Safety and Activity of Digoxin With Decitabine in Adult AML and MDS
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 1/Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Newly diagnosed AML/MDS 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
Decitabine will be administered in combination with Digoxin
Drug: Digoxin
Decitabine will be administered in combination with Digoxin
|
Experimental: Refractory or relapsed AML/MDS 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
Decitabine will be administered in combination with Digoxin
Drug: Digoxin
Decitabine will be administered in combination with Digoxin
|
Outcome Measures
Primary Outcome Measures
- 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 [1-2 months]
Maximum tolerated dose of digoxin in combination with standard dose of decitabine will be determined by a standard 3+3 dose de-escalation design
- Number of Grade II and IV Toxicities Due to of the Combination Therapy of Decitabine in Combination With Digoxin [1-3 years]
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.
- Number of MDS Patients With Complete Remission (CR) [1-3 years]
Complete response will be assessed by International Working Group (IWG) criteria for MDS
- Number of AML Patients With Complete Remission With Incomplete Blood Count Recovery (CRi) [1-3 years]
CRi will be assessed by IWG criteria for AML
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Fox Chase Cancer Center | Philadelphia | Pennsylvania | United States | 19111 |
2 | Jeans Hospital | Philadelphia | Pennsylvania | United States | 19111 |
Sponsors and Collaborators
- Fox Chase Cancer Center
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.- 16-1061
- HM-091
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Newly Diagnosed AML/MDS | Refractory or Relapsed AML/MDS |
---|---|---|
Arm/Group 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin | 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin |
Period Title: Overall Study | ||
STARTED | 1 | 0 |
COMPLETED | 0 | 0 |
NOT COMPLETED | 1 | 0 |
Baseline Characteristics
Arm/Group Title | Newly Diagnosed AML/MDS | Refractory or Relapsed AML/MDS | Total |
---|---|---|---|
Arm/Group 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin | 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin | Total of all reporting groups |
Overall Participants | 1 | 0 | 1 |
Age (Count of Participants) | |||
<=18 years |
0
0%
|
0
NaN
|
|
Between 18 and 65 years |
1
100%
|
1
Infinity
|
|
>=65 years |
0
0%
|
0
NaN
|
|
Sex: Female, Male (Count of Participants) | |||
Female |
1
100%
|
1
Infinity
|
|
Male |
0
0%
|
0
NaN
|
|
Race (NIH/OMB) (Count of Participants) | |||
American Indian or Alaska Native |
0
0%
|
0
NaN
|
|
Asian |
0
0%
|
0
NaN
|
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
NaN
|
|
Black or African American |
0
0%
|
0
NaN
|
|
White |
1
100%
|
1
Infinity
|
|
More than one race |
0
0%
|
0
NaN
|
|
Unknown or Not Reported |
0
0%
|
0
NaN
|
|
Region of Enrollment (participants) [Number] | |||
United States |
1
100%
|
1
Infinity
|
Outcome Measures
Title | 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 |
---|---|
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 |
Time Frame | 1-2 months |
Outcome Measure Data
Analysis Population Description |
---|
No patients analyzed because no patients underwent protocol treatment |
Arm/Group Title | Newly Diagnosed AML/MDS | Refractory or Relapsed AML/MDS |
---|---|---|
Arm/Group 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin | 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin |
Measure Participants | 0 | 0 |
Title | Number of Grade II and IV Toxicities Due to of the Combination Therapy of Decitabine in Combination With Digoxin |
---|---|
Description | 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. |
Time Frame | 1-3 years |
Outcome Measure Data
Analysis Population Description |
---|
No patients analyzed because no patients underwent protocol treatment |
Arm/Group Title | Newly Diagnosed AML/MDS | Refractory or Relapsed AML/MDS |
---|---|---|
Arm/Group 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin | 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin |
Measure Participants | 0 | 0 |
Title | Number of MDS Patients With Complete Remission (CR) |
---|---|
Description | Complete response will be assessed by International Working Group (IWG) criteria for MDS |
Time Frame | 1-3 years |
Outcome Measure Data
Analysis Population Description |
---|
No patients analyzed because no patients underwent protocol treatment |
Arm/Group Title | Newly Diagnosed AML/MDS | Refractory or Relapsed AML/MDS |
---|---|---|
Arm/Group 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin | 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin |
Measure Participants | 0 | 0 |
Title | Number of AML Patients With Complete Remission With Incomplete Blood Count Recovery (CRi) |
---|---|
Description | CRi will be assessed by IWG criteria for AML |
Time Frame | 1-3 years |
Outcome Measure Data
Analysis Population Description |
---|
No patients analyzed because no patients underwent protocol treatment |
Arm/Group Title | Newly Diagnosed AML/MDS | Refractory or Relapsed AML/MDS |
---|---|---|
Arm/Group 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin | 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin |
Measure Participants | 0 | 0 |
Adverse Events
Time Frame | 3 years | |||
---|---|---|---|---|
Adverse Event Reporting Description | Adverse event data was not collected because no patients underwent protocol treatment | |||
Arm/Group Title | Newly Diagnosed AML/MDS | Refractory or Relapsed AML/MDS | ||
Arm/Group 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin | 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. Decitabine: Decitabine will be administered in combination with Digoxin Digoxin: Decitabine will be administered in combination with Digoxin | ||
All Cause Mortality |
||||
Newly Diagnosed AML/MDS | Refractory or Relapsed AML/MDS | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/0 (NaN) | 0/0 (NaN) | ||
Serious Adverse Events |
||||
Newly Diagnosed AML/MDS | Refractory or Relapsed AML/MDS | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/0 (NaN) | 0/0 (NaN) | ||
Other (Not Including Serious) Adverse Events |
||||
Newly Diagnosed AML/MDS | Refractory or Relapsed AML/MDS | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/0 (NaN) | 0/0 (NaN) |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Dr. Henry Fung |
---|---|
Organization | Fox Chase Cancer Center |
Phone | 215-728-2674 |
Henry.Fung@tuhs.temple.edu |
- 16-1061
- HM-091