Phase I of Histone Deacetylase (HDAC) Inhibitor Panobinostat With Ipilimumab With Unresectable III/IV Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to find out if an investigational drug called panobinostat can be given safely with another drug called ipilimumab. Investigators want to learn more about the side effects of this combination of drugs using different doses of panobinostat and the same dose of ipilimumab.

Official Title
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A Phase 1 Study of HDAC Inhibitor Panobinostat (LBH 589) Administered in Combination With Ipilimumab in Subjects With Unresectable Stage III or Stage IV Melanoma

Conditions
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Melanoma, Skin Cancer

Intervention / Treatment
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* Drug: Panobinostat
* Drug: Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥ 18 years old Participants must be ipilimumab naïve with progressive unresectable Stage III or Stage IV melanoma who are either treatment naïve or may have been treated with up to 3 prior treatments for melanoma (e.g., chemotherapy, biologic or targeted therapy or IL-2). Histologic or cytologic confirmation of stage III or stage IV melanoma Measurable disease at baseline as assessed by CT and/or MRI Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Screening laboratory values must meet the following criteria: white blood count (WBCs) ≥ 2000/μL; Neutrophils ≥ 1500/μL; Platelets ≥ 100 x 10^3/μL; Hemoglobin ≥ 9.0 g/dL; Creatinine Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/minute (using Cockcroft/Gault formula); aspartic transaminase (AST) ≤ 3 x ULN; alanine transaminase (ALT) ≤ 3 x ULN; Total Bilirubin ≤ 1.5 x ULN (except those with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL) Men and women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study and for at least 12 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. Women must have a negative serum pregnancy test within 72 hours prior to the start of investigational product. Exclusion Criteria: Known or suspected brain metastasis, or brain as the only site of disease, with the following exceptions: controlled brain metastasis (no radiographic progression at least 4 weeks following radiation and/or surgical treatment, off steroids for at least 4 weeks, and have no new or progressing neurological signs or symptoms); history of prior malignancy with the exception of carcinoma in situ of the cervix or other malignancy diagnosed > 2 years ago that has undergone potentially curative therapy with no evidence of disease for the last ≥ 2 years and that is deemed by the investigator to be at a low risk of recurrence Active autoimmune disease or a history of known or suspected autoimmune disease with the exception of subjects with isolated vitiligo, treated thyroiditis or resolved childhood asthma/atopy Known human immunodeficiency virus (HIV), active hepatitis A, or hepatitis B or C infection History of any hepatitis (e.g., alcohol or non-alcohol steatohepatitis (NASH), drug- related, autoimmune) Evidence of active infection that requires anti-bacterial, anti-viral, or anti-fungal therapy ≤ 7 days prior to initiation of study drug therapy History of acute diverticulitis, or current chronic diarrhea Active peptic ulcer disease even if asymptomatic History of adrenal insufficiency (including subjects using replacement therapy) Prior organ allograft or allogeneic bone marrow transplantation Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: Myocardial infarction within the past 6 months; Uncontrolled angina within the past 6 months; Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation or Torsades de pointes). Controlled atrial fibrillation by itself is not an exclusion criterion.; Baseline corrected QT interval (QTc) interval greater than 500 milliseconds Baseline toxicities from prior anti-cancer treatments > Grade 1 Inability to be venipunctured and/or tolerate venous access Any major surgery within 4 weeks or a diagnostic procedure (e.g. incision, needle biopsy) within 1 day of study drug administration Any current or recent (within 3 months) gastrointestinal disease that could potentially impact the ability to swallow and/or absorb study drug (i.e., gastrointestinal surgery, malabsorption syndrome) Diabetes mellitus uncontrolled by medication Known drug or alcohol abuse Presence of underlying medical condition that in the opinion of the Investigator or Sponsor could adversely affect the ability of the subject to comply with or tolerate study procedures and/or study therapy, or confound the ability to interpret the tolerability of combined administration of panobinostat and ipilimumab in treated subjects History of allergy to components of ipilimumab or panobinostat, or known allergy to other antibody therapies. WOCBP who are unwilling or unable to use an acceptable method to minimize the risk of pregnancy for the entire study period and for at least 12 weeks after the last dose of investigational product Women who are pregnant or breastfeeding Women with a positive pregnancy test on enrollment or prior to investigational product administration Sexually active fertile men not using effective birth control if their partners are WOCBP Exposure to any investigational drug within 4 weeks of study drug administration. Any anti-cancer therapy (e.g., chemotherapy, biologics, radiotherapy, or hormonal treatment) within 4 weeks or at least 5 half-lives (whichever is longer) of study drug administration Prior therapy with an anti-CTLA4 antibody or an HDAC inhibitor Concurrent chemotherapy, hormonal therapy, immunotherapy regimens, or radiation therapy, standard or investigational Prisoners or subjects who are involuntarily incarcerated Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Dose Escalation of Panobinostat + Ipilimumab. Participants will be assigned to receive a certain dose of panobinostat (5, 10, 15, or 20 mg) along with a dose of ipilimumab of 3 mg per kg (mg/kg) of body weight. | Drug: Panobinostat<br>* Participants will be assigned to receive a certain dose of panobinostat (5, 10, 15, or 20 mg). The dose of panobinostat will depend on the time point the participant enters the study and the side effects of other participants already on the study.<br>* Other names: LBH 589;Drug: Ipilimumab<br>* Dose of ipilimumab of 3 mg per kg (mg/kg) of body weight.<br>* Other names: BMS-734016;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | MTD and recommended Phase 2 dose (RP2D) of panobinostat (PAN), administered in combination with ipilimumab (IPI) in participants with unresectable Stage III or Stage IV melanoma. The goal is to enroll up to 36 patients for determination of the MTD, but will be successfully concluded earlier if 12 patients are accrued at the dose determined to be the MTD, with 3 dose limiting toxicities (DLTs). All participants who receive study any drug therapy will be evaluated for safety. Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests. Triplicate 12-lead electrocardiograms (ECGs) will be collected prior to dosing on Day 1 of induction cycle 1. MTD of PAN in milligrams (mg), with IPI at 3 mg/kg. | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Related Overall Response Rate (ORR) | Tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related Response Criteria (irRC). RECIST: Best overall response from start of treatment until disease progression/recurrence. Immune-related Complete Response (irCR): Complete disappearance of all tumor lesions for at least 4 weeks from date of documentation of irCR. Immune-related Partial Response (irPR): Sum of the products of the 2 largest perpendicular diameters of all index lesions, measured and captured as the Sum of Product of Diameters (SPD) baseline. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD), taking as reference the smallest sum longest diameter (LD) since the treatment started. Immune-related Progressive Disease (irPD): At least a 25% increase in the SPD of all index lesions and new measurable lesions (irSPD) over the nadir SPD calculated for the index lesions. | Up to 36 months | 
| Progression Free Survival (PFS) | Progression Free Survival (PFS): is defined for each participant as the time from first dosing to the first observation of disease progression or death due to any cause. If a subject has not progressed or died at the time of analysis, PFS will be censored on the date of the last disease assessment. PFS will be calculated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progressive Disease (PD) = 20% increase in the sum of the longest diameter of target lesions. | Up to 6 months | 
| Overall Survival (OS) | Overall survival: The time from randomization until death from any cause. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage III Melanoma, Stage IV Melanoma, HDAC Inhibitor