A Randomized Phase II Study to Compare ATG or Post-Transplant Cyclophosphamide to Calcineurin Inhibitor-Methotrexate as GVHD Prophylaxis After Myeloablative Unrelated Donor Peripheral Blood Stem Cell Transplantation
Overview
- Phase
- Phase 2
- Status
- Withdrawn
- Locations
- 1
- Primary Endpoint
- Moderate to severe chronic graft versus host disease (GVHD) based on National Institute of Health 2014 consensus criteria
Overview
Brief Summary
This phase II trial studies how well 3 different drug combinations prevent graft versus host disease (GVHD) after donor stem cell transplant. Calcineurin inhibitors, such as cyclosporine and tacrolimus, may stop the activity of donor cells that can cause GVHD. Chemotherapy drugs, such as cyclophosphamide and methotrexate, may also stop the donor cells that can lead to GVHD while not affecting the cancer-fighting donor cells. Immunosuppressive therapy, such as anti-thymocyte globulin (ATG), is used to decrease the body's immune response and reduces the risk of GVHD. It is not yet known which combination of drugs: 1) ATG, methotrexate, and calcineurin inhibitor 2) cyclophosphamide and calcineurin inhibitor, or 3) methotrexate and calcineurin inhibitor may work best to prevent graft versus host disease and result in best overall outcome after donor stem cell transplant.
Detailed Description
OUTLINE:
CONDITIONING REGIMENS: Participants receive 1 of 3 regimens and are randomized to 1 of 3 arms for GVHD prophylaxis.
REGIMEN A: Participants undergo total body irradiation (TBI) twice daily (BID) on days -6 to -4 (-7 to -4 for those < 18 years), then receive cyclophosphamide IV over 1-2 hours on days -3 and -2. Participants randomized to Arm 2 only receive TBI on days -3 to -1 (-4 to -1 for those < 18 years).
REGIMEN B: Participants receive fludarabine phosphate IV and busulfan IV every 6 hours on days -5 to -2.
REGIMEN C: Participants receive busulfan orally (PO) or IV every 6 hours on days -7 to -4 and cyclophosphamide IV over 1-2 hours on days -3 and -2.
Myelofibrosis or other myeloproliferative neoplasms: Participants >= 18 years receive cyclophosphamide IV over 1-2 hours on days -7 and -6 and busulfan IV on days -5 to -2. Participants < 17 years receive busulfan IV every 6 hours on days -7 to -4 and cyclophosphamide IV on days -3 and -2.
All participants undergo peripheral blood stem cell transplantation on day 0.
ARM 1: Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV twice daily (BID) tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
ARM 2: Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day 5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the absence of disease progression or unacceptable toxicity.
ARM 3: Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 6 months, then annually up to 5 years.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- — to 65 Years (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •The following diseases will be permitted, although other diagnoses can be considered if approved by Fred Hutch Patient Care Conference or the participating institution's patient review committees and the principal investigator:
- •Acute lymphocytic leukemia (ALL) in complete remission (CR)1 with high risk features defined as evidence of adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL rearrangements or presence of minimal residual disease
- •Acute myeloid leukemia (AML) in CR1 with high risk features defined as:
- •Intermediate or adverse risk disease as defined by European LeukemiaNet (ELN) 2017
- •Greater than 1 cycle of induction therapy required to achieve remission
- •Preceding myelodysplastic syndrome (MDS) or myelofibrosis
- •Therapy-related AML
- •Presence of FLT3 internal tandem duplications
- •French-American-British (FAB) M6 or M7 classification
- •Acute leukemia (ALL or AML) in second (2nd) or greater CR (CR ≥ 2)
Exclusion Criteria
- •Prior autologous or allogeneic stem cell transplant
- •Performance status: Karnofsky score \<60 or Lansky score \<50 for patients \<16 years old
- •Uncontrolled infection. The protocol principal investigator (PI) will be final arbiter if there is uncertainty regarding whether a previous infection is under adequate control to allow enrollment in the study
- •Positive serology for human immunodeficiency virus (HIV)-1, 2 or human T-lymphotropic virus (HTLV)-1, 2
- •Left ventricular ejection fraction \< 45%. Uncontrolled arrhythmias or symptomatic cardiac disease
- •Symptomatic pulmonary disease. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO) =\< 50% of predicted (corrected for hemoglobin). Use of continuous supplemental oxygen
- •Calculated (Cockroft-Gault; or appropriate calculation for pediatric patients) serum creatinine clearance \<60 mL/min. If the calculated CrCl is 50-60 mL/min, but a measured CrCl by 24 hour urine collection is \> 60 mL/min, this measurement is acceptable
- •Total serum bilirubin more than twice upper normal limit
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 3-fold higher than laboratory upper normal limits
- •History of allergy or anaphylactic reaction to rabbit protein or to any product excipients
Arms & Interventions
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Anti-Thymocyte Globulin (Biological)
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Busulfan (Drug)
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide (Drug)
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclosporine (Drug)
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Fludarabine Phosphate (Drug)
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Methotrexate (Drug)
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Peripheral Blood Stem Cell Transplantation (Procedure)
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment (Other)
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Questionnaire Administration (Other)
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Tacrolimus (Drug)
Arm 1 (ATG, tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive anti-thymocyte globulin IV over 4-6 hours on days -3 to -1. Beginning day -1, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11 in the absence of disease progression or unacceptable toxicity.
Intervention: Total-Body Irradiation (Radiation)
Arm 2 (cyclophosphamide, tacrolimus or cyclosporine)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day 5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the absence of disease progression or unacceptable toxicity.
Intervention: Busulfan (Drug)
Arm 2 (cyclophosphamide, tacrolimus or cyclosporine)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day 5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide (Drug)
Arm 2 (cyclophosphamide, tacrolimus or cyclosporine)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day 5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclosporine (Drug)
Arm 2 (cyclophosphamide, tacrolimus or cyclosporine)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day 5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the absence of disease progression or unacceptable toxicity.
Intervention: Fludarabine Phosphate (Drug)
Arm 2 (cyclophosphamide, tacrolimus or cyclosporine)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day 5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the absence of disease progression or unacceptable toxicity.
Intervention: Peripheral Blood Stem Cell Transplantation (Procedure)
Arm 2 (cyclophosphamide, tacrolimus or cyclosporine)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day 5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment (Other)
Arm 2 (cyclophosphamide, tacrolimus or cyclosporine)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day 5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the absence of disease progression or unacceptable toxicity.
Intervention: Questionnaire Administration (Other)
Arm 2 (cyclophosphamide, tacrolimus or cyclosporine)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day 5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the absence of disease progression or unacceptable toxicity.
Intervention: Tacrolimus (Drug)
Arm 2 (cyclophosphamide, tacrolimus or cyclosporine)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Participants receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Beginning day 5, participants also receive tacrolimus IV or cyclosporine IV BID tapered at day 50 in the absence of disease progression or unacceptable toxicity.
Intervention: Total-Body Irradiation (Radiation)
Arm 3 (tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11.
Intervention: Busulfan (Drug)
Arm 3 (tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11.
Intervention: Cyclophosphamide (Drug)
Arm 3 (tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11.
Intervention: Cyclosporine (Drug)
Arm 3 (tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11.
Intervention: Fludarabine Phosphate (Drug)
Arm 3 (tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11.
Intervention: Methotrexate (Drug)
Arm 3 (tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11.
Intervention: Peripheral Blood Stem Cell Transplantation (Procedure)
Arm 3 (tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11.
Intervention: Quality-of-Life Assessment (Other)
Arm 3 (tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11.
Intervention: Questionnaire Administration (Other)
Arm 3 (tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11.
Intervention: Tacrolimus (Drug)
Arm 3 (tacrolimus or cyclosporine, methotrexate)
Participants receive conditioning regimen (see detailed description) and then undergo peripheral blood stem cell transplantation on day 0. Beginning day -1, participants receive tacrolimus IV or cyclosporine IV BID tapered at day 50, and methotrexate IV on days 1, 3, 6 and 11.
Intervention: Total-Body Irradiation (Radiation)
Outcomes
Primary Outcomes
Moderate to severe chronic graft versus host disease (GVHD) based on National Institute of Health 2014 consensus criteria
Time Frame: At 1 year
Probabilities of chronic GVHD at one year will be compared using a chi-square test.
Secondary Outcomes
- Grade III-IV acute GVHD(At 100 days)
- Survival(At 1 year post transplant)
- GVHD-free relapse-free survival (GRFS)(At 1 year post transplant)
- Chronic GVHD-free relapse-free survival (CRFS)(At 1 year post transplant)
- Grade II-IV acute GVHD(At 100 days)
- Relapse(At 1 year post transplant)
- Non-relapse mortality(At 1 year post transplant)