Leukemia, Myelocytic, Acute Myelodysplastic Syndromes, Myelodysplastic Syndromes
Conditions
Keywords
Leukemia, Myelocytic, Acute Myelodysplastic Syndromes
Brief summary
This study is to evaluate the safety and tolerability of vorinostat in combination with decitabine as well as the in vivo molecular and biological effects of vorinostat in patients with refractory or relapsed Acute Myelogenous Leukemia (AML) and intermediate or high risk as defined by International Prognostic Scoring System (IPSS) Myelodysplastic Syndrome (MDS). Participants with Acute Myelogenous Leukemia or Myelodysplastic Syndrome are eligible.
Interventions
DRUGvorinostat
DRUGdecitabine
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient is at least 18 years old with refractory/relapsed AML * If untreated AML, patient is older than 60 years old and not a candidate for standard chemotherapy * Patient is at least 4 weeks from prior treatment and has recovered from all prior treatment side effects * Patient has no known liver or kidney problems * Patient knows of no reason they can not receive transfusions of blood clotting cells (platelets) * Patient is able to swallow capsules * Patients both male and female are willing to practice birth control during the study
Exclusion criteria
* Patient has received prior treatment with valproic acid, decitabine or azacitidine * Being is less than 18 years of age or if patient has untreated AML is below 60 years of age * Patient is a women who is pregnant or breastfeeding. Patient has an active infection that requires antibiotics * Patient has uncontrolled illness including but not limited to the following: heart problems (congestive heart failure, unstable angina pectoris, cardiac arrhythmia), inflammation of the pancreas; a mental or social condition that may interfere with patient following study procedures * Patient has known human immunodeficiency virus (HIV) infection or HIV-related malignancy. Patient has a known history of hepatitis B or C infection * Patient currently has another active cancer other than certain types of skin cancer * Patient is heterosexual and able to have a child and is unwilling to practice birth control during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events | Day 1 to 28 of Cycle 1 | Participants who received at least one dose of vorinostat in combination with decitabine intravenous (IV) at a dose of 20 mg/m\^2 daily for 5 days along with oral vorinostat 400 mg once daily for 7 to 14 days in a 28-day cycle concurrently or sequentially, were evaluated to determine the maximum tolerable dose (MTD) determined by the number of participants experiencing dose limiting toxicity (DLT) events defined as any Grade 3 or 4 non-hematological toxicity (reported adverse event) and/or myelosuppression lasting \>42 days. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Refractory or Relapse Acute Myelogenous Leukemia (AML) | Approximately 6 months | Objective Response Rate was measured in participants with refractory or relapse AML (acute myelogenous leukemia) in combination with Decitabine who were treated with vorinostat and decitabine on either a concurrent or sequential regimen. The Objective response was defined as any confirmed complete remission or any confirmed partial remission for AML participants and complete remission, confirmed partial remission or confirmed hematologic improvement for Myelodysplastic Syndrome (MDS) participants. |
| Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Intermediate-high Risk Myelodysplastic Syndrome (MDS) or Untreated Acute Myelogenous Leukemia (AML) | Approximately 6 months | Objective Response Rate was measured in participants with intermediate-high risk MDS or untreated AML who were treated with vorinostat and decitabine either on a concurrent or sequential regimen. The Objective response was defined as any confirmed complete remission or any confirmed partial remission for AML participants and complete remission, confirmed partial remission or confirmed hematologic improvement for MDS participants. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat + Decitabine, Concurrent (concurrent) Vorinostat 400 mg capsules once daily given 7 days, 14 days with 8 day break after first 7 days or 14 days without break, out of 28 day cycles along with decitabine IV 20 mg/m\^2 daily for 5 days in each 28 day cycle. Up to 24 months of treatment. | 34 |
| Vorinostat + Decitabine, Sequential (sequential) Vorinostat 400 mg capsules once daily given 7, 10 or 14 days in 28 day cycles along with decitabine IV 20 mg/m\^2 daily for 5 days in each 28 day cycle. Up to 24 months of treatment. | 37 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 5 | 0 | 0 | 10 |
| Overall Study | Deviation from Protocol | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 2 | 0 | 0 | 4 |
| Overall Study | Physician Decision | 0 | 0 | 2 | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 3 | 1 | 12 | 3 | 3 | 12 |
| Overall Study | Withdrew Consent | 0 | 2 | 6 | 0 | 1 | 3 |
Baseline characteristics
| Characteristic | Vorinostat + Decitabine, Concurrent | Vorinostat + Decitabine, Sequential | Total |
|---|---|---|---|
| Age, Continuous | 63.9 years STANDARD_DEVIATION 13 | 66.6 years STANDARD_DEVIATION 13.8 | 65.3 years STANDARD_DEVIATION 13.4 |
| Sex: Female, Male Female | 11 Participants | 18 Participants | 29 Participants |
| Sex: Female, Male Male | 23 Participants | 19 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 27 / 28 | 3 / 3 | 4 / 4 | 29 / 31 |
| serious Total, serious adverse events | 3 / 3 | 1 / 3 | 21 / 28 | 2 / 3 | 4 / 4 | 25 / 31 |
Outcome results
Primary
Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events
Participants who received at least one dose of vorinostat in combination with decitabine intravenous (IV) at a dose of 20 mg/m\^2 daily for 5 days along with oral vorinostat 400 mg once daily for 7 to 14 days in a 28-day cycle concurrently or sequentially, were evaluated to determine the maximum tolerable dose (MTD) determined by the number of participants experiencing dose limiting toxicity (DLT) events defined as any Grade 3 or 4 non-hematological toxicity (reported adverse event) and/or myelosuppression lasting \>42 days.
Time frame: Day 1 to 28 of Cycle 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Concurrent, Vorinostat 400mg qd x 7d/4wk + Decitabine | Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events | 0 participants |
| Concurrent, Vorinostat 400mg qd x 7d/2wk + Decitabine | Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events | 0 participants |
| Concurrent, Vorinostat 400mg qd x 14d/4wk + Decitabine (MTD) | Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events | 0 participants |
| Sequential, Vorinostat 400mg qd x 7d/4wk + Decitabine | Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events | 0 participants |
| Sequential, Vorinostat 400mg qd x 10d/4wk + Decitabine | Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events | 0 participants |
| Sequential, Vorinostat 400mg qd x 14d/4wk + Decitabine (MTD) | Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events | 1 participants |
Other Pre-specified
Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Intermediate-high Risk Myelodysplastic Syndrome (MDS) or Untreated Acute Myelogenous Leukemia (AML)
Objective Response Rate was measured in participants with intermediate-high risk MDS or untreated AML who were treated with vorinostat and decitabine either on a concurrent or sequential regimen. The Objective response was defined as any confirmed complete remission or any confirmed partial remission for AML participants and complete remission, confirmed partial remission or confirmed hematologic improvement for MDS participants.
Time frame: Approximately 6 months
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Concurrent, Vorinostat 400mg qd x 7d/4wk + Decitabine | Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Intermediate-high Risk Myelodysplastic Syndrome (MDS) or Untreated Acute Myelogenous Leukemia (AML) | 35.0 percentage of participants | 170.3 |
| Concurrent, Vorinostat 400mg qd x 7d/2wk + Decitabine | Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Intermediate-high Risk Myelodysplastic Syndrome (MDS) or Untreated Acute Myelogenous Leukemia (AML) | 13.6 percentage of participants | 119.2 |
Other Pre-specified
Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Refractory or Relapse Acute Myelogenous Leukemia (AML)
Objective Response Rate was measured in participants with refractory or relapse AML (acute myelogenous leukemia) in combination with Decitabine who were treated with vorinostat and decitabine on either a concurrent or sequential regimen. The Objective response was defined as any confirmed complete remission or any confirmed partial remission for AML participants and complete remission, confirmed partial remission or confirmed hematologic improvement for Myelodysplastic Syndrome (MDS) participants.
Time frame: Approximately 6 months
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Concurrent, Vorinostat 400mg qd x 7d/4wk + Decitabine | Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Refractory or Relapse Acute Myelogenous Leukemia (AML) | 7.1 percentage of participants | 0 |
| Concurrent, Vorinostat 400mg qd x 7d/2wk + Decitabine | Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Refractory or Relapse Acute Myelogenous Leukemia (AML) | 0.0 percentage of participants | — |