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

Sponsor
Fox Chase Cancer Center (Other)
Overall Status
Terminated
CT.gov ID
NCT03113071
Collaborator
(none)
1
Enrollment
2
Locations
2
Arms
21.3
Actual Duration (Months)
0.5
Patients Per Site
0
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
1 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Intervention 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.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)
Primary Purpose:
Treatment
Official Title:
A Phase Ib/II Study of the Safety and Activity of Digoxin With Decitabine in Adult AML and MDS
Actual Study Start Date :
Jun 2, 2017
Actual Primary Completion Date :
Jan 8, 2019
Actual Study Completion Date :
Mar 11, 2019

Arms and Interventions

ArmIntervention/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

  1. 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

  2. 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.

  3. Number of MDS Patients With Complete Remission (CR) [1-3 years]

    Complete response will be assessed by International Working Group (IWG) criteria for MDS

  4. 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

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

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

  2. Age > 18 years.

  3. ECOG performance status 0 - 2.

  4. 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

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

  2. 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

  1. 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.

  2. 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.

  3. Pregnant or breast feeding

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1Fox Chase Cancer CenterPhiladelphiaPennsylvaniaUnited States19111
2Jeans HospitalPhiladelphiaPennsylvaniaUnited States19111

Sponsors and Collaborators

  • Fox Chase Cancer Center

Investigators

None specified.

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Fox Chase Cancer Center
ClinicalTrials.gov Identifier:
NCT03113071
Other Study ID Numbers:
  • 16-1061
  • HM-091
First Posted:
Apr 13, 2017
Last Update Posted:
Mar 16, 2021
Last Verified:
Feb 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group TitleNewly Diagnosed AML/MDSRefractory or Relapsed AML/MDS
Arm/Group DescriptionFor 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 Digoxinor 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
STARTED10
COMPLETED00
NOT COMPLETED10

Baseline Characteristics

Arm/Group TitleNewly Diagnosed AML/MDSRefractory or Relapsed AML/MDSTotal
Arm/Group DescriptionFor 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 Digoxinor 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 DigoxinTotal of all reporting groups
Overall Participants101
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

1. Primary Outcome
TitleMaximum 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
DescriptionMaximum tolerated dose of digoxin in combination with standard dose of decitabine will be determined by a standard 3+3 dose de-escalation design
Time Frame1-2 months

Outcome Measure Data

Analysis Population Description
No patients analyzed because no patients underwent protocol treatment
Arm/Group TitleNewly Diagnosed AML/MDSRefractory or Relapsed AML/MDS
Arm/Group DescriptionFor 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 Digoxinor 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 Participants00
2. Primary Outcome
TitleNumber of Grade II and IV Toxicities Due to of the Combination Therapy of Decitabine in Combination With Digoxin
DescriptionThe 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 Frame1-3 years

Outcome Measure Data

Analysis Population Description
No patients analyzed because no patients underwent protocol treatment
Arm/Group TitleNewly Diagnosed AML/MDSRefractory or Relapsed AML/MDS
Arm/Group DescriptionFor 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 Digoxinor 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 Participants00
3. Primary Outcome
TitleNumber of MDS Patients With Complete Remission (CR)
DescriptionComplete response will be assessed by International Working Group (IWG) criteria for MDS
Time Frame1-3 years

Outcome Measure Data

Analysis Population Description
No patients analyzed because no patients underwent protocol treatment
Arm/Group TitleNewly Diagnosed AML/MDSRefractory or Relapsed AML/MDS
Arm/Group DescriptionFor 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 Digoxinor 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 Participants00
4. Primary Outcome
TitleNumber of AML Patients With Complete Remission With Incomplete Blood Count Recovery (CRi)
DescriptionCRi will be assessed by IWG criteria for AML
Time Frame1-3 years

Outcome Measure Data

Analysis Population Description
No patients analyzed because no patients underwent protocol treatment
Arm/Group TitleNewly Diagnosed AML/MDSRefractory or Relapsed AML/MDS
Arm/Group DescriptionFor 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 Digoxinor 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 Participants00

Adverse Events

Time Frame3 years
Adverse Event Reporting Description Adverse event data was not collected because no patients underwent protocol treatment
Arm/Group TitleNewly Diagnosed AML/MDSRefractory or Relapsed AML/MDS
Arm/Group DescriptionFor 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 Digoxinor 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/MDSRefractory or Relapsed AML/MDS
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total0/0 (NaN) 0/0 (NaN)
Serious Adverse Events
Newly Diagnosed AML/MDSRefractory or Relapsed AML/MDS
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total0/0 (NaN) 0/0 (NaN)
Other (Not Including Serious) Adverse Events
Newly Diagnosed AML/MDSRefractory or Relapsed AML/MDS
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total0/0 (NaN) 0/0 (NaN)

Limitations/Caveats

[Not Specified]

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/TitleDr. Henry Fung
OrganizationFox Chase Cancer Center
Phone215-728-2674
EmailHenry.Fung@tuhs.temple.edu
Responsible Party:
Fox Chase Cancer Center
ClinicalTrials.gov Identifier:
NCT03113071
Other Study ID Numbers:
  • 16-1061
  • HM-091
First Posted:
Apr 13, 2017
Last Update Posted:
Mar 16, 2021
Last Verified:
Feb 1, 2021