LBH589 Plus Decitabine for Myelodysplastic Syndromes (MDS... | NCT00691938

NCT00691938

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Level 1	Experimental	LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle.	Drug: LBH589 Drug: Decitabine
Level 2	Experimental	LBH589 15 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle.	Drug: LBH589 Drug: Decitabine
Level 3	Experimental	LBH589 20 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle.	Drug: LBH589 Drug: Decitabine
Level 4	Experimental	LBH589 30 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle.	Drug: LBH589 Drug: Decitabine
Level 5	Experimental	LBH589 40 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m^2 IV on days 1-5 in a 28 day cycle.

Name	Type	Description	Arm Group Labels	Other Names
LBH589	Drug		Level 1 Level 2 Level 3 Level 4 Level 5 Level 5B Phase II

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Phase I: Maximum Tolerated Dose (MTD) of LBH589 When Given in Combination With Decitabine		Completion of Phase I enrollment for MTD (approximately 26 months)
Phase II: Overall Rate of Morphologic Complete Remission (CR) + Cytogenetic Complete Remission (CRc) + Morphologic Complete Remission With Incomplete Blood Count Recovery (CRi)	Morphologic complete remission (CR). A CR designation requires that the patient achieve the morphologic leukemia-free state with less than 5% blasts in an aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. There should be no blasts with Auer rods or persistence of extramedullary disease. Patients must also have an absolute neutrophil count of more than 1,000/μLand platelets of 100,000/μL. Cytogenetic complete remission (CRc). A CRc will be defined by the achievement of a CR with reversion to a normal karyotype in a minimum of 20 metaphases analyzed by cytogenetics. Morphologic complete remission with incomplete blood count recovery (CRi): Achievement of all of the criteria for CR except for residual neutropenia (< 1,000/μL) or thrombocytopenia (< 100,000/μL).	Up to 12 months

Secondary Outcomes

Measure	Description	Time Frame
Rate of Cytogenetic Complete Remission (CRc)	Cytogenetic complete remission (CRc). A CRc will be defined by the achievement of a CR with reversion to a normal karyotype in a minimum of 20 metaphases analyzed by cytogenetics.	Up to 12 months
Changes in Quality of Life Scores as Measured by the Function Assessment of Cancer Therapy-Leukemia (FACT-Leu) Version 4

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

AML (except t(15;17), inv(16) or t(8;21) and variants) or high risk MDS (IPSS Int-2 or High) diagnosed according to WHO criteria (see Appendix 1)
Age ≥ 60 years old
Not a candidate for allogeneic stem cell transplantation within next 12 weeks
Ability to provide written informed consent, obtained prior to participation in the study and any related procedures being performed
Patients must meet the following laboratory criteria:
Serum albumin ≥ 3 g/dL
Aspartate aminotransferase (AST)/SGOT and alanine aminotransferase (ALT)/SGPT ≤ 2.5 x upper limit of normal (ULN) ) or ≤ 5.0 x ULN if the transaminase elevation is due to leukemic involvement
Serum bilirubin ≤ 1.5 x ULN
Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min
Serum potassium ≥ lower limit of normal (LLN)
Serum phosphorus ≥ LLN
Serum total calcium (corrected for serum albumin) or serum ionized calcium ≥ LLN
Serum magnesium ≥ LLN, thyroid stimulating hormone (TSH) and free thyroxine (T4) within normal limits (WNL) (patients may be on thyroid hormone replacement)
Baseline MUGA or ECHO must demonstrate left ventricular ejection fraction (LVEF) ≥ the lower limit of the institutional normal.
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2

Exclusion Criteria:

Prior treatment for MDS / AML with Histone deacetylase (HDAC) inhibitor or hypomethylating agent (e.g., Decitabine, azacitidine etc.)
Active central nervous system (CNS) involvement with MDS/AML
Impaired cardiac function including any one of the following:
Screening electrocardiogram (ECG) with a QTc > 450 msec confirmed by central laboratory prior to enrollment to the study
Patients with congenital long QT syndrome
History of sustained ventricular tachycardia
Any history of ventricular fibrillation or torsades de pointes
Bradycardia defined as heart rate < 50 beats per minute. Patients with a pacemaker and heart rate ≥ 50 beats per minute are eligible.
Patients with a myocardial infarction or unstable angina within 6 months of study entry
Congestive heart failure (NY Heart Association class III or IV)
Right bundle branch block and left anterior hemiblock (bifasicular block)
Uncontrolled hypertension
Concomitant use of drugs with a risk of causing torsades de pointes
Patients with unresolved diarrhea > CTCAE grade 1
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589
Other concurrent severe and/or uncontrolled medical conditions
Patients who have received chemotherapy or any investigational drug < 2 weeks or hydroxyurea < 48 hours prior to starting study drug or who have not recovered from side effects of such therapy.
Concomitant use of any anti-cancer therapy or radiation therapy
Male patients whose sexual partners are women of child bearing potential (WOCBP) not using effective birth control
Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required
Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first LBH589 treatment
Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies
Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy.

Name	Affiliation	Role
Geoffrey Uy, M.D.	Washington Univerisity	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Washington University		St Louis	Missouri	63110	United States

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
	Background	Cashen, A., G. J. Schiller, et al. (2006). Phase II Study of Low-Dose Decitabine for the Front-Line Treatment of Older Patients with Acute Myeloid Leukemia (AML). ASH Annual Meeting Abstracts 108(11): 1984.
27740633	Derived	Uy GL, Duncavage EJ, Chang GS, Jacoby MA, Miller CA, Shao J, Heath S, Elliott K, Reineck T, Fulton RS, Fronick CC, O'Laughlin M, Ganel L, Abboud CN, Cashen AF, DiPersio JF, Wilson RK, Link DC, Welch JS, Ley TJ, Graubert TA, Westervelt P, Walter MJ. Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy. Leukemia. 2017 Apr;31(4):872-881. doi: 10.1038/leu.2016.282. Epub 2016 Oct 14.

Label	URL
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine	View source

Arm/Group Information

ID	Title	Description
FG000	Level 1	LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.
FG001	Level 2	LBH589 15 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.
FG002	Level 3	LBH589 20 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.
FG003	Level 4	LBH589 30 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.
FG004	Level 5	LBH589 40 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.
FG005	Level 5B	LBH589 40 mg/day three times a week on nonconsecutive days for the first 2 weeks in a 28 day cycle. Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.
FG006	Phase II	LBH589 will be given in the dose and in the schedule that was found to work in the Phase I portion which was dose from Level 5B. Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Level 1	LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.
BG001	Level 2	LBH589 15 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Level 1	LBH589 10 mg/day three times a week on nonconsecutive days in a 28 day cycle. Decitabine 20 mg/m2 IV on days 1-5 in a 28 day cycle.

ID	Term
D015470	Leukemia, Myeloid, Acute
D009190	Myelodysplastic Syndromes

ID	Term
D007951	Leukemia, Myeloid
D007938	Leukemia
D009370	Neoplasms by Histologic Type
D009369	Neoplasms

ID	Term
D000077767	Panobinostat
D000077209	Decitabine

ID	Term
D006877	Hydroxamic Acids
D006898	Hydroxylamines
D000588	Amines
D009930	Organic Chemicals