Adult Acute Myeloid Leukemia With 11q23 (MLL) AbnormalitiesPhase 1NCT00079378
Decitabine and Valproic Acid in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia or Previously Treated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
A Phase 1 study testing decitabine, valproic acid and pharmacological study in people with Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities and Adult Acute Myeloid Leukemia With Del(5q), run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
This phase I trial is studying the side effects and best dose of decitabine and valproic acid in treating patients with refractory or relapsed acute myeloid leukemia or previously treated chronic lymphocytic leukemia or small lymphocytic leukemia. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
- What is being tested?
- decitabine, valproic acid and pharmacological study
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 84 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2004to May 2011
- 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
- Patients with AML (Stratum I) or CLL/SLL (Stratum II) will be enrolled
- Patients in stratum I will have one of the following:
- Primary refractory or relapsed (in 1 year or less) disease and not a candidate for potentially curative therapy
- Untreated AML patients who are not candidates for chemotherapy
- Patients in stratum I must have a normal WBC (=< 10 x 10^9/L) or a WBC =< 40 x 10^9/L that is stable for 1 week (this may be sustained with hydroxyurea prior to starting therapy and during the first 4 days of therapy if clinically indicated)
- Patients in stratum II will have received at least one prior therapy for CLL/SLL that has included a purine analog; patients in stratum II with a history of severe autoimmune disease or requiring therapy with chronic corticosteroids or who have any other specific relative contraindications to receive a purine analog and, therefore, have received another form of therapy that include alkylating agents will be eligible to participate
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- Performance status - ECOG 0-2
- At least 12 weeks life expectancy
- Stratum II:
- No uncontrolled autoimmune hemolytic anemia
- No idiopathic thrombocytopenia purpura
- Bilirubin =< 1.5 mg/dL
- ALT and AST =< 2 times upper limit of normal
- Creatinine =< 2.0 mg/dL
- No active infection requiring IV antibiotics
- HIV negative
- No other severe medical condition that would preclude study participation
- No psychiatric condition that would preclude study compliance
- No history of seizures
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- More than 14 days since prior chemotherapy (except hydroxyurea)
- No prior FR901228 (depsipeptide) for step 2 of this study
- No other concurrent chemotherapy
- No concurrent corticosteroids for antiemetic therapy
- No concurrent hormonal therapy except for the following:
- Steroids for treatment of adrenal failure or septic shock
- Insulin for diabetes
- Tamoxifen or equivalent for breast cancer prevention or adjuvant therapy
- Estrogens or progestins for gynecologic indications
- More than 14 days since prior radiotherapy
- No concurrent palliative radiotherapy
- No concurrent anticonvulsant medication, including valproic acid
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country.
United States1 site
Ohio State University Medical Center
Columbus, Ohio, 43210
About this study
Official title: A Phase I Study of Decitabine in Combination With Valproic Acid in Patients With Selected Hematologic Malignancies
This phase I trial is studying the side effects and best dose of decitabine and valproic acid in treating patients with refractory or relapsed acute myeloid leukemia or previously treated chronic lymphocytic leukemia or small lymphocytic leukemia. Drugs used in chemotherapy, such as decitabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Valproic acid may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Combining decitabine with valproic acid may kill more cancer cells.
Read the detailed description
PRIMARY OBJECTIVES:
- Determine the minimally effective pharmacological dose (MEPD) of decitabine in patients with refractory or relapsed acute myeloid leukemia or with previously treated chronic lymphocytic lymphoma or small lymphocytic lymphoma.
II. Determine the maximum tolerated dose (MTD) of valproic acid in combination with the MEPD of decitabine in these patients.
III. Determine the MEPD of valproic acid in combination with decitabine in these patients.
IV. Determine the qualitative and quantitative toxic effects of decitabine alone and in combination with valproic acid, in terms of organ specificity, time course, predictability, and reversibility in these patients.
SECONDARY OBJECTIVES:
- Determine the therapeutic response in patients treated with decitabine alone and in combination with valproic acid.
II. Determine the pharmacokinetics of this regimen in these patients. III. Determine kinetics of methyltransferase activity and re-expression of select target genes in AML [p15, estrogen receptor (ER), WT-1, calcitonin, MYOD1] and in CLL/SLL [DERMO-1, DAPK, and ID4] known to be methylated in primary tumor cells.
IV. Correlate baseline and post-treatment changes in DNA methyltransferases (MT1, MT3a, and MT3b) expression with achievement of decitabine MEPD, toxicity, treatment resistance, and disease response in these patients.
- Determine kinetics of HDAC enzyme inhibition and changes in the acetylation status of histones H3 or H4 following treatment with the combination. These parameters will be used to define the MEPD of the combination.
VI. Examine baseline and post-therapy changes in the "histone code' in both AML and CLL cells by assessment of the acetylation and methylation status of histones H3 and H4 lysine residues using both Western Blot and Mass Spectrometry techniques.
OUTLINE: This is a dose-escalation study. Patients are stratified according to disease (refractory or relapsed acute myeloid leukemia vs chronic lymphocytic leukemia or small lymphocytic lymphoma).
Patients receive decitabine IV over 1 hour on days 1-5 or 1-10. Treatment repeats every 28 days.
Cohorts of 6 patients receive escalating doses of decitabine until the minimally effective pharmacological dose (MEPD) is determined. The MEPD is defined as the dose at which at least 5 of 6 patients meet gene methylation criteria and no more than 1 of 6 patients experiences dose-limiting toxicity (DLT).
Once the MEPD is determined, patients receive decitabine at that dose level administered as above and oral valproic acid three times daily on days 5-21. Treatment repeats every 28 days.
Cohorts of 3-6 patients receive escalating doses of valproic acid until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT. The MEPD of valproic acid is then determined using established gene methylation and toxicity criteria. Treatment continues for up to 24 months in the absence of disease progression or unacceptable toxicity.
Patients are followed for survival.
- Conditions
- Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), 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)
- Being tested
- decitabine, valproic acid, pharmacological study, laboratory biomarker analysis
- Medical subject headings
- Congenital Abnormalities, Leukemia, Myeloid, Acute, Leukemia, Lymphocytic, Chronic, B-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
decitabineDrug
Also called 5-aza-dCyd, 5AZA, DAC
Given IV
valproic acidDrug
Also called Alti-Valproic, Depakene, Novo-Valproic, VA
Given orally
Also called pharmacological studies
Correlative studies
laboratory biomarker analysisOther
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| Treatment (decitabine, valproic acid) | Experimental | Patients receive decitabine IV over 1 hour on days 1-5 or 1-10. Treatment repeats every 28 days.
Cohorts of 6 patients receive escalating doses of decitabine until the MEPD is determined. The MEPD is defined as the dose at which at least 5 of 6 patients meet gene methylation criteria and no more than 1 of 6 patients experiences DLT.
Once the MEPD is determined, patients receive decitabine at that dose level administered as above and oral valproic acid three times daily on days 5-21. Treatment repeats every 28 days.
Cohorts of 3-6 patients receive escalating doses of valproic acid until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT. The MEPD of valproic acid is then determined using established gene methylation and toxicity criteria. Treatment continues for up to 24 months in the absence of disease progression or unacceptable toxicity. Receives: Drug: decitabine; Drug: valproic acid; Other: pharmacological study; Other: laboratory biomarker analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
MEPD of single agent decitabine
Measured: 10 days
MTD of the combination of valproic acid with the MEPD of decitabine
Measured: Up to 21 days
MEPD of valproic acid in combination with decitabine
Measured: Up to 29 days
Qualitative and quantitative toxicities of single agent decitabine alone and in combination with valproic acid in regard to organ specificity, time course, predictability, and reversibility
Measured: Up to 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Mar 2004 (estimated)
- Study startFeb 2004
- Primary completionMay 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Adult Acute Myeloid Leukemia With 11q23 (MLL) AbnormalitiesStudies 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 84 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Kristie Blum, Principal investigator, Ohio State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00079378
- Sponsor's protocol ID
- NCI-2012-01447
- Other IDs
- NCI-2012-01447, NCI-6236, OSU-2003C0094, CDR0000355412, 0336, 6236, R21CA110496, U01CA076576
- Status last verified
- Sep 2013
- First submitted
- 8 Mar 2004
- Last updated
- 30 Sep 2013
- Results posted
- No
Publications
Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, Vukosavljevic T, Huynh L, Lozanski G, Kefauver C, Plass C, Devine SM, Heerema NA, Murgo A, Chan KK, Grever MR, Byrd JC, Marcucci G. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol. 2007 Sep 1;25(25):3884-91. doi: 10.1200/JCO.2006.09.4169. Epub 2007 Aug 6.
PubMed 17679729