LBH589 Plus Decitabine for Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML)

NCT00691938 | Completed Phase 1 Results DMC

• 1 other identifier: 08-0172 / 201012979
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief Summary

This study is designed to evaluate the combination of LBH589 and decitabine in patients age ≥ 60 years with high risk Myelodysplastic Syndrome (IPSS Int-2 or High) or Acute Myeloid Leukemia.

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Keywords

LBH589; Decitabine; panobinostat; histone deacetylase; methylation; hypomethylation

Outcome Measures

Primary Outcomes (2)

• 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 (10)

• Rate of Cytogenetic Complete Remission (CRc)

  Up to 12 months

• Changes in Quality of Life Scores as Measured by the Function Assessment of Cancer Therapy-Leukemia (FACT-Leu) Version 4

  Up to approximately 12 months after start of treatment

• Time to Response

  Up to 12 months

• Safety and Tolerability of Regimen as Measured by the Rate of the Most Common Adverse Events Experienced

  Up to 13 months after start of treatment

• Remission Duration

  Completion of follow-up (median follow-up was 58 months)

Study Arms (7)

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.

Drug: LBH589; Drug: Decitabine

Level 5B

EXPERIMENTAL

LBH589 40 mg/day three times a week on nonconsecutive days for the first 2 weeks in a 28 day cycle. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

Drug: LBH589; Drug: Decitabine

Phase II

EXPERIMENTAL

LBH589 will be given in the dose and in the schedule that was found to work in the Phase I portion which was Level 5B. Decitabine 20 mg/m\^2 IV on days 1-5 in a 28 day cycle.

Drug: LBH589; Drug: Decitabine

Interventions

LBH589 DRUG

Also known as: Panobinostat

Level 1; Level 2; Level 3; Level 4; Level 5; Level 5B; Phase II

Decitabine DRUG

Also known as: Dacogen, 5-aza-2'-deoxycytidine

Level 1; Level 2; Level 3; Level 4; Level 5; Level 5B; Phase II

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University

St Louis, Missouri, 63110, United States

Location

Related Publications (2)

• 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.

  BACKGROUND

• 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.

  PMID: 27740633 DERIVED

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Panobinostat; Decitabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Azacitidine; Aza Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Geoffrey Uy, M.D.
• Organization: Washington University School of Medicine

guy@wustl.edu

314-454-8304

Study Officials

• Geoffrey Uy, M.D.

  Washington Univerisity

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 4, 2008
• First Posted: June 6, 2008
• Study Start: June 1, 2008
• Primary Completion: July 1, 2013
• Study Completion: August 1, 2014
• Last Updated: October 13, 2016
• Results First Posted: October 13, 2016

Record last verified: 2016-08

Locations

US (1)