CLAG-M or FLAG-Ida 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 | Recruiting Phase 1 DMC FDA Drug

• 4 other identifiers: RG1006914NCI-2020-02616P30CA01570410457
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the best dose of total body irradiation when given with cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) or idarubicin, fludarabine, cytarabine and filgrastim (FLAG-Ida) 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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• Rate of hematopoietic cell transplantation (HCT) failure

  Defined as graft rejection (\< 5% donor T-cell chimerism).

  Within 200 days post-transplant

• Rate of disease progression

  Defined by European LeukemiaNet (ELN) 2017 criteria and International Working Group (IWG).

  Within 200 days post-transplant

Secondary Outcomes (5)

• Incidence of adverse events

  Up to 100 days post-transplant

• Rates of stem cell engraftment and donor chimerism

  At 80 days (+/- 7 days)

• Rates of grades II-IV acute graft versus host disease (GVHD) and chronic GVHD requiring systemic immunosuppressive treatment

  Up to 2 years

• Disease response

  Up to 2 years

• Duration of remission

  Up to 2 years

Study Arms (2)

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis)

EXPERIMENTAL

See detailed description.

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; Procedure: Multigated Acquisition Scan; Procedure: Echocardiography Test; Procedure: X-Ray Imaging; Procedure: Bone Marrow Biopsy; Procedure: Bone Marrow Aspiration; Procedure: Biospecimen Collection

Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

EXPERIMENTAL

See detailed description.

Drug: Cyclophosphamide; Drug: Cyclosporine; Procedure: Hematopoietic Cell Transplantation; Drug: Mycophenolate Mofetil; Drug: Mycophenolate Sodium; Radiation: Total-Body Irradiation; Drug: Idarubicin; Drug: Fludarabine; Drug: Cytarabine; Procedure: Multigated Acquisition Scan; Procedure: Echocardiography Test; Procedure: X-Ray Imaging; Procedure: Bone Marrow Biopsy; Procedure: Bone Marrow Aspiration; Procedure: Biospecimen Collection

Interventions

Hematopoietic Cell Transplantation PROCEDURE

Undergo HCT

Also known as: HCT, Hematopoietic Stem Cell Transplantation, HSCT, Stem Cell Transplant, stem cell transplantation, Hematopoietic Stem Cell Infusion

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Mitoxantrone DRUG

Given IV

Also known as: Dihydroxyanthracenedione, Mitozantrone

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis)

Mycophenolate Mofetil DRUG

Given IV or PO

Also known as: Cellcept, MMF

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Mycophenolate Sodium DRUG

Given PO

Also known as: ERL 080, ERL 080A, Socium Mycophenolate

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Total-Body Irradiation RADIATION

Undergo TBI

Also known as: TBI, Total Body Irradiation, Whole Body Irradiation, Whole-Body Irradiation, SCT_TBI

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Idarubicin DRUG

Given IV

Also known as: 4-DMDR

Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Fludarabine DRUG

Given IV

Also known as: Fluradosa, 9-Beta-D-arabinofuranosyl-2-fluoroadenine

Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Cytarabine DRUG

Given IV

Also known as: .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

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA

Also known as: Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Echocardiography Test PROCEDURE

Undergo ECHO

Also known as: EC

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

X-Ray Imaging PROCEDURE

Undergo x-ray

Also known as: Conventional X-Ray, Diagnostic Radiology, Medical Imaging

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy and aspirate

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow biopsy and aspirate

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Cladribine DRUG

Given IV

Also known as: 2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis)

Cyclosporine DRUG

Given IV then PO

Also known as: 27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Cyclosporine Modified, Gengraf, Neoral, OL 27-400, Sandimmune, SangCya

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Filgrastim BIOLOGICAL

Given SC

Also known as: G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tevagrastim, Nivestym, Filgrastim-aafi, Filgrastim-ayow, Releuko

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-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

Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis); Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>= 18 years with an Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) =\< 5 for patients over 60 years -(Enrollment of patients \>= 75 years of age will require case presentation at the transplant Patient Care Conference (PCC) and approval by consensus)
• 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, unrelated or haploidentical donor for collection of stimulated peripheral blood stem cells or HLA-matched or near-matched cord blood unit 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, idarubicin- or cladribine/fludarabine-based regimen for MDS or AML. If the patient has received CLAG-M or FLAG-Ida 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)

You may not qualify if:

• 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
• Since detection of anti-donor-specific antibodies (anti-DSA) is associated with higher graft rejection rate, patients will be screened for anti-DSA pre-transplant. Patient with DSA mean fluorescent intensity (MFI) \<5000 after desensitization treatment, will be considered eligible to participate in the study.

Sponsors & Collaborators

• National Cancer Institute (NCI): collaborator
• Fred Hutchinson Cancer Center: lead

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Leukemia, Biphenotypic, Acute

Interventions

Cladribine; Cyclophosphamide; Cyclosporine; Cyclosporins; Cytarabine; Filgrastim; Granulocyte Colony-Stimulating Factor; Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Mitoxantrone; Mycophenolic Acid; Whole-Body Irradiation; Idarubicin; fludarabine; X-Rays

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Proteins; Biological Factors; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Quinones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Radiotherapy; Investigative Techniques; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Glycosides; Electromagnetic Radiation; Electromagnetic Phenomena; Magnetic Phenomena; Physical Phenomena; Radiation; Radiation, Ionizing

Study Officials

• Filippo Milano

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Filippo Milano

CONTACT

206.667.5925; fmilano@fredhutch.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2020
• First Posted: May 5, 2020
• Study Start: December 3, 2020
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): March 17, 2027
• Last Updated: March 5, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)