Trial Information

Fludarabine-based Conditioning for Allogeneic Marrow Transplantation From HLA-compatible Unrelated Donors in Severe Aplastic Anemia (BMT CTN #0301)

BACKGROUND:

Aplastic anemia (AA) remains a life-threatening illness. Treatment options include
supportive care (transfusions, growth factors, etc.), immunosuppression therapy and stem
cell transplantation. Only the latter two have favorably impacted the natural history of
the disease. The prognosis of AA patients, particularly SAA, as defined by Camitta et al.,
who fail to respond to immunosuppressive therapy (IS) or who relapse after an initial
response to IS is poor. Although many of these patients can be supported in the short term
with growth factors, transfusions and possibly rechallenged successfully with IS, the
cumulative morbidity and mortality from infection, hemorrhage or transfusion-related
complications is substantial.

While allogeneic bone marrow transplantation is potentially curative in AA, no more than 25%
of patients have an HLA-identical sibling donor. Cyclophosphamide (CY)-ATG has been
recommended as the preparative regimen of choice in sibling donor transplants. Results of
bone marrow transplantation from alternative donors, such as matched unrelated donors and
mismatched related donors in AA patients who have failed IS, have largely been
unsatisfactory. The cyclophosphamide-ATG conditioning regimen has proved inadequate in
ensuring engraftment in allogeneic transplants from matched, unrelated donors for AA. This
was the major reason why total body radiation (TBI) has been added to the conditioning
regimen.

Graft failure is a very serious and frequently life-threatening or fatal event following MUD
allografts in aplastic anemia. It is an immunologically mediated event. Risk factors for
graft failure include the use of HLA nonidentical or unrelated donors, a poor marrow
nucleated cell dose as well as prolonged transfusional support prior to BMT (which increases
the probability of patient sensitization to multiple antigens). While some patients may
achieve autologous hematopoietic recovery, prolonged pancytopenia is common and
infection-related morbidity and mortality are very substantial. Reconditioning for a second
allograft from the same or a different donor is frequently not successful. While the
addition of TBI and intensive pre-transplant conditioning has led to a sizable improvement
in engraftment rates, this has come with a price, particularly in adult patients.
Transplant-related toxicity has been a major and frequent problem. Radiation-induced
pulmonary toxicity in particular has been common, usually in the form of diffuse alveolar
damage or diffuse interstitial pneumonitis. In addition, GVHD-related morbidity and
mortality in these patients have also been substantial.

DESIGN NARRATIVE:

The study is a prospective Phase I/II dose optimization study. All patients are given a
fixed dose of ATG (either thymoglobulin: 3 mg/kg IV daily x 3 or ATGAM 30 mg/kg IV daily x
3, on Days -4 to -2), Fludarabine (30 mg/m^2 IV daily x 4, on Days - 5 to -2), and TBI (200
cGy from a linear accelerator at less than 20 cGy/min on Day -1). The starting CY dose will
be 150 mg/kg (50 mg/kg intravenously daily, Days -4 to -2), and will be de-escalated
depending on engraftment and toxicity. The Phase I portion of the trial (maximum of 24-27
patients) tests each of four dose levels of CY for adequate safety and graft retention. The
Phase II portion of the trial refines the dose selection and allocates an additional 70
patients to the optimal dose, at which two-year post-transplant survival will be assessed.
The combined enrollment in Phase I and II will total 94 patients.

The study is a prospective single-arm Phase I/II dose-selection and evaluation study. The
study will seek the optimal dose level of CY based on assessments of graft failure, toxicity
and early death during 100 days of follow-up post-transplant. A brief synopsis is given
below.

Phase I - Test Each Dose for Adequate Safety and Graft Retention

1. Proceed from the highest dose (150 mg/kg CY) to the lowest dose (0 mg/kg CY), treating
a minimum of six patients at each dose.

2. Evaluate the 100-Day outcomes for toxicity, death and graft failure on each patient
enrolled at the current dose, or until stopping criteria are met.

3. If there are three or more graft failures at the current dose, the current dose and all
lower doses are closed to further enrollment.

4. If there are five or more severe regimen-related toxicities and/or early deaths at the
current dose, the current dose is closed to further enrollment, and the next lower dose
is tested.

5. Dose de-escalation ceases once all four doses are tested or closed to further
enrollment.

Phase II - Refine Dose Selection and Allocate Patients to the Optimal Dose

1. Treat each newly enrolled patient at the most desirable of the dose levels remaining
open to enrollment. This can involve de-escalation, escalation, or no change in dose.

2. As each patient completes the observation period, evaluate the 100-Day outcomes for
graft failure, toxicity and/or early death for this patient, or until stopping criteria
are met.

3. If there are excess (according to the criteria in Table 5.8) graft failures, that
patient's dose and all lower doses are closed to further enrollment.

4. If there are excess (according to the criteria in Table 5.8) toxicities and/or early
deaths, that patient's dose is closed to further enrollment.

5. Re-evaluate the desirability of the current dose level based on the 100-Day outcomes
for toxicity and/or early death and graft failure.

6. Repeat steps 1-5 until 54 patients are enrolled in Phase II, or all dose levels are
closed to further enrollment.

Dosage Levels for CY:

3 Days (Day -4, -3, -2): Dose of 50 mg/kg/day; total dose of 150 mg/kg; dose level 3

2 Days (Day -3, -2): Dose of 50 mg/kg/day; total dose of 100 mg/kg; dose level 2

1 Day (Day -2): Dose of 50 mg/kg/day; total dose of 50 mg/kg; dose level 1

0 Days (None): No dose; no total dose; dose level 0

There may be wait periods between enrollment of successive patients and/or cohorts for
endpoint assessment. Under these circumstances, the final decision about waiting versus
treating the patient off study will be made at the local transplant center.

Primary Outcomes:

1. Graft Failure: Neutrophil engraftment is defined as the achievement of an ANC ≥ 0.5 x
10^9/L for three consecutive measurements on different days. Primary graft failure is
defined by the lack of neutrophil engraftment; i.e., ANC < 0.5 x 10^9/L measured for
three consecutive measurements on different days by 100 days post-transplant.
Secondary graft failure prior to Day 100 post-transplant will count towards the graft
failure endpoint.

2. Regimen-related Toxicity (RRT): RRT will be scored according to the Bearman scale.
Major RRT is defined as severity of grade 4 in any organ system or grade 3 for
pulmonary, cardiac, renal, oral mucosal or hepatic, in keeping with the approach
adopted in FHCRC Protocol #800. The assessment for RRT will be carried out weekly
until Day 100 post-transplant. The NCI's CTCAE version 3.0 will be used to supplement
the Bearman toxicity criteria.

3. Early Death:This endpoint is defined as death prior to Day 100 post-transplant.

Secondary Outcomes:

1. Post-transplant survival- as defined as time from transplant to death from any cause.

2. Secondary Graft Failure - This endpoint is defined (in patients surviving at least 100
days) by initial neutrophil engraftment followed by subsequent decline in the ANC to <
0.5 x 10^9/L for 3 consecutive measurements on different days, unresponsive to growth
factor therapy.

3. Acute GVHD of Grades 2-4 and 3-4 - Acute GVHD is graded according to the Blood and
Marrow Transplant Clinical Trials Network (BMT CTN) Manual of Procedures (MOP). The
first day of acute GVHD onset at a certain grade will be used to calculate cumulative
incidence curves for that GVHD grade (e.g., if the onset of grade 1 acute GVHD is on
Day 19 post-transplant and onset of grade 3 is on Day 70 post-transplant, time to grade
3 is Day 70). This endpoint will be evaluated through 100 days.

4. Chronic GVHD - Chronic GVHD is scored according to the BMt CTN MOP. The first day of
chronic GVHD onset will be used to calculate cumulative incidence curves.