Acute Myeloid Leukemia, Myelodysplastic Syndrome
Conditions
Brief summary
This phase I trial tests the safety, side effects, best dose and how well arsenic trioxide works to prevent relapse in patients undergoing allogenic stem cell transplantation for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Chemotherapy drugs, such as arsenic trioxide, 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 arsenic trioxide may be safe, tolerable and/or effective in preventing relapse in patients undergoing allogenic stem cell transplant for AML or MDS.
Interventions
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Given IV
DRUGArsenic Trioxide
Given IV
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy
DRUGBusulfan
Given IV
DRUGFludarabine
Given fludarabine
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* AML or MDS patients eligible to receive first allogeneic HCT. Eligibility inclusion for HCT is defined as per University of Michigan bone marrow transplant (BMT) standard of care criteria * Presence of high-risk AML/MDS with probable biallelic TP53 deletion or mutation status, defined by one of the following in prior blood or bone marrow assessments: * TP53 loss by karyotype (chromosome 17 or 17p deletion) or single nucleotide polymorphism (SNP) (Cancer Microarray) AND ≥ one clonal TP53 mutation by next generation sequencing (NGS) (VAF \> 10%). * ≥ one TP53 mutation by NGS testing (with VAF \> 40%) * ≥ two distinct TP53 mutation(s) by NGS (VAF \>10%) * Evidence that at least one TP53 allele harbors a structural TP53 missense mutation. In cases where the mutation type is unclassified, molecular pathology assessment is required to determine if one of the lesions is a missense mutation (as described in NGS report) * Patients may be enrolled with either active disease or in morphological remission, provided the bone marrow blast count on the pre-HCT assessment does not exceed 30% * Age \> 21 years at enrollment and receiving allogeneic HCT in the adult transplant program * Karnofsky performance score (KPS) ≥ 70% * Documentation of adequate pulmonary function by forced expiratory volume and 1 second (FEV1) ≥ 50% of predicted, forced vital capacity (FVC) ≥ 50% of predicted and DLCO (corrected for hemoglobin) ≥ 50% of predicted (must meet all criteria at time of enrollment based on standard of care pre HCT testing) * Transthoracic echocardiogram with ejection fraction ≥ 50% (must meet all criteria at time of enrollment based on standard of care pre HCT testing) * Estimated glomerular filtration rate ≥ 50% ml/min/1.73m\^2 by the Cockcroft-Gault equation. Glomerular filtration rate (GFR) should be corrected for body surface area (BSA) (must meet all criteria at time of enrollment based on standard of care pre HCT testing) * Total bilirubin ≤ 2 x upper limit of normal (unless directly attributed to Gilbert's Syndrome) (must meet all criteria at time of enrollment based on standard of care pre HCT testing) * Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 5 x upper limit of normal (must meet all criteria at time of enrollment based on standard of care pre HCT testing) * Electrocardiogram (ECG) with corrected QT (QTc) ≤ 450 msec (using the Framingham correction) (must meet all criteria at time of enrollment based on standard of care pre HCT testing) * Availability of an 8 of 8 HLA matched unrelated donor with matching at HLA A, B, C and DRB1 * Availability of a peripheral blood stem cell (PBSC) product * Ability to understand and the willingness to sign a written informed consent * Willingness to agree to use adequate contraception methods (subjects of reproductive potential only): * Females of reproductive potential must agree to use effective contraception (e.g., hormonal contraception, intrauterine device, tubal occlusion, vasectomized partner, abstinence) during treatment with ATO and for 6 months after the final dose. * Males with female partners of reproductive potential must agree to use effective contraception during treatment with ATO and for 3 months after the final dose
Exclusion criteria
* Uncontrolled infections. Patients still under therapy for presumed or proven infection are eligible provided there is clear evidence (radiologic, clinical and/or culture) that the infection is well controlled * Patients may NOT have evidence or symptoms of central nervous system (CNS) disease at the time of enrollment * HIV or human t-lymphotropic virus (HTLV) 1 / HTLV 2 (seropositivity and/or polymerase chain reaction \[PCR\] positivity) * Pregnant and nursing mothers are excluded * Any physical, psychological or psychosocial condition that, in the opinion of the investigator, would pose unacceptable risk to the patient * Other malignancy requiring systemic therapy or with life expectancy of \< 1 year * Receipt of prior allogeneic HCT * History of severe cardiac conduction abnormalities (complete heart block, Left Bundle Branch Block, Torsades de Pointes, or other ventricular arrythmias). History of any cardiac arrhythmia (e.g. rate controlled atrial fibrillation) is not an exclusion * QTc \> 450 msec (using the Framingham correction) * Patients under 40 years of age at time of evaluation will be screened for Shwachman-Diamond syndrome (SDS), which is a rare, inherited disorder characterized primarily by exocrine pancreatic insufficiency, bone marrow failure, and skeletal abnormalities. These patients commonly progress to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Given potential for increased liver toxicities in this population, these patients will be excluded from the study. All patients under 40 years old will be screened through the University of Michigan Prevention Genetics Clinic prior to enrollment * Patients with known hypersensitivity to arsenic
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose limiting toxicities | From baseline to day 35 post hematopoietic stem cell transplant (HCT) | Assessed via the incidence and severity of adverse events as graded by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival (PFS) | At 6 and 12 months post HCT | Malignancy relapse is defined as: evidence of persistent morphological or cytogenetic findings of acute leukemia or myelodysplastic syndrome consistent with pretransplant features occurring after primary neutrophil engraftment or day 35, whichever occurs sooner. Progression-free survival (PFS) is defined as the duration of time from HCT (Day 0) to time of death or progression of primary malignancy detected by bone marrow assessment or other clinical monitoring. Will be estimated using Kaplan-Meier methods, with specific focus on estimates and 95% confidence intervals for PFS at 6- and 12-months. If no loss to follow-up is observed, then PFS will be estimated using observed proportions. |
| Absolute neutrophil recovery | From day 0 to day 35 post HCT | Engraftment for neutrophils is defined as the first of three consecutive days in which the absolute neutrophil count is \> 500/uL. |
| Incidence of severe cardiac arrythmia | From baseline to day 35 post HCT | Defined as grade 3 or greater cardiac arrythmia by CTCAE v 5.0. |
| Incidence of hepatic sinusoidal obstruction syndrome/veno-occlusive disease | From baseline to day 35 post HCT | Any Grade 3 or greater SOS/VOD by CTCAE v5.0 by day 35 post HCT will be considered for meeting this endpoint. |
| PFS | At 12 months post HCT | Defined as whether a subject is alive and free of relapse. Will be estimated using Kaplan-Meier methods, with specific focus on estimates and 95% confidence intervals for PFS at 6- and 12-months. If no loss to follow-up is observed, then PFS will be estimated using observed proportions. |
| Incidence of non-relapse mortality (NRM) | At 6 and 12 months post HCT | An event for NRM is death without prior evidence of relapse/progression of the primary disease, where relapse/progression is treated as a competing risk. Will be estimated using the methods of Fine and Gray in order to treat death as a competing event, rather than a censoring event. |
| Incidence of acute graft versus host disease | At 6 months post HCT | Will be estimated using the methods of Fine and Gray in order to treat death as a competing event, rather than a censoring event. |
| Incidence and severity of chronic graft versus host disease | At 6 and 12 months post HCT | Will be estimated using the methods of Fine and Gray in order to treat death as a competing event, rather than a censoring event. |
Countries
United States
Contacts
CONTACTTracey Churay
PRINCIPAL_INVESTIGATORJohn M Magenau
University of Michigan Rogel Cancer Center
Outcome results
None listed