Clinical Trials /

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

NCT04375631

Description:

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.

Related Conditions:
  • Acute Leukemia of Ambiguous Lineage
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: CLAG-M Chemotherapy Followed Immediately by Related/Unrelated Reduced-Intensity Conditioning (RIC) Allogeneic Hematopoietic Cell Transplantation for Adults With Relapsed/Refractory Acute Myeloid Leukemia (CLAG-M/RIC): A Phase 1 Study

Clinical Trial IDs

  • ORG STUDY ID: RG1006914
  • SECONDARY ID: NCI-2020-02616
  • SECONDARY ID: RG1006914
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT04375631

Conditions

  • Acute Leukemia of Ambiguous Lineage
  • Recurrent Acute Myeloid Leukemia
  • Recurrent Acute Undifferentiated Leukemia
  • Recurrent Chronic Myelomonocytic Leukemia
  • Recurrent Mixed Phenotype Acute Leukemia
  • Recurrent Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory Chronic Myelomonocytic Leukemia
  • Refractory Mixed Phenotype Acute Leukemia
  • Refractory Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Cladribine2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)
Cyclophosphamide(-)-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- 138719Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Cyclosporine Modified, Gengraf, Neoral, OL 27-400, Sandimmune, SangCyaTreatment (CLAG-M, TBI, HCT, GVHD prophylaxis)
Cytarabine.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-28453Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)
FilgrastimG-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, TevagrastimTreatment (CLAG-M, TBI, HCT, GVHD prophylaxis)
MitoxantroneDihydroxyanthracenedione, MitozantroneTreatment (CLAG-M, TBI, HCT, GVHD prophylaxis)
Mycophenolate MofetilCellcept, MMFTreatment (CLAG-M, TBI, HCT, GVHD prophylaxis)
Mycophenolate SodiumERL 080, ERL 080A, Socium MycophenolateTreatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)ExperimentalPatients 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.
  • Cladribine
  • Cyclophosphamide
  • Cyclosporine
  • Cytarabine
  • Filgrastim
  • Mitoxantrone
  • Mycophenolate Mofetil
  • Mycophenolate Sodium

Eligibility Criteria

        Inclusion Criteria:

          -  Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) =< 5 for patients over
             60 years

          -  Acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic
             myelomonocytic leukemia (CMML) (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, at least 4 cycles of azanucleoside
             monotherapy-based lower-intensity therapy), or at least 2 cycles of venetoclax in
             combination with either low-dose cytarabine or an azanucleoside, or is in early
             (remission duration =< 6 months) untreated 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 acute leukemia of ambiguous lineage (acute undifferentiated leukemia,
             mixed phenotype acute leukemia) are 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
             DLCO correct >= 70% mmHg or carbon monoxide diffusing capability test (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

          -  An 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

          -  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:

          -  Active central nervous system (CNS) disease

          -  Prior treatment with cladribine, cytarabine and filgrastim (CLAG) or CLAG-M
             chemotherapy

          -  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 leukemia 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
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of hematopoietic cell transplantation (HCT) failure
Time Frame:Within 200 days post-transplant
Safety Issue:
Description:Defined as graft rejection (< 5% donor T-cell chimerism).

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 100 days post-transplant
Safety Issue:
Description:
Measure:Rates of stem cell engraftment and donor chimerism
Time Frame:At 84 days (+/- 7 days)
Safety Issue:
Description:
Measure:Rates of grades II-IV acute graft versus host disease (GVHD) and chronic GVHD requiring systemic immunosuppressive treatment
Time Frame:Up to 4 years
Safety Issue:
Description:
Measure:Disease response
Time Frame:Up to 4 years
Safety Issue:
Description:
Measure:Duration of remission
Time Frame:Up to 4 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated

May 1, 2020