Safety and Activity of Digoxin With Decitabine in Adult AML and MDS

Study Overview
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Brief Summary
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The primary hypothesis is that digoxin can be safely added to decitabine and will increase the response rates in medically unfit patients with newly diagnosed AML/MDS or those with relapsed/refractory AML/MDS. Furthermore, it is hypothesized that the addition of digoxin to decitabine will result in distinct epigenetic alterations in AML/MDS patients.

Official Title
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A Phase Ib/II Study of the Safety and Activity of Digoxin With Decitabine in Adult AML and MDS

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Decitabine
* Drug: Digoxin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a confirmed diagnosis of one of the following: Newly diagnosed AML (excluding APL) Newly diagnosed intermediate-2 (INT-2) or high-risk MDS Relapsed or Refractory AML, or INT-2 or high-risk MDS For patients with refractory disease they must be at least 4 weeks out from most recent therapeutic intervention. Age > 18 years. ECOG performance status 0 - 2. Patients must have normal organ function as defined below: Total bilirubin within normal institutional limits AST/ALT (SGOT/SGPT) < 2 times institutional normal limits Creatinine within normal institutional limits OR Creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal Ability to understand and willingness to sign a written informed consent and HIPAA consent document. Agreement on the part of any male participant to use effective contraception during sexual activity throughout the duration of treatment and for 2 months after discontinuation, for protection against the risk of embryofetal toxicity. Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events (less than or equal to Grade 1 toxicity) due to agents administered more than 4 weeks earlier. Patients receiving any other investigational agents. Patients with known brain metastases, active infection, or untreated CNS leukemia. Patients with prior or current history of digoxin exposure. Patients requiring treatment with one or more medications known to interact adversely with digoxin, namely thiazide and/or loop diuretics, quinidine, ritonavir, amiodarone, cyclosporine, itraconazole, propafenone, spironolactone, verapamil. Patients requiring treatment with one or more beta-blockers (metoprolol, atenolol, propranolol) or calcium channel blockers with AV-nodal blocking activity (verapamil, diltiazem). Patient with history of prior exposure to decitabine. Patients eligible for intensive induction chemotherapy and Medically unfit based on a TRM score ≥ 13.1* TRM Score= A scoring model which predicts early death following intensive induction chemotherapy in newly diagnosed AML. Model looks at ECOG PS, Age, Platelet Count, Albumin, 2nd AML, WBC, % Peripheral Blasts, Creatinine Score above 13.1 associated with 31%+ chance of death after induction Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Known HIV-positive patients on combination anti-retroviral therapy are ineligible because of the potential for pharmacokinetic interactions with digoxin. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Pregnant or breast feeding

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: For Group#1 a total of 37 patients with newly diagnosed MDL or MDS will be enrolled, including the eligible patients originally enrolled in the phase Ib portion (safe dose group) of the study, with the goal of determining the clinical activity of our experimental regimen. In the phase II segment, all new patients who are enrolled will initially be randomized in a 1 to 1 fashion to receive decitabine alone or decitabine plus digoxin for one cycle before receiving decitabine plus digoxin for all subsequent cycles for a total of 6 cycles. For Group#2 the target will be to enroll a total of 60 patients with relapsed or refractory AML/MDS, including the eligible patients enrolled in the phase Ib group. This group will have randomization and treatments similar to Group#1.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Newly diagnosed AML/MDS<br>For Group#1 a total of 37 patients with newly diagnosed MDL or MDS will be enrolled, including the eligible patients originally enrolled in the phase Ib portion (safe dose group) of the study, with the goal of determining the clinical activity of our experimental regimen. In the phase II segment, all new patients who are enrolled will initially be randomized in a 1 to 1 fashion to receive decitabine alone or decitabine plus digoxin for one cycle before receiving decitabine plus digoxin for all subsequent cycles for a total of 6 cycles. | Drug: Decitabine<br>* Decitabine will be administered in combination with Digoxin<br>Drug: Digoxin<br>* Decitabine will be administered in combination with Digoxin<br>|
| Experimental: Refractory or relapsed AML/MDS<br>or Group#2 the target will be to enroll a total of 60 patients with relapsed or refractory AML/MDS, including the eligible patients enrolled in the phase Ib group. This group will have randomization and treatments similar to Group#1. | Drug: Decitabine<br>* Decitabine will be administered in combination with Digoxin<br>Drug: Digoxin<br>* Decitabine will be administered in combination with Digoxin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Digoxin in Combination With Standard Dose of Decitabine in Patients Newly Diagnosed AML/MDS or Those With Relapsed or Refractory AML/MDS Considered Unfit for Induction Therapy | Maximum tolerated dose of digoxin in combination with standard dose of decitabine will be determined by a standard 3+3 dose de-escalation design | 1-2 months | 
| Number of Grade II and IV Toxicities Due to of the Combination Therapy of Decitabine in Combination With Digoxin | The safety of the combination therapy will be determined by the number of grade III or IV non-hematologic toxicities as per NCI CTCAE v4.03 criteria. | 1-3 years | 
| Number of MDS Patients With Complete Remission (CR) | Complete response will be assessed by International Working Group (IWG) criteria for MDS | 1-3 years | 
| Number of AML Patients With Complete Remission With Incomplete Blood Count Recovery (CRi) | CRi will be assessed by IWG criteria for AML | 1-3 years |