LBH589 in Refractory Myelodysplastic Syndromes (MDS)

Study Overview
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Brief Summary
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This will be a single arm Phase II study.

Detailed Description
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LBH589 (20 mg PO) will be administered three times a week on Monday, Wednesday and Friday. Treatment will be given over 21 days followed by a 7 day rest period and repeated every 28 days. Patients will be assessed for toxicity on an ongoing basis and disease assessment will be determined every 2 treatment cycles (8 weeks). Patients will be allowed to continue on treatment for a maximum of eight four week treatment cycles. Treatment will be discontinued if there is evidence of disease progression, unacceptable toxicity and/or at the discretion of the investigator.

Official Title
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A Phase II Trial of LBH589 in Refractory Myelodysplastic Syndromes (MDS) Patients

Conditions
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Myelodysplastic Syndromes (MDS)

Intervention / Treatment
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* Drug: Panobinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytological documented diagnosis of myelodysplastic syndrome (MDS). Male or female patients aged >= 18 years old. MDS patients who have failed hypomethylating (azacitidine or decitabine) therapy. Patients with 5q-cytogenic abnormalities must also have progressed on or been intolerant to lenalidomide. Patients with up to and including 30% blasts (FAB RAEB-T) will be eligible to enroll. CMML with >= 5% blasts will be eligible to enroll. ECOG PS 0, 1 or 2. Laboratory values must be as follows: Bilirubin <= 1.5 mg/dL AST/SGOT <= 2.5 x ULN ALT/SGPT Creatinine <= 2.0 mg/dL or 24-hour Creatinine Clearance >= 50 ml/min Albumin >= 3 g/dL Potassium >= lower limit normal (LLN) Phosphorous >= LLN Calcium >= LLN Magnesium >= LLN Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to start of treatment. Life expectancy >= 12 weeks. Exclusion Criteria: Prior treatment with an HDAC inhibitor. Prior intensive chemotherapy or high dose ara-C (>= 1 gm/m2) More than one prior single agent chemotherapy regimen. Prior hydroxyurea for cytoreduction will be permitted however. Impaired cardiac function Active CNS disease, including leptomeningeal metastases. Unresolved diarrhea > CTCAE grade 1. Chemotherapy, investigational drug therapy, major surgery < 4 weeks prior to starting study drug or patients that have not recovered from side effects of previous therapy. Patient is < 5 years free of another primary malignancy except if the other primary malignancy is not currently clinically significant or requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and 3 months after the end of treatment. One of these methods of contraception must be a barrier method. Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom. Patients with gastrointestinal (GI) tract disease, causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis). Other concurrent severe, uncontrolled systemic fungal, bacterial, viral or other infection or intercurrent illness, including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with uncontrolled coagulopathy. Abnormal thyroid function (TSH or free T4) detected at screening. Patients with known hypothyroidism who are stable on thyroid replacement are eligible.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panobinostat 20 mg<br>Treatment with LBH589 (Panobinostat) 20 mg | Drug: Panobinostat<br>* Panobinostat(20 mg or 30 mg PO) will be administered three times a week on Monday, Wednesday and Friday. Treatment will be given over 21 days followed by a 7 day rest period and repeated every 28 days. Patients will be assessed for toxicity on an ongoing basis and disease assessment will be determined every 2 treatment cycles (8 weeks). Patients will be allowed to continue on treatment for a maximum of eight four week treatment cycles. Treatment will be discontinued if there is evidence of disease progression, unacceptable toxicity and/or at the discretion of the investigator.<br>* Other names: LBH589;|
| Experimental: Panobinostat 30 mg<br>Treatment with LBH589 (Panobinostat) 30 mg | Drug: Panobinostat<br>* Panobinostat(20 mg or 30 mg PO) will be administered three times a week on Monday, Wednesday and Friday. Treatment will be given over 21 days followed by a 7 day rest period and repeated every 28 days. Patients will be assessed for toxicity on an ongoing basis and disease assessment will be determined every 2 treatment cycles (8 weeks). Patients will be allowed to continue on treatment for a maximum of eight four week treatment cycles. Treatment will be discontinued if there is evidence of disease progression, unacceptable toxicity and/or at the discretion of the investigator.<br>* Other names: LBH589;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (CR, Marrow CR + PR) of LBH in Patients With Relapsed or Refractory MDS. | Overall response rate (ORR) is defined by the modified International Working Group (IWG) Response Criteria for MDS. In the marrow, Complete Response (CR) is <= 5% blasts present with normal maturation of all cell lines. In peripheral blood, CR is defined as hemoglobin >= 11 g/dL, ANC >= 1000/mL, and platelets >= 100,000 with 0% blasts present. Partial Response (PR) is defined the same as CR with blasts decreased by >= 50% and >= 5% blasts in the marrow. | Every 8 weeks up to 24 months on-study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression | Time to disease progression is defined as the time between day 1 cycle 1 and time to first documented disease progression. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Every 8 weeks up to 24 months on-study, every 3 months in follow-up until progression of disease | 
| Hematologic Improvement, Including Transfusion Independence | Hematologic measures will include total WBC and platelets | Every 8 weeks up to 24 months on-study | 
| Duration of Response | Duration of response is defined as the time from when objective response is realized until time to first documented disease progression. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Objective Response = CR + PR. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. | Every 8 weeks up to 24 months on-study | 
| Median Time to Treatment Failure | Time to treatment failure is defined as measuring the time between cycle 1 day 1 to discontinuation for any reason. | 24 months | 
| Median Overall Survival | The Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death | 24 months on-study, patients followed every 3 months in follow-up | 
| Safety and Tolerability of LBH589 in Patients With Relapsed/Refractory MDS by Measuring the Number of Participants With Adverse Events | The reported incidence of AEs and SAEs with an onset on or after the initiation of therapy was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic Syndromes (MDS), Refractory, LBH589