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CLAG-M Chemotherapy and Reduced-Intensity Conditioning Donor Stem Cell Transplant for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelomonocytic Leukemia

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ClinicalTrials.gov Identifier: NCT04375631
Recruitment Status : Recruiting
First Posted : May 5, 2020
Last Update Posted : October 31, 2022
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Center

Brief Summary:
This phase I trial studies the best dose of total body irradiation when given with CLAG-M chemotherapy reduced-intensity conditioning regimen before stem cell transplant in treating patients with acute myeloid leukemia, myelodysplastic syndrome, or chronic myelomonocytic leukemia that has come back (relapsed) or does not respond to treatment (refractory). Giving chemotherapy and total body irradiation before a donor peripheral blood stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can attack the body's normal cells called graft versus host disease. Giving cyclophosphamide, cyclosporine, and mycophenolate mofetil after the transplant may stop this from happening.

Condition or disease Intervention/treatment Phase
Recurrent Acute Myeloid Leukemia Recurrent Chronic Myelomonocytic Leukemia Recurrent Myelodysplastic Syndrome Refractory Acute Myeloid Leukemia Refractory Chronic Myelomonocytic Leukemia Refractory Mixed Phenotype Acute Leukemia Refractory Myelodysplastic Syndrome Refractory Acute Leukemia of Ambiguous Lineage Refractory Acute Undifferentiated Leukemia Drug: Cladribine Drug: Cyclophosphamide Drug: Cyclosporine Drug: Cytarabine Biological: Filgrastim Procedure: Hematopoietic Cell Transplantation Drug: Mitoxantrone Drug: Mycophenolate Mofetil Drug: Mycophenolate Sodium Radiation: Total-Body Irradiation Phase 1

Detailed Description:

OUTLINE: This a dose-escalation study of TBI.

Patients receive filgrastim (G-CSF) subcutaneously (SC) daily on days -9 to -4, cladribine intravenously (IV) over 2 hours daily on days -8 to -4, cytarabine IV over 2-4 hours daily on days -8 to -4, and mitoxantrone IV daily on days -8 to -6. If white blood cell (WBC) > 20,000/uL, filgrastim on days -9 and -8 may be omitted at physician discretion. Patients undergo TBI and HCT on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours daily on days 3-4, cyclosporine IV over 1-2 hours twice daily (BID) on days 5-60, and mycophenolate mofetil IV or orally (PO) BID on days 5-28 (transplant with related donors) or three times daily (TID) on days 5-35 (transplant with unrelated donors). After day 60, patients continue to receive cyclosporine tapered through day 180 at the discretion of the treating physician in the absence of GVHD.

After completion of study treatment, patients are followed up at 100 days, at 6, 12, and 24 months post-transplant, then annually thereafter.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CLAG·M Chemotherapy Followed Immediately by Related/Unrelated Reduced-Intensity Conditioning (RIC) Allogeneic Hematopoietic Cell Transplantation for Adults With Myeloid Malignancies at High Risk of Relapse: A Phase 1 Study
Actual Study Start Date : December 3, 2020
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2025


Arm Intervention/treatment
Experimental: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Patients receive filgrastim SC daily on days -9 to -4, cladribine IV over 2 hours daily on days -8 to -4, cytarabine IV over 2-4 hours daily on days -8 to -4, and mitoxantrone IV daily on days -8 to -6. If WBC > 20,000/uL, filgrastim on days -9 and -8 may be omitted at physician discretion. Patients undergo TBI and HCT on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours daily on days 3-4, cyclosporine IV over 1-2 hours BID on days 5-60, and mycophenolate mofetil IV or PO BID on days 5-28 (transplant with related donors) or TID on days 5-35 (transplant with unrelated donors). After day 60, patients continue to receive cyclosporine tapered through day 180 at the discretion of the treating physician in the absence of GVHD.

Drug: Cladribine
Given IV
Other Names:
  • 2-CdA
  • 2CDA
  • CdA
  • Cladribina
  • Leustat
  • Leustatin
  • Leustatine
  • RWJ-26251

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
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Cyclosporine Modified
  • Gengraf
  • Neoral
  • OL 27-400
  • 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:
  • G-CSF
  • Neupogen
  • r-metHuG-CSF
  • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
  • rG-CSF
  • Tevagrastim
  • Nivestym
  • Filgrastim-aafi

Procedure: Hematopoietic Cell Transplantation
Undergo HCT
Other Names:
  • HCT
  • Hematopoietic Stem Cell Transplantation
  • HSCT
  • Stem Cell Transplant
  • stem cell transplantation
  • Hematopoietic Stem Cell Infusion

Drug: Mitoxantrone
Given IV
Other Names:
  • Dihydroxyanthracenedione
  • Mitozantrone

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 TBI
Other Names:
  • TBI
  • Total Body Irradiation
  • Whole Body Irradiation
  • Whole-Body Irradiation
  • SCT_TBI




Primary Outcome Measures :
  1. Rate of hematopoietic cell transplantation (HCT) failure [ Time Frame: Within 200 days post-transplant ]
    Defined as graft rejection (< 5% donor T-cell chimerism).

  2. Rate of disease progression [ Time Frame: Within 200 days post-transplant ]
    Defined by European LeukemiaNet (ELN) 2017 criteria and International Working Group (IWG).


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 100 days post-transplant ]
  2. Rates of stem cell engraftment and donor chimerism [ Time Frame: At 80 days (+/- 7 days) ]
  3. Rates of grades II-IV acute graft versus host disease (GVHD) and chronic GVHD requiring systemic immunosuppressive treatment [ Time Frame: Up to 4 years ]
  4. Disease response [ Time Frame: Up to 4 years ]
  5. Duration of remission [ Time Frame: Up to 4 years ]


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

Inclusion Criteria:

  • Age 18-75 years with an Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) =< 5 for patients over 60 years
  • Acute myeloid leukemia (AML) (2016 World Health Organization [WHO] criteria) that is either primary refractory (as defined by failure of 2 cycles of 7+3-like chemotherapy, 1 cycle of high-dose cytarabine-based chemotherapy, or at least 2 cycles of venetoclax in combination with other therapies), or is in untreated or unsuccessfully treated first or subsequent relapse. Patients in morphological remission (i.e. < 5% blasts in the bone marrow) but evidence of minimal residual disease (MRD) by multiparameter flow cytometry, cytogenetics/fluorescence in situ hybridization (FISH), or molecular means will be eligible for trial participation. Patients with relapsed or refractory acute leukemia of ambiguous lineage (acute undifferentiated leukemia, mixed phenotype acute leukemia) that is either primary refractory or is in untreated or unsuccessfully treated first or subsequent relapse are also eligible
  • Subjects with previously treated myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) whose disease progressed, relapsed, or was refractory to HMA treatment as follows: 1) patients who have failed at least 4 cycles of monotherapy with azacitidine or decitabine, 2) patients who received at least 2 cycles of HMA in combination with another therapeutic agent. Subjects with MDS and CMML who failed at least 1 cycle of induction chemotherapy will be also eligible
  • The use of hydroxyurea prior to initiation of study treatment is allowed. Patients with symptoms/signs of hyperleukocytosis, WBC > 100,000/uL or with concern for other complications of high tumor burden (e.g. disseminated intravascular coagulation) can be treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500 mg/m^2 per dose) prior to start of study treatment
  • Karnofsky score >= 70; Eastern Cooperative Oncology Group (ECOG) 0-1
  • Adequate cardiac function defined as absence of decompensated congestive heart failure and/or uncontrolled arrhythmia and left ventricular ejection fraction >= 45%
  • Bilirubin =< 2.5 x institutional upper limit of normal unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis
  • Adequate pulmonary function defined as absence of oxygen (O2) requirements and either carbon monoxide diffusing capability test (DLCO) correct >= 70% mmHg or DLCO corrected 60-69% mmHg and partial pressure of oxygen (pO2) >= 70 mmHg
  • Serum creatinine =< 1.5 mg/dL
  • Prior autologous HCT is permissible if relapse occurred > 3 months but =< 6 months after HCT
  • Prior TBI-containing allogeneic HCT up to 3 Gy is permissible if > 6 months after HCT
  • A human leukocyte antigen (HLA)-matched or near-matched related or unrelated donor for collection of stimulated peripheral blood stem cells must be identified and readily available
  • Women of childbearing potential and men must agree to use adequate contraception beginning at the signing of the consent until at least 12 months post-transplant
  • Patients may have previously received chemotherapy with a mitoxantrone- or cladribine-based regimen for MDS or AML. If the patient has received CLAG-M before and has been sensitive to this regimen, eligibility will be determined on a case-by-case basis by the study principal investigator (PI)
  • Ability to understand and sign a written informed consent document (or legal representative)
  • DONOR: Patients must have an HLA-matched related donor or an HLA-matched unrelated donor who meets standard SCCA and/or National Marrow Donor Program (NMDP) or other donor center criteria for peripheral blood stem cell (PBSC) donation as follows:

    • Related donor: related to the patient and genotypically or phenotypically identical for HLA-A, B, C, DRB1 and DQB1. Phenotypic identity must be confirmed by high-resolution typing
    • Unrelated donor:

      • Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; OR
      • Mismatched for a single allele without antigen mismatching at HLA-A, B, or C as defined by high resolution typing but otherwise matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing
      • Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment. The recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain 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 crossmatch is an absolute donor exclusion
      • Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed

Exclusion Criteria:

  • Patients >= 18 years being treated at Seattle Children's Hospital
  • Active central nervous system (CNS) disease
  • Concomitant illness associated with a likely survival of < 1 year
  • Active systemic fungal, bacterial, viral, or other infection, unless disease is under treatment with anti-microbials and/or controlled or stable. Patients with fever thought to be likely secondary to myeloid malignancy are eligible
  • Known hypersensitivity or contraindication to any study drug used in this trial
  • Pregnancy or lactation
  • Concurrent treatment with any other approved or investigational anti-leukemia agent

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): NCT04375631


Contacts
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Contact: Filippo Milano 206.667.5925 fmilano@fredhutch.org

Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Filippo Milano    206-667-5925    fmilano@fredhutch.org   
Principal Investigator: Filippo Milano         
Sponsors and Collaborators
Fred Hutchinson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Filippo Milano Fred Hutch/University of Washington Cancer Consortium
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Responsible Party: Fred Hutchinson Cancer Center
ClinicalTrials.gov Identifier: NCT04375631    
Other Study ID Numbers: RG1006914
NCI-2020-02616 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RG1006914 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
10457 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
First Posted: May 5, 2020    Key Record Dates
Last Update Posted: October 31, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myelodysplastic Syndromes
Syndrome
Recurrence
Acute Disease
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Disease Attributes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Cytarabine
Cyclosporine
Mycophenolic Acid
Cyclophosphamide
Mitoxantrone
Cladribine
2-chloro-3'-deoxyadenosine
Cyclosporins
Lenograstim
Immunosuppressive Agents