Clinical Trial 21721

• Overview

  Study Title:

  A Randomized Double-Blind Trial of Abatacept Extended Dosing Versus Abatacept Short-Term Dosing for Graft Versus Host Disease Prophylaxis: "ABA3"

  Summary:

  This is a multicenter randomized, double blind, Phase 2 trial for patients receiving transplants from 7 of 8 HLA matched donors, in which an extended dosing regimen of abatacept, and a short-term dosing regimen + placebo, when added to standard calcineurin inhibitor + methotrexate-based prophylaxis, will be compared for their ability to improve outcomes in patients with a minimum follow-up of one year post-transplant. All patients will receive 4 doses of abatacept (Days -1, +5, +14, +28). Prior to the fifth dose, patients will be randomly assigned to the 4-dose abatacept arm and receive 4 doses of placebo or 8-dose abatacept arm and receive 4 more doses of abatacept. The primary endpoint of the study will be severe AGVHD-free, severe CGVHD-free, relapse-free survival (SGRFS). The study will end when the last patient has reached 2 years after transplant.

  Objective:

  To determine whether an 8-dose regimen of abatacept will improve the rate of severe (Gr III-IV) acute GVHD (AGVHD)-free, severe CGVHD-free, relapse-free survival ( SGRFS ) compared to a 4-dose regimen, during HLA-mismatched unrelated-donor hematopoietic stem cell transplantation (HCT) for patients with hematologic malignancies. SGRFS will be modeled as a time-to-event outcome, and as such, failures that occur beyond one year and before study end will be considered in the analysis. The primary endpoint analysis will be performed using all randomized patients

• Treatments

  Therapies:

  Bone Marrow Transplant; Chemotherapy (NOS); Immunotherapy; Therapy (NOS)

  Medications:

  Abatacept (); Alkeran (Melphalan); Cyclosporine (); FK506 (Tacrolimus); MESNA (); Melphalan (); Placebo (); Tacrolimus (); Thiotepa (Thioplex); busulfan (); cyclophosphamide (); cytoxan (cyclophosphamide); etoposide (); fludarabine (Fludarabine phosphate); methotrexate ()

• Inclusion Criteria

  Inclusion Criteria:
  • Must have a willing unrelated 8/8 or 7/8 matched adult donor (bone marrow or peripheral blood). Donors may have a single mismatch (i.e. be a 7/8) and this mismatch may be at the allele or antigen level; however, donors with allele level disparity should be given preference over those with antigen level disparity. Patients for whom a donor is available with disparity only in the host versus graft direction (because of recipient homozygosity), will not be eligible, since this mismatching does not increase the risk for GVHD. Centers may perform extended typing (e.g. DQB1 and DPB1) according to institutional practices and use these results in selecting donors; however, it is recommended that this extending typing be used only to select between donors who are equally well matched with the recipient at the A, B, C and DRB1.
  • All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
  • Must have a hematologic malignancy treatable by HCT (except for those stipulated below under study Exclusion Criteria), which is in remission by standard testing (no patients in relapse will be included).
  • Karnofsky performance score or Lanskey Play-Performance Scale score >/= 80. If the patient does not meet defined eligibility requirements, the PI/study committee must be contacted to determine eligibility.
  • Other criteria may apply

• Exclusion Criteria

  Exclusion Criteria:
  • Patients with the following hematologic malignancies will be excluded: Chronic Lymphocytic Leukemia, Myeloma and Primary Myelofibrosis.
  • Active Relapse (>5% blasts based on morphology and confirmed by multidimensional flow cytometry) of their primary malignancy.
  • For patients with Acute Lymphocytic Leukemia (ALL) with pre-transplant MRD testing performed as standard practice at the treating institution, patients with MRD >0.01% will be ineligible.
  • For patients with Acute Myeloid Leukemia (AML) with pre-transplant MRD testing as standard of practice at the treating institution, patients with any MRD status are eligible and should be enrolled at the discretion of provider.
  • For patients with MDS, those with >5% blasts ( based on morphology and confirmed by multidimensional flow cytometry) will be excluded.
  • Prior allogeneic HCT.
  • Uncontrolled viral, bacterial, fungal or protozoal infection at the time of study enrollment.
  • HIV infection.
  • Serious psychiatric disease including schizophrenia, bipolar disorder and severe depression, if uncontrolled and in the opinion of the physician and/or protocol Chair, are likely to interfere with the adherence of the protocol activities. If a patient with any of these diseases is well-controlled, they may be enrolled.
  • Prisoners or others who are compulsorily detained.
  • Any patient with a known or suspected germline predisposition to cancer should be discussed with the study team prior to screening for eligibility. (a) Patients with a known germline or constitutional predisposition to transplant morbidities, including, but not limited to Fanconi Anemia, Dyskeratosis Congenita, Shwachman-Diamond Syndrome and Down Syndrome will be excluded.(b) Patients with known germline or constitutional predisposition to non-hematologic cancers including, but not limited to Li-Fraumeni syndrome, BRCA1 and BRCA2 mutations will be excluded.
  • Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, and are disease free for > Incompletely treated active tuberculosis Infection.
  • Pregnancy (positive serum b-HCG) or breastfeeding.
  • Estimated GFR of > Cardiac ejection fraction > T.bilirubin > 2 × upper limit of normal or ALT > 4 × upper limit of normal or unresolved veno-occlusive disease.
  • Pulmonary disease with FVC, FEV1 or DLCO parameters > For patients receiving a 7/8 HLA-mismatched transplant, presence of donor cell antibodies to a mismatched donor HLA class I antigen (including A, B and C) and/or HLA class II antigen (including DR, DQ and DP)
  • Post-enrollment randomization exclusion criteria: Patients who have developed severe AGVHD, severe CGVHD or relapse will not be randomized prior to 5th dose of abatacept/placebo (but who will remain on-protocol and on-study)
  • Exclusion Criteria Prior to Randomization (prior to 5th dose of abatacept/placebo) (a) Severe allergic reaction during the first 4 doses of abatacept (b) If any clinical events occur that preclude further dosing of abatacept, those patients will be deemed ineligible for randomization.
  • Other criteria may apply

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