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

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

Sponsors

Lead Sponsor: Fred Hutchinson Cancer Research Center

Collaborator: National Cancer Institute (NCI)

Source Fred Hutchinson Cancer Research 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.

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.

Overall Status Recruiting
Start Date 2020-12-03
Completion Date 2025-12-31
Primary Completion Date 2023-12-31
Phase Phase 1
Study Type Interventional
Primary Outcome
Measure Time Frame
Rate of hematopoietic cell transplantation (HCT) failure Within 200 days post-transplant
Rate of disease progression Within 200 days post-transplant
Secondary Outcome
Measure Time Frame
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 4 years
Disease response Up to 4 years
Duration of remission Up to 4 years
Enrollment 72
Condition
Intervention

Intervention Type: Drug

Intervention Name: Cladribine

Description: Given IV

Arm Group Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Intervention Type: Drug

Intervention Name: Cyclophosphamide

Description: Given IV

Arm Group Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Intervention Type: Drug

Intervention Name: Cyclosporine

Description: Given IV

Arm Group Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Intervention Type: Drug

Intervention Name: Cytarabine

Description: Given IV

Arm Group Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Intervention Type: Biological

Intervention Name: Filgrastim

Description: Given SC

Arm Group Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Intervention Type: Procedure

Intervention Name: Hematopoietic Cell Transplantation

Description: Undergo HCT

Arm Group Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Intervention Type: Drug

Intervention Name: Mitoxantrone

Description: Given IV

Arm Group Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Intervention Type: Drug

Intervention Name: Mycophenolate Mofetil

Description: Given IV or PO

Arm Group Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Intervention Type: Drug

Intervention Name: Mycophenolate Sodium

Description: Given PO

Arm Group Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Intervention Type: Radiation

Intervention Name: Total-Body Irradiation

Description: Undergo TBI

Arm Group Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Eligibility

Criteria:

Inclusion Criteria: - 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 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 refractory acute leukemia of ambiguous lineage (acute undifferentiated leukemia, mixed phenotype acute leukemia) are 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: patients who have failed at least 6 cycles of azacitidine or 4 cycles of decitabine - 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

Gender:

All

Minimum Age:

18 Years

Maximum Age:

75 Years

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Filippo Milano Principal Investigator Fred Hutch/University of Washington Cancer Consortium
Overall Contact

Last Name: Filippo Milano

Phone: 206.667.5925

Email: [email protected]

Location
Facility: Status: Contact: Investigator: Fred Hutch/University of Washington Cancer Consortium Filippo Milano 206-667-5925 [email protected] Filippo Milano Principal Investigator
Location Countries

United States

Verification Date

2021-06-01

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: Treatment (CLAG-M, TBI, HCT, GVHD prophylaxis)

Type: Experimental

Description: 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.

Patient Data No
Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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