Trial Information

Abatacept Combined With a Calcineurin Inhibitor and Methotrexate for Graft Versus Host Disease Prophylaxis: A Randomized Controlled Trial

Acute Graft versus Host Disease (aGvHD) is the most deadly complication facing children who
have allogeneic hematopoietic stem cell transplant (HSCT). aGvHD occurs, in large part,
because the T cells in the bone marrow graft do not "accept" the presence of the transplant
recipient's cells. They mount a severe, debilitating, and often deadly attack against the
recipient, striking the skin, the liver, and the gastrointestinal track, most prominently.
For patients receiving bone marrow from an unrelated donor, the rate of aGvHD can reach as
high as 80%, with up to half of patients dying from this complication. Given the lack of
success in preventing aGvHD with current therapies, novel therapies to prevent this disease
are desperately needed.

Hypothesis and Aims: This trial is being conducted as a step toward testing the long-term
hypothesis that the costimulation blockade agent abatacept can be added to a standard acute
graft-versus-host disease (aGvHD) prophylaxis regimen (which includes a calcineurin
inhibitor (CNI) and methotrexate), to improve disease-free survival after unrelated
hematopoietic stem cell transplantation (HSCT) for patients with hematologic malignancies.
As a phase II study, the overall aim of this trial is to make a preliminary assessment of
abatacept's clinical safety and efficacy using short-term outcomes. Thus, this trial is
designed to test two hypotheses:

1. A primary hypothesis that the addition of abatacept to calcineurin inhibition +
methotrexate can decrease the incidence of early-onset (before day 100 post-transplant)
severe (grades 3-4) aGvHD.

2. A secondary hypothesis that its addition will not hinder post-transplant reconstitution
of protective immunity against latent viruses.

To test these two hypotheses, this study will have the following Specific Aims.

Specific Aim #1: To conduct a multicenter Phase II, randomized, double-blind, placebo
controlled trial to assess the impact of abatacept on the incidence of aGVHD and its
biology. To make this assessment patients will be randomized either to standard aGVHD
prophylaxis with a CNI, methotrexate and placebo or to investigational prophylaxis with a
CNI, methotrexate and abatacept. Correlative immunology studies will be performed to
elucidate abatacept's effects on the graft-versus-host response.

Specific Aim #2: To assess the impact of abatacept on post-transplant reconstitution of
protective immunity against viruses. This will involve monitoring the longitudinal recovery
of lymphocyte subsets and virus-specific immunity, using tetramer analysis and viral
stimulation assays. It will also involve monitoring viral infection and disease.

Background and Rationale:

The Unmet Need: Allogeneic HSCT is an effective treatment for aggressive leukemias and
other hematological malignancies, often representing the only option for cure. However,
some of its benefit, especially in the case of unrelated donor transplantation, is off-set
by a high rate of transplant-related mortality (approximately 30% of recipients of unrelated
donor transplantation will die of transplant-related complications) stemming largely from
severe aGVHD and infection. 1-7 aGvHD occurs when reconstituting donor T cells8 become
activated against recipient tissues.9 This activation can result in severe immune-mediated
tissue damage to the host, with the skin, liver and GI tract being the most common targets.
aGvHD-mediated damage to these vital organs can result in significant morbidity, and in
death. While whole-scale T cell depletion of the allograft can successfully reduce rates of
aGvHD, patients receiving T cell-depleted grafts exhibit profound defects in protective
immunity, and often die of infection or relapse of their primary disease.10-12 This has
created an unmet clinical need for a strategy that more effectively prevents severe aGvHD
while preserving the transplant recipient's protective immune response.

Targeting T cell costimulation to prevent aGvHD: The immune activation observed in aGvHD
bears close resemblance to the immune activation that occurs during both organ rejection and
autoimmunity. Studies in these diseases have led to the development of a new class of
agents, called 'costimulation blockade' reagents, which specifically target activated T
cells and block their ability to become fully activated effector cells. 13 One of the most
studied of the costimulatory pathways is the CD28:CD80/86 receptor:coreceptor interaction.14
Considerable work on this pathway has been accomplished, and has demonstrated the efficacy
of inhibition of CD28:CD80/86 signaling in inhibiting T cell-mediated immune activation. The
first CD80/86-directed costimulation blockade agent, CTLA4Ig, or 'abatacept,' is approved
for use in rheumatoid arthritis, both in adults and in children older than 6 years.15-18 The
experience with abatacept from 3 large randomized, placebo-controlled clinical trials, two
in adults with rheumatoid arthritis and one in children with juvenile idiopathic arthritis
(ages 6 and older) indicates that it is a safe agent.19-21 In these three trials, abatacept
was dosed at 10 mg/kg and was administered IV on day 1, 15, 29 (one trial used day 30) and
then every 28 days for a total of 6 to 10 months of total treatment. Collectively, most
patients also received weekly, oral, low-dose methotrexate and low dose prednisone
concurrently. In these trials, abatacept was well tolerated. Acutely, infusional reactions
were rare and mild and occurred at rates that did not differ significantly from those with
placebo. Abatacept was not associated with any hematologic, renal, cardiac, pulmonary,
hepatic or neurologic abnormalities. Similarly, the rates of both total and serious adverse
events were low, and did not differ from those with placebo. Abatacept has been shown to be
safe, even in extended open label trials,22,23 not associated with excessive PTLD or other
malignancies. 22-25 However, chronically-treated patients did experience a slightly higher
risk of infections. 22,24,25 Phase III studies of a second-generation, higher avidity
abatacept analog, belatacept (which is identical to abatacept except for two amino acid
substitutions) have demonstrated efficacy in preventing renal transplant rejection. 26,27
Patients who received 10mg/kg of belatacept on days 1, 5, 14, 28, and every 28 days
thereafter demonstrated improved renal function compared to those receiving cyclosporine,
and similar graft survival.26,27 These results have led to the FDA approval of belatacept
for a renal transplant indication. While overall rates of patient death, infection and
serious infection in patients receiving belatacept were not different than in those
receiving traditional immunosuppression,26,28 belatacept was associated with a
statistically-significant increased rate of EBV-associated PTLD compared to
cyclosporine-based immunosuppression (especially in patients that were EBV sero-negative
prior to transplant).26,28 This observation raises an important question about the negative
impact that belatacept and related compounds may have on protective immune responses to
latent viruses. Rates of PTLD were much lower in EBV sero-positive patients,26,28
suggesting that any defect in protective immunity induced by belatacept may be more
significant in the setting of primary EBV infection than during EBV reactivation. These
observations underscore the critical importance of evaluating novel immunosuppressive
strategies for their impact both on alloreactivity and on the post-transplant protective
immune response.

Prior to our work, abatacept had not been tested for its ability to prevent GvHD in BMT
patients. However, there was considerable evidence from murine models to suggest that it
might be an active compound against the immune activation that occurs during GvHD.29-33 In
addition, our research group developed a non-human primate model of GvHD 34 and used this
model to demonstrate that an abatacept-containing immunosuppressive regimen could
significantly protect against the development of primate GvHD. 34 These results, along with
the clinical evidence for efficacy of abatacept and belatacept in both autoimmunity and
solid organ transplantation provided the rationale for the development of a first-in-disease
feasibility trial of abatacept for GvHD prevention (Clinical Trials.org #NCT01012492). This
trial, which has now completed enrollment, has documented encouraging early results with
respect to both the safety and efficacy of abatacept for GvHD prevention (Kean et al., ASH
2011). These results have led to the creation of the current Phase II clinical trial of
abatacept for prevention of severe aGvHD.

Research Design and Methods Study Design: This will be a phase II, multi-center, randomized,
double-blind, placebo-controlled trial.

Study Population, Subject Recruitment and Selection: Patients will be recruited from the
Children's Healthcare of Atlanta Pediatric Blood and Marrow Transplant Program, the Emory
University Adult Blood and Marrow Transplant Program, the University of Florida Adult Blood
and Marrow Transplant Program and from participating centers in the Pediatric Blood and
Marrow Transplant Consortium (PBMTC). A total of 104 patients will be enrolled on this
study.