Belinostat and Azacitidine in Treating Patients With Advanced Hematologic Cancers or Other Diseases
|Accelerated Phase of Disease Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11 Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1 Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative Blastic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Chronic Myelomonocytic Leukemia de Novo Myelodysplastic Syndrome Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia Previously Treated Myelodysplastic Syndrome Primary Myelofibrosis Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Recurrent Disease Secondary Acute Myeloid Leukemia Secondary Myelodysplastic Syndrome||Drug: Belinostat Drug: Azacitidine Other: Laboratory Biomarker Analysis||Phase 1|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study of PXD101 in Combination With Azacitidine (5-Aza) for Advanced Hematologic Malignancies|
- Maximum tolerated dose of belinostat in combination with azacitidine [ Time Frame: Course 1 (28 days) ]Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 or 4.0.
- Changes in pharmacodynamic variables (target gene expression, apoptosis) [ Time Frame: Course 1 (baseline to day 5) ]Compared between the two groups using two-sample t tests.
- Association of methylation status, categorized as positive or negative, with changes in target gene expression [ Time Frame: Baseline, days 4 or 5, and days 25-28 ]Distinguished by sequence-specific polymerase chain reaction (PCR) primers. Compared using a two-sample t or Wilcoxon nonparametric test.
- Clinical activity (complete remission, partial remission, stable disease, hematologic improvement) [ Time Frame: After 4, 8, and 16 weeks ]Recorded and tabulated for both the MTD and randomized cohorts.
|Study Start Date:||June 2006|
|Study Completion Date:||March 2013|
|Primary Completion Date:||March 2013 (Final data collection date for primary outcome measure)|
Experimental: Arm I (chemotherapy)
Patients receive azacitidine SC on days 1-5.
Other Names:Other: Laboratory Biomarker Analysis
Experimental: Arm II (chemotherapy, enzyme inhibitor therapy)
Patients receive azacitidine as in arm I and belinostat at the MTD IV over 30 minutes on days 1-5.
Other Names:Drug: Azacitidine
Other Names:Other: Laboratory Biomarker Analysis
I. Determine the maximum tolerated dose of PXD101 (belinostat) when given in combination with azacitidine (when azacitidine is utilized at a dose range where its effects on cellular differentiation are known to be predominant) in patients with advanced hematologic cancers or other diseases.
I. Identify any additive or synergistic effects of this regimen on pharmacodynamic parameters, including apoptosis and re-expression of specific target genes.
II. Assess any evidence of clinical activity (complete remission, partial remission, hematologic improvement, stable disease) of this regimen in these patients.
OUTLINE: This is a dose-escalation study of belinostat followed by a randomized study.
Patients receive azacitidine subcutaneously (SC) and belinostat intravenously (IV) over 30 minutes on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of belinostat until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. After the MTD is determined, additional patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (with trilineage dysplasia or arising from MDS) are randomized to 1 of 2 treatment arms.
Arm I: Patients receive azacitidine SC on days 1-5.
Arm II: Patients receive azacitidine as in arm I and belinostat at the MTD IV over 30 minutes on days 1-5.
In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After receiving one course, patients randomized to arm I may crossover to receive treatment on arm II.
For patients enrolled in the randomized portion of the study, bone marrow aspirates are obtained at baseline, and after course 1 for correlative studies. Samples are examined by gene expression analysis of p15 and p21, DNA methylation of p15INK4B, and apoptosis by RT-PCR and flow cytometry. Pharmacodynamic assays are also performed.
After completion of study treatment, patients are followed periodically for up to 2 years.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00351975
|United States, Illinois|
|University of Chicago Comprehensive Cancer Center|
|Chicago, Illinois, United States, 60637|
|United States, Wisconsin|
|University of Wisconsin Hospital and Clinics|
|Madison, Wisconsin, United States, 53792|
|University Health Network-Princess Margaret Hospital|
|Toronto, Ontario, Canada, M5G 2M9|
|Princess Margaret Hospital|
|Cashmere, Canterbury, New Zealand, 8022|
|Principal Investigator:||Olatoyosi Odenike||University of Chicago Comprehensive Cancer Center|