Abatacept as GVHD Prophylaxis Phase 2

This is a phase II multi-center, randomized, double blind, placebo-controlled trial.

The investigators are doing this study to see if a new drug, abatacept, can be used together with a calcineurin inhibitor (cyclosporine or tacrolimus) and methotrexate to provide better protection against Acute Graft versus Host Disease (aGvHD) without causing more infections.

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, the Seattle Cancer Consortium including University of Washington, Seattle Children's Hospital, Seattle Cancer Care Alliance and from participating centers in the Pediatric Blood and Marrow Transplant Consortium (PBMTC). A total of 40 randomized 7/8 HLA matched patients and 140 8/8 HLA matched patients will be enrolled on this study. Patients who are enrolled, but determined to be Assignment Failures before receiving study drug/placebo will be replaced. 7/8 HLA matched patients enrolled prior to Protocol Amendment 4 and who were randomized to the study drug/placebo arm are not counted in either group of 40 or 140.