Vorinostat, Cytarabine, and Etoposide in Treating Patients With Relapsed and/or Refractory Acute Leukemia or Myelodysplastic Syndromes or Myeloproliferative Disorders
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|ClinicalTrials.gov Identifier: NCT00357305|
Recruitment Status : Completed
First Posted : July 27, 2006
Last Update Posted : May 3, 2013
|Condition or disease||Intervention/treatment||Phase|
|Accelerated Phase Chronic Myelogenous Leukemia Adult Acute Basophilic Leukemia Adult Acute Eosinophilic Leukemia 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) Adult Erythroleukemia (M6a) Adult Pure Erythroid Leukemia (M6b) Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative Blastic Phase Chronic Myelogenous Leukemia Chronic Eosinophilic Leukemia Chronic Myelomonocytic Leukemia Chronic Neutrophilic Leukemia de Novo Myelodysplastic Syndromes Essential Thrombocythemia Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable Polycythemia Vera Previously Treated Myelodysplastic Syndromes Primary Myelofibrosis Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Relapsing Chronic Myelogenous Leukemia Secondary Acute Myeloid Leukemia Secondary Myelodysplastic Syndromes||Drug: vorinostat Drug: cytarabine Drug: etoposide Other: pharmacological study Other: laboratory biomarker analysis||Phase 1|
I. Determine the feasibility, tolerability, and toxicities, in terms of the maximum tolerated dose (MTD), of the sequential combination of vorinostat (SAHA) followed by cytarabine and etoposide in patients with relapsed and/or refractory acute leukemia or transforming myelodysplastic syndromes or myeloproliferative disorders.
II. Determine whether the addition of SAHA to cytarabine and etoposide chemotherapy improves outcome, in terms of complete response rate, duration of response, and overall survival, in these patients.
III. Determine the effects of SAHA on induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors DR4 and DR5 and other pro-apoptotic mediators in patient-derived cancer cells (leukemia blast cells) and somatic cells (buccal mucosa cells, using pre-SAHA and on SAHA treatment samples).
IV. Determine the ability of SAHA to block leukemia blast cells in the G1 phase of the cell cycle (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).
V. Determine the effects of SAHA on the expression of P-glycoprotein/MDR1/ABCB1, and the breast cancer resistance protein (BCRP/ABCG2), using functional and mRNA/protein assays for these transporters (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).
OUTLINE: This is a dose-escalation study of vorinostat (SAHA).
Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine intravenously (IV) over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14. Treatment repeats approximately every 6-7 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Patients who achieve complete response after 1 course of therapy may receive 1 or 2 more courses of therapy. Patients who achieve partial response after 1 course of therapy may receive 1 more course of therapy. Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional 10 patients are treated at that dose. Blood, buccal cells, and bone marrow samples are collected prior to and during treatment. Samples are used for pharmacokinetic and pharmacodynamic studies, protein expression studies, and gene expression profiling. After completion of study treatment, patients are followed within 30 days.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||25 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid, or SAHA) in Combination With Cytosine Arabinoside (Ara-C) and Etoposide for Patients With Relapsed and/or Refractory Acute Leukemias, Myelodysplasias and Myeloproliferative Disorders|
|Study Start Date :||May 2006|
|Actual Primary Completion Date :||November 2011|
Experimental: Treatment (enzyme inhibitor, chemotherapy)
Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine IV over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14. Treatment repeats approximately every 6-7 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Other: pharmacological study
Other Name: pharmacological studies
Other: laboratory biomarker analysis
- Maximum tolerated dose (MTD) of vorinostat (SAHA) in combination with cytarabine and etoposide [ Time Frame: Course 1 ]Based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
- Response rate [ Time Frame: Baseline, day 4-7 of course 1, and after each course ]Measured using a bone marrow aspirate and/or biopsy. 90% confidence interval will be calculated
- Progression-free survival [ Time Frame: At 30 days after completion of study treatment and continued follow up visits ]Estimated using the Kaplan-Meir method.
- Disease-specific survival [ Time Frame: At 30 days after completion of study treatment and continued follow up visits ]Estimated using the Kaplan-Meir method.
- One-year survival [ Time Frame: At 1 year ]Estimated using the Kaplan-Meir method.
- Overall survival [ Time Frame: At 30 days after completion of study treatment and continued follow up visits ]Measured from time of enrollment onto this study to the time of death. Estimated using the Kaplan-Meir method.
- Degree of upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors and proteins associated with apoptosis [ Time Frame: Baseline and days 4-7 of course 1 ]Performed by the Rnase protection assay.
- Alterations in cell cycle phase [ Time Frame: Baseline and days 4-7 of course 1 ]Patient-derived bone marrow or peripheral blood mononuclear cells will be evaluated for cell cycle phase distribution, using the hypotonic propidium-iodide method and flow cytometry.
- Expression of MDR proteins at MTD of SAHA [ Time Frame: Baseline and days 4-7 of course 1 ]Using quantitative, real-time polymerase chain reaction (PCR) methods with product detected using specific hybridization probes.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00357305
|United States, Maryland|
|University of Maryland Greenebaum Cancer Center|
|Baltimore, Maryland, United States, 21201-1595|
|United States, Pennsylvania|
|University of Pittsburgh|
|Pittsburgh, Pennsylvania, United States, 15232|
|Principal Investigator:||Douglas Ross||University of Maryland Greenebaum Cancer Center|