Clinical Trials /

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

NCT03113071

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 16-1061
  • NCT ID: NCT03113071

Conditions

  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
DecitabineNewly diagnosed AML/MDS
DigoxinNewly diagnosed AML/MDS

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Newly diagnosed AML/MDSExperimentalFor 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.
  • Decitabine
  • Digoxin
Refractory or relapsed AML/MDSExperimentalor 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.
  • Decitabine
  • Digoxin

Eligibility Criteria

        Inclusion Criteria:

          1. 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

          2. For patients with refractory disease they must be at least 4 weeks out from most
             recent therapeutic intervention.

          3. Age > 18 years.

          4. ECOG performance status 0 - 2.

          5. 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

          6. Ability to understand and willingness to sign a written informed consent and HIPAA
             consent document.

          7. 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:

          1. 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.

          2. Patients receiving any other investigational agents.

          3. Patients with known brain metastases, active infection, or untreated CNS leukemia.

          4. Patients with prior or current history of digoxin exposure.

          5. 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.

          6. Patients requiring treatment with one or more beta-blockers (metoprolol, atenolol,
             propranolol) or calcium channel blockers with AV-nodal blocking activity (verapamil,
             diltiazem).

          7. Patient with history of prior exposure to decitabine.

          8. 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

          9. 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.

         10. 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.

         11. Pregnant or breast feeding
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Time Frame:1-2 months
Safety Issue:
Description:Maximum tolerated dose of digoxin in combination with standard dose of decitabine will be determined by a standard 3+3 dose de-escalation design

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fox Chase Cancer Center

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