Guadecitabine and Donor Lymphocyte Infusion in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome Relapsing After Allogeneic Stem Cell Transplant

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Trial to Assess the Efficacy and Toxicity of SGI-110 With DLI for the Treatment of AML or MDS Relapsing After Allogeneic Stem Cell Transplantation

Conditions
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Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Recurrent Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: Donor Lymphocytes
* Drug: Guadecitabine
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (guadecitabine, DLI)<br>Patients receive guadecitabine SC 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 IV over 10-30 minutes on day 6 of cycles 2, 4, and 6 in the absence of disease progression or unacceptable toxicity. | Biological: Donor Lymphocytes<br>* Given IV<br>Drug: Guadecitabine<br>* Given SC<br>* Other names: SGI-110;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate (Cohort 1 and 2) |  | After enrollment | 
| Relapse free survival (RFS) (Cohort 3) | The Bayesian method of Thall et al will be used to monitor RFS time in this cohort. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of hematologic and non-hematologic toxicity | Using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Will be tabulated within each subgroup (minimal residual disease and relapsed). | Assessed up to 4 courses (16 weeks) | 
| Overall response rate |  | Up to 12 courses (48 weeks) | 
| Duration of remission |  | Duration of time from start of treatment to time of remission, assessed up to 12 courses (48 weeks) | 
| Incidence of acute graft versus host disease (GVHD) |  | Up to day 6 of second course of guadecitabine (day 34) | 
| Incidence of chronic GVHD |  | Up to 12 courses (48 weeks) | 
| Overall survival (OS) | Within each treatment cohorts, these events will be tabulated and the distributions of OS time estimated using the method of Kaplan and Meier. | At 1 year | 
| Disease-free survival time (DFS) | Within each treatment cohorts, these events will be tabulated and the distributions of DFS time estimated using the method of Kaplan and Meier. | At 1 year |