Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of LBH489B in adult patients with refractory Cutaneous T-Cell Lymphoma.

Official Title
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A Phase II Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma

Conditions
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Cutaneous T-Cell Lymphoma

Intervention / Treatment
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* Drug: Panobinostat


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Written informed consent obtained prior to any screening procedures Age ≥ 18 years old Patients with biopsy-confirmed stages IB-IVA mycosis fungoides or Sézary syndrome. Patients with SS who have bone marrow involvement are also eligible. Patients must have received at least two prior treatment regimens at least one of which was a systemic therapy regimen. Systemic regimens include oral bexarotene, PUVA, photophoresis, oral corticosteroids, total skin electron bean therapy, chemotherapy such as methotrexate, and interferon. Topical steroids alone are not considered as a treatment regimen. Patients must have had disease progression on or following their most recent treatment regimen or an inadequate response to their most recent treatment regimen. Patients will be accrued to one of two groups: Patients previously treated with oral bexarotene and patients who have not had prior oral bexarotene treatment. Exclusion criteria: Prior treatment with an HDAC inhibitor. Patients with visceral disease including CNS involvement (i.e. stage IVB CTCL). Note; Patients with SS who have bone marrow involvement are eligible. Impaired cardiac function Concomitant use of drugs with a risk of causing torsades de pointes Patients who have received chemotherapy or any investigational drug or undergone major surgery < 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy Less than 3 months since prior electron beam therapy Female patients who are pregnant or breast feeding, or patients of reproductive potential not using an effective method of birth control, and male patients whose sexual partners are women of childbearing potential not using effective birth control Uncontrolled hypertension Concomitant use of any anti-cancer therapy or radiation therapy. Low potency topical steroid use is permitted. Topical bexarotene use is prohibited during the trial Concomitant use of CYP3A4/5 inhibitors. Patients with unresolved diarrhea > CTCAE grade 1 Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589 Other concurrent severe and/or uncontrolled medical conditions Patients who would need to receive valproic acid for any reason during the study or ≤ 5 days prior to starting study drug. Other protocol-defined inclusion/exclusion criteria may apply

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: Previously treated with oral bexarotene<br>Participants received Panobinostat 20 milligrams per day (mg/day) capsule orally, once a day (OD) on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). | Drug: Panobinostat<br> <br> * Other names: LBH589;|
| Experimental: No prior oral bexarotene treatment<br>Participants received Panobinostat 20 milligrams per day (mg/day) capsule orally, once a day (OD) on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). | Drug: Panobinostat<br> <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 of Participants Using the Modified Severity-Weighted Assessment Tool (mSWAT) | Skin response was primarily classified based on an assessment using mSWAT, provided there was documented evidence of stable disease or better in lymph node/viscera.The mSWAT is a tool specifically developed to evaluate the extent of skin disease in CTCL (Olsen et al 2007). Responses in the skin based on SWAT are defined as: Complete Response (CR): no evidence of skin disease Partial Response (PR): ≥ 50% decrease of the modified SWAT score compared with baseline Stable Disease (SD): Neither CR, PR, or PD as compared with baseline, i.e. change from baseline is less than a 50% decrease but also less than a 25 % increase in the modified SWAT score Progressive Disease (PD): ≥ 25% increase in the modified SWAT score compared with baseline. | Baseline up to 6 Months of Follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Overall Response Rate Using mSWAT Skin Score | Estimate of the response rate of participants with resistant cutaneous T-cell lymphoma (CTCL) treated with Panobinostat using the mSWAT skin scores and 95% CI will be analyzed. | Baseline up to Cycle 12, an average of 12 months | 
| Time to Response for Responders | Time to response were summarized. A Kaplan-Meier analysis of time to progression was performed, including estimation and 95% confidence interval of the median time to progression and progression-free survival. | Baseline up to Cycle 12, an average of 12 months | 
| Duration of Response (DOS) | Duration of response and time to response were summarized. A Kaplan-Meier analysis of time to progression was performed, including estimation and 95% confidence interval of the median time to progression and progression-free survival. | Baseline up to Cycle 12, an average of 12 months | 
| Progression-free Survival (PFS) | PFS is defined as time from first dose of study treatment to progression or death due to any cause, based on modified European Society for Bone and Marrow Transplantation (EBMT) criteria per Investigator's assessment | Baseline up to Cycle 12, an average of 12 months | 
| Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 | Skin index measurement (Skindex-29) was a self-administered 29-item dermatology patient-reported outcome measure that explores the domains of Functioning, Emotions and Symptoms. Data from the Skindex-29 came from the Dermatology Survey page. Scoring of the Skindex-29 was performed as per the developers' scoring algorithms. The score for each dimension was found by adding responses of 1 to 5 for each question, with higher scores indicating worse quality of life. The Skindex-29 yields three scale scores that assess emotions scores range from 29 to 116, with higher scores indicating worse health-related quality of life. Average sub-scores for emotions, physical symptoms, and functioning was displayed. | Baseline up to Cycle 12, an average of 12 months | 
| Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 | Skindex-29 was a self-administered 29-item dermatology patient-reported outcome measure that explores the domains of Functioning, Emotions and Symptoms. Data from the Skindex-29 came from the Dermatology Survey page. Scoring of the Skindex-29 was performed as per the developers' scoring algorithms. The score for each dimension was found by adding responses of 1 to 5 for each question, with higher scores indicating worse quality of life. The Skindex-29 yields three scale scores that assess functioning scores range from 29 to 116, with higher scores indicating worse health-related quality of life. Average sub-scores for emotions, physical symptoms, and functioning was displayed. | Baseline up to Cycle 12, an average of 12 months | 
| Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 | Skindex-29 was a self-administered 29-item dermatology patient-reported outcome measure that explores the domains of Functioning, Emotions and Symptoms. Data from the Skindex-29 came from the Dermatology Survey page. Scoring of the Skindex-29 was performed as per the developers' scoring algorithms. The score for each dimension was found by adding responses of 1 to 5 for each question, with higher scores indicating worse quality of life. The Skindex-29 yields three scale scores that assess physical symptoms scores range from 29 to 116, with higher scores indicating worse health-related quality of life. Average sub-scores for emotions, physical symptoms, and functioning was displayed. | Baseline up to Cycle 12, an average of 12 months | 
| Maximum Plasma Concentration (Cmax) of Panobinostat | Cmax is defined as the maximum observed drug concentration observed in plasma over all PK sample concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Cmax will be missing for that subject. Cmax will be reported in units of ng/mL. | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | 
| Time to Peak Concentration (Tmax) of Panobinostat | Tmax is defined as the time at which the Cmax occurs. It will be obtained from the Tmax parameter calculated by WinNonlin®. If there is no measurable Cmax in the subject's PK profile, then Tmax will be missing for that subject. Tmax will be reported in units of h. | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | 
| Area Under the Plasma Concentration AUC0-24, AUC0-48 and AUC 0-infinity of Panobinostat | AUC is defined as the area under concentration-time curve as a measure of drug exposure. The area under the plasma concentration-time curve from time zero to 24 hours. The area under the plasma concentration-time curve from time zero to 48 hours. AUC (0-inf) is defined as the area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | 
| Time of Clast (Tlast) of Panobinostat | Time of Clast (Tlast) will be obtained from the Tlast parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Tlast will be missing for that participants. Tlast will be reported in units of h. | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | 
| Last Observed Plasma Concentration (Clast) of Panobinostat | Clast is defined as the Last observed (quantifiable) plasma concentration (Clast), in units of ng/mL. Blood samples were collected to assess Clast. | Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cutaneous T-Cell Lymphoma, adults, Mycosis Fungoides, Sézary Syndrome, CTCL