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Donor Stem Cell Transplant With Treosulfan, Fludarabine, and Total-Body Irradiation for the Treatment of Hematological Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04195633
Recruitment Status : Not yet recruiting
First Posted : December 12, 2019
Last Update Posted : March 4, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Brief Summary:
This phase II trial studies how well a donor stem cell transplant, treosulfan, fludarabine, and total-body irradiation work in treating patients with blood cancers (hematological malignancies). Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells.

Condition or disease Intervention/treatment Phase
Acute Leukemia Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Adult Diffuse Large Cell Lymphoma Anaplastic Large Cell Lymphoma Burkitt Lymphoma Chronic Myelogenous Leukemia, BCR-ABL1 Positive Chronic Myelomonocytic Leukemia Hodgkin Lymphoma Lymphoblastic Lymphoma Lymphoplasmacytic Lymphoma Mantle Cell Lymphoma Mixed Phenotype Acute Leukemia Myelodysplastic Syndrome Prolymphocytic Leukemia Refractory Chronic Lymphocytic Leukemia Refractory Follicular Lymphoma Refractory Marginal Zone Lymphoma Refractory Small Lymphocytic Lymphoma Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Cyclophosphamide Drug: Cyclosporine Biological: Filgrastim Drug: Fludarabine Drug: Mycophenolate Mofetil Drug: Mycophenolate Sodium Radiation: Total-Body Irradiation Drug: Treosulfan Phase 2

Detailed Description:

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM A (HIGH DOSE TREOSULFAN): Patients receive high dose treosulfan intravenously (IV) over 120 minutes on days -6 to -4 and fludarabine IV over 60 minutes on days -6 to -2. Patients then undergo total-body irradiation on day -1 and allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3-4. Beginning on day 5, patients receive cyclosporine IV twice daily (BID) over 1-2 hours or orally (PO) (after 3 months, in the absence of GVHD, cyclosporine tapering will start by 5-10% per week, until drug withdrawal at 6 months post-transplant). Beginning on day 5, patients also receive mycophenolate sodium PO three times daily (TID) or mycophenolate mofetil IV or PO TID until day 35 (may be continued if active GVHD is present). Beginning on day 5, patients also receive filgrastim until the absolute neutrophil count is > 1,000/uL for 3 consecutive days.

ARM B (LOW DOSE TREOSULFAN): Patients receive low dose treosulfan IV over 120 minutes on days -6 to -4 and fludarabine IV over 60 minutes on days -6 to -2. Patients then undergo total-body irradiation and allogeneic hematopoietic stem cell transplantation, and receive cyclophosphamide, cyclosporine, mycophenolate sodium or mycophenolate mofetil, and filgrastim as in Arm A.

After completion of transplant, patients are followed up at 28, 56, 84, 365, and 730 days.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hematopoietic Stem Cell Transplantation From Haploidentical Donors in Patients With Hematological Malignancies Using a Treosulfan-Based Preparative Regimen
Estimated Study Start Date : July 1, 2020
Estimated Primary Completion Date : December 27, 2022
Estimated Study Completion Date : December 27, 2022


Arm Intervention/treatment
Experimental: Arm A (high dose treosulfan)
Patients receive high dose treosulfan IV over 120 minutes on days -6 to -4 and fludarabine IV over 60 minutes on days -6 to -2. Patients then undergo total-body irradiation on day -1 and allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3-4. Beginning on day 5, patients receive cyclosporine IV BID over 1-2 hours or PO (after 3 months, in the absence of GVHD, cyclosporine tapering will start by 5-10% per week, until drug withdrawal at 6 months post-transplant). Beginning on day 5, patients also receive mycophenolate sodium PO TID or mycophenolate mofetil IV or PO TID until day 35 (may be continued if active GVHD is present). Beginning on day 5, patients also receive filgrastim until the absolute neutrophil count is > 1,000/uL for 3 consecutive days.
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic stem cell transplantation
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT
  • Stem Cell Transplantation, Allogeneic

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamide Monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Cyclosporine
Given IV or PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Cyclosporine Modified
  • Gengraf
  • Neoral
  • OL 27-400
  • Sandimmune
  • SangCya

Biological: Filgrastim
Given IV
Other Names:
  • G-CSF
  • Neupogen
  • r-metHuG-CSF
  • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
  • rG-CSF
  • Tevagrastim

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF

Drug: Mycophenolate Sodium
Given PO
Other Names:
  • ERL 080
  • ERL 080A
  • Socium Mycophenolate

Radiation: Total-Body Irradiation
Undergo total-body irradiation
Other Names:
  • TBI
  • Total Body Irradiation
  • Whole Body Irradiation
  • Whole-Body Irradiation

Drug: Treosulfan
Given IV
Other Names:
  • 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-
  • Dihydroxybusulfan
  • Ovastat
  • Treosulphan
  • Tresulfon

Experimental: Arm B (low dose treosulfan)
Patients receive low dose treosulfan IV over 120 minutes on days -6 to -4 and fludarabine IV over 60 minutes on days -6 to -2. Patients then undergo total-body irradiation and allogeneic hematopoietic stem cell transplantation, and receive cyclophosphamide, cyclosporine, mycophenolate sodium or mycophenolate mofetil, and filgrastim as in Arm A.
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic stem cell transplantation
Other Names:
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT
  • Stem Cell Transplantation, Allogeneic

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamide Monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Cyclosporine
Given IV or PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Cyclosporine Modified
  • Gengraf
  • Neoral
  • OL 27-400
  • Sandimmune
  • SangCya

Biological: Filgrastim
Given IV
Other Names:
  • G-CSF
  • Neupogen
  • r-metHuG-CSF
  • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
  • rG-CSF
  • Tevagrastim

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Drug: Mycophenolate Mofetil
Given IV or PO
Other Names:
  • Cellcept
  • MMF

Drug: Mycophenolate Sodium
Given PO
Other Names:
  • ERL 080
  • ERL 080A
  • Socium Mycophenolate

Radiation: Total-Body Irradiation
Undergo total-body irradiation
Other Names:
  • TBI
  • Total Body Irradiation
  • Whole Body Irradiation
  • Whole-Body Irradiation

Drug: Treosulfan
Given IV
Other Names:
  • 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-
  • Dihydroxybusulfan
  • Ovastat
  • Treosulphan
  • Tresulfon




Primary Outcome Measures :
  1. Graft failure/rejection [ Time Frame: Up to 2 years post-transplant ]
    The analysis for graft failure will be conducted among all patients as well as separately among patients by Arm A versus Arm B.


Secondary Outcome Measures :
  1. Progression free survival [ Time Frame: At 1 year post-transplant ]
    Defined as the probability of being alive without sign of disease relapse or progression. Will be summarized using Kaplan-Meier and cumulative incidence estimates, as appropriate.

  2. Non-relapse mortality [ Time Frame: At day 100 and 1 year post-transplant ]
    Defined as death from any cause without sign of disease progression or relapse. Will be summarized using Kaplan-Meier and cumulative incidence estimates, as appropriate.

  3. Acute graft versus host disease [ Time Frame: Up to 2 years post-transplant ]
    Will be summarized using Kaplan-Meier and cumulative incidence estimates, as appropriate.

  4. Chronic graft versus host disease [ Time Frame: Up to 2 years post-transplant ]
    Will be summarized using Kaplan-Meier and cumulative incidence estimates, as appropriate.

  5. Clinically significant infections [ Time Frame: Up to 2 years post-transplant ]
    Clinically significant infections include infections that have a significant impact on patient's clinical recovery, for instance infections that require in-patient hospitalization or prolongs existing hospitalization. Will be summarized using Kaplan-Meier and cumulative incidence estimates, as appropriate.

  6. Platelet engraftment [ Time Frame: At day 100 post-transplant ]
    Defined as the first of three consecutive days with platelet count >= 20,000/uL on the peripheral blood, without platelet transfusion in the previous seven days. Will be summarized using Kaplan-Meier and cumulative incidence estimates, as appropriate.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Acute leukemia (AL) that includes acute myeloid leukemia (AML) / acute lymphoblastic leukemia (ALL) / mixed phenotype leukemia (MPAL) in complete morphological remission (CR) with or without detectable minimal residual disease (MRD); complete morphological remission is defined by the presence of less than 5% of detectable blasts in bone marrow specimen, evaluated no earlier than one month before conditioning regimen start. Patients with documented CR but without hematologic recovery since last chemotherapy are considered eligible to the study
  • Chronic myelogenous leukemia (CML), except refractory blast crisis. To be eligible in first chronic phase, patients must have failed or be intolerant to at least one tyrosine-kinase inhibitor
  • Chronic myelomonocytic leukemia (CMML)
  • Myelodysplastic syndromes (MDS)
  • Lymphoblastic, Burkitt's and other high-grade lymphoma in any complete (CR) or partial (PR) response

    • CR and PR are defined according to Lugano classification: Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification
  • Low grade lymphoma (chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL], marginal zone lymphoma, follicular lymphoma) progressed after two treatment regimens, in CR/PR

    • For CLL/SLL, CR and PR are defined according to: International Workshop on CLL (iwCLL) guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL
    • CR and PR are defined according to Lugano classification: Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification
  • Large cell lymphoma in > second CR (CR2)/ >= PR2

    • CR and PR are defined according to Lugano classification: Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification
  • Mantle cell lymphoma, lymphoplasmacytic lymphoma and prolymphocytic leukemia may be eligible after initial therapy if in CR/PR

    • CR and PR are defined according to Lugano classification: Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification
    • For prolymphocytic leukemia (PLL), CR is defined as a normalization of lymphadenopathies (long-axis diameter < 1 cm) and splenomegaly (< 13 cm), absence of constitutional symptoms, PLL cells < 5% in bone marrow and circulating lymphocytes count < 4 x 10^9/L. Patients without hematopoietic recovery are considered eligible to the study. PR is defined as a decrease of >= 30% of the sum of lymphadenopathies' long-axis diameters, a decrease of >= 50% in spleen vertical length beyond normal from baseline, peripheral blood (PB) lymphocytes =< 30 x 10^9/L (and a decrease of >= 50% from baseline)
  • Hodgkin Lymphoma in > CR2/PR2

    • CR and PR are defined according to Lugano classification: Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification
  • Karnofsky >= 70 or Eastern Cooperative Oncology Group (ECOG) 0-1 (for adults)
  • Lansky score >= 50 (for children)
  • Adequate cardiac function defined as absence of decompensated congestive heart failure or uncontrolled arrhythmia AND left ventricular ejection fraction >= 40% or shortening fraction > 22%
  • Adequate pulmonary function defined as absence of oxygen (O2) requirements and one of the following:

    • Diffusion capacity of the lung for carbon monoxide (DLCO) corrected > 70% mm Hg
    • DLCO corrected between 60% - 69% mm Hg and partial pressure of oxygen (pO2) >= 70 mm Hg
    • DLCO corrected between 50% - 59% mm Hg and pO2 >= 80 mm Hg Pediatric patients unable to perform pulmonary function tests must have O2 saturation >= 92% on room air. May not be on supplemental oxygen
  • Total bilirubin < 2 x upper limit of normal (ULN) unless felt to be related to Gilbert's disease or hemolysis
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
  • Alkaline phosphatase =< 5 x ULN
  • Creatinine < 2.0 mg/dl (adults) or estimated creatinine clearance > 40 ml/min (pediatrics)

    • All adults with a creatinine > 1.2 or a history of renal dysfunction must have estimated creatinine clearance > 40 ml/min
  • If recent mold infection, e.g., aspergillus, must be cleared by infectious disease to proceed
  • Patients who have undergone prior allogeneic hematopoietic cell transplant are eligible, but the first transplant must have been performed at least 6 months prior to enrollment, unless in case of graft failure from the prior transplant
  • Written and signed informed consent
  • DONOR: Donors must be haploidentical relatives of the patients. Donor-recipient compatibility will be tested through HLA typing at high resolution for the HLA loci (-A, -B, -C, -DRB1, -DQB1). Donor and recipient should share at least 5/10 HLA loci
  • DONOR: Age >= 12 years
  • DONOR: Weight >= 40 Kg
  • DONOR: Ability of donors younger than 18 years of age to undergo apheresis without use of a vascular access device. Vein check must be performed and verified by an apheresis nurse prior to arrival at the Seattle Cancer Care Alliance (SCCA)
  • DONOR: Donor must meet selection criteria as defined by the Foundation of the Accreditation of Cell Therapy (FACT) and will be screened per the American Association of Blood Banks (AABB) guidelines
  • DONOR: In case of more available haploidentical donors, selection criteria should include, in this order:

    • For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative donor
    • Red blood cell compatibility

      • Red blood cell (RBC) cross match compatible
      • Minor ABO incompatibility
      • Major ABO incompatibility

Exclusion Criteria:

  • Patients with evidence of liver synthetic dysfunction or severe cirrhosis will be excluded
  • Active, uncontrolled, life-threatening viral, bacterial or fungal infection requiring treatment at time of conditioning regiment administration and transplantation
  • Presence of a malignancy other than the one for which the transplant is being performed, with an expected survival less than 75% at 5 years
  • Pregnant or breastfeeding
  • Known hypersensitivity to treosulfan, fludarabine or cyclophosphamide
  • Dosing with another investigational agent within 30 days prior to entry in the study
  • Central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy and/or cranial radiation prior to initiation of conditioning (day -6)
  • DONOR: Since detection of anti-donor-specific-antigen antibodies (anti-DSA) is associated with higher graft rejection rate, patients will be screened for anti-DSA pre-transplant, and in case of positivity, the donor will be excluded

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04195633


Contacts
Layout table for location contacts
Contact: Filippo Milano 206.667.5925 fmilano@fredhutch.org

Locations
Layout table for location information
United States, Washington
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Contact: Filippo Milano    206-667-5925    fmilano@fredhutch.org   
Principal Investigator: Filippo Milano         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Filippo Milano Fred Hutch/University of Washington Cancer Consortium

Layout table for additonal information
Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT04195633    
Other Study ID Numbers: RG1005742
NCI-2019-07697 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RG1005742 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
First Posted: December 12, 2019    Key Record Dates
Last Update Posted: March 4, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Burkitt Lymphoma
Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Mantle-Cell
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphoma, Large B-Cell, Diffuse
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Lymphoma, Large-Cell, Anaplastic
Leukemia, Prolymphocytic
Waldenstrom Macroglobulinemia
Myelodysplastic Syndromes
Acute Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Lymphoid
Leukemia, B-Cell
Myeloproliferative Disorders
Lymphoma, B-Cell
Epstein-Barr Virus Infections