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Early Allogeneic Hematopoietic Cell Transplantation in Treating Patients With Relapsed or Refractory High-Grade Myeloid Neoplasms

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ClinicalTrials.gov Identifier: NCT02756572
Recruitment Status : Recruiting
First Posted : April 29, 2016
Last Update Posted : February 15, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Washington

Brief Summary:
This clinical trial studies how well early stem cell transplantation works in treating patients with high-grade myeloid neoplasms that has come back after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as filgrastim, cladribine, cytarabine and mitoxantrone 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 before a donor peripheral blood 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. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells. Early stem cell transplantation may result in more successful treatment for patients with high-grade myeloid neoplasms.

Condition or disease Intervention/treatment Phase
Blasts 10 Percent or More of Bone Marrow Nucleated Cells Chronic Myelomonocytic Leukemia-2 High Grade Malignant Neoplasm Myelodysplastic Syndrome Myelodysplastic Syndrome With Excess Blasts-2 Myeloid Neoplasm Previously Treated Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Cladribine Drug: Cyclosporine Drug: Cytarabine Biological: Filgrastim Drug: Fludarabine Phosphate Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Other: Laboratory Biomarker Analysis Drug: Melphalan Drug: Mitoxantrone Hydrochloride Drug: Mycophenolate Mofetil Other: Questionnaire Administration Drug: Sirolimus Radiation: Total-Body Irradiation Drug: Melphalan Hydrochloride Not Applicable

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the feasibility of "early" allogeneic hematopoietic cell transplant (HCT) for patients with relapsed or refractory (R/R) high-grade myeloid neoplasms.

SECONDARY OBJECTIVES:

I. Estimate relapse-free survival (RFS), acute graft versus host disease (GVHD), treatment related mortality (TRM), event-free survival (EFS), overall survival (OS), and complete remission (with or without measurable disease) among patients who receive early HCT.

II. Assess factors that distinguish patients who receive early HCT from those who do not.

III. Compare RFS, EFS, OS, acute GVHD, and TRM between patients in the feasibility study and matched patients who were transplanted with standard scheduling.

IV. Demonstrate the feasibility of collecting patient-reported outcomes and resource utilization data for trial participants.

V. Describe the outcomes of patients enrolled who went on to allogeneic HCT off-study.

OUTLINE:

RE-INDUCTION CHEMOTHERAPY: Patients receive filgrastim subcutaneously (SC) on days 0-5, mitoxantrone hydrochloride intravenously (IV) over 60 minutes on days 1-3, cladribine IV over 2 hours on days 1-5, and cytarabine IV over 2 hours on days 1-5. Treatment continues for a maximum of 2 courses in the absence of disease progression or unacceptable toxicity.

CONDITIONING REGIMEN: Beginning 14-60 days after re-induction chemotherapy, patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2, melphalan IV on days -3 to -2, cyclosporine orally (PO) twice daily (BID) on day -3, and sirlolimus PO BID on day -3. Patients > 55 years or with significant co-morbidities also receive total body irradiation (TBI) on day -1 or day 0.

EARLY TRANSPLANT: Patients undergo allogeneic HCT after conditioning regimen on day 0.

GVHD PROPHYLAXIS: Patients receive mycophenolate mofetil PO three times daily (TID) on days 0-30, then BID until day 40, and cyclosporine PO BID on days -3 to 96, with a taper until day 150. Patients with matched unrelated donors also receive sirolimus PO on days -3 to 150, with a taper until day 180.

After completion of study treatment, patients are followed up periodically.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Feasibility Study of "Early" Allogeneic Hematopoietic Cell Transplantation for Relapsed or Refractory High-Grade Myeloid Neoplasms
Actual Study Start Date : September 22, 2016
Estimated Primary Completion Date : November 1, 2019


Arm Intervention/treatment
Experimental: Treatment (chemotherapy, HCT)
See Detailed Description
Drug: Cladribine
Given IV
Other Names:
  • 2-CdA
  • 2CDA
  • CdA
  • Cladribina
  • Leustat
  • Leustatin
  • Leustatine
  • RWJ-26251

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

Drug: Cytarabine
Given IV
Other Names:
  • .beta.-Cytosine arabinoside
  • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-.beta.-D-Arabinofuranosylcytosine
  • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
  • 1-Beta-D-arabinofuranosylcytosine
  • 1.beta.-D-Arabinofuranosylcytosine
  • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
  • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
  • Alexan
  • Ara-C
  • ARA-cell
  • Arabine
  • Arabinofuranosylcytosine
  • Arabinosylcytosine
  • Aracytidine
  • Aracytin
  • Aracytine
  • Beta-cytosine Arabinoside
  • CHX-3311
  • Cytarabinum
  • Cytarbel
  • Cytosar
  • Cytosine Arabinoside
  • Cytosine-.beta.-arabinoside
  • Cytosine-beta-arabinoside
  • Erpalfa
  • Starasid
  • Tarabine PFS
  • U 19920
  • U-19920
  • Udicil
  • WR-28453

Biological: Filgrastim
Given SC
Other Names:
  • FILGRASTIM, LICENSE HOLDER UNSPECIFIED
  • G-CSF
  • Neupogen
  • r-metHuG-CSF
  • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
  • rG-CSF
  • Tevagrastim

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

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

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Melphalan
Given IV
Other Names:
  • Alanine Nitrogen Mustard
  • CB-3025
  • L-PAM
  • L-Phenylalanine Mustard
  • L-sarcolysin
  • L-Sarcolysin Phenylalanine mustard
  • L-Sarcolysine
  • Melphalanum
  • Phenylalanine Mustard
  • Phenylalanine nitrogen mustard
  • Sarcoclorin
  • Sarkolysin
  • WR-19813

Drug: Mitoxantrone Hydrochloride
Given IV
Other Names:
  • CL 232315
  • DHAD
  • DHAQ
  • Dihydroxyanthracenedione Dihydrochloride
  • Mitoxantrone Dihydrochloride
  • Mitoxantroni Hydrochloridum
  • Mitozantrone Hydrochloride
  • Mitroxone
  • Neotalem
  • Novantrone
  • Onkotrone
  • Pralifan

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

Other: Questionnaire Administration
Ancillary studies

Drug: Sirolimus
Given PO
Other Names:
  • AY 22989
  • RAPA
  • Rapamune
  • Rapamycin
  • SILA 9268A
  • WY-090217

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

Drug: Melphalan Hydrochloride
Given IV
Other Names:
  • 241286
  • 3-(p-(bis(2-chloroethyl)amino)phenyl)-L-Alanine
  • Hydrochloride
  • Alkeran
  • Alkerana
  • Evomela




Primary Outcome Measures :
  1. Feasibility of early allogeneic hematopoietic cell transplant assessed by enrollment and incidence of early transplant [ Time Frame: Up to 60 days of start of chemotherapy ]
    Success will be defined as enrollment of at least 30 patients per year with transplants occurring in 15 of these 30 (50%) within 60 days of enrollment or start of induction chemotherapy, whichever is earlier.


Secondary Outcome Measures :
  1. Event free survival [ Time Frame: Up to 12 months ]
    Will be estimated with the Kaplan-Meier method. Log-rank tests and Cox regression will be used for survival outcomes.

  2. Factors that distinguish patients who receive early hematopoietic cell transplant [ Time Frame: Up to 12 months ]
    Patients who receive early hematopoietic cell transplant will be compared to those that don't using Fisher's exact test for categorical variables (e.g., gender) and the Wilcoxon rank sum test for quantitative variables (e.g., age).

  3. Hematopoietic cell transplant Incidence of complete remission, defined as < 5% blasts on bone marrow biopsy with hematologic recovery, defined as absolute neutrophil count > 1000/ul and platelets > 100,000 /ml [ Time Frame: Up to 12 months ]
  4. Incidence of acute graft versus host disease (graft versus host disease graded II, III, or IV) [ Time Frame: At day 100 ]
    Cumulative incidence will be calculated and remission rates will be tabulated. Cumulative incidence regression will be used to compare outcomes subject to competing risks (acute graft versus host disease).

  5. Incidence of complete remission by platelets, defined as platelets < 100,000/ul [ Time Frame: Up to 12 months ]
  6. Incidence of complete remission with insufficient hematologic recovery, defined as absolute neutrophil count < 1000/ul or platelets < 100,000/ul [ Time Frame: Up to 12 months ]
  7. Incidence of relapse, defined as > 5% blasts in bone marrow, flow cytometry, or manual differential OR treatment for active relapsed disease [ Time Frame: Up to 12 months ]
    Prophylaxis against relapse or treatment for minimal residual disease (including donor lymphocyte infusion, genetically modified T cells or withdrawal of immunosuppression) will not be considered relapse for the purposes of this trial.

  8. Incidence of treatment related mortality [ Time Frame: At day 100 ]
    Cumulative incidence will be calculated and remission rates will be tabulated. Cumulative incidence regression will be used to compare outcomes subject to competing risks (treatment related mortality).

  9. Overall survival [ Time Frame: Up to 12 months ]
    Will be estimated with the Kaplan-Meier method. Log-rank tests and Cox regression will be used for survival outcomes.

  10. Patient-reported outcomes assessed by European quality of life five dimension [ Time Frame: Up to 12 months ]
    Results and resource utilization will be summarized descriptively and information gathering process will be assessed for feasibility.

  11. Patient-reported outcomes assessed by functional assessment cancer therapy-leukemia, and functional assessment cancer therapy-bone marrow transplant subscale [ Time Frame: Up to 12 months ]
    Results and resource utilization will be summarized descriptively and information gathering process will be assessed for feasibility.

  12. Patient-reported outcomes assessed by MD Anderson Symptom Inventory [ Time Frame: Up to 12 months ]
    Results and resource utilization will be summarized descriptively and information gathering process will be assessed for feasibility.

  13. Relapse free survival [ Time Frame: Up to 12 months ]
    Will be estimated with the Kaplan-Meier method. Log-rank tests and Cox regression will be used for survival outcomes.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

INCLUSION CRITERIA (ENROLLMENT)

  • Relapsed or refractory high-grade myeloid neoplasms, defined as having a blast count of >= 10% blasts at initial diagnosis; examples include excess blasts (EB)-2, with >= 10% blasts at initial diagnosis, acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML-2); standard definitions of relapse will apply (i.e., characterized by >= 5% abnormal blasts as assessed by multiparameter flow cytometry or morphologic examination; peripheral blood blasts; or extramedullary granulocytic sarcoma, per European LeukemiaNet [ELN] 2017 guidelines); bone marrow aspirate/biopsy will be accepted if performed outside University of Washington/Fred Hutchinson Cancer Research Center (UW/FHCRC); determination of disease status should occur within 30 days of signing informed consent

    • R/R high-grade myeloid neoplasm following intensive induction chemotherapy; relapsed high-grade myeloid neoplasm: patients will be classified as relapsed if they have >= 5% blasts after being in a complete remission (CR) following treatment for high-grade myeloid neoplasm; refractory high-grade myeloid neoplasm: patients may be classified as refractory if they have received at least one prior cycle of induction chemotherapy, whether with cladribine cytarabine mitoxantrone (GCLAM) or another regimen

      • Patients may have received up to two courses of intensive induction chemotherapy during initial treatment prior to enrollment on this protocol; for example, patients who have received two courses of granulocyte colony stimulating factor (G-CSF) GCLAM (or similar) chemotherapy, with most recent high-dose cytarabine-containing chemotherapy > 6 months ago and CR lasting > 6 months, will be eligible for this protocol; regimens "similar to GCLAM" would include cytarabine at doses of 1g/m^2 for at least 5 doses; examples of regimens "similar to GCLAM" would be GCLA, fludarabine cytarabine granulocyte (FLAG), and FLAG-idarubicin (ida); however, patients who received more than two courses of GCLAM (or similar) chemotherapy, or patients who received two courses of GCLAM and had CR lasting < 6 months, would not be eligible
    • R/R high-grade myeloid neoplasm following less intensive induction chemotherapy. Patients who have received at least three cycles of treatment with a hypomethylating agent (HMA; such as azacitidine or decitabine) and still have >= 10% blasts will be eligible for the study (they will be considered refractory); similarly, patients who have received three or more cycles of HMA therapy who have had a response (e.g., achieving CR with < 5% blasts), but who then progress using standard definitions of relapse, will also be eligible (they will be considered relapsed)
  • Potentially eligible for reduced intensity conditioning based on known organ function (formal organ function testing may occur after consent)
  • Caregiver capable of providing post-HCT care
  • Written informed consent

INCLUSION CRITERIA (TRANSPLANT)

  • Matched related or unrelated (8/8 matched at human leukocyte antigen [HLA]-A, -B, -C, -DRB1) donor according to institutional standards
  • Caregiver capable of providing post-HCT care, who will be present once induction therapy with filgrastim, cladribine, cytarabine, mitoxantrone hydrochloride (GCLAM) begins
  • Written informed consent for transplant
  • Either bone marrow or peripheral blood is allowed

Exclusion Criteria:

EXCLUSION CRITERIA (ENROLLMENT)

  • Prior allogeneic HCT
  • More than two prior courses of induction chemotherapy
  • Relapse after minimal residual disease (MRD)-negative CR within 3 months of most recent GCLAM chemotherapy
  • Low likelihood of being eligible for reduced intensity conditioning HCT based on known information

    • Cardiac ejection fraction < 40% or symptomatic coronary artery disease or uncontrolled arrhythmia
    • Diffusing capacity of the lungs for carbon monoxide (DLCOc) < 40% or forced expiratory volume in 1 second (FEV1) < 50%
    • Estimated glomerular filtration rate (GFR) < 40 ml/min
    • Need for supplemental oxygen
    • Direct bilirubin or alanine aminotransferase (ALT) > 2 x upper limit of normal, unless these abnormalities are thought to be related to Gilbert's disease or leukemic infiltration of hepatic parenchyma
  • Known human immunodeficiency virus (HIV) positivity
  • Pregnant or nursing (to be confirmed with quantitative human chorionic gonadotropin [HCG] testing)
  • Invasive solid tumor within 5 years; non-melanoma skin cancer or in situ malignancies are allowed

EXCLUSION CRITERIA (TRANSPLANT)

  • Donor specific antibodies against donor HLA-DQ or -DP
  • Active bacterial, fungal or viral infections unresponsive to medical therapy
  • Active leukemia in the central nervous system (CNS)
  • HIV positive
  • Cardiac ejection fraction < 40% or symptomatic coronary artery disease or uncontrolled arrhythmia
  • DLCOc < 40% or FEV1 < 50%
  • Estimated GFR < 40 ml/min
  • Need for supplemental oxygen
  • Direct bilirubin or ALT > 2 x upper limit of normal, unless these abnormalities are thought to be related to Gilbert's disease or leukemic infiltration of hepatic parenchyma

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): NCT02756572


Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Mary-Elizabeth M. Percival    206-606-1320    mperciva@seattlecca.org   
Principal Investigator: Mary-Elizabeth M. Percival         
Sponsors and Collaborators
University of Washington
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Mary-Elizabeth Percival Fred Hutch/University of Washington Cancer Consortium

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Responsible Party: University of Washington
ClinicalTrials.gov Identifier: NCT02756572     History of Changes
Other Study ID Numbers: 9567
NCI-2016-00477 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9567 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
RG1016011 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
First Posted: April 29, 2016    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019

Additional relevant MeSH terms:
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Syndrome
Leukemia
Neoplasms
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Anemia, Refractory, with Excess of Blasts
Disease
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Anemia, Refractory
Anemia
Fludarabine
Cytarabine
Sirolimus
Melphalan
Mycophenolic Acid
Mitoxantrone
Fludarabine phosphate
Mechlorethamine
Cladribine
Nitrogen Mustard Compounds
Cyclosporins