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Chemotherapy, Total Body Irradiation, and Post-Transplant Cyclophosphamide in Reducing Rates of Graft Versus Host Disease in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant

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ClinicalTrials.gov Identifier: NCT03192397
Recruitment Status : Recruiting
First Posted : June 20, 2017
Last Update Posted : April 18, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
This phase II trial studies how well chemotherapy, total body irradiation, and post-transplant cyclophosphamide work in reducing rates of graft versus host disease in patients with hematologic malignancies undergoing a donor stem cell transplant. Drugs used in the chemotherapy, such as fludarabine phosphate and melphalan hydrochloride, 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. 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. 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft versus host disease). Giving cyclophosphamide after the transplant may stop this from happening.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia in Remission Adult Acute Lymphoblastic Leukemia in Complete Remission Chronic Myelogenous Leukemia, BCR-ABL1 Positive in Remission Chronic Myelomonocytic Leukemia in Remission Graft Versus Host Disease Hodgkin Lymphoma Minimal Residual Disease Myelodysplastic Syndrome Myeloproliferative Neoplasm Non-Hodgkin Lymphoma Plasma Cell Myeloma Severe Aplastic Anemia Waldenstrom Macroglobulinemia Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Cyclophosphamide Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Drug: Melphalan Hydrochloride Drug: Mycophenolate Mofetil Drug: Sirolimus Radiation: Total-Body Irradiation Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the cumulative incidence of extensive chronic graft versus host disease (GVHD) at 1 year after transplantation utilizing the novel conditioning/GVHD prophylactic regimen for patients undergoing allogeneic hematopoietic cell transplantation, in patients who do not progress before day 100.

SECONDARY OBJECTIVES:

I. To evaluate clinical response, engraftment rate, progression-free survival (PFS) at one year and, overall survival (OS).

II. To determine the cumulative incidence of relapse. III. To evaluate the day 100 transplant-related mortality rate. IV. To determine the cumulative incidence of grade III-IV acute GVHD.

OUTLINE: This is a dose-escalation study of melphalan hydrochloride.

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -2 and melphalan hydrochloride IV over 30 minutes on day -2. Patients undergo total body irradiation (TBI) on day -1.

STEM CELL INFUSION: Patients undergo allogeneic hematopoietic stem cell transplant on day 0.

GVHD PROPHYLAXIS REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days 3-4, mycophenolate mofetil IV over 2 hours on days 5-35, and tacrolimus IV and then orally (PO) once tolerated on days 5-180 with a taper beginning on day 100.

After completion of study treatment, patients are followed up for 12 months and then annually thereafter.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Phase II Trial of Fludarabine/Melphalan/Total Body Irradiation With Post Transplant Cyclophosphamide as Graft Versus Host Disease Prophylaxis in Matched-Related and Matched-Unrelated Allogeneic Hematopoietic Cell Transplantation
Actual Study Start Date : August 3, 2017
Estimated Primary Completion Date : July 1, 2021
Estimated Study Completion Date : July 1, 2022


Arm Intervention/treatment
Experimental: Prevention (chemotherapy, TBI, cyclophosphamide)

CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and melphalan hydrochloride IV over 30 minutes on day -2. Patients undergo TBI on day -1.

STEM CELL INFUSION: Patients undergo allogeneic hematopoietic stem cell transplant on day 0.

GVHD PROPHYLAXIS REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days 3-4, mycophenolate mofetil IV over 2 hours on days 5-35, and sirolimus IV and then PO once tolerated on days 5-180 with a taper beginning on day 100.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic stem cell transplant
Other Names:
  • allogeneic stem cell transplantation
  • HSC
  • HSCT

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
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Melphalan Hydrochloride
Given IV
Other Names:
  • Alkeran
  • Alkerana
  • Evomela

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

Drug: Sirolimus
Given IV and PO
Other Name: Rapamune

Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation




Primary Outcome Measures :
  1. Extensive chronic graft versus host disease (GVHD) [ Time Frame: Up to 365 days ]
    Will be analyzed for each stratum. Will examine in a post-hoc analysis potential chronic GVHD rates of response by human leukocyte antigen (HLA) matching status.


Secondary Outcome Measures :
  1. Clinical response assessed as per bone marrow transplant (BMT) standard of care [ Time Frame: Up to 4 years ]
    Will utilize either straight Kaplan-Meier based estimators or extensions of nonparametric survival models to account for competing risks.

  2. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) [ Time Frame: Up to 4 years ]
    Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts. Will examine in a post-hoc analysis potential chronic GVHD rates of response by human leukocyte antigen (HLA) matching status.

  3. Cumulative incidence of relapse [ Time Frame: Up to 4 years ]
    Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts.

  4. Engraftment rate assessed as per bone marrow transplant (BMT) standard of care [ Time Frame: Up to 4 years ]
    Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts.

  5. Overall survival assessed as per bone marrow transplant (BMT) standard of care [ Time Frame: Up to 4 years ]
    Will utilize either straight Kaplan-Meier based estimators or extensions of nonparametric survival models to account for competing risks.

  6. Progression free survival (PFS) assessed as per bone marrow transplant (BMT) standard of care [ Time Frame: At 1 year ]
    Will utilize either straight Kaplan-Meier based estimators or extensions of nonparametric survival models to account for competing risks.

  7. Treatment-related mortality rates [ Time Frame: Up to 4 years ]
    Will be analyzed in a descriptive fashion with means +/- standard deviations or frequency counts.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The patient must have a diagnosis of one of the following (one must be yes):

    • Acute myeloid leukemia (AML)
    • Acute lymphoblastic leukemia (ALL)
    • Chronic myelogenous leukemia (CML) (chronic phase intolerant or unresponsive to tyrosine kinase inhibitors, accelerated phase, history of blast crisis)
    • Myelodysplastic syndrome (MDS)
    • Myeloproliferative neoplasm (MPN)
    • Chronic myelomonocytic leukemia (CMML)
    • Non-Hodgkin lymphoma (NHL)
    • Hodgkin lymphoma (HL) (received and failed frontline therapy or failed autologous transplantation or inability to collect enough peripheral blood stem cells [PBSC] for autologous hematopoietic cell transplant [auto-HCT])
    • Multiple myeloma (MM)
    • Waldenstrom's macroglobulinemia
    • Severe aplastic anemia
  • Histocompatible donor identified:

    • Related donor or unrelated donor matched 5/6 or better (A, B, DRB1)
  • Patients with benign hematological disorders such as severe aplastic anemia do not have disease requirements. Patients with malignant hematologic disorder must be in CR (MRD is allowed) with the exception of the following:

    • Patients with MDS/MPN only require <5% myeloblast on bone marrow evaluation.
    • Patients with AML or ALL may be in CRi, patients with MM may be in VGPR
  • Have a Karnofsky performance status score of > 50%
  • Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% predicted, corrected for hemoglobin and/or alveolar ventilation
  • Left ventricular ejection fraction > 40%
  • Bilirubin =< 3 x upper limit of normal
  • Liver alkaline phosphatase =< 3 x upper limit of normal
  • Serum glutamic-oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) =< 3 x upper limit of normal
  • Calculated creatinine clearance > 40 cc/min by the modified Cockroft-Gault formula
  • Patient must be cleared pre-transplant by Radiation Oncology to be able to receive 400 cGy
  • Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Patients who have failed a prior autologous or allogeneic transplant are eligible; however, at least 6 months must have elapsed between the start of this reduced intensity conditioning regimen and the last transplant if patient had a prior autologous or myeloablative allogeneic bone marrow transplant (BMT)
  • At least 2 weeks since prior chemotherapy, radiation treatment and/or surgery
  • Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

  • Bone marrow failure disorders:

    • Paroxysmal nocturnal hemoglobinuria (PNH)
    • Hereditary bone marrow failure disorders include Diamond-Blackfan anemia, Shwachman- Diamond syndrome, Kostmann syndrome, and congenital amegakaryocytic thrombocytopenia
    • Other non-malignant hematologic or immunologic disorders that require transplantation:

      • Quantitative or qualitative congenital platelet disorders (including but not limited to congenital megakaryocytopenia, absent-radii syndrome, Glanzmann?s thrombasthenia)
      • Quantitative or qualitative congenital neutrophil disorders (including but not limited to chronic granulomatous disease, congenital neutropenia)
      • Congenital primary immunodeficiencies (including but not limited to severe combined immunodeficiency syndrome, Wiskott-Aldrich syndrome, CD40 ligand deficiency, T-cell deficiencies)
      • Hemoglobinopathies (including sickle cell disease and thalassemia)
  • Presence of human leukocyte antigen (HLA) antibodies
  • Uncontrolled central nervous system (CNS) disease (for hematologic malignancies)
  • Child-Pugh class B and C liver failure
  • Patients who in the opinion of the treating physician are unlikely to comply with the restrictions of allogeneic stem cell transplantation based on formal psychosocial screening. (i.e., serious, uncontrolled psychiatric illness/social situations that would limit compliance with study requirements)
  • Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or other condition which, in the opinion of treating physician, would make this protocol unreasonably hazardous for the patient
  • Known human immunodeficiency virus (HIV) positive
  • Pregnant or nursing female participants
  • Unwilling or unable to follow protocol requirements
  • Any condition which in the Investigator?s opinion deems the participant an unsuitable candidate to receive study drug

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): NCT03192397


Locations
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United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Roswell Park    877-275-7724    ASKRPCI@roswellpark.org   
Principal Investigator: Christine M. Ho         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Christine Ho Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT03192397     History of Changes
Other Study ID Numbers: I 44417
NCI-2017-01069 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 44417 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
First Posted: June 20, 2017    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Waldenstrom Macroglobulinemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Multiple Myeloma
Neoplasm, Residual
Myelodysplastic Syndromes
Anemia, Aplastic
Myeloproliferative Disorders
Graft vs Host Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Lymphoid
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hemorrhagic Disorders