A Research Study of Bone Marrow Transplantation From Unrelated or Partially Matched Related Donors

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Thomas Jefferson University
Sponsor:
Information provided by (Responsible Party):
Thomas Jefferson University
ClinicalTrials.gov Identifier:
NCT01349101
First received: April 26, 2011
Last updated: July 24, 2014
Last verified: July 2014
  Purpose

It is hypothesized that engraftment when administering cyclophosphamide post the stem cell infusion will increase, the incidence of graft versus host disease (GVHD) and day 100 mortality will decrease, and the use of cyclophosphamide post stem cell infusion with alternative donors will be as safe and as effective as traditional matched transplants.


Condition Intervention Phase
Hematological Malignancies
Radiation: Total Body Irradiation
Drug: Cyclophosphamide
Drug: Tacrolimus
Drug: Mycophenolate mofetil
Drug: Fludarabine
Drug: Thiotepa
Genetic: Hematopoietic stem cell transplantation
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Post Transplant Cyclophosphamide for Unrelated and Related Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

Resource links provided by NLM:


Further study details as provided by Thomas Jefferson University:

Primary Outcome Measures:
  • Successful Engraftment Using Cyclophosphamide Post-Transplant [ Time Frame: Through 100 days post-transplant ] [ Designated as safety issue: No ]

    Hematopoietic engraftment will be defined as:

    ANC >/= 0.5x10e9/L for at least 3 days. Platelet engraftment >20,000 with no transfusions X 7 days.



Secondary Outcome Measures:
  • Incidence of Grade III-IV GVHD [ Time Frame: Through 100 days post-transplant ] [ Designated as safety issue: Yes ]
    Assess incidence of Grade III-IV graft-versus-host disease (GVHD); goal is less than 10%.

  • Incidence of GVHD Unresponsive to Corticosteroids and Photopheresis [ Time Frame: Through 100 days post-treatment ] [ Designated as safety issue: Yes ]
    Assess incidence of graft-versus-host disease (GVHD) unresponsive to corticosteroids and photopheresis; goal is less than 15%.

  • Transplant-Related Mortality [ Time Frame: 100 days post-transplant ] [ Designated as safety issue: No ]
    Assess day 100 transplant-related mortality; goal is less than 15%.


Estimated Enrollment: 36
Study Start Date: February 2011
Estimated Study Completion Date: February 2016
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Myeloablative HSCT
Myeloablative Hematopoietic Stem Cell Transplantation (HSCT): Patients will receive myeloablative transplants or nonmyeloablative transplants depending on their disease type.
Radiation: Total Body Irradiation

Myeloablative HSCT Arm: Total body irradiation (TBI) is given in 8 fractions over 4 days (total dose of 12 Gy)

Reduced Intensity HSCT Arm: TBI is given in one fraction (total dose of 2 Gy)

Other Names:
  • TBI
  • radiotherapy
Drug: Cyclophosphamide
Cyclophosphamide is administered on the third day after the hematopoietic stem cell transplantation (HSCT) to help reduce graft-versus-host disease (GVHD). It is given at a dose of 60 mg/kg/d for 2 days.
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • Cytophosphane
  • Cy
Drug: Tacrolimus
Started the fifth day after the transplant to help prevent graft-versus-host disease (GVHD).
Other Names:
  • FK-506
  • Fujimycin
Drug: Mycophenolate mofetil
Started the fifth day after the transplant to help prevent graft-versus-host disease (GVHD).
Other Names:
  • CellCept
  • MMF
Genetic: Hematopoietic stem cell transplantation
Allogeneic marrow transplantation given after the last dose of total body irradiation (TBI)
Other Name: HSCT
Experimental: Reduced Intensity HSCT
Reduced Intensity Hematopoietic Stem Cell Transplantation (HSCT): Patients who have received a previous transplant, patients who have received dose limiting radiation, and patients with a DLCO <45% will receive the reduced intensity conditioning regimen.
Radiation: Total Body Irradiation

Myeloablative HSCT Arm: Total body irradiation (TBI) is given in 8 fractions over 4 days (total dose of 12 Gy)

Reduced Intensity HSCT Arm: TBI is given in one fraction (total dose of 2 Gy)

Other Names:
  • TBI
  • radiotherapy
Drug: Cyclophosphamide
Cyclophosphamide is administered on the third day after the hematopoietic stem cell transplantation (HSCT) to help reduce graft-versus-host disease (GVHD). It is given at a dose of 60 mg/kg/d for 2 days.
Other Names:
  • Endoxan
  • Cytoxan
  • Neosar
  • Procytox
  • Revimmune
  • Cytophosphane
  • Cy
Drug: Tacrolimus
Started the fifth day after the transplant to help prevent graft-versus-host disease (GVHD).
Other Names:
  • FK-506
  • Fujimycin
Drug: Mycophenolate mofetil
Started the fifth day after the transplant to help prevent graft-versus-host disease (GVHD).
Other Names:
  • CellCept
  • MMF
Drug: Fludarabine
Started the fifth day before the transplant. Given for four days at 30 mg/m2/d.
Other Names:
  • fludarabine phosphate
  • Fludara
Drug: Thiotepa
Started the fifth day before the transplant. Given for three days at 5 mg/kg.
Other Name: N,N'N'-triethylenethiophosphoramide
Genetic: Hematopoietic stem cell transplantation
Allogeneic marrow transplantation given after the last dose of total body irradiation (TBI)
Other Name: HSCT

Detailed Description:

The primary rationale for the development of this research study is to find out if the use of cyclophosphamide after a "blood" stem cell transplant is an effective treatment for patients with blood cancers who require transplant for long-term survival but are without an available matched-sibling donor. Historically, survival rates for patients undergoing partially matched related or unrelated donor transplants (henceforth to be called alternative donor transplants) have been much lower than those observed after matched sibling stem cell transplants. Survival post alternative donor stem cell transplant has also been affected by the requirement to remove or reduce the numbers of donor T cells resulting in higher rates of infection, graft rejection, and relapse. One significant limitation to conventional donor transplants with HLA matched siblings has been that over 50% of patients do not have HLA matched siblings so that increasing the safety of alternative donor transplants could have a significant influence on the number of patients who could safely receive transplants. Because of the historically low overall survival (OS) after alternative donor transplants, it has become a procedure of "last resort" in many centers unwilling to consider it unless all other options are exhausted. There fore several centers including ours have sought to overcome problems using various strategies. The strategy the investigators have proposed for this study (which has been used similarly by other centers) has been to administer cyclophosphamide post the stem cell infusion (traditionally it is given before the stem cell infusion) thereby hopefully destroying the activated T-cells causing graft-versus host disease (GVHD) and allow T cell tolerization and engraftment; but, not the inactivated T cells thereby hopefully preserving the anti-tumor effects of the donor immune system. Thus, the major aim of this study will be to measure the engraftment with this regimen and secondarily to measure incidence of GVHD and day 100 mortality. The goal is to see if in the first 3 months the use of cyclophosphamide post stem cell infusion with alternative donors is as safe and as effective as traditional matched transplants.

  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 a hematological or oncological diagnosis in which allogeneic hematopoietic stem cell transplantation (HSCT) is thought to be beneficial.

    1. Patients without morphological or molecular evidence of disease
    2. For patients with "indolent diseases," if the patient has evidence of disease the disease burden must be minimal (at least PR) and the disease must be chemoresponsive. Thus for example patients with acute leukemia (not an indolent disease) must be in a morphological CR or CRp.
  2. For patients with MDS the inclusion criteria is specifically as follows:

    • For patients with RA or RARS or isolated 5q- they can proceed to transplant without any treatment.
    • For patients with RAEB-1, RCMD+/-RS, or MDS NOS must have stable disease for 6 months (as documented by serial bone marrow examinations) in the absence of any therapy but growth factors or transfusion support. Patients who require treatment to "control their disease" must show chemo-responsiveness
    • For patients with CMML or RAEB-2 they must demonstrate chemo-responsiveness
    • Chemo-responsiveness is defined as a blast percentage decrease by at least 5 percentage points and there must be less than 10% blasts after treatment and at the time of transplant, if there are more than 10% blasts at any point during the disease course
    • Chemo-responsiveness must also include at least one of the following if applicable:

      • A cytogenetic response
      • A well-documented decrease in transfusion requirements.
  3. Patients must have a related donor who is zero, one, two, three, or four antigen mismatched at the HLA-A; B; C; DR loci or an unrelated donor up to a two antigen mismatch. DNA will be retained by the tissue typing laboratory for possible typing for DQ and DP. When multiple related donor options are available donor selection will be determined the same as in the TJU two-step protocols. When multiple unrelated donors are available care will be made to avoid HLA-A and HLA-B mismatches if possible based on data from the Japanese Marrow Donor Registry studies. An HLA antibody screen will be performed on each patient.
  4. All patients must have adequate organ function:

    1. Patients with related donors must have an LVEF of >35%. Patients with unrelated donors must have an LVEF >45%. Patients with LVEF ≤50% and all patients with symptoms or history of heart failure or coronary artery disease must have a stress echo or equivalent test and a cardiological evaluation.
    2. Patients with related donors must have a DLCO >35% of predicted corrected for hemoglobin. Patients with unrelated donors must have a DLCO >45% of predicted corrected for hemoglobin. For related donors if the DLCO is less than 45% the EF must be greater than 45% and vice versa.
    3. Patients with related donors must have an adequate liver function as defined by a serum bilirubin <3.0, AST and ALT <3.0X upper limit of normal. Patients with unrelated donors must have an adequate liver function as defined by a serum bilirubin <1.8, AST and ALT < 2.5X upper limit of normal. Exceptions may be granted for patients with "benign" liver disorders such as Gilbert's disease.
    4. Patients with related donors or with unrelated donors must have a creatinine clearance of > 60 ml/min/1.73 m^2.
    5. Patients with related donors must have a performance status > 60% (TJU Karnofsky14) (Appendix A). Patients with unrelated donors must have a Performance status > 70% (TJU Karnofsky).
    6. Patients with related donors must have a HCT-CI Score < 6 Points (Appendix B). Patients with unrelated donors must have a HCT-CI Score < 5 Points.
    7. Patients must be willing to use contraception if they are of childbearing potential.
    8. Patients must be able to give informed consent or have a care giver who can give consent.
    9. Patients that are HIV positive will be eligible for the study if they have an undetectable viral load and meet the above criteria for patients with unrelated donors.

Exclusion Criteria:

  1. Patients with related donors who have a combination of Performance status of < 70% (TJU Karnofsky) and an HCT-CI of 4 points or more. Patients with unrelated donors with a combination of Performance status of < 80% (TJU Karnofsky) and an HCT-CI of 4 points or more.
  2. Patients with active involvement of the central nervous system with malignancy. Patients with a disease with potential for CNS involvement should have documentation of the lack of CNS involvement via lumbar puncture or similar procedure performed within two months of admission or as per TJU standard practice guidelines.
  3. Patients with a psychiatric disorder that would preclude patients from complying with the protocol even with a caregiver. Patients with a lack of social support that would interfere with the ability to receive appropriate medical care will also be excluded.
  4. Pregnancy
  5. Patients with life expectancy of < 6 months for reasons other than their underlying hematological/oncological disorder.
  6. Patients who have received alemtuzumab within 8 weeks of the transplant admission, or who have recently received horse or rabbit ant-thymocyte globulin and have an ATG level of > 2 μg/ml. Patients on systemic corticosteroids at a dose equivalent of prednisone 7.5mg/day or higher.
  7. Patients who cannot receive cyclophosphamide.
  8. Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol.
  9. Patients with refractory disease.
  10. Patients with preformed antibodies to their donors.
  11. Patients who require supplemental oxygen other than for sleep apnea will be excluded.
  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: NCT01349101

Contacts
Contact: John L Wagner, MD 215-955-8874
Contact: Donna Zuccarello 215-955-6612

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

Additional Information:
No publications provided

Responsible Party: Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT01349101     History of Changes
Other Study ID Numbers: 11D.51, 2010-54
Study First Received: April 26, 2011
Last Updated: July 24, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Thomas Jefferson University:
hematopoietic stem cell transplantation
HSCT
allogeneic marrow transplantation
cyclophosphamide
graft-versus-host disease
GVHD

Additional relevant MeSH terms:
Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Hematologic Diseases
Cyclophosphamide
Mycophenolate mofetil
Thiotepa
Fludarabine phosphate
Tacrolimus
Fludarabine
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Enzyme Inhibitors
Antibiotics, Antineoplastic
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on July 31, 2014