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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Leukemia

Intervention / Treatment
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* Drug: panobinostat
* Genetic: gene expression analysis
* Genetic: reverse transcriptase-polymerase chain reaction
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (panobinostat)<br>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<br>* 40 mg Monday, Wednesday and Friday of every week in a 28 day cycle<br>Genetic: gene expression analysis<br>* Day 1 and day 28 samples<br>Genetic: reverse transcriptase-polymerase chain reaction<br>* Day 1 and day 28 samples<br>Other: laboratory biomarker analysis<br>* Day 1 and day 28 samples<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Philadelphia chromosome positive adult precursor acute lymphoblastic leukemia, recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia