A Research Study of Bone Marrow Transplantation From Unrelated or Partially Matched Related Donors
Information source: Thomas Jefferson University
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hematological Malignancies
Intervention: Total Body Irradiation (Radiation); Cyclophosphamide (Drug); Tacrolimus (Drug); Mycophenolate mofetil (Drug); Fludarabine (Drug); Busulfan (Drug); Hematopoietic stem cell transplantation (Genetic)
Phase: Phase 2
Status: Recruiting
Sponsored by: Thomas Jefferson University Official(s) and/or principal investigator(s): John L Wagner, MD, Principal Investigator, Affiliation: Thomas Jefferson University
Overall contact: John L Wagner, MD, Phone: 215-955-8874
Summary
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.
Clinical Details
Official title: Post Transplant Cyclophosphamide for Unrelated and Related Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies
Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Successful Engraftment Using Cyclophosphamide Post-Transplant
Secondary outcome: Incidence of Grade III-IV GVHDIncidence of GVHD Unresponsive to Corticosteroids and Photopheresis Transplant-Related Mortality
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
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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.
Locations and Contacts
John L Wagner, MD, Phone: 215-955-8874
Thomas Jefferson University, Philadelphia, Pennsylvania 19107, United States; Recruiting John L Wagner, MD, Phone: 215-955-8874 Donna Zuccarello, Phone: 215-955-6612 John L Wagner, MD, Principal 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 Margaret Kasner, MD, Sub-Investigator Lisa Kearns, CRNP, Sub-Investigator William O'Hara, PharmD, Sub-Investigator Mark Weiss, MD, Sub-Investigator Maria Werner-Wasik, MD, Sub-Investigator Ubaldo Martinez-Outschoorn, MD, Sub-Investigator Manish Sharma, MD, Sub-Investigator Thomas Klumpp, MD, Sub-Investigator
Additional Information
Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center Thomas Jefferson University Hospitals
Starting date: February 2011
Last updated: March 9, 2015
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