Reduced Intensity, Partially HLA Mismatched BMT to Treat Hematologic Malignancies
NCT ID: NCT01203722
Last Updated: 2025-04-30
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE1/PHASE2
89 participants
INTERVENTIONAL
2010-09-30
2024-05-28
Brief Summary
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The primary goal for phase 1 is to identify a transplant regimen associated with acceptable rates of severe acute GVHD and NRM by Day 100 and for phase 2 estimate the 6-month probability of survival without having had acute grade III- IV GVHD or graft failure.
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Detailed Description
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Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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REGIMEN B
Pre-BMT :
* Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV
* Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV
* Day -1: 400 cGy total body irradiation (TBI) administered in a single fraction
Day 0: Allogeneic blood or marrow transplantation (BMT)
Post-Transplantation Immunosuppression Consisting of:
* Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV
* Day 5: Sirolimus loading dose 6 mg PO once
* Day 5 thru Day 35: Mycophenolate Mofetil (MMF) 15 mg/kg PO TID (maximum daily dose 3 g/day)
* Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL
Fludarabine
Fludarabine 30 mg/m2/day
Cytoxan
Pre-BMT: Cytoxan 14.5 mg/kg/day administered IV; Post-Transplantation: High-dose Cytoxan 50mg/kg/day
Total Body Irradiation
400 cGy TBI administered in a single fraction
Allogeneic Blood or Marrow Transplant
Mycophenolate Mofetil
15mg/kg by mouth three times daily
Sirolimus
Loading Dose: Sirolimus 6mg by mouth once; Maintenance dose: Sirolimus 2mg by mouth daily
REGIMEN C
Pre-BMT:
* Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV
* Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV
* Day -1: 400 cGy TBI administered in a single fraction
Day 0: BMT
Post-Transplantation Immunosuppression Consisting of:
* Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV
* Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day)
* Day 5 thru Day 180: Tacrolimus 1 mg administered IV QD
Fludarabine
Fludarabine 30 mg/m2/day
Cytoxan
Pre-BMT: Cytoxan 14.5 mg/kg/day administered IV; Post-Transplantation: High-dose Cytoxan 50mg/kg/day
Total Body Irradiation
400 cGy TBI administered in a single fraction
Allogeneic Blood or Marrow Transplant
Mycophenolate Mofetil
15mg/kg by mouth three times daily
Tacrolimus
Tacrolimus 1mg intravenously, daily
REGIMEN B2
Pre-PBSCT:
* Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV
* Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV
* Day -1: 400 cGy TBI administered in a single fraction
Day 0: Peripheral Blood Stem Cell Transplant (PBSCT)
Post-Transplantation Immunosuppression Consisting of:
* Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV
* Day 5: Sirolimus loading dose 6 mg PO once
* Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day)
* Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL
Fludarabine
Fludarabine 30 mg/m2/day
Cytoxan
Pre-BMT: Cytoxan 14.5 mg/kg/day administered IV; Post-Transplantation: High-dose Cytoxan 50mg/kg/day
Total Body Irradiation
400 cGy TBI administered in a single fraction
Peripheral Blood Stem Cell Transplant
Mycophenolate Mofetil
15mg/kg by mouth three times daily
Sirolimus
Loading Dose: Sirolimus 6mg by mouth once; Maintenance dose: Sirolimus 2mg by mouth daily
REGIMEN B3: HIV patients with CCRd32 homozygous donors
Pre-PBSCT:
* Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV
* Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV
* Day -1: 400 cGy TBI administered in a single fraction
Day 0: Peripheral Blood Stem Cell Transplant (PBSCT)
Post-Transplantation Immunosuppression Consisting of:
* Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV
* Day 5: Sirolimus loading dose 6 mg PO once
* Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day)
* Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL
Fludarabine
Fludarabine 30 mg/m2/day
Cytoxan
Pre-BMT: Cytoxan 14.5 mg/kg/day administered IV; Post-Transplantation: High-dose Cytoxan 50mg/kg/day
Total Body Irradiation
400 cGy TBI administered in a single fraction
Peripheral Blood Stem Cell Transplant
Mycophenolate Mofetil
15mg/kg by mouth three times daily
Sirolimus
Loading Dose: Sirolimus 6mg by mouth once; Maintenance dose: Sirolimus 2mg by mouth daily
Interventions
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Fludarabine
Fludarabine 30 mg/m2/day
Cytoxan
Pre-BMT: Cytoxan 14.5 mg/kg/day administered IV; Post-Transplantation: High-dose Cytoxan 50mg/kg/day
Total Body Irradiation
400 cGy TBI administered in a single fraction
Allogeneic Blood or Marrow Transplant
Peripheral Blood Stem Cell Transplant
Mycophenolate Mofetil
15mg/kg by mouth three times daily
Sirolimus
Loading Dose: Sirolimus 6mg by mouth once; Maintenance dose: Sirolimus 2mg by mouth daily
Tacrolimus
Tacrolimus 1mg intravenously, daily
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Absence of a suitable related or unrelated bone marrow donor who is molecularly matched at HLA-A, B, Cw, DRB1, and DQB1.
3. Absence of a suitable partially HLA-mismatched (haploidentical), first-degree related donor. Donors who are homozygous for the CCR5delta32 polymorphism are given preference.
4. Eligible diagnoses:
1. Relapsed or refractory acute leukemia in second or subsequent remission, with remission defined as \<5% bone marrow blasts morphologically
2. Poor-risk acute leukemia in first remission, with remission defined as \<5% bone marrow blasts morphologically:
* AML with at least one of the following:
* AML arising from MDS or a myeloproliferative disorder, or secondary AML
* Presence of Flt3 internal tandem duplications
* Poor-risk cytogenetics: Complex karyotype \[\> 3 abnormalities\], inv(3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7
* Primary refractory disease
* ALL (leukemia and/or lymphoma) with at least one of the following:
* Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL rearrangement
* Clear evidence of hypodiploidy
* Primary refractory disease
* Biphenotypic leukemia
3. MDS with at least one of the following poor-risk features:
* Poor-risk cytogenetics (7/7q minus or complex cytogenetics)
* IPSS score of INT-2 or greater
* Treatment-related MDS
* MDS diagnosed before age 21 years
* Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy
* Life-threatening cytopenias, including those generally requiring greater than weekly transfusions
4. Interferon- or imatinib-refractory CML in first chronic phase, or non-blast crisis CML beyond first chronic phase.
5. Philadelphia chromosome negative myeloproliferative disease.
6. Chronic myelomonocytic leukemia.
7. Juvenile myelomonocytic leukemia.
8. Low-grade non-Hodgkin lymphoma (including SLL and CLL) or plasma cell neoplasm that has:
* progressed after at least two prior therapies (excluding single agent rituximab and single agent steroids), or
* in the case of lymphoma undergone histologic conversion;
* patients with transformed lymphomas must have stable disease or better.
9. Poor-risk CLL or SLL as follows:
* 11q deletion disease that has progressed after a combination chemotherapy regimen,
* 17p deletion disease,
* or histologic conversion;
* patients with transformed lymphomas must have stable disease or better.
10. Aggressive non-Hodgkin lymphoma as follows, provided there is stable disease or better to last therapy:
* NK or NK-T cell lymphoma, hepatosplenic T-cell lymphoma, or subcutaneous panniculitic T-cell lymphoma, blastic/ blastoid variant of mantle cell lymphoma
* Hodgkin or aggressive non Hodgkin lymphoma that has failed at least one multiagent regimen, and the patient is either ineligible for autologous BMT or autologous BMT is not recommended.
* Eligible subtypes of aggressive non-Hodgkin lymphoma include:
* mantle cell lymphoma
* follicular grade 3 lymphoma
* diffuse large B-cell lymphoma or its subtypes, excluding primary CNS lymphoma
* primary mediastinal large B-cell lymphoma
* large B-cell lymphoma, unspecified
* anaplastic large cell lymphoma, excluding skin-only disease
* Burkitt's lymphoma or atypical Burkitt's lymphoma (high-grade B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt's), in complete remission
5. Patients with CLL, SLL, or prolymphocytic leukemia must have \< 20% bone marrow involvement by malignancy (to lower risk of graft rejection).
6. One of the following, in order to lower risk of graft rejection:
* Cytotoxic chemotherapy, an adequate course of 5-azacitidine or decitabine, or alemtuzumab within 3 months prior to start of conditioning; or
* Previous BMT within 6 months prior to start of conditioning.
NOTE: Patients who have received treatment outside of these windows may be eligible if it is deemed sufficient to reduce graft rejection risk; this will be decided on a case-by-case basis by the PI or co-PI.
7. Any previous BMT must have occurred at least 3 months prior to start of conditioning.
8. Adequate end-organ function as measured by:
1. Left ventricular ejection fraction greater than or equal to 35%, or shortening fraction \> 25%, unless cleared by a cardiologist
2. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST \< 5 x ULN
3. FEV1 and FVC \> 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation \>92% on room air
9. ECOG performance status \< 2 or Karnofsky or Lansky score \> 60
1. Potential donors consist of:
* Unrelated donors
* Second-degree relatives
* First cousins
2. The donor and recipient must be identical at at least 5 HLA alleles based on high resolution typing of HLA-A, -B, -Cw, -DRB1, and -DQB1, with at least one allele matched for a HLA class I gene (HLA-A, -B, or -Cw) and at least one allele matched for a class II gene (HLA-DRB1 or -DQB1).
3. Meets institutional selection criteria and medically fit to donate. 4 . Lack of recipient anti-donor HLA antibody. Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry. This will be decided on a case-by-case basis by the PI and one of the immunogenetics directors. Pheresis to reduce anti-HLA antibodies is permissible; however eligibility to proceed with the transplant regimen would be contingent upon the result.
Exclusion Criteria
* No uncontrolled bacterial, viral, or fungal infection.
* Note: HIV-infected patients are potentially eligible. Eligibility of HIV-infected patients will be determined on a case-by-case basis.
* No previous allogeneic BMT (syngeneic BMT permissible).
* Active extramedullary leukemia or known active CNS involvement by malignancy. Such disease treated into remission is permitted.
* Donor must not be HLA identical to the recipient.
* Has not donated blood products to recipient.
6 Months
75 Years
ALL
Yes
Sponsors
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National Cancer Institute (NCI)
NIH
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
OTHER
Responsible Party
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Principal Investigators
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Richard Ambinder, MD
Role: PRINCIPAL_INVESTIGATOR
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Locations
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Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
Countries
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References
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Rappazzo KC, Zahurak M, Bettinotti M, Ali SA, Ambinder AJ, Bolanos-Meade J, Borrello I, Dezern AE, Gladstone D, Gocke C, Fuchs E, Huff CA, Imus PH, Jain T, Luznik L, Rahmat L, Swinnen LJ, Wagner-Johnston N, Jones RJ, Ambinder RF. Nonmyeloablative, HLA-Mismatched Unrelated Peripheral Blood Transplantation with High-Dose Post-Transplantation Cyclophosphamide. Transplant Cell Ther. 2021 Nov;27(11):909.e1-909.e6. doi: 10.1016/j.jtct.2021.08.013. Epub 2021 Aug 20.
Kasamon YL, Ambinder RF, Fuchs EJ, Zahurak M, Rosner GL, Bolanos-Meade J, Levis MJ, Gladstone DE, Huff CA, Swinnen LJ, Matsui WH, Borrello I, Brodsky RA, Jones RJ, Luznik L. Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide. Blood Adv. 2017;1(4):288-292. doi: 10.1182/bloodadvances.2016002766. Epub 2017 Jan 6.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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NA_00039823
Identifier Type: OTHER
Identifier Source: secondary_id
J1055
Identifier Type: -
Identifier Source: org_study_id
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