A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Thomas Jefferson University
Sponsor:
Information provided by (Responsible Party):
Thomas Jefferson University
ClinicalTrials.gov Identifier:
NCT01384513
First received: June 27, 2011
Last updated: March 11, 2014
Last verified: March 2014
  Purpose

The purpose of this research study is to compare the survival rates of patients with better risk disease undergoing hematopoietic stem cell transplant (HSCT) to the survival rates reported in the medical literature of similar patients undergoing reduced intensity HSCT from matched related donors.


Condition Intervention Phase
Adult Acute Lymphoblastic Leukemia in Remission
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Adult Nasal Type Extranodal NK/T-cell Lymphoma
Aplastic Anemia
Childhood Acute Lymphoblastic Leukemia in Remission
Childhood Acute Myeloid Leukemia in Remission
Childhood Myelodysplastic Syndromes
Chronic Eosinophilic Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Essential Thrombocythemia
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Juvenile Myelomonocytic Leukemia
Mastocytosis
Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Nodal Marginal Zone B-cell Lymphoma
Polycythemia Vera
Previously Treated Myelodysplastic Syndromes
Primary Myelofibrosis
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
Recurrent Adult Grade III Lymphomatoid Granulomatosis
Recurrent Adult Hodgkin Lymphoma
Recurrent Childhood Acute Lymphoblastic Leukemia
Recurrent Childhood Acute Myeloid Leukemia
Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Mycosis Fungoides/Sezary Syndrome
Recurrent Small Lymphocytic Lymphoma
Recurrent/Refractory Childhood Hodgkin Lymphoma
Refractory Anemia
Refractory Anemia With Ringed Sideroblasts
Refractory Hairy Cell Leukemia
Refractory Multiple Myeloma
Secondary Myelodysplastic Syndromes
Splenic Marginal Zone Lymphoma
T-cell Large Granular Lymphocyte Leukemia
Waldenström Macroglobulinemia
Drug: Fludarabine
Drug: Thiotepa
Radiation: Total Body Irradiation (TBI)
Biological: Donor Lymphocyte Infusion (DLI)
Drug: Cyclophosphamide (CY)
Drug: Tacrolimus
Drug: Mycophenolate mofetil
Device: Allogeneic hematopoietic stem cell transplantation
Procedure: Peripheral blood stem cell transplantation (PBSCT)
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Two Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematologic Malignancies

Resource links provided by NLM:


Further study details as provided by Thomas Jefferson University:

Primary Outcome Measures:
  • Overall Survival (OS) in patients with haploidentical family donors with hematological malignancies in morphological or radiographic remission or with chemosensitive, indolent diseases [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
    The primary null hypothesis is that 2 year OS rate is at most 35%. This hypothesis will be rejected if the 95% confidence interval for year OS rate computed from the estimated Kaplan-Meier survival curves will be entirely above 0.35.


Secondary Outcome Measures:
  • Treatment Related Mortality (TRM) [ Time Frame: At 2 years ] [ Designated as safety issue: Yes ]
    To compare the treatment related mortality rate (TRM) for patients treated on this study to the historical TRM rates of patients undergoing reduced intensity conditioning (RIC) matched-sibling hematopoietic stem cell transplant (HSCT) as reported in the literature

  • Incidence and severity of GVHD, graded according to standard criteria [ Time Frame: Assessed up to 2 years ] [ Designated as safety issue: No ]
    The estimates of incidence rates will be presented with corresponding 95% confidence intervals using the exact method

  • Relapse Rate [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
    Evaluated by estimating Kaplan-Meier survival curves. From these curves, the 95% confidence interval for 2 year rates will be computed.

  • Engraftment Rates [ Time Frame: Assessed up to 2 years ] [ Designated as safety issue: No ]
    The estimates of incidence rates will be presented with corresponding 95% confidence intervals using the exact method.

  • Incidence of Treatment Related Mortality (TRM) [ Time Frame: At 100 days ] [ Designated as safety issue: No ]
    The estimates of incidence rates will be presented with corresponding 95% confidence intervals using the exact method.

  • Relapse Related Mortality [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
    Evaluated by estimating Kaplan-Meier survival curves. From these curves, the 95% confidence interval for 2 year rates will be computed.

  • Lymphoid Reconstitution [ Time Frame: 100 days post-transplant ] [ Designated as safety issue: No ]
    To evaluate lymphoid reconstitution in patients treated on the Two Step approach


Estimated Enrollment: 50
Study Start Date: August 2011
Estimated Study Completion Date: July 2017
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (Allogeneic PBSCT)

REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 60 minutes on days -11 to -8 and thiotepa IV over 2 hours on days -11 to -9. Patients undergo TBI on day -6. Patients also receive cyclophosphamide IV over 2 hours on days -3 and -2.

TRANSPLANTATION: Patients undergo DLI on day -6 and CD-34+ allogeneic PBSCT on day 0.

GVHD PROPHYLAXIS: Beginning on day -1, patients receive tacrolimus IV or PO with taper beginning on day 42. Patients also receive mycophenolate mofetil IV BID on days -1 to 28.

Drug: Fludarabine
Given IV
Other Names:
  • fludarabine phosphate
  • Fludara
Drug: Thiotepa
Given IV
Other Names:
  • N,N'N'-triethylenethiophosphoramide
  • ThioTEPA
Radiation: Total Body Irradiation (TBI)
2 Gy administered as part of the conditioning regimen
Other Name: radiotherapy
Biological: Donor Lymphocyte Infusion (DLI)
Undergo DLI
Other Name: buffy coat fusion
Drug: Cyclophosphamide (CY)
Given IV
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • cytophosphane
Drug: Tacrolimus
Given IV or PO
Other Names:
  • FK-506
  • Fujimycin
Drug: Mycophenolate mofetil
Given IV
Other Names:
  • MMF
  • CellCept
Device: Allogeneic hematopoietic stem cell transplantation
Undergo CD34+ allogeneic PBSCT
Other Name: CliniMACS
Procedure: Peripheral blood stem cell transplantation (PBSCT)
Undergo CD34+ allogeneic PBSCT
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation
  • peripheral blood stem cell

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare the overall survival (OS) rate at 2 years post treatment using the Jefferson 2 step reduced intensity conditioning (RIC) approach in patients with haploidentical family donors with hematological malignancies in morphological or radiographic remission or with chemosensitive, indolent diseases to historical OS rates in similar populations after RIC matched donor HSCT as reported in the literature.

SECONDARY OBJECTIVES:

I. To compare the treatment-related mortality (TRM) rate at 2 years for patients treated on this study to the historical TRM rates of patients undergoing RIC matched-sibling HSCT as reported in the literature.

II. To compare the 2 year relapse rates and relapse related mortality of patients with myeloid diseases to that of patients with lymphoid diseases who are treated on this Thomas Jefferson University (TJU) RIC 2 step approach.

III. To determine the incidence and severity of graft-versus-host disease (GVHD) in patients undergoing treated on the TJU RIC 2 step approach.

IV. To evaluate engraftment rates and lymphoid reconstitution in patients treated on the TJU RIC 2 step approach.

V. To evaluate the incidence of TRM at 100 days in patients treated on the TJU RIC 2 step approach.

OUTLINE:

REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 60 minutes on days -11 to -8 and thiotepa IV over 2 hours on days -11 to -9. Patients undergo total body irradiation (TBI) on day -6. Patients also receive cyclophosphamide IV over 2 hours on days -3 and -2.

TRANSPLANTATION: Patients undergo donor lymphocyte infusion (DLI) on day -6 and cluster of differentiation (CD)-34+ allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0.

GVHD PROPHYLAXIS: Beginning on day -1, patients receive tacrolimus IV or orally (PO) with taper beginning on day 42. Patients also receive mycophenolate mofetil IV twice daily (BID) on days -1 to 28.

After completion of study treatment, patients are followed up periodically for 2 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Any patient with hematologic or oncologic diagnosis in which allogeneic HSCT is thought to be beneficial, and in whom front-line therapy has already been applied. Patients treated on this protocol will be without morphological evidence of disease (complete remission or "CR"), or if the patient has evidence of disease, the patient must have had at least a good partial response (PR) to the most recent therapy and the disease must be chemoresponsive.
  2. Patients treated on this study will have:

    • Acute leukemia in 1st or 2nd CR
    • MDS (myelodysplastic syndrome), specific subtypes of RA (refractory anemia) or RARS (refractory anemia with ringed sideroblasts) subtypes.
    • Hodgkin or Indolent Non-Hodgkin's lymphoma with chemosensitive disease
    • Myeloma without morphological evidence of disease, or a deep PR to the most recent therapy
    • Myeloproliferative disorders with at least a PR to current therapy
    • Aplastic Anemia
    • A hematological or oncological disease (not listed) that meets the criteria reviewed above (in CR or with a good PR).
  3. Patients must have a related donor who is HLA mismatched at 2, 3, or 4 antigens at the HLA-A; B; C; DR loci in the GVHD direction. (Patients with related donors who are HLA identical or are a 1-antigen mismatch may be treated on this therapeutic approach, but will have their outcomes will not be part of the statistical aims of the study (see Summary section).
  4. Patients must adequate organ function:

    • LVEF (Left ventricular end diastolic function) of >50%
    • DLCO (Diffusing Capacity of the Lung for Carbon Monoxide ) ≥50% of predicted corrected for hemoglobin
    • Adequate liver function as defined by a serum bilirubin <1.8, AST or ALT < 2.5X upper limit of normal
    • Creatinine Clearance of ≥ 60 mL/min
  5. Performance status ≥ 80% (TJU Karnofsky) for patients ≥ 60 years old or ≥70% for patients < 60 years old.
  6. HCT-CI Score ≤ 4 points for patients ≥ 60 years old or ≤ 5 points for patients < 60 years old.
  7. Patients must be willing to use contraception if they have childbearing potential
  8. Able to give informed consent

Exclusion Criteria:

  1. Performance status < 80% (TJU Karnofsky) for patients ≥ 60 years old or <70% for patients < 60.
  2. Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) Score > 4 points for patients ≥ 60 years old or > 5 points for patients < 60.
  3. HIV positive
  4. Active involvement of the central nervous system with malignancy
  5. Inability to obtain informed consent
  6. Pregnancy
  7. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder
  8. Patients who have received alemtuzumab within 8 weeks of the transplant admission, or who have recently received horse or rabbit anti-thymocyte globulin and have an anti-thymocyte globulin level of > 2 ugm/ml
  9. Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01384513

Contacts
Contact: Dolores Grosso, DNP, CRNP 215-955-8874
Contact: Donna Zuccarello 215-955-6612

Locations
United States, Pennsylvania
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Dolores Grosso, DNP, CRNP    215-955-8874      
Contact: Donna Zuccarello    215-955-6612      
Principal Investigator: Dolores Grosso, DNP, CRNP         
Principal Investigator: Neal Flomenberg, MD         
Sub-Investigator: S. Onder Alpdogan, MD         
Sub-Investigator: Matthew Carabasi, MD         
Sub-Investigator: Joanne Filicko-O'Hara, MD         
Sub-Investigator: Margaret Kasner, MD         
Sub-Investigator: Ubaldo Martinez-Outschoorn, MD         
Sub-Investigator: John L Wagner, MD         
Sub-Investigator: Mark Weiss, MD         
Sub-Investigator: Maria Werner-Wasik, MD         
Sub-Investigator: Wenyin Shi, MD, PhD         
Sub-Investigator: William O'Hara, PharmD         
Sponsors and Collaborators
Thomas Jefferson University
Investigators
Principal Investigator: Dolores Grosso, DNP, CRNP Thomas Jefferson University
Principal Investigator: Neal Flomenberg, MD Thomas Jefferson University
  More Information

Additional Information:
No publications provided

Responsible Party: Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT01384513     History of Changes
Other Study ID Numbers: 11D.247, 2011-31
Study First Received: June 27, 2011
Last Updated: March 11, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Thomas Jefferson University:
Allogeneic HSCT
Hematopoietic stem cell transplantation

Additional relevant MeSH terms:
Congenital Abnormalities
Primary Myelofibrosis
Anemia
Anemia, Aplastic
Anemia, Refractory
Neoplasms
Hodgkin Disease
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Hairy Cell
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Chronic
Leukemia, Neutrophilic, Chronic
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Lymphomatoid Granulomatosis
Waldenstrom Macroglobulinemia
Mastocytosis
Urticaria Pigmentosa
Multiple Myeloma
Neoplasms, Plasma Cell
Mycoses
Mycosis Fungoides
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute

ClinicalTrials.gov processed this record on July 23, 2014