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Safety Study of Bone Marrow Transplant Using Mismatched Tissue Followed by Chemotherapy

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ClinicalTrials.gov Identifier: NCT00796562
Recruitment Status : Completed
First Posted : November 24, 2008
Results First Posted : March 14, 2019
Last Update Posted : March 14, 2019
Sponsor:
Collaborators:
Otsuka Pharmaceutical Co., Ltd.
National Center for Research Resources (NCRR)
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information
First Submitted Date  ICMJE November 20, 2008
First Posted Date  ICMJE November 24, 2008
Results First Submitted Date  ICMJE February 12, 2019
Results First Posted Date  ICMJE March 14, 2019
Last Update Posted Date March 14, 2019
Actual Study Start Date  ICMJE December 2008
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2019)
Engraftment as Measured by Donor Chimerism [ Time Frame: Day 60 ]
Percentage of participants who achieved donor chimerism >=95%.
Original Primary Outcome Measures  ICMJE
 (submitted: November 21, 2008)
To estimate the incidence of graft rejection and severe graft versus-host disease (GVHD) following myeloablative, HLA-mismatched BMT for patients with high risk hematologic malignancies [ Time Frame: Day 14-60 ]
Change History Complete list of historical versions of study NCT00796562 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2019)
  • Non-relapse Mortality [ Time Frame: Day 100, 1 year ]
    Number of participants deceased for reasons other than disease relapse or progression.
  • Acute GVHD [ Time Frame: Day 100 ]
    Percentage of participants who experience grade II-IV or III-IV acute graft-versus-host-disease (GVHD) by Przepiorka criteria. The stages are defined as follows:
    • Stage II: Rash on >50% of skin, bilirubin 2-3 mg/dL, or diarrhea 500-1000 mL/day
    • Stage III: Bilirubin 3-15 mg/dL or diarrhea >1000 mL/day
    • Stage IV: Generalized erythroderma with bullae or bilirubin >15 mg/dL This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)
  • Chronic GVHD [ Time Frame: 6 months, 12 months ]
    Percentage of participants who experience chronic GVHD. Chronic GVHD is graded using NIH consensus criteria and Seattle criteria. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)
  • Survival [ Time Frame: 1 year, 2 years, 3 years ]
    Percentage of participants alive (overall survival) and alive without disease relapse, progression, or diagnosis of myeloid malignancy (event-free survival). Estimated using Kaplan-Meier method.
  • Relapse [ Time Frame: 1 year, 3 years ]
    Percentage of participants who experienced disease progression or relapse. This outcome was estimated using proportional subdistribution hazard regression model for competing risks (Fine and Gray 1999)
Original Secondary Outcome Measures  ICMJE
 (submitted: November 21, 2008)
To estimate overall survival, relapse, non-relapse mortality, and event-free survival in patients receiving myeloablative conditioning and transplantation of partially human leukocyte antigen (HLA)-mismatched bone marrow from first-degree relatives [ Time Frame: 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety Study of Bone Marrow Transplant Using Mismatched Tissue Followed by Chemotherapy
Official Title  ICMJE A Phase II Trial of Myeloablative Conditioning and Transplantation of Partially HLA-mismatched Bone Marrow for Patients With Hematologic Malignancies
Brief Summary The purpose of this study is to see if giving high dose chemotherapy and total body irradiation before and repeating high dose chemotherapy after a bone marrow transplant could reduce the incidence of graft rejection and disease for patients with blood cancers
Detailed Description

Allogeneic blood or marrow transplantation (alloBMT), following either marrow-ablative or nonmyeloablative conditioning, is a potentially curative treatment for a variety of hematologic malignancies and non-malignant hematologic disorders. Of all the potential sources of allografts, transplantation of stem cells from a human leukocyte antigen (HLA)-matched sibling has generally produced the best overall outcomes, i.e. overall and progression-free survival. Unfortunately, only about a third of candidates for alloBMT have HLA-matched siblings.

For patients who lack HLA-matched siblings, there are three alternative sources of stem cells for alloBMT: 1) volunteer unrelated donors; 2) umbilical cord blood; and 3) partially HLA-mismatched, or haploidentical, related donors. Since any patient shares exactly one HLA haplotype with each biological parent or child and half of siblings, an eligible haploidentical donor can be identified rapidly in nearly all cases. However, haploidentical BMT has been associated with significant risks of graft rejection and severe GVHD, which are manifestations of excessive alloreactivity by host and donor T cells, respectively.

The risk of severe GVHD may be reduced in intensively conditioned recipients of grafts that have been rigorously depleted of mature T cells or selectively depleted of alloreactive T cells, but the risks of serious infection and death from prolonged immune compromise in these patients remains high. Cyclophosphamide(Cy) is a highly immunosuppressive antineoplastic agent that has an established role in conditioning for alloBMT.

Typically, the drug is administered prior to transplantation to prevent graft rejection by suppressing the host immune system. However, pre-transplantation conditioning with Cy increases the risk of GVHD following allogeneic T cell infusion in mouse models. In contrast, administration of a properly timed, high dose of Cy after BMT inhibits both graft rejection and GVHD.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • MDS
  • Leukemias
  • Lymphomas
Intervention  ICMJE
  • Drug: Busulfan
    Participant will receive Busulfan injections, 4 times a day for 4 days with dilantin prophylaxis (in patients 10 years of age or older). Busulfan levels in the blood will be measured and dose adjusted, if needed.
  • Drug: Cyclophosphamide
    Patient will receive Cy by IV once a day for 2 days.
    Other Names:
    • Cy
    • Cytoxan
    • CTX
  • Radiation: Total body irradiation
    Patients will receive TBI once a day for 4 days.
    Other Name: TBI
Study Arms  ICMJE Experimental: Myeloablative haploidentical BMT
  • All participants except those with acute lymphoblastic leukemia and lymphoblastic lymphoma: Busulfan will be administered 1 mg/kg oral (or 0.8 mg/kg IV) four times per day for four days, followed by cyclophosphamide 50 mg/kg once per day for two days.
  • Participants with acute lymphocytic leukemia or lymphoblastic lymphoma: Cyclophosphamide will be administered 50 mg/kg once per day for two days, followed by total body irradiation at 300 cGy per day for four days.
Interventions:
  • Drug: Busulfan
  • Drug: Cyclophosphamide
  • Radiation: Total body irradiation
Publications * Fine J.P. and Gray, R.J. (1999), A proportional hazards model for the subdistribution of a competing risk, Journal of the American Statistical Association, 94:496-509.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 13, 2019)
107
Original Estimated Enrollment  ICMJE
 (submitted: November 21, 2008)
20
Actual Study Completion Date  ICMJE November 2016
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Acute lymphocytic leukemia in high risk CR1
  • Acute myeloid leukemia in CR1
  • Therapy-related AML
  • RAEB with >5% and <20% bone marrow blasts
  • Chronic myelogenous leukemia beyond 1st chronic phase; Patients cannot be in blast crisis
  • CMMoL
  • JMML
  • Chemotherapy-resistant Hodgkins Lymphoma or intermediate or high grade Non-Hodgkins lymphoma (Less than a PR after standard or salvage chemotherapy)
  • Mantle cell lymphoma: chemotherapy refractory (Less than a PR after standard or salvage chemotherapy) or patients beyond CR1 with chemosensitive disease
  • Follicular Lymphoma, Grade 3
  • Transformed indolent lymphomas

Exclusion Criteria:

  • Poor cardiac function: left ventricular ejection fraction <45% as determined by MUGA or ECHO. For pediatric patients LVEF <45% or a shortening fraction below normal limits for age.
  • Poor pulmonary function: FEV1 and FVC <50% predicted for patients who have not received thoracic or mantle irradiation. For patients who have received thoracic or mantle irradiation, FEV1 and FVC <70% predicted or DLCO < 50 of predicted. For children unable to perform PFTs because of developmental stage pulse oximetry < 85% on RA
  • Poor liver function: bilirubin >2 mg/dl (not due to hemolysis, Gilbert's or primary malignancy)
  • Poor renal function: Creatinine >2.0mg/dl or creatinine clearance
  • HIV-positive
  • Positive leukocytotoxic crossmatch
  • Women of childbearing potential who currently are pregnant or who are not practicing adequate contraception
  • Uncontrolled viral, bacterial, or fungal infections Patients with symptoms consistent with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed for the above viruses and if positive are not eligible for the trial until they are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms secondary to the nature of the assay.
  • Indolent lymphomas (Follicular Grade 1 and 2, marginal zone, chronic lymphocytic leukemia, small lymphocytic lymphoma, MALT)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00796562
Other Study ID Numbers  ICMJE J0820
NA_00015795 ( Other Identifier: JHMIRB )
KL2RR025006 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE
  • Otsuka Pharmaceutical Co., Ltd.
  • National Center for Research Resources (NCRR)
Investigators  ICMJE
Principal Investigator: Heather Symons, M.D. Johns Hopkins University
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date March 2019

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