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Panobinostat in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia

This study has been terminated.
(Terminated early due to a lack of efficacy)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT00723203
First received: July 25, 2008
Last updated: September 3, 2014
Last verified: September 2014
  Purpose

RATIONALE: Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial is studying the side effects of panobinostat and to see how well it works in treating patients with relapsed or refractory acute lymphoblastic leukemia or acute myeloid leukemia.


Condition Intervention Phase
Leukemia
Drug: panobinostat
Genetic: gene expression analysis
Genetic: reverse transcriptase-polymerase chain reaction
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of LBH589, a Novel Histone Deacetylase Inhibitor, in Relapsed and Refractory Adult Patients With Acute Leukemia (AL) or in Newly Diagnosed Patients Over the Age of 60

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • Hematological Response Rate [ Time Frame: Up to 6 cycles of treatment, up to 24 weeks. ] [ Designated as safety issue: No ]
    Morphologic CR: morphologic leukemia-free state with absolute neutrophil count > 1000/uL and platelet count ≥ 100,000/uL and independent of blood transfusions. Cytogenic CR: morphologic CR along with reversion to a normal karyotype by cytogenetic analysis. Molecular CR: morphologic CR with no residual disease by molecular or flow cytometric detection methods. Morphologic CR with incomplete blood recovery (CRi): morphologic CR except for residual neutropenia (<1000/uL) and/or thrombocytopenia (<1000,000/uL). PR: same hematologic values for a CR but with a decrease of at least 50% in percentage of blasts to a post-treatment value of 5% to 25% in bone marrow aspirate. (If the pre-treatment blast percentage was 50-100% this must decrease to a value between 5-25%. If the pre-treatment blast percentage was 20-49% this must decrease by at least half to a value > 5%.) A value ≤ 5% is also considered a PR if Auer rods are present. Hematological response = morphologic CR+PR.


Enrollment: 16
Study Start Date: April 2008
Study Completion Date: September 2010
Primary Completion Date: September 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (panobinostat)

Patients receive oral panobinostat once on days 1, 3, and 5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

panobinostat: 40 mg Monday, Wednesday and Friday of every week in a 28 day cycle

Drug: panobinostat
40 mg Monday, Wednesday and Friday of every week in a 28 day cycle
Genetic: gene expression analysis
Day 1 and day 28 samples
Genetic: reverse transcriptase-polymerase chain reaction
Day 1 and day 28 samples
Other: laboratory biomarker analysis
Day 1 and day 28 samples

Detailed Description:

OBJECTIVES:

Primary

  • To determine the antitumor activity of panobinostat, in terms of objective response rate, time to progression, and survival, in patients with relapsed or refractory acute lymphoblastic leukemia or acute myeloid leukemia.
  • To assess the toxicity of panobinostat in these patients.

Secondary

  • To perform correlative laboratory studies to assess changes in various proteins that may be altered by histone deacetylase inhibition therapy.

OUTLINE: Patients receive oral panobinostat once on days 1, 3, and 5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo peripheral blood and bone marrow sample collection at baseline and on day 28 of course 1 for correlative laboratory studies. Samples are analyzed by RT-PCR for reactivation of FANCG, FOXO3A, GADD45A, GADD45B, GADD45G, H2AX, and TP73.

After completion of study treatment, patients are followed for at least 4 weeks.

PROJECTED ACCRUAL: A total of 74 patients (37 with acute myeloid leukemia and 37 with acute lymphoblastic leukemia) will be accrued for this study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically or cytologically confirmed acute myeloid leukemia or acute lymphoblastic leukemia (ALL)

    • Relapsed or refractory disease
  • Patients with Philadelphia chromosome-positive (Ph+) ALL refractory to BCR/ABL inhibitors are eligible
  • Patients who have relapsed after prior autologous or allogenic stem cell transplant are eligible
  • No active CNS disease

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-2
  • Serum albumin ≥ 3 g/dL
  • AST and ALT ≤ 2.5 times upper limit of normal (ULN) (5.0 times ULN if transaminase elevation is due to leukemic involvement)
  • Bilirubin ≤ 1.5 times ULN
  • Creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 50 mL/min
  • Potassium ≥ lower limit of normal (LLN)
  • Phosphorous ≥ LLN
  • Serum total calcium (corrected for serum albumin) or serum ionized calcium ≥ LLN
  • Magnesium ≥ LLN
  • Thyroid stimulating hormone and free T4 normal (thyroid hormone replacement therapy allowed)
  • LVEF ≥ LLN by MUGA or ECHO
  • No impaired cardiac function, including any of the following:

    • QTc > 450 msec
    • Congenital long QT syndrome
    • History of sustained ventricular tachycardia
    • History of ventricular fibrillation or torsades de pointes
    • Bradycardia (i.e., heart rate < 50 beats per minute)

      • Pacemaker allowed provided heart rate ≥ 50 beats per minute
    • Myocardial infarction or unstable angina within the past 6 months
    • New York Heart Association class III-IV congestive heart failure
    • Right bundle branch block and left anterior hemiblock (bifascicular block)
  • No uncontrolled hypertension
  • No unresolved diarrhea > CTCAE grade 1
  • No impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective double-barrier contraception during and for 3 months after completion of study treatment
  • No other primary malignancy within the past 5 years, other than curatively treated carcinoma in situ of the cervix or basal cell or squamous cell carcinoma of the skin
  • No HIV or hepatitis C positivity
  • No other concurrent severe and/or uncontrolled medical condition
  • No significant history of non-compliance to medical regimens or inability to give reliable informed consent

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Recovered from all prior therapy
  • More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy
  • More than 4 weeks since prior valproic acid
  • No other prior treatment with a histone deacetylase inhibitor
  • No concurrent medication that may cause QTc prolongation or induce torsades de pointes
  • No concurrent CYP3A4 inhibitors
  • No concurrent grapefruit, grapefruit juice, or Seville (sour) oranges
  • No concurrent radiotherapy
  • No other concurrent anticancer therapy or investigational therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00723203

Locations
United States, California
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010-3000
South Pasadena Cancer Center
Pasadena, California, United States, 91030
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Leslie Popplewell, MD Beckman Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT00723203     History of Changes
Other Study ID Numbers: 07174, P30CA033572, CHNMC-07174, NOVARTIS-CHNMC-07174, CDR0000601203
Study First Received: July 25, 2008
Results First Received: June 12, 2014
Last Updated: September 3, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by City of Hope Medical Center:
Philadelphia chromosome positive adult precursor acute lymphoblastic leukemia
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Leukemia, Myeloid
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Histone Deacetylase Inhibitors
Panobinostat
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014