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Cyclophosphamide and Abatacept for the Treatment of Graft-Versus-Host Disease after Stem Cell Transplantation in Patients with Hematologic Cancers

Trial Status: Active

This phase II trial studies how well cyclophosphamide and abatacept work in reducing the incidence of moderate and severe chronic graft-versus-host disease (GVHD) following donor stem cell transplantation in patients with hematologic (blood) cancers. GVHD occurs when the cells from the donor (the graft) see the body's cells (the host) as different and attack them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunosuppressive therapy, such as abatacept, is used to decrease the body’s immune response. The combination of cyclophosphamide and abatacept following donor stem cell transplantation may work better in reducing the incidence of moderate and severe chronic GVHD compared to standard of care.

Inclusion Criteria

  • High risk hematologic malignancy justifying the need for an allogeneic hematopoietic stem cell transplantation: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML) in accelerated or blast phase, myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, and multiple myeloma
  • Eastern Cooperative Oncology Group (ECOG) performance score 0-2
  • Creatinine clearance >= 40 (by Cockcroft-Gault)
  • Total bilirubin < 2.0 mg/dl
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN)
  • Ejection fraction (EF) > 50%
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
  • Ability to understand and willingness to sign a written informed consent

Exclusion Criteria

  • Patients with hematologic malignancies for which transplant is not the only curative option, such as AML with good or intermediate cytogenetics or molecular markers in CR1 or CML in chronic phase
  • Inability to identify an 10/10 HLA-matched (related or unrelated) donor
  • Active malignant disease relapse
  • Active, uncontrolled infection, uncontrolled cardiac angina, symptomatic congestive heart failure or any other uncontrolled medical condition that in the opinion of the investigator will put the patient at increased risk by participating in this clinical trial or would interfere with data collection or interpretation
  • Life expectancy < 3 months
  • Pregnancy or lactation
  • Inability to comply with treatment regimen
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to abatacept
  • Patients may not be receiving any other investigational agents in the last 28 days
  • Patients with chronic myeloid leukemia in first chronic phase

California

San Diego
University of California San Diego
Status: ACTIVE
Contact: Dimitrios Tzachanis
Phone: 858-534-2185

PRIMARY OBJECTIVE:

I. To examine if the novel combination of post transplant high dose cyclophosphamide and abatacept can induce tolerance.

SECONDARY OBJECTIVES:

I. To estimate the rate of other important transplant outcomes with the two GVHD prophylaxis strategies:

Ia. Donor engraftment by day 28.

Ib. Grades II-IV and III-IV acute GVHD.

Ic. Chronic GVHD of all grades.

Id. Relapse rate.

Ie. Disease free survival over the course of the study.

If. Overall survival.

Ig. Transplant related mortality by 1 year after transplantation.

II. To estimate the infectious, renal, cognitive and other toxicity caused by the two GVHD prophylaxis strategies.

EXPLORATORY OBJECTIVES:

I. Post-transplantation immune reconstitution studies will include measuring T cell and natural killer (NK) cell phenotype, PD-1 expression, and alloreactivity to recipient and third party at predetermined time points.

II. Compare and contrast the findings between the treatment and control arm and correlate those with disease relapse and presence of acute or chronic GVHD.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I:

CONDITIONING REGIMEN: Patients with matched related or unrelated donor receive fludarabine intravenously (IV) over 60 minutes and busulfan IV over 3 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity.

Patients with acute lymphoblastic leukemia (ALL) and a matched related or unrelated donor may receive either of the following at the investigator’s discretion: cyclophosphamide IV over 2 hours on days -5 and -4 followed by total body irradiation (TBI) on days -3 to -1; OR TBI on days -7 to -4 followed by etoposide on day -3.

TRANSPLANT: Patients undergo stem cell transplantation on day 0.

GVHD PROPHYLAXIS: Patients receive standard tacrolimus IV starting on day -2 and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.

ARM II:

CONDITIONING REGIMEN: Patients with matched related or unrelated donor receive fludarabine IV over 60 minutes and busulfan IV over 3 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity.

Patients with ALL and a matched related or unrelated donor may undergo TBI on days -3 to -1 at the investigator’s discretion.

TRANSPLANT: Patients undergo stem cell transplantation on day 0.

GVHD PROPHYLAXIS: Patients receive abatacept IV on days 5, 14 , 28, 56, 84, 112, 140, and 168, as well as cyclophosphamide IV on days 3 and 4 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year after transplant.

Trial Phase Phase II

Trial Type Supportive care

Lead Organization
University of California San Diego

Principal Investigator
Dimitrios Tzachanis

  • Primary ID 180383
  • Secondary IDs NCI-2019-08418
  • Clinicaltrials.gov ID NCT03680092