de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Secondary Myelodysplastic Syndromes
Conditions
Brief summary
This phase II trial is studying how well belinostat works in treating patients with myelodysplastic syndromes. Belinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer.
Detailed description
OBJECTIVES: I. Establish the efficacy and safety of PXD101 (belinostat) in patients with myelodysplastic syndromes that progressed after or is ineligible for azacitidine treatment. II. Assess the biological activity of PXD101 in these patients via assays of histone acetylation, gene expression profiling, and DNA methylation. OUTLINE: This is a multicenter study. Patients receive belinostat intravenously (IV) over 30 minutes on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving complete response, partial response, or hematologic improvement after 4 courses receive 4 additional courses of therapy. After completion of study treatment, patients are followed every 3-6 months for up to 3 years.
Interventions
DRUGbelinostat
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed myelodysplastic syndromes (MDS) * De novo or secondary MDS * Patients with \< 5 % bone marrow blasts must meet ≥ 1 of the following criteria: * Symptomatic anemia with either hemoglobin \< 10.0 g/dL or required RBC transfusions within the past 3 months * Thrombocytopenia with ≥ 2 platelet counts \< 50,000/mm³ or significant hemorrhage requiring platelet transfusions * Neutropenia with ≥ 2 absolute neutrophil counts \< 1,000/mm³ * No acute myeloid leukemia (≥ 20% bone marrow blasts) * ECOG performance status 0-2 * Life expectancy \> 12 weeks * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * AST ≤ 2 times ULN * Creatinine ≤ 2.0 mg/dL * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No history of allergic reactions attributed to compounds of similar chemical or biologic composition to PXD101 * No HIV positivity * QTc interval ≤ 500 msec * No long QT syndrome * No significant cardiovascular disease, including any of the following: * Unstable angina pectoris * Uncontrolled hypertension * Congestive heart failure related to primary cardiac disease * Condition requiring anti-arrhythmic therapy * Ischemic or severe valvular heart disease * Myocardial infarction within the past 6 months * No other uncontrolled serious medical condition (e.g., cardiac arrhythmias or diabetes) * Recovered from prior therapy * No more than 2 prior therapies for MDS * Prior hematopoietic growth factors, androgens, and other supportive care agents allowed and are not considered in the prior therapy total * No prior allogeneic stem cell transplantation * More than 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) * No prior histone deacetylase (HDAC) inhibitors for treatment of MDS * More than 2 weeks since prior valproic acid or other HDAC inhibitors * No other concurrent investigational agents * No concurrent medication that may cause torsades depointes, including any of the following: * Disopyramide * Dofetilide * Ibutilide * Procainamide * Quinidine * Sotalol * Bepridil * Methadone * Amiodarone hydrochloride * Arsenic trioxide * Cisapride * Calcium-channel blockers (e.g., lidoflazine) * Anti-infective agents (i.e., clarithromycin, erythromycin, halofantrine, pentamidine, or sparfloxacin) * Domperidone or droperidol * Antipsychotic agents (i.e., chlorpromazine, haloperidol, mesoridazine, thioridazine, or pimozide)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Confirmed Responses (Complete Response, Partial Response, or Hematologic Improvement) Noted on 2 Consecutive Evaluations at Least 4 Weeks Apart | 12 weeks | Complete Response (CR) A CR is defined as a participant with bone marrow showing less than 5% myeloblasts with no evidence of dysplasia and with adequate peripheral blood counts for at least 2 months (hemoglobin \> 11 g/dl, neutrophils ≥ 1500/mm3, platelets ≥ 100,000/mm3) and with no blasts in the peripheral. Partial Response (PR) All the CR criteria except bone marrow blasts decreased by ≥ 50% over pretreatment, or a less advanced WHO classification than pretreatment. Hematologic Improvement (HI) A 2g/dl increase in hemoglobin for participants with \<11g/dl hemoglobin at pretreatment, or an increase of \>30,000/mm\^3 platelets for participants with \<100,000/mm\^3 at pretreatment, or a 100% increase in neutrophil counts for participants with \<1500/mm\^3 at pretreatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | Time from registration to the date of progression or last follow-up, assessed up to 3 years | Estimated using the method of Kaplan-Meier. |
| Overall Survival | From date of registration to the date of last follow-up or death due to any cause, assessed up to 3 years | Estimated using the method of Kaplan-Meier. |
| Duration of Response | From the date of documented response until the date of progression or last follow-up, assessed up to 3 years | Estimated using the method of Kaplan-Meier. |
| Toxicity of Belinostat in Patients With Myelodysplastic Syndrome | Prior to each course (every 21 days), and every 3 months for up to 3 years after completion of study treatment | Graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Reporting events deemed at least possibly related to study treatment. |
Countries
United States
Participant flow
Recruitment details
Twenty-one patients were accrued, and all were eligible and\> evaluable.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Enzyme Inhibitor Therapy) Patients receive belinostat IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. | 21 |
| Total | 21 |
Baseline characteristics
| Characteristic | Treatment (Enzyme Inhibitor Therapy) |
|---|---|
| Age, Continuous | 67 years |
| Region of Enrollment United States | 21 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 21 / 21 |
| serious Total, serious adverse events | 10 / 21 |
Outcome results
Primary
Number of Confirmed Responses (Complete Response, Partial Response, or Hematologic Improvement) Noted on 2 Consecutive Evaluations at Least 4 Weeks Apart
Complete Response (CR) A CR is defined as a participant with bone marrow showing less than 5% myeloblasts with no evidence of dysplasia and with adequate peripheral blood counts for at least 2 months (hemoglobin \> 11 g/dl, neutrophils ≥ 1500/mm3, platelets ≥ 100,000/mm3) and with no blasts in the peripheral. Partial Response (PR) All the CR criteria except bone marrow blasts decreased by ≥ 50% over pretreatment, or a less advanced WHO classification than pretreatment. Hematologic Improvement (HI) A 2g/dl increase in hemoglobin for participants with \<11g/dl hemoglobin at pretreatment, or an increase of \>30,000/mm\^3 platelets for participants with \<100,000/mm\^3 at pretreatment, or a 100% increase in neutrophil counts for participants with \<1500/mm\^3 at pretreatment
Time frame: 12 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Number of Confirmed Responses (Complete Response, Partial Response, or Hematologic Improvement) Noted on 2 Consecutive Evaluations at Least 4 Weeks Apart | Confirmed Partial Response (PR) | 0 participants |
| Treatment (Enzyme Inhibitor Therapy) | Number of Confirmed Responses (Complete Response, Partial Response, or Hematologic Improvement) Noted on 2 Consecutive Evaluations at Least 4 Weeks Apart | Confirmed Hematologic Improvement (HI) | 1 participants |
| Treatment (Enzyme Inhibitor Therapy) | Number of Confirmed Responses (Complete Response, Partial Response, or Hematologic Improvement) Noted on 2 Consecutive Evaluations at Least 4 Weeks Apart | COnfirmed Complete Response (CR) | 0 participants |
Secondary
Duration of Response
Estimated using the method of Kaplan-Meier.
Time frame: From the date of documented response until the date of progression or last follow-up, assessed up to 3 years
Population: One participant had a confirmed Hematologica Improvement. For patient confidentiality, we are not reporting response data.
Secondary
Overall Survival
Estimated using the method of Kaplan-Meier.
Time frame: From date of registration to the date of last follow-up or death due to any cause, assessed up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Overall Survival | 17.9 months |
Secondary
Time to Progression
Estimated using the method of Kaplan-Meier.
Time frame: Time from registration to the date of progression or last follow-up, assessed up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Time to Progression | 14.9 months |
Secondary
Toxicity of Belinostat in Patients With Myelodysplastic Syndrome
Graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Reporting events deemed at least possibly related to study treatment.
Time frame: Prior to each course (every 21 days), and every 3 months for up to 3 years after completion of study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Toxicity of Belinostat in Patients With Myelodysplastic Syndrome | Grade 3 Hematologic Adverse Event | 13 participants |
| Treatment (Enzyme Inhibitor Therapy) | Toxicity of Belinostat in Patients With Myelodysplastic Syndrome | Grade 4 Hematologic Adverse Events | 11 participants |
| Treatment (Enzyme Inhibitor Therapy) | Toxicity of Belinostat in Patients With Myelodysplastic Syndrome | Grade 3 Non-Hemeatologic Adverse Events | 5 participants |
| Treatment (Enzyme Inhibitor Therapy) | Toxicity of Belinostat in Patients With Myelodysplastic Syndrome | Grade 4 Non-hematologic Adverse Events | 1 participants |