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- Klinische proef NCT00079378
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 I Study of Decitabine in Combination With Valproic Acid in Patients With Selected Hematologic Malignancies
Studie Overzicht
Toestand
Conditie
- Terugkerende volwassen acute myeloïde leukemie
- Volwassen acute myeloïde leukemie met 11q23 (MLL) afwijkingen
- Volwassen acute myeloïde leukemie met Del(5q)
- Acute myeloïde leukemie bij volwassenen met Inv(16)(p13;q22)
- Acute myeloïde leukemie bij volwassenen met t(16;16)(p13;q22)
- Acute myeloïde leukemie bij volwassenen met t(8;21)(q22;q22)
- Onbehandelde volwassen acute myeloïde leukemie
- Terugkerend klein lymfocytisch lymfoom
- Refractaire chronische lymfatische leukemie
- Volwassen acute myeloïde leukemie met t(15;17)(q22;q12)
Gedetailleerde beschrijving
PRIMARY OBJECTIVES:
I. 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:
I. 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.
V. 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.
Studietype
Inschrijving (Werkelijk)
Fase
- Fase 1
Contacten en locaties
Studie Locaties
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Ohio
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Columbus, Ohio, Verenigde Staten, 43210
- Ohio State University Medical Center
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Deelname Criteria
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
Accepteert gezonde vrijwilligers
Geslachten die in aanmerking komen voor studie
Beschrijving
Inclusion Criteria:
- 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
- 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
Studie plan
Hoe is de studie opgezet?
Ontwerpdetails
- Primair doel: Behandeling
- Toewijzing: NVT
- Interventioneel model: Opdracht voor een enkele groep
- Masker: Geen (open label)
Wapens en interventies
Deelnemersgroep / Arm |
Interventie / Behandeling |
---|---|
Experimenteel: Treatment (decitabine, valproic acid)
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. |
Correlatieve studies
Correlatieve studies
Andere namen:
IV gegeven
Andere namen:
Given orally
Andere namen:
|
Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Tijdsspanne |
---|---|
MEPD of single agent decitabine
Tijdsspanne: 10 days
|
10 days
|
MTD of the combination of valproic acid with the MEPD of decitabine
Tijdsspanne: Up to 21 days
|
Up to 21 days
|
MEPD of valproic acid in combination with decitabine
Tijdsspanne: Up to 29 days
|
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
Tijdsspanne: Up to 24 months
|
Up to 24 months
|
Medewerkers en onderzoekers
Sponsor
Onderzoekers
- Hoofdonderzoeker: Kristie Blum, Ohio State University
Publicaties en nuttige links
Studie record data
Bestudeer belangrijke data
Studie start
Primaire voltooiing (Werkelijk)
Studieregistratiedata
Eerst ingediend
Eerst ingediend dat voldeed aan de QC-criteria
Eerst geplaatst (Schatting)
Updates van studierecords
Laatste update geplaatst (Schatting)
Laatste update ingediend die voldeed aan QC-criteria
Laatst geverifieerd
Meer informatie
Termen gerelateerd aan deze studie
Aanvullende relevante MeSH-voorwaarden
- Pathologische processen
- Ziekten van het immuunsysteem
- Neoplasmata per histologisch type
- Neoplasmata
- Lymfoproliferatieve aandoeningen
- Lymfatische ziekten
- Immunoproliferatieve aandoeningen
- Ziekte attributen
- Leukemie, B-cel
- Lymfoom
- Leukemie
- Leukemie, myeloïde
- Leukemie, myeloïde, acuut
- Herhaling
- Leukemie, lymfatische, chronische, B-cel
- Leukemie, Lymfoïde
- Fysiologische effecten van medicijnen
- Neurotransmitter agenten
- Moleculaire mechanismen van farmacologische werking
- Depressiva van het centrale zenuwstelsel
- Enzymremmers
- Antimetabolieten, antineoplastische
- Antimetabolieten
- Antineoplastische middelen
- Rustgevende agenten
- Psychotrope medicijnen
- GABA-agenten
- Anticonvulsiva
- Antimanische middelen
- Decitabine
- Valproïnezuur
- Azacitidine
Andere studie-ID-nummers
- NCI-2012-01447 (Register-ID: CTRP (Clinical Trial Reporting Program))
- U01CA076576 (Subsidie/contract van de Amerikaanse NIH)
- 6236 (CTEP)
- NCI-6236
- OSU-2003C0094
- CDR0000355412
- 0336 (Andere identificatie: Ohio State University Medical Center)
- R21CA110496 (Subsidie/contract van de Amerikaanse NIH)
Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .
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