Accelerated Phase of DiseasePhase 1NCT00351975
Belinostat and Azacitidine in Treating Patients With Advanced Hematologic Cancers or Other Diseases
A Phase 1 study testing Belinostat, Azacitidine and Laboratory Biomarker Analysis in people with Accelerated Phase of Disease and Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11, run by National Cancer Institute (NCI) at 4 sites in 3 countries.
Trial summary
This phase I trial is studying the side effects and best dose of belinostat when given together with azacitidine in treating patients with advanced hematologic cancers or other diseases. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- 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
- What is being tested?
- Belinostat, Azacitidine and Laboratory Biomarker Analysis
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 56 participants
- Where
- 4 sitesin 3 countries
- Study dates
- Jun 2006to Mar 2013
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed diagnosis of 1 of the following:
- Relapsed or refractory acute myeloid leukemia (AML)
- Relapsed or refractory acute promyelocytic leukemia (must have failed both tretinoin and arsenic trioxide)
- Relapsed or refractory acute lymphoblastic leukemia
- Secondary AML, including AML arising from antecedent hematologic diseases, such as myelodysplastic syndromes (MDS) or myeloproliferative disorders, OR therapy-related AML
- Chronic myelogenous leukemia in accelerated or blast phase
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- Advanced phases of Philadelphia chromosome-negative (Ph-) chronic myeloproliferative disorders, as defined by ≥ 1 of the following:
- Presence of anemia (hemoglobin < 10 g/dL and/or red blood cell transfusion dependent)
- Presence of palpable splenomegaly
- MDS, including chronic myelomonocytic leukemia
- Must have intermediate or high-risk International Prognostic Scoring System (IPSS) scores (≥ 0.5)
- Low-risk IPSS scores allowed provided ≥ 1 of the following criteria are met:
- Hemoglobin < 10 g/dL and/or red blood cell transfusion dependent
- Platelet count < 50,000/mm³
- Absolute neutrophil count < 1,000/mm³
- Refractory disease OR no standard therapy exists
- Evidence of AML associated with dysplasia on bone marrow histology for elderly patients (i.e., > 60 years old) who are previously untreated and not candidates for or unwilling to undergoing induction therapy
- No known active CNS involvement with disease
- CALGB performance status (PS) 0-2 OR Karnofsky PS 60-100%
- Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome)
- ALT ≤ 3 times upper limit of normal (unless due to disease)
- Creatinine ≤ 2 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 or Azacitidine
- No history of allergic reactions to mannitol
- No history of dose-limiting toxicity during prior treatment with Azacitidine
- No concurrent uncontrolled illness including, but not limited to, the following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness or social situation that would preclude compliance with study requirements
- No marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 500 msec)
- No long QT syndrome
- No uncontrolled cardiovascular disease, including the following:
- Severe uncontrolled hypertension
- Uncontrolled congestive heart failure related to primary cardiac disease
- Uncontrolled cardiac arrhythmia
- Uncontrolled ischemic or severe valvular heart disease
- Myocardial infarction within the past 6 months
- See Disease Characteristics
- Recovered from prior therapy
- At least 2 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)
- At least 2 weeks since prior radiotherapy
- At least 4 weeks since prior investigational agents
- At least 24 hours since prior hydroxyurea
- At least 2 weeks since prior valproic acid
- No concurrent combination antiretroviral therapy for HIV-positive patients
- No other concurrent investigational agents
- No concurrent medication that may cause torsade de pointes
- No other concurrent anticancer therapy, including chemotherapy, radiotherapy, or biological agents
Who cannot join
None listed.
Trial locations and contacts
4 sites in 3 countries.
4 sites in 3 countries
United States2 sites
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, 53792
Canada1 site
University Health Network-Princess Margaret Hospital
Toronto, Ontario, M5G 2M9
About this study
Official title: A Phase I Study of PXD101 in Combination With Azacitidine (5-Aza) for Advanced Hematologic Malignancies
This phase I trial is studying the side effects and best dose of belinostat when given together with azacitidine in treating patients with advanced hematologic cancers or other diseases. 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. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving belinostat together with azacitidine may kill more cancer cells.
Read the detailed description
PRIMARY OBJECTIVES:
- 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.
SECONDARY OBJECTIVES:
- 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.
- Conditions
- 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
- Being tested
- Belinostat, Azacitidine, Laboratory Biomarker Analysis
- Medical subject headings
- Leukemia, Myelomonocytic, Acute, Leukemia, Promyelocytic, Acute, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative, Blast Crisis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Myelomonocytic, Chronic, Myeloproliferative Disorders, Primary Myelofibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BelinostatDrug
Also called Beleodaq, PXD 101, PXD101
Given IV
AzacitidineDrug
Also called 5-AC, 5-AZC, U-18496
Given SC
Laboratory Biomarker AnalysisOther
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| Arm I (chemotherapy) | Experimental | Patients receive azacitidine SC on days 1-5. Receives: Drug: Azacitidine; Other: Laboratory Biomarker Analysis |
| Arm II (chemotherapy, enzyme inhibitor therapy) | Experimental | Patients receive azacitidine as in arm I and belinostat at the MTD IV over 30 minutes on days 1-5. Receives: Drug: Belinostat; Drug: Azacitidine; Other: Laboratory Biomarker Analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum tolerated dose of belinostat in combination with azacitidine
Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 or 4.0.
Measured: Course 1 (28 days)
Secondary outcomes (3)
Changes in pharmacodynamic variables (target gene expression, apoptosis)
Compared between the two groups using two-sample t tests.
Measured: Course 1 (baseline to day 5)
Association of methylation status, categorized as positive or negative, with changes in target gene expression
Distinguished by sequence-specific polymerase chain reaction (PCR) primers. Compared using a two-sample t or Wilcoxon nonparametric test.
Measured: Baseline, days 4 or 5, and days 25-28
Clinical activity (complete remission, partial remission, stable disease, hematologic improvement)
Recorded and tabulated for both the MTD and randomized cohorts.
Measured: After 4, 8, and 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jul 2006 (estimated)
- Study startJun 2006
- Primary completionMar 2013
- Study completionMar 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Accelerated Phase of DiseaseStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 56 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Olatoyosi Odenike, Principal investigator, University of Chicago Comprehensive Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00351975
- Sponsor's protocol ID
- NCI-2009-00146
- Other IDs
- NCI-2009-00146, UCCRC-14510A, NCI-7285, CDR0000486418, 14510A, 7285, U01CA069852, U01CA132123
- Status last verified
- Oct 2013
- First submitted
- 13 Jul 2006
- Last updated
- 23 Dec 2014
- Results posted
- No