Adult Acute Erythroid Leukemia (M6), Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Acute Promyelocytic Leukemia (M3), Recurrent Adult Acute Myeloid Leukemia, Refractory Cytopenia With Multilineage Dysplasia, Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia
Conditions
Brief summary
Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for their growth. Giving the drug in different ways may kill more cancer cells. This randomized phase II trial is studying two different schedules of vorinostat to see how well they work in treating patients with acute myeloid leukemia.
Detailed description
PRIMARY OBJECTIVES: I. Determine the toxicity and the proportion of complete remissions associated with two different treatment schedules of vorinostat (SAHA) in patients with acute myeloid leukemia. SECONDARY OBJECTIVES: I. Determine the toxic effects of SAHA in this study population. II. Examine for preliminary evidence of re-expression of silenced genes in leukemic blasts in response to SAHA. OUTLINE: This is a multicenter, randomized study. Patients are stratified according to disease status (relapsed vs untreated). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral vorinostat (SAHA) once a day on days 1-21. In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive oral SAHA three times a day on days 1-14. In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 2 years. PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.
Interventions
Given orally once daily
Sponsors
Study design
Eligibility
Inclusion criteria
* Diagnosis of acute myeloid leukemia (AML), meeting 1 of the following criteria: * Relapsed AML in the following categories: * Good-risk cytogenetics \[inv(16), t (8;21)\] in second relapse or in first relapse following a remission of \< 12 months * Acute promyelocytic leukemia (M3) in second relapse or greater AND must have relapsed following both tretinoin-anthracycline-based therapy and arsenic trioxide-based therapy * All other relapsed patients are eligible * Untreated AML in the following categories: * At least 65 years of age * Myelodysplastic syndromes-AML (AML with trilineage dysplasia) * AML with del5Q or monosomy 5, monosomy 7, or complex cytogenetics (≥ 3 cytogenetic abnormalities) * Refused or ineligible for potentially curative options such as allogeneic stem cell transplantation * No clinical evidence of CNS or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia * ECOG performance status (PS) 0-2 or Karnofsky PS ≥ 60% * Life expectancy ≥ 3 months * Bilirubin normal unless attributed to hemolysis or Gilbert's disease in the opinion of the investigator * AST/ALT ≤ 2.5 times upper limit of normal (ULN) * Creatinine normal OR creatinine clearance ≥ 60 mL/min * No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat * No uncontrolled intercurrent illness, including any of the following: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness or social situation that would limit compliance with study requirements * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No known HIV positivity * More than 4 weeks since prior radiotherapy * More than 2 weeks since prior valproic acid * More than 3 weeks since other prior treatment for AML, including hematopoietic growth factors * Hydroxyurea for WBC \> 30,000/mm\^3 allowed * Recovered from prior therapy * No concurrent filgrastim (G-CSF), sargramostim (GM-CSF), epoetin alfa, or darbepoetin alfa * No other concurrent investigational agents * No other concurrent anticancer agents or therapies for this cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Complete Response (CR) Rate | Up to 2 years | The confirmed complete response rate was estimated by the number of participants with CR divided by the total number of evaluable participants. According to the International Working Group (IWG) Criteria for response in AML, to be considered a CR, the following must be met for at least 4 weeks: ANC \> 1500/mL, platelets \> 100000/mL, no circulating blasts, bone marrow cellularity \>20% (biopsy), trilineage maturation, \< 5% bone marrow blasts, no auer rods and no extramedullary disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) | Duration of study (up to 2 years) | Time to Progression (TTP) for each patient will be calculated as the number of days from date of registration to either date when disease progression was documented or date of last evaluation without disease progression. The TTP distribution will be estimated using the method of Kaplan-Meier |
| Overall Survival (OS) | Duration of study (up to 2 years) | Overall survival (OS) was defined as the time from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method. |
| Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events | Duration of study (up to 2 years) | Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. Description of Grades: Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Death |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure (TTF) | Duration of treatment (up to 17 cycles) | Time to treatment failure (TTF) was defined as the time from registration to until the date of treatment discontinuation of any reason. Patients receiving treatment at the time of analysis were considered censored. The median TTF with 95% CI was estimated using the Kaplan Meier method. |
Countries
United States
Participant flow
Recruitment details
A total of 37 participants were enrolled into this trial between January 2006 and August 2007. One patient on Arm A was ineligible; this participant was included in all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Once Daily Vorinostat) Patients receive oral vorinostat (SAHA) once a day on days 1-21. Treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. | 15 |
| Arm B (Thrice Daily Vorinostat) Patients receive oral SAHA three times a day on days 1-14. Treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. | 22 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | All other reasons | 3 | 2 |
| Overall Study | Alternative Treatment | 4 | 4 |
| Overall Study | Death | 3 | 2 |
| Overall Study | Disease Progression | 1 | 3 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | Arm B (Thrice Daily Vorinostat) | Total | Arm A (Once Daily Vorinostat) |
|---|---|---|---|
| Age, Continuous | 67 years | 67 years | 67 years |
| AML disease classification All other relapsed AML | 16 participants | 28 participants | 12 participants |
| AML disease classification Relapsed AML with good risk cytogenetics | 0 participants | 0 participants | 0 participants |
| AML disease classification Untreated AML patients >= 65 years old | 3 participants | 6 participants | 3 participants |
| AML disease classification Untreated AML patients with MDS-AML | 3 participants | 3 participants | 0 participants |
| AML disease classification Untreated AML with >= 3 cytogenetic abnnormalities | 0 participants | 0 participants | 0 participants |
| Disease status Relapsed | 16 participants | 28 participants | 12 participants |
| Disease status Untreated | 6 participants | 9 participants | 3 participants |
| Region of Enrollment United States | 22 participants | 37 participants | 15 participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Male | 17 Participants | 27 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 15 | 21 / 22 |
| serious Total, serious adverse events | 10 / 15 | 16 / 22 |
Outcome results
Confirmed Complete Response (CR) Rate
The confirmed complete response rate was estimated by the number of participants with CR divided by the total number of evaluable participants. According to the International Working Group (IWG) Criteria for response in AML, to be considered a CR, the following must be met for at least 4 weeks: ANC \> 1500/mL, platelets \> 100000/mL, no circulating blasts, bone marrow cellularity \>20% (biopsy), trilineage maturation, \< 5% bone marrow blasts, no auer rods and no extramedullary disease.
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Once Daily Vorinostat) | Confirmed Complete Response (CR) Rate | 0 percentage of participants |
| Arm B (Thrice Daily Vorinostat) | Confirmed Complete Response (CR) Rate | 4.5 percentage of participants |
Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. Description of Grades: Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Death
Time frame: Duration of study (up to 2 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Once Daily Vorinostat) | Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events | 10 participants |
| Arm B (Thrice Daily Vorinostat) | Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events | 17 participants |
Overall Survival (OS)
Overall survival (OS) was defined as the time from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method.
Time frame: Duration of study (up to 2 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Once Daily Vorinostat) | Overall Survival (OS) | 105 days |
| Arm B (Thrice Daily Vorinostat) | Overall Survival (OS) | 153 days |
Time to Progression (TTP)
Time to Progression (TTP) for each patient will be calculated as the number of days from date of registration to either date when disease progression was documented or date of last evaluation without disease progression. The TTP distribution will be estimated using the method of Kaplan-Meier
Time frame: Duration of study (up to 2 years)
Population: This data was not (and will never be) analyzed. In place of this outcome, time to treatment failure, analyzed and reported as a secondary outcome.
Time to Treatment Failure (TTF)
Time to treatment failure (TTF) was defined as the time from registration to until the date of treatment discontinuation of any reason. Patients receiving treatment at the time of analysis were considered censored. The median TTF with 95% CI was estimated using the Kaplan Meier method.
Time frame: Duration of treatment (up to 17 cycles)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Once Daily Vorinostat) | Time to Treatment Failure (TTF) | 42 days |
| Arm B (Thrice Daily Vorinostat) | Time to Treatment Failure (TTF) | 46 days |