Metabolically Optimized, Non-cytotoxic Low Dose Weekly Decitabine/Venetoclax in MDS and AML

Study Overview
=================
Brief Summary
-----------------
Myeloid malignancies which include AML (acute myeloid leukemia) and MDS (myelodysplatic syndrome) are cancers of the bone marrow which lead to bone marrow failure. The bone marrow is the place or factory in the body where components of blood such as red cells, platelets and white cells are made. In bone marrow failure, the ability of the bone marrow to make these cells is decreased. The decreased bone marrow function is the result from abnormalities that develop in the malignant cells which prevent the normal maturation process by which bone marrow cells develop into red blood cells, white blood cells and platelets. The malignant cells in the bone marrow are not good at maturing to make the components of the blood that you need, they occupy space in the bone marrow and prevent the function of remaining normal bone marrow cells. DNA is a chemical substance within cells that stores information needed for cell growth and cell behavior. One approach to treating the malignant cells is to give chemotherapy which damages DNA within these cells and causes their death. Unfortunately, such therapy has side-effects, since even normal cells can be affected by the treatment. Decitabine is FDA approved for treatment of MDS and AML. Venetoclax is approved for AML in combination with Azacitidine for patients with AML or are over age 75 or unfit for chemotherapy. In this study, Decitabine and venetoclax will be administered using a low dose weekly schedule in an attempt to improve efficacy by decreasing the side effects often seen when these drugs are given at standard dosing.

Detailed Description
-----------------
The combination of Azacitidine and venetoclax (Aza/Ven) is FDA approved for patients AML > 75 and/or unfit for induction chemotherapy. However, majority of patients receiving standard dosing of Aza/Ven require dose interruptions, treatment delays and dose reductions. In addition, Aza/ven has limited activity in various subgroups of myeloid malignancies such as P53 mutant MDS/AML. The severe cytopenias encountered with Aza/ven is particularly challenging for patients with poor hematopoietic bone marrow reserve such as MDS and MF (myelofibrosis). Also some elderly patients with comorbidities cannot tolerate the prolonged cytopenias caused by Aza/ven. This pilot clinical trial will evaluate the tolerability of a non-cytotoxic regimen for patients with myeloid malignancies who either cannot tolerate or are not known to benefit from standard Aza/ven dosing. This will be a single arm, open label pilot study of weekly dosing of subcutaneous decitabine and venetoclax Patients will be treated for a minimum of 12 weeks in the absence of clear evidence of progressive disease. Patients who have any response will be permitted to continue treatment until relapse or progression of disease. Primary endpoint will be the percentage of patients who will require dose interruptions due to cytopenias. Secondary endpoints will include assessment of response rates, transfusion dependence, quality of life, rate of infections and hospitalizations. Decitabine is given at a dose of 0.1-0.2 mg/kg/day for 1-2 days per week. All patients will receive at least one dose Decitabine every week. If decided by treating physician that the patient needs a more rapid debulking of high disease burden, a second dose can be added. If Decitabine is given twice a week, should preferably be given on two consecutive days. Venetoclax is dosed at 400 mg by mouth one day a week a day prior to the first decitabine dose. If patients are taking another CYP3A4 inhibitor dose adjustments should be made as recommended by pharmacist for a goal dose of venetoclax of 400 mg. If patient receives two days of decitabine a week, they still only take venetoclax on the day prior to the first dose of decitabine.

Official Title
-----------------
Metabolically Optimized, Non-cytotoxic Low Dose Weekly Decitabine/Venetoclax in MDS and AML

Conditions
-----------------
MDS, AML

Intervention / Treatment
-----------------
* Drug: Venetoclax
* Drug: Decitabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient must have a diagnosis of MDS (myelodysplastic syndrome), AML (acute myeloid leukemia) or MDS/MPN (myelodysplastic/myeloproliferative neoplasms) with a histopathologic diagnosis confirmed by hematopathology review Indication for therapy with potential sensitivity to HMA (hypomethylating agents) therapy, defined as prior published evidence of response to HMA. Patients must be 18 years of age or older Patients must have an ECOG (Eastern Cooperative Oncology Group) performance status of ≥ 3 Patients must have adequate end organ function defined as. AST (aspartate aminotransferase) and ALT (alanine transaminase) < 4× the upper limit of normal (ULN) Bilirubin ≤ 2× the ULN (upper limit of normal). If elevated bilirubin is due to impaired conjugation (e.g Gilbert's disease or concomitant medication) or disease related hemolysis, then direct bilirubin ≤ 1.5× the ULN. As decitabine and venetoclax have little renal metabolism, and have proven safety even in dialysis patients, renal function with a creatinine clearance ≥30 mL/min or on dialysis is allowed.18 Subjects must have the ability to understand and the willingness to sign a written informed consent document and complete study related procedures. Exclusion Criteria: APL (acute promyelocytic leukemia) Core binding factor AML who are candidates for chemotherapy Prior Treatment with azacitidine, decitabine or venetoclax No other disease directed therapy, save for hydroxyurea, including experimental or investigational drug therapy for 14 days prior to study entry. Currently pregnant or breast-feeding. Females of child bearing (FOCBP) potential must have negative serum pregnancy test within 72 hours from treatment start. (NOTE: FOCBP is any biologic female, regardless of sexual or gender orientation, having undergone tubal ligation, or remaining celibate by choice, who has not undergone a documented hysterectomy or bilateral oophorectomy or has had a menses any time in the preceding 12 months (therefore not naturally post-menopausal for > 12 months) Uncontrolled intercurrent illness that could limit life expectancy or ability to complete study correlates. This includes, but is not limited to: Ongoing or active infection. As patients with myeloid malignancies are prone to infections, if patients are actively being treated with appropriate antibiotics or antifungal therapy with clinical evidence of infection control, then they will be considered eligible for study. Uncontrolled concurrent malignancy Congestive heart failure of NYHA (New York Heart Association) class III/IV. Patients with compensated heart failure are permitted. Unstable angina pectoris New or unstable cardiac arrhythmia. Stable or controlled arrhythmias are permitted Decompensated liver cirrhosis (Child-Pugh score ≥12 or a MELD (Model for Enst-Stage Liver Disease) score ≥21 Psychiatric illness/social situations that would limit compliance with study requirements. Any other prior or ongoing condition, in the opinion of the investigator, that could adversely affect the safety of the patient or impair the assessment of study results. WOCBP (Women of Child-Bearing Potential) and males that are unwilling to agree to use dual contraceptive measures (i.e., hormonal or barrier method of birth control; abstinence, condom) prior to study entry and for the duration of study participation. Should a female subject become pregnant or suspect she is pregnant while participating in this study, she should inform the treating physician immediately Sexually active male who is unwilling to use a condom when engaging in any sexual contact with a female with child-bearing potential, beginning at the screening visit and continuing until 4 weeks after taking the last dose of Decitabine/venetoclax. Patients with uncontrolled active HIV infection, as this will further increase the risk for opportunistic infections. However, patients with HIV with undetectable viral load by PCR (polymerase chain reaction), without opportunistic infection, and on a stable regimen of antiretroviral therapy would be eligible. Known allergy or hypersensitivity to any component of decitabine or venetoclax formulations

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Decitabine/Venetoclax (Single Arm)<br>Administration: Decitabine is reconstituted with 5 ml sterile water to facilitate subcutaneous administration. Decitaboine is given by subcutaneous injection. Venetoclax is taken as a tablet prepared by patients pharmacy. Venetoclax is given at a dose of 400 mg po once per week concurrently with the Decitabine dose (+/- 1 day allowed ). | Drug: Venetoclax<br>* Venetoclax 400 mg po on days 1, 8, 15 and 28 of each cycle (28day cycle)<br>Drug: Decitabine<br>* Decitabine 0.2 mg/kg SQ (subcutaneous) on days 2, 9, 16, 23 (for aggressive disease will add decitabine on days 3, 10, 17, 24)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Percentage of participants who are able to continue on treatment without dose interruptions or delays | Defined as delaying or interrupting treatment due to toxicity or intolerability for more than two weeks | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with complete remission (CR) and complete remission with incomplete marrow recovery (CRi) | This will be calculated based on current International Working Group (IWG) criteria. CR is defined as absolute neutrophil count > 1000/ microliter (mcL), platelets > 100k/mcL, red cell transfusion independence, and bone marrow with < 5% blasts. CRi is defined as bone marrow with less than 5% blasts, and absolute neutrophils of <= 10000/mcL or platelets <= 100k/mcL | 3 months | 
| Event-free survival (EFS) | EFS will be defined as the number of days from randomization to the date of progressive disease, relapse from CR or CRi, treatment failure or death from any cause. | 12 months | 
| Global health status/quality of life (GHS/QoL) [ Time Frame: Measured at participant's Day 1 of Cycle 1 (each cycle is 28 days) and at Day 1 of every Cycle thereafter] | Improvement in GHS/QoL will be assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30). | 12 months | 
| Complete remission or complete remission with partial hematologic recovery rate (CR+CRh) | A response of CRh is defined as Bone marrow with <5% blasts, peripheral blood neutrophil count >0.5*10^3/mcL and peripheral blood platelet count >0.5*10^5/mcL. | 3 months | 
| Post baseline transfusion independence rate | Transfusion Independence is defined as a period of 56 days with no transfusion between first dose of study drug and the last dose of study drug + 30 days. The rate of conversion for red blood cells (RBC) and platelets is defined as percentage of participants being post-baseline transfusion independent from baseline transfusion dependence. | 12 months | 
| Rate of Hospitalization | Defined as hospitalization for complication related to myeloid malignancy or treatment. Initial admission for diagnosis or initiation of therapy will not be considered an event. | 12 months | 
| Infection rate requiring hospitalization | Defined as being hospitalized due to an infection or sepsis. | 12 months |