Treosulfan-Based Versus Clofarabine-Based Conditioning Before Donor Hematopoietic Stem Cell Transplant for the Treatment of Myelodysplastic Syndromes or Acute Myeloid Leukemia

Registration Number
NCT04994808
Lead Sponsor
Fred Hutchinson Cancer Center
Brief Summary

This phase II trials studies the effect of treosulfan-based versus clofarabine-based conditioning regimens before donor hematopoietic stem cell transplant in treating patients with myelodysplastic syndromes or acute myeloid leukemia. Chemotherapy drugs, such as treosulfan, fludarabine, and clofarabine, work in different ways to stop the growth of cancer cell...

Detailed Description

OUTLINE: Patients are randomized to 1 of 2 arms.
...

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
80
Inclusion Criteria
  • Age >= 18 years and =< 75 years
  • Diagnosis of MDS-EB or AML: must have < 5% marrow blasts (by morphology and/or flow cytometry) at time of transplant
  • Karnofsky performance score (KPS) >= 60% on pre-HCT evaluation
  • Able to give informed consent
  • Patients with previous autologous or allogeneic HCT may enroll
  • DONOR: Human leukocyte antigen (HLA)-identical related donors or unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 as defined by high resolution deoxyribonucleic acid (DNA) typing; mismatch for only one HLA allele at class I is allowed
  • DONOR: Donors able to undergo peripheral blood stem cell collection. Only granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cell (PBSC) will be permitted as an hematopoietic stem cell (HSC) source on this protocol
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Exclusion Criteria

  • Presence of circulating blasts (in the blood) detected by standard pathology for patients with AML

  • Presence of >= 5% circulating leukemic blasts (in the blood) detected by standard pathology for patients with MDS-EB

  • Patients with promyelocytic AML

  • Organ dysfunction

    • Cardiac: Ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease. Patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist

    • Pulmonary:

      • Diffusion capacity of the lung for carbon monoxide (DLCO) < 40%, total lung capacity (TLC) < 40%, forced expiratory volume in 1 second (FEV1) < 40% and/or receiving supplementary continuous oxygen. When pulmonary function test (PFT)s cannot be obtained, the 6-minute walk test (6 minute walk functional test [6MWT], also known as exercise oximetry) will be used: Any patient with oxygen saturation on room air of < 89% during a 6MWT will be excluded
      • The principal investigator (PI) must approve enrollment of all patients with pulmonary nodules

    • Renal: Serum creatinine should be within normal limits as specified by Standard Practice guidelines. For subjects with serum creatinine > upper limit of normal, a 24-hour creatinine clearance will be performed and should be equal to or more than the lower limit of normal

    • Hepatic: Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension. Patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary disease

  • With active infectious disease requiring deferral of conditioning, as recommended by an infectious disease specialist

  • Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month

  • With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis because of possible risk of lethal infection when treated with immunosuppressive therapy

  • With central nervous system (CNS) leukemia at the time of treatment

  • Patients with active non-hematologic malignancies (except non-melanoma skin cancers) or those with non-hematologic malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease but have a greater than 20% chance of having disease recurrence within five years. This exclusion does not apply to patients with non-hematologic malignancies that do not require therapy

  • With life expectancy severely limited by diseases other than malignancy

  • Fertile men and women unwilling to used contraceptive techniques during treatment and for 12 months following

  • Women who are pregnant or lactating

  • With known hypersensitivity to treosulfan, fludarabine, or clofarabine

  • The use of non-Food and Drug Administration (FDA) approved investigational drugs would not be allowed within 4 weeks of the initiation of conditioning (day -6 for both arms)

  • Unable to give informed consent

  • Patients suitable for and willing to receive a standard high intensity preparative regimen

  • DONOR: Donor (or centers) who will exclusively donate marrow

  • DONOR: Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of PBSC

  • DONOR: Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment. This determination is based on the standard practice of the individual institution. The recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT. If the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained. The donor should be excluded if any of the cytotoxic cross match assays are positive. For those patients with an HLA Class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results. A positive anti-donor cytotoxic cross match is an absolute donor exclusion

  • DONOR: Donor is excluded if a patient is homozygous in the graft-rejection vector against the donor's mismatched HLA class I allele

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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Arm A (treosulfan, fludarabine, TBI, HCT)Multigated Acquisition ScanPatients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm A (treosulfan, fludarabine, TBI, HCT)FludarabinePatients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm A (treosulfan, fludarabine, TBI, HCT)Hematopoietic Cell TransplantationPatients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm A (treosulfan, fludarabine, TBI, HCT)Total-Body IrradiationPatients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm A (treosulfan, fludarabine, TBI, HCT)TreosulfanPatients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm A (treosulfan, fludarabine, TBI, HCT)EchocardiographyPatients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm A (treosulfan, fludarabine, TBI, HCT)Lumbar PuncturePatients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm A (treosulfan, fludarabine, TBI, HCT)Bone Marrow AspirationPatients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm A (treosulfan, fludarabine, TBI, HCT)Bone Marrow BiopsyPatients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm A (treosulfan, fludarabine, TBI, HCT)Biospecimen CollectionPatients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm B (clofarabine, TBI, HCT)ClofarabinePatients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm B (clofarabine, TBI, HCT)Hematopoietic Cell TransplantationPatients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm B (clofarabine, TBI, HCT)Total-Body IrradiationPatients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm B (clofarabine, TBI, HCT)EchocardiographyPatients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm B (clofarabine, TBI, HCT)Multigated Acquisition ScanPatients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm B (clofarabine, TBI, HCT)Lumbar PuncturePatients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm B (clofarabine, TBI, HCT)Bone Marrow AspirationPatients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm B (clofarabine, TBI, HCT)Bone Marrow BiopsyPatients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Arm B (clofarabine, TBI, HCT)Biospecimen CollectionPatients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.
Primary Outcome Measures
NameTimeMethod
Relapse-free survivalAt 6 months after transplant
Secondary Outcome Measures
NameTimeMethod
Rate of non-relapse mortalityAt 1 year after transplant
Relapse rateAt 1 year after transplant
Incidence of acute graft versus host diseaseAt 1 year after transplant
Overall survivalAt 1 year after transplant
Duration of hospitalizationUp to day 100 post HCT

Trial Locations

Locations (1)

Fred Hutch/University of Washington Cancer Consortium

🇺🇸

Seattle, Washington, United States

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