Trial Information

Blood and Marrow Transplant Clinical Research Network

BACKGROUND:

Several new developments in the field of allogeneic hematopoietic stem cell transplantation
have substantially decreased transplant-related morbidity and promise to make major
improvements in both the safety and efficacy of transplantation, allowing transplantation to
be extended to more patients. Use of matched unrelated marrow donors, unrelated cord blood
units, and partially matched family donors have greatly expanded the options for patients
who lack an HLA identical sibling donor. Use of stem cells mobilized and collected from
peripheral blood rather than harvested from bone marrow speeds engraftment and may improve
treatment outcome. Manipulation of the transplant to adjust the dose of stem cells and
lymphocytes to optimum numbers (graft engineering) may also be beneficial. The use of
non-myeloablative transplants (mini-transplants) promises to extend the safe application of
stem cell allografts to individuals over 60 years and to patients with non-lethal
hematologic diseases. Recently identified human minor histocompatibility antigens may
provide another variable for predicting the severity of graft-versus-host disease.

There is an urgent need to evaluate these promising new therapeutic approaches to
hematopoietic stem cell transplantation and to disseminate the findings to health care
professionals, patients and the public. Each year, thousands of patients undergo
hematopoietic stem cell transplants in the United States, yet few of these patients are
offered the option to enroll in a research protocol to study and improve the outcome of this
life-saving but toxic and expensive procedure. There are several reasons why a blood and
marrow transplant clinical research network would accelerate clinical research and evaluate
new approaches to transplantation. The heterogeneity of hematopoietic stem cell transplant
patients makes it difficult to accumulate a large number of comparable patients in one
center. Multi-center trials will reduce the number of patients needed at each clinical
center and allow accrual to be completed more rapidly. Further, a common treatment protocol
will reduce variables that contribute to patient outcome and allow valid comparisons between
treatments. Finally, the Network approach will increase the number of comparative trials
that are conducted by providing a framework for rapid initiation of important studies, a
focus on randomized studies, and efficient use of pooled clinical expertise and data
management resources.

The Request for Applications was released in January, 2001. Awards were made in September,
2001.

DESIGN NARRATIVE:

Protocols are under development. Three that have been approved and are currently accruing
patients follow.

The Trial of Fluconazole versus Voriconazole for the Prevention of Invasive Fungal
Infections in Allogeneic Blood and Marrow Transplant Recipients (BMT CTN Protocol 0101).
The trial is a Phase III, randomized, double-blinded, placebo-controlled, multicenter
comparative study of fluconazole versus voriconazole. Recipients will be stratified by
center and donor type (sibling vs. unrelated) and randomized to either the fluconazole or
voriconazole arm in a 1:1 ratio. The primary objective is to compare the fungal free
survival rates between the study arms through day 180. Secondary objectives will be to
compare the frequency of invasive fungal infection, time to invasive fungal infection,
survival rate, duration of amphotericin B therapy for possible invasive fungal infection,
time to neutrophil and platelet engraftment, time to and severity of acute and chronic graft
versus host disease (GVHD), and utility of the galactomannan assay in detection of
aspergillis. There will be an estimated 600 subjects with leukemia or myelodysplastic
syndrome who have received a myeloablative, 6/6 HLA-matched allogeneic blood or marrow
transplant, are two years of age or older, and have adequate physical function. Subjects
receive the study drug on day 0 and continue until day 100 post-transplant or until invasive
infection occurs, or the subject develops toxicity attributable to the study drug. For
recipients of any type of graft receiving at least 1.0 mg/kg/day of prednisone on day 100 or
for recipients of T-cell depleted grafts whose CD4+ count is <200 uL on day 100, the study
drug will be continued until day 180. Follow-up continues for a least one year
post-transplant.

A Trial of Tandem Autologous Stem Cell Transplants +/- Post Second Autologous Transplant
Maintenance Therapy Versus Single Autologous Stem Cell Transplant Followed by Matched
Sibling Non-Myeloablative Allogeneic Stem Cell Transplant for Patients with Multiple Myeloma
(BMT CTN Protocol 0102). The study is a phase III, multicenter trial of tandem autologous
transplants versus the strategy of autologous followed by HLA-matched sibling
non-myeloablative allogeneic transplant. Study subjects will be biologically assigned to the
appropriate arm depending on the availability of an HLA-matched sibling. There is a nested
randomized phase III trial of observation versus maintenance therapy following the second
autologous transplant for patients on the tandem autologous transplant arm. The primary
objective of the post-tandem autologous transplant randomized trial of maintenance versus
observation is to compare progression-free survival at three years between the two arms. The
secondary objectives of the post-tandem autologous trial are to compare 'current'
myeloma-stable survival, three-year overall survival, and incidence of progression. The
primary objective of the tandem autologous transplants versus autologous transplant followed
by HLA-matched sibling non-myeloablative allogeneic transplant is to compare
progression-free survival at three years between the two arms. The secondary objectives of
the tandem trial are to compare 'current' myeloma-stable survival, three year overall
survival, and incidence of progression. Mobilization therapy will not be specified for the
study. All patients will undergo a first autologous peripheral blood stem cell transplant
(PBSC) with high-dose melphalan given on day 2. Melphalan will be given between 2 and 8
weeks after initiation of mobilization therapy. Patients with adequate recovery will
receive either a second autologous PBSC transplant or a non-myeloablative PBSC allogeneic
transplant from an HLA-matched sibling. This post-transplant therapy will be initiated at
least 60 days (preferably 60-120 days) following the initial autologous transplant.
Patients without an HLA-matched sibling donor will be randomized to either observation or
one year of maintenance therapy with dexamethasone and thalidomide to begin following
recovery from their second autologous PBSC transplant. This post-transplant therapy will be
initiated at least 60 days (preferably 60-120 days) following the second autologous
transplant. A total of 150 standard risk multiple myeloma patients with an HLA-matched
sibling donor will be accrued. During this time, it is expected that at least 350 standard
risk multiple myeloma patients without a sibling donor will also be entered in the trial. In
addition, high-risk patients with and without HLA-matched siblings will also be entered in
the trial during the same period. The estimated accrual period is three years. Patients will
be followed for at least three years after their second transplant.

A Phase III Randomized Multicenter Study Comparing G-CSF Mobilized Peripheral Blood Stem
Cell with Marrow Transplantation from HLA Compatible Unrelated Donors (BMT CTN Protocol
0201). The study compares granulocyte colony stimulating factor (G-CSF)-mobilized peripheral
blood stem cells (PBSC) versus marrow from unrelated donors for transplantation in patients
with hematologic malignancies. Recipients will be stratified by transplant center and
disease risk and will be randomized to either the PBSC or marrow arm in a 1:1 ratio. The
primary objective is to compare two-year survival rates between patients in the two study
arms using an intent-to-treat analysis. Patients randomized to the two study arms and
actually transplanted will be compared for the following endpoints: survival, incidences of
neutrophil and platelet engraftment, graft failure, acute or chronic
graft-versus-host-disease, time off all immunosuppressive therapy, relapse, infections,
adverse events, immune reconstitution, and quality of life. Donors in each arm of the study
will be compared for time to return to baseline functional score, toxicity score, and CBC
and WBC differential values after donation and quality of life. Eligible patients are up to
66 years of age, have acute leukemia, myelodysplasia, chronic myeloid leukemia or other
myeloproliferative disorders,

Autologous vs Non-myeloablative Hematopoietic Cell Transplantation (HCT) for Patients with
Relapse Follicular Non-Hodgkin's Lymphoma (BMT CTN Protocol 0202). A minimum of 360
patients diagnosed with low grade non-Hodgkin's lymphoma will be accrued. This study is
designed as a Phase II/III, multi-center trial, comparing two transplant strategies, to
determine whether non-myeloablative allogeneic HCTwill improve long-term progression free
survival as compared to autologous HCT. Recipients will be biologically assigned to the
appropriate arm depending on the availability of an HLA-matched sibling. The estimated
accrual period will be three years. The primary objective is to compare progression-free
survival at three years between the two transplant arms.

The following trials are under development.

Initial System Treatment of Acute GVHD: A Phase II Randomized Trial Evaluating Etanercept,
Mycophenolate Mofetil (MMF), Denileukin Diftitox (Ontak) and Pentostatin in Addition to
Corticosteroids (BMT CTN Protocol 0302). In this trial, patients with newly diagnosed GVHD
will receive corticosteroids plus one of four new agents. A control arm of only
corticosteroids will not be used. Each agent will be assessed for safety and efficacy. The
primary objective is to estimate the cumulative incidence of complete response (CR) by day
28 of therapy. Patients will be followed for 9 months following initiation of therapy. In
addition to prescribed study drug plus corticosteroids, all patients will receive
transfusion support as per institutional practice, anti-infective prophylaxis against
cytomegalovirus (CMV), gram positive bacteria, pneumocystis carinii, and fungal infections.

Transplants of HLA-Matched, CD34+ Enriched, T Cell Depleted Peripheral Blood Stem Cells
Isolated by the CliniMACS System in the Treatment of Patients with AML in Second Complete
Remission (BMT CTN Protocol 0303) . The single arm, multicenter phase II trial will assess
the event-free survival at six months post-transplant. Death or the occurrence of grades
II-IV acute GVHD or graft failure (primary or secondary) or relapse will be considered
events for this endpoint. A total of 35 patients, ages 18 to 80, with acute myelomonocytic
leukemia (AML) in second remission and with an HLA-identical sibling donor will be enrolled.

Purine Analog-Based Conditioning for Allogeneic Stem Cell Transplantation in Patients with
Severe Aplastic Anemia.(BMT CTN Protocol 0301)

Two targeted Monoclonal Antibody Therapies (Rituxan versus Bexxar) Combined with BEAM
Conditioning Followed by Autologous Transplant for Patients with Persistent or Relapsed
Chemotherapy Sensitive Diffuse Large B-Cell Non-Hodgkins Lymphoma (BMT CTN Protocol 0401)

Tacrolimus Combined with Sirolimus versus Methotrexate as GvHD Prophylaxis after HLA-Matched
Related Donor Stem Cell Transplantation (BMT CTN Protocol 0402)

Soluble Tumor Necrosis Factor Receptor Treatment of Non-Infectious Pulmonary Dysfunction
(Idiopathic Pneumonia Syndrome) Following Allogeneic Stem Cell Transplantation (BMT CTN
Protocol 0403)