHD

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Trial for Patients With Advanced Hematologic Malignancies Undergoing Reduced Intensity Allogeneic HCT With a T-cell Depleted Graft With Infusion of Conventional T-cells and Regulatory T-cells
Actual Study Start Date : September 7, 2021
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : June 2024


Arm Intervention/treatment
Experimental: Arm A: Matched related/matched unrelated donor transplantation
Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/unrelated donor transplant. All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus. Fludarabine (160 mg/m2)/ Melphalan (50 mg/m2)/TBI (4Gy)
Drug: Purified regulatory T-cells (Treg) plus CD34+ HSPC
Purified regulatory T-cells (Treg) plus CD34+ hematopoietic progenitor cells ("CD34+ HSPC"), Manufactured at SCTT Laboratory, dose 1x10^6 cells/kg to 3x10^6 cells/kg

Drug: Fludarabine
Fludarabine (160 mg/m2)
Other Names:
  • Beneflur
  • SH T 586
  • fludarabine monophosphate

Drug: Melphalan
Melphalan (50 mg/m2) in Arm A; Melphalan (100 mg/m2) in Arm B
Other Name: Melphalanum

Device: CliniMACS CD34 Reagent System
The CliniMACS® CD34 Reagent System is a medical device that is used in vitro to select and enrich specific cell populations is manufactured by Miltenyi Biotec

Drug: Tacrolimus
4-6ng/mL
Other Names:
  • Prograf
  • Advagraf
  • fujimycin

Drug: Cyclophosphamide
40mg/kg
Other Name: alkylating agent

Drug: Plerixafor
Dose 0.24 mg/kg, manufactured by Genzyme
Other Names:
  • Mozobil
  • AMD 3100
  • LM-3100

Drug: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent
Single-use vials contain either 300 mcg or 480 mcg filgrastim at a fill volume of 1.0 mL or 1.6 mL
Other Name: filgrastim XM02

Experimental: Arm B: Haploidentical transplantation
Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning. Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus. Fludarabine (160 mg/m2)/ Melphalan (100 mg/m2)/TBI (4Gy)
Drug: Purified regulatory T-cells (Treg) plus CD34+ HSPC
Purified regulatory T-cells (Treg) plus CD34+ hematopoietic progenitor cells ("CD34+ HSPC"), Manufactured at SCTT Laboratory, dose 1x10^6 cells/kg to 3x10^6 cells/kg

Drug: Fludarabine
Fludarabine (160 mg/m2)
Other Names:
  • Beneflur
  • SH T 586
  • fludarabine monophosphate

Drug: Melphalan
Melphalan (50 mg/m2) in Arm A; Melphalan (100 mg/m2) in Arm B
Other Name: Melphalanum

Device: CliniMACS CD34 Reagent System
The CliniMACS® CD34 Reagent System is a medical device that is used in vitro to select and enrich specific cell populations is manufactured by Miltenyi Biotec

Drug: Tacrolimus
4-6ng/mL
Other Names:
  • Prograf
  • Advagraf
  • fujimycin

Drug: Cyclophosphamide
40mg/kg
Other Name: alkylating agent

Drug: Plerixafor
Dose 0.24 mg/kg, manufactured by Genzyme
Other Names:
  • Mozobil
  • AMD 3100
  • LM-3100

Drug: Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent
Single-use vials contain either 300 mcg or 480 mcg filgrastim at a fill volume of 1.0 mL or 1.6 mL
Other Name: filgrastim XM02




Primary Outcome Measures :
  1. Determine the GVHD-free relapse-free survival (GRFS) post-HCT ( Arm-A) [ Time Frame: 12 months ]
    Clinical effect will be assessed as graft vs host disease (GVHD)-free relapse free survival (GRFS), GVHD-free is defined as no GVHD symptoms, and relapse free survival is defined as survival at 12 months without relapse. The outcome will be measured in Arm A only.

  2. Determine the overall survival (OS) post-HCT ( Arm-B) [ Time Frame: 2 years ]
    Overall survival is measured as number of participants alive. Alive at the time of last observation will be censored.

  3. Incidence of Grade III-IV acute GVHD [ Time Frame: At baseline, day +30, 60, 90, 180, year 1 and year 2 ]
    Acute GVHD will be staged and graded per Mount Sinai Acute GvHD International Consortium (MAGIC) Standardization criteria.

  4. The incidence and timing of primary graft failure [ Time Frame: 2 years from the Day 0 (day of CD34+ peripheral blood stem cell infusion ]
    Primary graft failure is defined as being alive with donor CD3 chimerism <5% at day +30 after transplant without recovery of neutrophils (i.e. without achieving an absolute neutrophil count [ANC] ≥ 500/mm3 for 3 consecutive days) at Day+28

  5. Donor CD3 chimerism at Day+60 post-HCT [ Time Frame: 2 years from the Day 0 (day of CD34+ peripheral blood stem cell infusion) ]
    Defined as a percentage on donor CD3 cells chimerism at day +60 after transplantation.


Secondary Outcome Measures :
  1. GVHD-relapse-free survival [ Time Frame: 12 months ]
    Clinical effect will be assessed as graft vs host disease (GVHD)-free relapse free survival (GRFS), GVHD-free is defined as no GVHD grade 3 and 4, and relapse free survival is defined as survival at 12 months without relapse.

  2. Overall survival [ Time Frame: 12 months ]
    Overall survival is measured as number of participants alive. Alive at the time of last observation will be censored.

  3. Secondary graft failure [ Time Frame: from Day 0 through 100 days ]
    Secondary graft failure (defined by donor CD3 chimerism <5% at day +30 after transplant) and neutrophil engraftment followed by subsequent decline in ANC < 500/mm3 unresponsive to growth factor therapy, by Day +100

  4. Treatment-emergent adverse events (TEAs) [ Time Frame: from Day 0 through 100 days ]
    TEAEs will be categorized by the System Organ Class and preferred term and will be graded according to the CTCAE version 5.0

  5. Acute GVHD (all grades) [ Time Frame: from Day 0 through 100 days ]
    Acute GVHD (all grades) will be reported

  6. Steroid-refractory acute GVHD [ Time Frame: within 3-5 days of therapy onset ]
    Steroid refractory acute GVHD will be defined as per the EBMT-NIH-CIBMTR Task Force position statement

  7. Non-relapse mortality (NRM) [ Time Frame: 12 months ]
    Non-relapse mortality is measured as number of participants died without relapse/ recurrent disease. Subjects without evidence of relapse/progression at last follow-up date or date of death will be censored.

  8. Disease-free survival (DFS) [ Time Frame: 12 months ]
    Overall survival is measured as number of participants alive and in remission. Alive in remission at the time of last observation will be censored.


Other Outcome Measures:
  1. Time to Neutrophil engraftment [ Time Frame: from Day 0 through 100 days ]
    Neutrophil engraftment is defined as having an ANC ≥ 500 cells/µL for three consecutive days. The first of three days will be designated as the day of engraftment.

  2. Time to Platelet engraftment [ Time Frame: from Day 0 through 100 days ]
    Platelet engraftment is defined as achieving a platelet count > 20,000 cells/µL for three consecutive days without platelet transfusion in the preceding 7 days. The first of three days will be designated as the day of engraftment.

  3. Incidence of serious infections (grade 2 and greater) [ Time Frame: from Day 0 through 100 days ]
    Incidence of serious infections will be measured as event of infections that led to hospitalization or death or required antibiotic treatment. Infections will be graded according to the CTCAE version 5.0



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Recipient Inclusion Criteria

  1. Patients with the following diseases that are histopathologically-confirmed are eligible

    • Acute myeloid, lymphoid, or mixed phenotype leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi) or beyond first complete remission (CR1) without the presence of minimal residual disease
    • Acute myeloid, leukemia, or mixed phenotype leukemia that is either:
    • Not in morphologic CR with bone marrow infiltration by leukemic blasts of ≤10%, or
    • In morphologic CR with evidence of minimal residual disease positivity by either multiparametric flow cytometric analysis or by a nucleic acid-based technique
    • Primary refractory acute myeloid, lymphoid, or mixed phenotype leukemia
    • Chronic myelogenous leukemia (accelerated, blast or second chronic phase)
    • Myelodysplastic syndromes
    • Myelofibrosis that is transplant-eligible
    • Myeloproliferative syndromes
    • Blastic plasmacytoid dendritic cell neoplasm
    • Non-Hodgkin lymphoma with poor risk features not suitable for autologous HCT
  2. Match to the patient as follows:

a. For Arm A:

  • Availability of a 8/8 or 7/8 HLA-matched donor (related or unrelated) defined by Class I (HLA-A, -B, -C) serologic typing (or higher resolution) and Class II (HLA-DRB1) molecular typing.
  • If the donor is a 7/8 HLA-match, the mismatch must be a permissive allelic mismatch as assessed by an independent HLA and transplantation expert. b. For Arm B:
  • Availability of a haploidentical donor who is a ≥ 4/8 but <7/8 match at HLA-A, -B, -C, and -DRB1 (typed using DNA-based high-resolution methods), with at most one mismatch per locus c. Age ≥ 18 and ≤75 years old at the time of enrollment. d. Left ventricular ejection fraction (LVEF) ≥ 45% e. Diffusing capacity of the lungs for carbon monoxide (DLCO) ≥ 50% f. Calculated creatinine clearance ≥ 50 mL/min or creatinine < 2.0 mg/dL g. SGPT and SGOT ≤ 5 x ULN, unless elevated secondary to disease Total bilirubin ≤ 3 x ULN (patients with Gilbert's syndrome may be included at the discretion of the PI or where hemolysis has been excluded h. Negative serum or urine beta-HCG test in females of childbearing potential within 3 weeks of registration i. Karnofsky performance status ≥ 70%

Donor Inclusion Criteria

  1. Age ≥ 18 and ≤ 75 years of age
  2. Karnofsky performance status of ≥ 70% defined by institutional standards
  3. Seronegative for HIV-1 RNA PCR; HIV 1 and HIV 2 ab (antibody); HTLV-1 and HTLV-2 ab; PCR+ or sAg (surface antigen) hepatitis B ; or PCR or sAg negative for hepatitis C; negative for the Treponema palladum antibody Syphillis screen; and negative for HIV-1 and hepatitis C by nucleic acid testing (NAT) within 30 days of apheresis collection.
  4. In the case that T palladum antibody tests are positive, donors must:

Be evaluated and show no evidence of syphilis infection of any stage by physical exam and history Have completed effective antibiotic therapy to treat syphilis Have a documented negative non-treponemal test (such as RPR) or in the case of a positive non-treponemal test must be evaluated by an infectious disease expert to evaluate for alternative causes of test positivity and confirm no evidence of active syphilitic disease e. Match to the patient as follows:

a. Arm A:

  • Must be a related or unrelated, 8/8 or 7/8-HLA match to recipient at HLAA, -B, -C, and -DRB1. If 7/8 HLA-matched, must be with permissive allelic HLA mismatch as assessed by an independent HLA and transplantation expert. b. Arm B:
  • Must be a haploidentical donor who is ≥ 4/8 but < 7/8 match at HLA-A, -B,

    • C, and -DRB1, with at most one mismatch per locus. f. Must be willing to donate PBSC for up two consecutive days g. Female donors of child-bearing potential must have a negative serum or urine beta HCG test within 3 weeks of mobilization h. Capable of undergoing leukapheresis, have adequate venous access, and be willing to undergo insertion of a central catheter should leukapheresis via peripheral vein be inadequate i. Agreeable to 2nd donation of PBPC (or bone marrow harvest) in the event of graft failure j. The donor or legal guardian greater than 18 years of age, capable of signing an IRB approved consent form. k. Meets other criteria for donation as specified by standard NMDP guidelines (NMDP donors) or institutional standards (non-NMDP donors)

Exclusion Criteria:

Recipient Exclusion Criteria

  1. Seropositive for any of the following:

    HIV antibodies; hepatitis B surface antigen (sAg); hepatitis C antibodies

  2. Prior myeloablative therapy or hematopoietic cell transplant
  3. Patients deemed candidates for fully myeloablative preparative conditioning regimens
  4. Candidate for autologous transplant
  5. HIV-positive
  6. Active uncontrolled bacterial, viral or fungal infection, defined as currently taking antimicrobial therapy and progression of clinical symptoms.
  7. Uncontrolled CNS disease involvement
  8. Pregnant or a lactating female
  9. Positive serum or urine beta-HCG test in females of childbearing potential within 3 weeks of registration
  10. Psychosocial circumstances that preclude the patient being able to go through transplant or participate responsibly in follow-up care
  11. Known allergy or hypersensitivity to, or intolerance of, tacrolimus
  12. Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥ 5
  13. Positive anti-donor HLA antibodies against a mismatched allele in the selected donor determined by either:

    • A positive crossmatch of any titer; or
    • The presence of anti-donor HLA antibody to any HLA locus
  14. Any uncontrolled autoimmune disease requiring active immunosuppressive treatment
  15. Concurrent malignancies or active disease within 1 year, except nonmelanomatous skin cancers that have been curatively resected

Donor Exclusion Criteria

  1. Evidence of active infection
  2. Seropositive for HIV-1 or-2, HTLV-1 or -2
  3. Medical, physical, or psychological reason that would place the donor at increased risk for complications from growth factor or leukapheresis
  4. Lactating female

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05088356


Contacts
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Contact: Khanh Nguyen 650-721-2372 khanhpn@stanford.edu

Locations
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United States, California
Stanford University Recruiting
Stanford, California, United States, 94304
Contact: Khanh Nguyen    650-721-2372    khanhpn@stanford.edu   
Principal Investigator: Everett Meyer, MD, PhD         
Sponsors and Collaborators
Stanford University
Orca Biosystems, Inc.
Investigators
Layout table for investigator information
Principal Investigator: Everett Meyer, MD,PhD Stanford Universiy
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Responsible Party: Stanford University
ClinicalTrials.gov Identifier: NCT05088356    
Other Study ID Numbers: IRB-60439
BMT372 ( Other Identifier: Stanford )
First Posted: October 21, 2021    Key Record Dates
Last Update Posted: October 29, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by Stanford University:
Reduced intensity conditioning (RIC)
GVHD
Additional relevant MeSH terms:
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Leukemia
Neoplasms
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Hematologic Neoplasms
Myelodysplastic Syndromes
Myeloproliferative Disorders
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Myeloid
Neoplasms by Site
Plerixafor
Cyclophosphamide
Melphalan
Fludarabine
Fludarabine phosphate
Tacrolimus
Alkylating Agents
Lenograstim
Sargramostim
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites