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

Leukemia Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00723203
• Other study ID #: 07174
• Secondary ID: P30CA033572CHNMC
• Status: Terminated
• Phase: Phase 2
• First received: July 25, 2008
• Last updated: September 3, 2014
• Start date: April 2008
• Est. completion date: September 2010

Study information

• Verified date: September 2014
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 16
• Est. completion date: September 2010
• Est. primary completion date: September 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid, Acute
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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
• reverse transcriptase-polymerase chain reaction
Day 1 and day 28 samples

Other:
• laboratory biomarker analysis
Day 1 and day 28 samples

Locations

Country	Name	City	State
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	South Pasadena Cancer Center	Pasadena	California

Sponsors (2)

Lead Sponsor	Collaborator
City of Hope Medical Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hematological Response Rate	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.	Up to 6 cycles of treatment, up to 24 weeks.	No