Reduced Intensity, Partially HLA Mismatched BMT to Treat Hematologic Malignancies

This study is currently recruiting participants.
Verified March 2014 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01203722
First received: September 15, 2010
Last updated: March 20, 2014
Last verified: March 2014

September 15, 2010
March 20, 2014
September 2010
September 2017   (final data collection date for primary outcome measure)
Phase 1: Identify a transplant regimen with acceptable rates of severe acute GVHD (< 25%) and transplant-related NRM (< 20%) Phase 2: Estimate the 6-month probability of survival without having grade III-IV GVHD or evidence of graft failure. [ Time Frame: Study Day 100 ] [ Designated as safety issue: Yes ]
Two immunosuppressive regimens with Fludarabine-Cytoxan-TBI conditioning will be studied in reduced-intensity, partially HLA mismatched allogeneic BMT from unrelated or non-first-degree related donors.
Identify a transplant regimen associated with acceptable rates of severe acute GVHD (< 25%) and transplant-related NRM (< 20%) by Day 100 [ Time Frame: by Day 100 ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01203722 on ClinicalTrials.gov Archive Site
  • Estimate the progression-free survival, event-free survival, overall survival, cumulative incidence of progression or relapse, and cumulative incidence of NRM. [ Time Frame: 7 years ] [ Designated as safety issue: No ]
    All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression.
  • Estimate the cumulative incidence of acute grade II-IV GVHD, acute grade III-IV GVHD, and chronic GVHD. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    All suspected cases of acute GVHD must be confirmed histologically by biopsy of an affected organ (skin, liver, or gastrointestinal tract). Date of symptom onset, date of biopsy confirmation of GVHD, maximum clinical grade, and dates and types of treatment will be recorded. Dates of symptom onset of grade II or higher GVHD and grade III-IV GVHD will be recorded.
  • 1. Estimate the event-free survival, overall survival, cumulative incidence of progression or relapse, and cumulative incidence of NRM.
  • 2. Estimate the cumulative incidence of acute grade II-IV GVHD, acute grade III-IV GVHD, and chronic GVHD.
  • 3. Determine the need for systemic immunosuppressive treatment for GVHD beyond the originally planned prophylaxis regimen.
  • 4. Describe graft failure frequency, kinetics of T-cell donor chimerism and total leukocyte donor chimerism in peripheral blood, and kinetics of neutrophil and platelet recovery.
  • 5. Characterize immune reconstitution and the immunobiology of sirolimus and post-transplantation Cy by analyzing peripheral blood mononuclear cells collected prospectively at defined time points.
Not Provided
Not Provided
 
Reduced Intensity, Partially HLA Mismatched BMT to Treat Hematologic Malignancies
Reduced Intensity, Partially HLA Mismatched Allogeneic BMT for Hematologic Malignancies Using Donors Other Than First-degree Relatives

If transplantation using mismatched unrelated donors or non-first-degree relatives could be performed with an acceptable toxicity profile, an important unmet need would be served. Towards this goal, the current study extends our platform of nonmyeloablative, partially HLA-mismatched BMT to the use of such donors, investigating up to several postgrafting immunosuppression regimens that incorporate high-dose Cy. Of central interest is the incorporation of sirolimus into this postgrafting immunosuppression regimen. The primary goal is to identify a transplant regimen associated with acceptable rates of severe acute GVHD and NRM by Day 100.

Not Provided
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Hematologic Malignancies
  • Other: Fludarabine, Cytoxan, TBI, Sirolimus + MMF

    Pre-transplantation:

    • 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: 200 cGy TBI administered in a single fraction

    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
    Other Names:
    • Fludarabine
    • High-dose Cytoxan
    • Mycophenolate Mofetil
    • MMF
    • Sirolimus
  • Other: Fludarabine, Cytoxan, TBI, Tacrolimus + MMF

    Pre-transplantation:

    • 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: 200 cGy TBI administered in a single fraction

    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
    Other Names:
    • Fludarabine
    • High-dose Cytoxan
    • Mycophenolate Mofetil
    • MMF
    • Tacrolimus
  • Active Comparator: REGIMEN B
    Fludarabine, Cytoxan, TBI, Mycophenolate Mofetil (MMF), Sirolimus
    Intervention: Other: Fludarabine, Cytoxan, TBI, Sirolimus + MMF
  • Active Comparator: REGIMEN C
    Fludarabine, Cytoxan, TBI, Mycophenolate Mofetil (MMF), Tacrolimus
    Intervention: Other: Fludarabine, Cytoxan, TBI, Tacrolimus + MMF
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
40
December 2017
September 2017   (final data collection date for primary outcome measure)

Patient Inclusion Criteria:

  1. Patient age 0.5-75 years
  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.
  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
    9. Poor-risk CLL or SLL
    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
      • 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
        • peripheral T-cell lymphoma, including angioimmunoblastic T-cell lymphoma
        • 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.
  9. ECOG performance status < 2 or Karnofsky or Lansky score > 60

Patient Exclusion Criteria:

  1. Not pregnant or breast-feeding.
  2. HIV positive.
  3. No uncontrolled bacterial, viral, or fungal infection.
  4. No previous allogeneic BMT (syngeneic BMT permissible).
  5. Active extramedullary leukemia or known active CNS involvement by malignancy. Such disease treated into remission is permitted.

Donor Inclusion Criteria:

  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.

Donor Exclusion Criteria:

  1. Donor must not be HLA identical to the recipient.
  2. Has not donated blood products to recipient.
Both
6 Months to 75 Years
Yes
Contact: Yvette Kasamon, MD 410-955-8839 ykasamo1@jhmi.edu
United States
 
NCT01203722
J1055, NA_00039823
Yes
Sidney Kimmel Comprehensive Cancer Center
Sidney Kimmel Comprehensive Cancer Center
Not Provided
Principal Investigator: Yvette Kasamon, MD Sidney Kimmel Comprehensive Cancer Center
Sidney Kimmel Comprehensive Cancer Center
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP