Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Recurrent Myelodysplastic Syndrome
Conditions
Brief summary
This phase IIa trial studies how well guadecitabine works in treating patients with acute myelogenous leukemia and myelodysplastic syndrome that has returned after a period of improvement after allogeneic stem cell transplant. Guadecitabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving guadecitabine before the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them. Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect.
Detailed description
PRIMARY OBJECTIVES: I. To determine the complete response (CR) rate of guadecitabine (SGI-110) with or without donor lymphocyte infusion (DLI) either for the treatment of morphologic relapse or the presence of minimal residual disease (MRD) in patients with acute myeloid leukemia or myelodysplastic syndrome after hematopoietic stem cell transplantation in patients with AML and MDS (cohort 1 and 2). II. The relapse-free survival with the use of SGI-110 as maintenance therapy in patients with high risk acute myeloid leukemia or myelodysplastic syndrome after hematopoietic stem cell transplantation (cohort 3). SECONDARY OBJECTIVES: I. To determine the safety and toxicity of SGI-110 with or without DLI in this subject population. II. To evaluate overall response and survival. OUTLINE: Patients receive guadecitabine subcutaneously (SC) once daily (QD) on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive DLI intravenously (IV) over 10-30 minutes on day 6 of cycles 2, 4, and 6 in the absence of disease progression or unacceptable toxicity.
Interventions
BIOLOGICALDonor Lymphocytes
Given IV
DRUGGuadecitabine
Given SC
OTHERLaboratory Biomarker Analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of acute myeloid leukemia (AML) and myelodysplastic syndrome (including chronic myelomonocytic leukemia \[CMML\]) according to WHO classification that underwent first allogeneic hematopoietic cell transplant (HSCT) with either peripheral blood or bone marrow as the source of the hematopoietic stem cells * No more than 1 antigen mismatch at human leukocyte antigen (HLA)-A, B, C, DRB1 and DQB1 locus for either related or unrelated donor * High risk AML and MDS patients will be included * Cohort 1: morphological relapse after stem cell transplant: * MDS patients: re-appearance of dysplastic changes in the bone marrow, with or without increase in bone marrow last count, which is pathologically consistent with myelodysplastic syndrome; * AML patients: bone marrow blast count \>= 5% * Cohort 2: Persistence or reappearance of minimal residual disease by flow cytometry or cytogenetic or molecular testing while being in morphological remission after allogeneic stem cell transplantation * Cohort 3: High risk AML and MDS patients who are in complete remission morphologically with no evidence of minimal residual disease by flow cytometry or cytogenetic or molecular testing after allogeneic stem cell transplantation * MDS patients: * Cytogenetics consistent with poor or very poor risk group by 5-risk classification; * Cytogenetics consistent with monosomal karyotype * Bone marrow blast count \> 5% but less than 20% at any time during their disease course before HSCT * Peripheral blood blast =\< 5% at HSCT * Therapy-related MDS * AML patients: * Cytogenetics and molecular features consistent with adverse risk group by European LeukemiaNet classification for AML; * Presence of minimal residual disease by multi-color flow cytometry or cytogenetics or molecular studies at the time of HSCT; * Presence of active disease defined as bone marrow blast count \> 5% but less than =\< 10% at the time of HSCT * Peripheral blood blast count =\< 5% at HSCT * Therapy-related AML * Be able to start the drug therapy between 42 to 100 days following allogeneic SCT; * No more than 1 prior allogeneic SCT * Post-transplant bone marrow consistent with complete remission with no evidence of minimal residual disease by flow-cytometry or cytogenetics or molecular testing * Adequate engraftment within 14 days prior to starting study drug: absolute neutrophil count (ANC) \>= 1.0 x 10\^9/L without daily use of myeloid growth factor; and, platelet \>= 50 x 10\^9/L without platelet transfusion within 1 week * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Serum creatinine =\< 1.5 mg/dL or creatinine clearance greater or equal than 40 cc/min as defined by the Cockcroft-Gault equation * Serum bilirubin =\< 1.5 x upper limit of normal (ULN) * Aspartate transaminase (aspartate aminotransferase \[AST\]) or alanine transaminase (alanine aminotransferase \[ALT\]) =\< 2.5 x ULN * Alkaline phosphatase =\< 2.5 x upper limit (UL) * No active bleeding * No uncontrolled graft versus host disease (GVHD) * No clinical evidence of life-threatening infection * Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent * Human immunodeficiency virus (HIV) negative and hepatitis B surface antigen (HBs-Ag) negative * Negative serum or urine pregnancy test for women with reproductive potential; the only subjects who will be exempt from this criterion are postmenopausal women (defined as women who have been amenorrheic for \> 12 months) or subjects who have been surgically sterilized or otherwise proven sterile
Exclusion criteria
* Use of any anti-leukemic agents after relapse is documented (note that the use of these anti-leukemic agents given as post-transplant maintenance therapy is allowed in this study, e.g., subcutaneous or oral 5-azacytidine or FLT3 inhibitors for maintenance) for cohorts 1 and 2 * Bone marrow blast count \> 60% for cohort 1 * Use of any of the following after transplantation and prior to starting study therapy for cohort 3: * Investigational agents/therapies * Anti-leukemic agents given as post-transplant maintenance therapy (e.g., subcutaneous or oral 5-azacytidine or FLT3 inhibitors for maintenance) * Active acute graft versus host disease (GVHD) grade II or higher * Active chronic GVHD that is extensive * Concurrent use of systemic immune suppressive other than calcineurin inhibitors and sirolimus * Active uncontrolled systemic fungal, bacterial or viral infection * Symptomatic or uncontrolled arrhythmias * Significant active cardiac disease within the previous 6 months, including: New York Heart Association (NYHA) class III or IV congestive heart failure; unstable angina or angina requiring surgical or medical intervention, and/or; myocardial infarction * Known active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) * Prior history of solid tumor unless the subject has been free of the disease for \>= 1 year; however, subjects with the following history/concurrent conditions are allowed: basal or squamous cell carcinoma of the skin; carcinoma in situ of the cervix; carcinoma in situ of the breast; incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis \[TNM\] clinical staging system)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieved Complete Response (CR) | Within the first 6 cycles, up to 168 days. | Complete remission (CR): Bone marrow with \</= 5% bone marrow blasts with normal maturation of all cell lines in the absence of extramedullary disease in addition to a peripheral blood granulocyte count \>/= 1 X 10\^9/L and a platelet count \>/= 100 x 10\^9 /L. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | At 1 year | Number of participants that are alive 1 year after study enrollment. |
| Disease-free Survival | At 1 year | Number of participants that are disease free and alive 1 year after study enrollment. |
Countries
United States
Participant flow
Recruitment details
All participants were registered at MD Anderson Cancer Center.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Relapsed Leukemia Post-transplant Patients with morphological relapse for AML and MDS at least 90 days post-transplant.
MDS patients: Re-appearance of dysplastic changes in the bone marrow, with or without increase in bone marrow blast count, which is pathologically consistent with myelodysplastic syndrome.
AML patients:
Bone marrow blast count \>/= 5%. | 13 |
| Cohort 2: MRD(Minimal Residual Disease) Post-transplant Cohort 2: Persistence or reappearance of minimal residual disease by flow cytometry or cytogenetic or molecular testing while being in morphological remission after allogeneic stem cell transplantation. | 18 |
| Cohort 3: Maintenance Treatment Post-transplant Cohort 3: High risk AML and MDS patients who are in complete remission morphologically with no evidence of minimal residual disease by flow cytometry or cytogenetic or molecular testing after allogeneic stem cell transplantation. | 24 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: Relapsed Leukemia Post-transplant | Cohort 2: MRD(Minimal Residual Disease) Post-transplant | Cohort 3: Maintenance Treatment Post-transplant | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 8 Participants | 11 Participants | 24 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 10 Participants | 13 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 17 Participants | 22 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 13 participants | 18 participants | 24 participants | 55 participants |
| Sex: Female, Male Female | 5 Participants | 11 Participants | 11 Participants | 27 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 13 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 13 | 6 / 18 | 14 / 24 |
| other Total, other adverse events | 3 / 13 | 8 / 18 | 10 / 24 |
| serious Total, serious adverse events | 9 / 13 | 11 / 18 | 12 / 24 |
Outcome results
Primary
Number of Participants Achieved Complete Response (CR)
Complete remission (CR): Bone marrow with \</= 5% bone marrow blasts with normal maturation of all cell lines in the absence of extramedullary disease in addition to a peripheral blood granulocyte count \>/= 1 X 10\^9/L and a platelet count \>/= 100 x 10\^9 /L.
Time frame: Within the first 6 cycles, up to 168 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Relapsed Leukemia Post-transplant | Number of Participants Achieved Complete Response (CR) | 3 Participants |
| Cohort 2: MRD(Minimal Residual Disease) Post-transplant | Number of Participants Achieved Complete Response (CR) | 9 Participants |
| Cohort 3: Maintenance Treatment Post-transplant | Number of Participants Achieved Complete Response (CR) | 16 Participants |
Secondary
Disease-free Survival
Number of participants that are disease free and alive 1 year after study enrollment.
Time frame: At 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Relapsed Leukemia Post-transplant | Disease-free Survival | 5 Participants |
| Cohort 2: MRD(Minimal Residual Disease) Post-transplant | Disease-free Survival | 7 Participants |
| Cohort 3: Maintenance Treatment Post-transplant | Disease-free Survival | 20 Participants |
Secondary
Overall Survival (OS)
Number of participants that are alive 1 year after study enrollment.
Time frame: At 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Relapsed Leukemia Post-transplant | Overall Survival (OS) | 12 Participants |
| Cohort 2: MRD(Minimal Residual Disease) Post-transplant | Overall Survival (OS) | 12 Participants |
| Cohort 3: Maintenance Treatment Post-transplant | Overall Survival (OS) | 10 Participants |