Clinical trial NCT02032810
Conditions: Melanoma Skin Cancer
Keywords: Stage III Melanoma Stage IV Melanoma HDAC Inhibitor
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2014-01-07; Completion date: 2019-09-25
Enrollment: 17 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
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.

Detailed description:

Arms: arm 1: 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.
Interventions: intervention 1: Panobinostat intervention 2: Ipilimumab
Intervention descriptions: intervention 1: 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. intervention 2: Dose of ipilimumab of 3 mg per kg (mg/kg) of body weight.

Protocol documents:
Prot_SAP_000.pdf: 
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  
NCT02032810 
Version 6.0 
December 21, 2015 


MCC 17439 – version 6-  December 21, 2015 
TITLE OF STUDY: 
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 
PROTOCOL NUMBER: 
MCC 17439 
IND NUMBER: 
PRINCIPAL INVESTIGATOR: 
Nikhil Khushalani, MD 
SPONSOR: 
Moffitt Cancer Center 
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MCC 17439 – version 6-  December 21, 2015 
SYNOPSIS 
 
Clinical Protocol MCC 17439 
 
Title of Study: 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 
 
Indication: Advanced Melanoma  
 
Estimated Number of Study Centers and Countries/Regions: 1 site in the United States – Moffitt Cancer 
Center  
 
Study Phase: 1 
 
Research Hypothesis: We hypothesize that addition of a pan-HDAC inhibitor Panobinostat will be well 
tolerated and augment the clinical efficacy of ipilimumab.   
 
The purpose of this study is to evaluate the safety profile, tolerability, and immunoregulatory 
(pharmacodynamic; PD) activity of Panobinostat administered in combination with ipilimumab (anti-CTLA4 
antibody) to subjects with unresectable Stage III or Stage IV melanoma. 
 
Primary Objective: 
• 
To define the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and 
recommended Phase 2 dose (RP2D) of Panobinostat administered in combination with ipilimumab in subjects 
with unresectable Stage III or Stage IV melanoma 
 
Secondary Objectives: 
• 
To describe the preliminary anti-tumor activity of panobinostat administered in combination with 
ipilimumab to subjects with unresectable Stage III or Stage IV melanoma 
• 
To monitor trough concentrations of ipilimumab administered in combination with panobinostat 
• 
To evaluate the pharmacodynamic (PD) effect of the combination dose regimen on biomarkers in 
peripheral blood samples and tumor biopsy specimens 
Exploratory Objectives: 
• 
To explore potential relationships between panobinostat exposure, biomarker measures, anti- tumor 
activity and adverse event, for the combination dose regimen 
 
Study Design: This is a Phase 1, open label, dose escalation cohort study. The study will consist of a dose 
escalation assessment of the safety and tolerability of panobinostat administered concurrently in combination 
with ipilimumab to subjects with advanced melanoma. Treatment will be divided into induction and maintenance 
phases.  
 
It is anticipated that this clinical study will enable selection of the RP2D and dose schedule of this combination 
for further clinical testing. The trial will include an assessment of the PD activity of panobinostat administered in 
combination with ipilimumab. A study schematic is presented below: 
 
Each treatment cycle will be 42 days (6 weeks) during the induction phase, and 84 days (12 weeks) during the 
maintenance phase. Panobinostat will be administered orally thrice weekly (TIW)  on Days 1-42 of each 42-day 
treatment cycle. Ipilimumab will be administered intravenously (IV) over 90 minutes on Days 1 and 22 of each 
treatment cycle. The induction phase will last for 2 treatment cycles. During the maintenance phase, panobinostat 
will be administered orally thrice weekly on Days 1-84 of each 84 day treatment cycle. Subjects will continue 
maintenance treatment with their panobinostat dose regimen until progression of disease, discontinuation due to 
toxicity, withdrawal of consent or any other reason as specified in Section 3.4. 
 
Dose escalation: This is a modification of the traditional 3+3 design. Subjects will be enrolled in successive 
cohorts of 6. An initial cohort of 3 subjects will be enrolled at the given dose level of panobinostat, and 
additional subjects will be added to the same dose level (eg, increase the total number of enrolled subjects from 3 
to 6, 9 or 12) based on a modified version of a toxicity probability interval (TPI) design. The modified TPI 
(mTPI) design uses Bayes rule in a decision theoretic framework to determine the MTD based on a pre-specified 
 
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MCC 17439 – version 6-  December 21, 2015 
target toxicity (eg, dose limiting toxicity; DLT) probability pT. A fixed total number of subjects will be used 
during the dose escalation portion for each arm. As the dose escalation proceeds under this design, the number of 
subjects enrolled at a given dose level depends on the number of the toxicities observed at that dose such that 
multiples of 3 subjects each may be enrolled to enable a dose escalation decision. The MTD is selected as the 
dose with an observed toxicity rate closest to the pre-specified target toxicity probability PT. In this study, a tight 
18% target toxicity (PT) is used. 
 
Dose escalation will evaluate panobinostat at doses ranging from 5 to 20 mg thrice weekly administered in 
combination with ipilimumab at doses of 3 mg/kg. The first cohort will receive panobinostat orally at a dose of 5 
mg thrice weekly; ipilimumab will be administered IV at a dose of 3 mg/kg. Enrollment will proceed with 
administration of escalating doses of panobinostat in combination with ipilimumab as described in Table 1 
below: 
 
Table 1      Dose Escalation regimen for Panobinostat and Ipilimumab 
 
Dose Cohort 
Panobinostat Dose 
Ipilimumab Dose 
1 
5 mg po TIW 
3 mg/kg 
2 
10 mg po TIW 
3 mg/kg 
3 
               15 mg po TIW 
3 mg/kg 
4 
20 mg po TIW 
3 mg/kg 
-1 
5 mg po TIW 
1 mg/kg 
 
 
Additional dose levels of panobinostat beyond 20 mg thrice weekly dose cohort may be added if appropriate 
based on the safety and tolerability profile of the combination, and after consultation and agreement between 
Investigators and Novartis. It is expected that all subsequent dose levels of panobinostat will be no more than 
33% higher than the preceding dose. If cohort 1 shows unacceptable toxicity, then cohort -1 will be tested as 
indicated in table 1. There will be no intra-subject dose escalation. Decisions regarding dose escalation 
between individual dose levels will be guided by the incidence of drug-related dose limiting toxicities (DLTs) 
occurring within 84 days (12 weeks; through Day 42 of induction cycle 2) of initiation of study therapy. This 
observation interval is based upon inclusion of the known median times to onset of common immune-related 
adverse events attributed to ipilimumab (Section 4.3.3.1) and allows for a substantial amount of time for 
unexpected toxicities with the combined administration of panobinostat and ipilimumab to emerge. Subjects who 
do not complete the DLT observation period for reasons other than drug-related toxicity will be replaced. 
 
One of the following five decisions will be made at the end of the DLT period for each cohort of 3-6 or more 
subjects if required based on the number of DLTs observed: 
 
S: stay at the same dose and enroll a cohort of 3 more subjects at that dose E: escalate to the next higher dose by 
enrolling 3 more subjects D: de-escalate to the lower dose, and enroll 3 more subjects at that dose, DU:  
declare the current dose as unacceptable and unsafe, de-escalate to the lower dose, and enroll 3 more subjects at 
the lower dose, or C: Study completed and dose is declared to be the MTD 
 
Note that decisions S or E are allowed by the design when determined that the corresponding doses are safe 
based on the target toxicity. Decisions D or DU are based on evidence of exceeding predetermined toxicity. 
With a target toxicity rate of 18%, allowing any dose with estimated PT in the (17%, 19%) interval to be selected 
as the MTD in this study, and with a maximum fixed total of 12 subjects at the dose escalation phase in each 
arm, the algorithm for dose escalation decisions based on possible total number of subjects at each dose cohort is 
described in Table 3.2. 
 
Based on the above design, escalation to the next higher dose level can occur if DLTs are observed in 0 of 3 or  
1of 6 subjects, in up to 2 of 12 subjects, and so on. If DLTs are observed in a greater number of subjects and 
escalation is not yet permitted, additional subjects in cohorts of 3 will be enrolled at the same dose in order to 
better estimate the true DLT rate at that dose until either the dose is deemed safe and an escalation is allowed, the 
dose is deemed unacceptable and should not be used, or de-escalation is recommended, based on decision rules 
outlined in Table 3.2. At the end of the dose escalation phase, the MTD will be estimated by isotonic regression 
or another Bayesian model-based approach (eg logistic regression) using observed toxicities at all studied doses. 
 
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MCC 17439 – version 6-  December 21, 2015 
The combination dose with posterior probability of toxicity closest to the target toxicity, PT, will be declared as 
the MTD. 
 
The dose escalation plan (see table above) uses a modified Ji design, with dose escalation decisions made 
every three patients.  The trial will enroll 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 at most 3 toxicities. 
 
De-escalation.  The dose escalation plan (Table 1) follows a simple order restriction, that is, each dose 
cohort is as high or higher in both doses compared to all lower cohorts.  While cohort -1 is below cohort 1, 
its relative unacceptable toxicity rate is unclear.  If de-escalation from cohort 1 is needed, it will go to 
cohort -1.  As long as the decisions are to “stay” at the same dose, cohort -1 will be grown to match that of 
cohort 1, and then they will be alternated.  If for the same number of patients treated, the toxicity 
differential between them reaches 2, the other cohort will be dropped from further study.  It is possible that 
both cohorts could be considered “the MTD”.  In such an event, other features such as patient response 
would be used to determine which would be the recommended phase 2 dose (RP2D).  If the MTD is a 
unique cohort, that will also be called the RP2D. 
 
This phase I study design has tended to be applied to a fixed sample size of 30.  Due to the increased 
complexity of this combination-dose trial, we have chosen a sample size of 36. 
 
All available clinical and laboratory data, and the nature, time of onset and time to resolution of DLTs observed 
during dose escalation will be reviewed to determine whether an alternate dose schedule should be examined 
after consultation between the Investigators and Novartis if needed. If agreed upon, the alternate schedule will be 
identified by a protocol amendment and the MTD determined for the revised dose schedule. 
 
In addition to the Investigator’s review of study data, the existing Moffitt Protocol Monitoring Committee (PMC) 
will be utilized to advise on aggregate safety data from this study and more specifically to review all Grade 3 or 
greater immune-related adverse events (irAEs). 
 
Dose Limiting Toxicity: For the purpose of guiding dose escalation decision making, hematologic and non-
hematologic (hepatic versus non-hepatic) DLT will be defined separately and will be determined based on the 
incidence, severity, and duration of study drug-related AEs occurring within 84 days (12 weeks; through Day 42 
of induction cycle 2) of initiation of study therapy. For the purposes of subject management, DLTs will lead to 
dose modification regardless of the cycle in which a DLT occurs (see Section 4.3.6 for specific guidelines). 
 
Duration of Study: It is expected that approximately 24 months will be required to complete enrollment in the 
study. Subjects may discontinue from treatment because of disease progression, unacceptable toxicity, 
withdrawal of consent, or at the discretion of the Investigator. The last visit for each subject will be defined as 
the follow up visit which is no less than 90 days after the subject’s end-of-treatment visit. The last visit is either 
90 days after last dose or whenever a study drug related toxicity has resolved, stabilized, or been deemed 
reversible, whichever is latest. The end of the trial will occur on the last visit of the last patient. 
 
Number of Subjects: A total of up to 36 subjects are expected to be treated on the study.  
 
Study Population: Male and female subjects ≥ 18 years of age with a histologic or cytologic diagnosis of 
unresectable Stage III or Stage IV melanoma and who meet the eligibility criteria (see Sections 3.2.1 and 3.2.2) 
will participate in the study.  
 
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s): Panobinostat is available as 5, 10, 15, and 20 mg capsules and will be administered orally. 
Ipilimumab is available as sterile dose formulation at 5 mg/mL and will be administered intravenously (IV) as an 
infusion over 90 minutes. Ipilimumab is not to be administered as an IV push or bolus injection. Panobinostat 
will be administered at 5, 10 mg, 15 mg, or 20 mg thrice weekly in combination with ipilimumab administered at 
a dose of 3 mg/kg according to the dose schedule in Table 1. Panobinostat doses beyond 20 mg PO TIW may be 
considered if appropriate as outlined under study design. 
. 
Study Assessments and Primary Endpoints: Subjects will be required to visit the investigator’s office or clinic 
for physical examinations, vital sign measurements, ECOG performance status evaluation, adverse event 
 
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MCC 17439 – version 6-  December 21, 2015 
assessment, laboratory testing, pharmacodynamic (PD) sample collection, and administration of study drug as 
per the study schedule. 
• 
Safety Outcome Measures: All subjects who receive study 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. Single 12- lead ECGs will be collected at 
screening, prior to dosing on Day 1 of all treatment cycles (with the exception of induction cycle 1 as above) and 
at the end of treatment.  
 
Adverse events will be categorized using the most current version of MedDRA and adverse events and 
laboratory tests will be graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v4.0. Hepatic adverse events (AST, ALT, T Bili) will also be recorded relative to ULN. 
Immune-related adverse experiences (irAEs) among treated subjects will be specifically assessed as well. 
• 
Efficacy Measures: Tumor response will be determined for all subjects by RECIST 1.1 (see Appendix 3) 
as well as by immune-related response criteria (irRC; see Appendix 4). RECIST 1.1 will be used for statistical 
analysis of efficacy in this study. Treatment decisions related to subject management may be based on the irRC 
criteria, but for the purposes of reporting efficacy RECIT 1.1 criteria will be used. Assessments of tumor status 
will be made during screening, then at 6 weeks and 12 weeks, and subsequently every 12 weeks. Tumor 
assessments at the end-of-treatment (EOT) or 90-day follow-up visit will be performed only if not assessed 
within the prior 12 weeks. Individual subject’s best overall response (BOR) will be assessed, and progression 
free survival (PFS) will be calculated by RECIST 1.1 response criteria. Other endpoints are Objective response 
(OR) defined as BOR outcome of CR or PR for RECIST 1.1, disease control (DC) defined as BOR outcome of 
CR, PR, or Stable Disease by RECIST 1.1. Duration of response and duration of disease control will also be 
calculated.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
Statistical Methods: 
Sample Size Determination: 
Dose Escalation: This is a Phase I dose escalation trial and the sample size at each dose depends on the observed 
toxicity. A total of 36 subjects at the dose-escalation phase allows sufficient number of subjects if needed, e.g. 
more than 6 subjects if dose-limiting toxicities are observed among 2 of 6 subjects, to better estimate the toxicity 
rates per dose, and more accurately determine the MTD. Cohorts of 3 subjects with possible expansions to 6, 9, 
or 12 subjects will be treated at each suggested dose level until MTD is defined. 
 
Statistical Analysis: Safety Analyses: All recorded adverse events will be listed and tabulated by system organ 
class, preferred term, and dose and coded according to the most current version of MedDRA. The incidence of 
adverse events will be tabulated and reviewed for potential significance and clinical importance. Vital signs and 
clinical laboratory test results will be listed and summarized by dose. Any significant physical examination 
findings and results of clinical laboratory tests will be listed. ECG listings will be evaluated by the investigator 
and abnormalities, if present, will be listed. A separate listing and summary of all immune-related adverse events 
(irAE) and inflammatory events regardless of causality (IERC) will be provided. In addition, the irAE rate will 
be estimated and a 90% confidence interval will be constructed for the irAE and the grade 3-4 GI irAE rate in 
each arm, based on the Clopper-Pearson method. The relationship between panobinostat exposure/dose and 
adverse event may be explored graphically and appropriate model may be fit. 
 
Efficacy Analyses: Listings of tumor measurements will be provided by subject and study day in each arm. Each 
individual subject’s best overall response (BOR) and progression free survival (PFS) will be listed based on 
RECIST 1.1 (all subjects during dose escalation and cohort expansion portions of the study). 
To describe the anti-tumor activity of panobiostat administered in combination with ipilimumab, Objective 
Response Rate (ORR) will be tabulated and estimated by 90% confidence intervals based on Clopper-Pearson 
method. Disease Control Rate (DCR) will be similarly summarized. Duration of response and duration of disease 
control will also be calculated for the subjects with such outcome, based on both efficacy criteria. 
 
For all patients, duration of response, and duration of disease control will be estimated by Kaplan-Meier method 
and with 95% confidence intervals based on both response criteria. Kaplan Meier plots will be provided for all 
time-to-event variables at the MTD of each arm, based on both response criteria.  We will also fit the survival 
function using a parametric survival approach, as this approach provides a more accurate estimate of the median 
PFS.  The above analyses will include subjects from the dose expansion as well as subjects from the dose 
escalation portion who were treated at the MTD. Additional assessments eg, sensitivity analyses may be provided 
to assess clinical activity. The relationship between panobinostat exposure/dose and clinical efficacy (e.g. tumor 
response based on both RECIST 1.1 criteria) may be explored graphically and appropriate model may be fit. 
 
 
 
 
 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
TABLE OF CONTENTS 
SYNOPSIS..................................................................................................................................... 2 
Table 1      Dose Escalation regimen for Panobinostat and Ipilimumab .................................... 3 
1 
INTRODUCTION AND STUDY RATIONALE ................................................................. 10 
1.1 
Study Rationale ............................................................................................................. 10 
1.1.1 
Rationale for Subject Population Selection for the Study ..................................... 10 
1.2 
Research Hypothesis ..................................................................................................... 13 
1.3 
Objectives ..................................................................................................................... 13 
Primary Objective: ............................................................................................................. 13 
Secondary Objectives: ........................................................................................................ 13 
Exploratory Objectives: ..................................................................................................... 13 
1.4 
Background ................................................................................................................... 13 
1.4.1 
Summary of Results from Panobinostat Investigational Program ......................... 13 
1.4.1.1 
Preclinical pharmacology .............................................................................. 14 
1.4.1.2 
Animal pharmacokinetics and drug metabolism ........................................... 14 
1.4.1.3 
Non-clinical safety and toxicology ................................................................ 15 
1.4.1.4 
Human pharmacokinetics and Safety ............................................................ 15 
1.4.2 
Summary of Results from Ipilimumab Investigational Program ........................... 16 
1.4.2.1 
Nonclinical Pharmacology ............................................................................ 16 
1.4.2.2 
Clinical Safety ............................................................................................... 17 
Immune-Related Adverse Events (irAEs) ................................................................ 17 
1.4.2.3 
Clinical Efficacy ............................................................................................ 18 
1.4.3 
Rationale for Starting Doses of Panobinostat and Ipilimumab ............................. 19 
1.4.4 
Rationale for Dose Escalation Phase I Design ...................................................... 19 
1.4.5 
Rationale for use of Immune-related Response Criteria (irRC) to Guide Clinical 
Care and Assessment of Clinical Activity ............................................................................ 20 
1.4.6 
Rationale for use of Blood and Tumor Tissue Biomarkers ................................... 20 
1.5 
Overall Risk/Benefit Assessment ................................................................................. 21 
2 
ETHICAL CONSIDERATIONS .......................................................................................... 24 
2.1 
Good Clinical Practice .................................................................................................. 24 
2.2 
Institutional Review Board/Independent Ethics Committee ......................................... 25 
2.3 
Informed Consent ......................................................................................................... 25 
3 
INVESTIGATIONAL PLAN ............................................................................................... 25 
3.1 
Study Design and Duration ........................................................................................... 25 
Table 3.1 Dose Escalation regimen for Panobinostat and Ipilimumab ............................... 26 
Table 3.2 Decision Rules on dose escalation based on number of DLTs** .................... 27 
3.2 
Study Population ........................................................................................................... 28 
3.2.1 
Inclusion Criteria ................................................................................................... 28 
3.2.2 
Exclusion Criteria .................................................................................................. 29 
3.2.3 
Women of Childbearing Potential ......................................................................... 30 
3.3 
Concomitant Treatments ............................................................................................... 31 
3.3.1 
Prohibited and/or Restricted Concomitant Treatments.......................................... 31 
3.3.2 
Other Restrictions and Precautions........................................................................ 31 
3.4 
Discontinuation of Subjects from Treatment ................................................................ 31 
4 
TREATMENTS .................................................................................................................... 32 
4.1 
Study Treatments .......................................................................................................... 32 
4.1.1 
Investigational Product .......................................................................................... 32 
4.1.1.1 
Ipilimumab (BMS-734016) ........................................................................... 32 
4.1.1.2 
PANOBINOSTAT (LBH-589) ...................................................................... 33 
4.1.2 
Handling and Dispensing ...................................................................................... 33 
 
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MCC 17439 – version 6-  December 21, 2015 
4.2 
Method of Assigning Subject Identification ................................................................. 34 
4.3 
Selection and Timing of Dose for Each Subject ........................................................... 34 
4.3.1 
Study Treatments During Dose Escalation ............................................................ 34 
Table 4.1 Dose Escalation regimen for Panobinostat and Ipilimumab ........................... 34 
4.3.2 
Administration of ipilimumab ............................................................................... 35 
4.3.3 
Dose Limiting Toxicity ......................................................................................... 35 
4.3.3.1 
Definition of non hematologic dose-limiting toxicity ................................... 35 
A: Hepatic Non-Hematologic DLT ............................................................................ 35 
B: Non-Hepatic Non-Hematologic DLT.................................................................... 35 
C: Immune-related Adverse Experiences (irAEs) and DLT ................................... 36 
Dose-limiting immune-related AEs will be defined as the follows: ........................ 36 
D: Infusion Reaction and DLT .................................................................................. 36 
4.3.3.2 
Definition of hematologic DLT ..................................................................... 36 
4.3.4 
Duration of Treatment ........................................................................................... 37 
4.3.5 
Intra-subject Dose Escalation ................................................................................ 37 
4.3.6 
Guidelines for Dose Modification ......................................................................... 37 
Table 4.2 Criteria for dosing delays, dose-reductions, and re-initiation of treatment due to study 
drug-related QTcF abnormalities .............................................................................................. 38 
Table 4.3  Dose Modification Guidelines for Panobinostat and Ipilimumab ............ 40 
4.3.7 
Supportive Care Guidelines ................................................................................... 41 
4.3.7.1 
Guidelines For Infusion Reactions ................................................................ 41 
4.3.7.2 
Guidelines for Management of Gastrointestinal AEs and ............................. 42 
4.4 
Blinding/Unblinding ..................................................................................................... 42 
4.5 
Destruction and Return of Study Drug ......................................................................... 42 
4.5.1 
Destruction of Study Drug ..................................................................................... 42 
5 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 43 
5.1 
Flow Chart/Time and Events Schedule ........................................................................ 43 
Table 5.11  Screening Days -28 to -1 .................................................................................. 43 
Table 5.12  During Treatment, Day 1 onward .................................................................. 44 
5.2 
Study Materials ............................................................................................................. 44 
5.3 
Safety Assessments ....................................................................................................... 45 
5.3.1 
Laboratory Test Assessments ................................................................................ 45 
Hematology ...................................................................................................................... 45 
Serum Chemistry ............................................................................................................ 45 
Serology ............................................................................................................................ 46 
Other Assays .................................................................................................................... 46 
Urinalysis ......................................................................................................................... 46 
Coagulation Profile ......................................................................................................... 46 
Other Analyses ................................................................................................................ 46 
5.4 
Efficacy Assessments ................................................................................................... 46 
5.5 
Biomarker Assessments ................................................................................................ 46 
5.5.1 
Absolute Lymphocyte Count ................................................................................. 47 
5.5.2 
Serum and Intracellular Cytokines ........................................................................ 47 
5.5.3 
Flow Cytometry and Cellular Immune Assays ...................................................... 47 
5.5.4 
mRNA Expression Analysis .................................................................................. 47 
5.5.5 
Tumor Biopsies ..................................................................................................... 47 
6 
ADVERSE EVENTS ............................................................................................................ 48 
6.1 
Serious Adverse Events ................................................................................................ 48 
6.1.1 
Serious Adverse Event Collection and Reporting ................................................. 49 
6.2 
Nonserious Adverse Events .......................................................................................... 50 
6.2.1 
Nonserious Adverse Event Collection and Reporting ........................................... 50 
 
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MCC 17439 – version 6-  December 21, 2015 
6.3 
Laboratory Test Abnormalities ..................................................................................... 51 
6.4 
Pregnancy ..................................................................................................................... 51 
6.5 
Overdose ....................................................................................................................... 51 
6.6 
Other Safety Considerations ......................................................................................... 51 
7 
DATA MONITORING COMMITTEE ................................................................................ 52 
8 
STATISTICAL CONSIDERATIONS .................................................................................. 52 
8.1 
Sample Size Determination .......................................................................................... 52 
Table 8.1 Decision Rules on dose escalation based on number of DLTs** .................... 52 
8.2 
Endpoint Definitions ..................................................................................................... 53 
8.2.2 
Efficacy Endpoints ................................................................................................ 53 
8.2.2.1 
Efficacy Endpoints based on RECIST 1.1 ..................................................... 53 
8.2.2.2 
Efficacy Endpoints based on Immune Related Criteria (irCR) ..................... 54 
8.2.3 
Biomarker Endpoints ............................................................................................. 54 
8.3 
Analyses ........................................................................................................................ 55 
8.3.1 
Demographics and Baseline Characteristics .......................................................... 55 
8.3.2 
Efficacy Analyses .................................................................................................. 55 
8.3.3 
Safety Analyses ..................................................................................................... 55 
8.3.4 
Biomarker Analyses .............................................................................................. 55 
9 
STUDY MANAGEMENT ................................................................................................... 56 
9.1 
Compliance with the Protocol and Protocol Revisions ................................................. 56 
9.2 
Monitoring .................................................................................................................... 56 
9.3 
Records ......................................................................................................................... 57 
9.3.1 
Records Retention ................................................................................................. 57 
9.3.2 
Study Drug Records .............................................................................................. 57 
9.3.3 
Case Report Forms ................................................................................................ 57 
10 
REFERENCES...................................................................................................................... 59 
APPENDIX 1 – ECOG Performance Status ................................................................................. 62 
APPENDIX 2 – CYP3A4 Inhibitors, Inducers, and Substrates .................................................... 63 
APPENDIX 3 – RECIST 1.1 Criteria ........................................................................................... 64 
APPENDIX 4 – Immune Related Response Criteria .................................................................... 66 
4.1 
Tumor Assessments ...................................................................................................... 66 
4.2 
Radiological Assessment of Tumor Lesions................................................................. 66 
4.2.1 
CT/MRI ................................................................................................................. 66 
4.2.2 
Bone Scans ............................................................................................................ 67 
4.3 
Definition of Measurable / Non-Measurable Lesions ................................................... 67 
4.4 
Definition of Index / Non-Index Lesions ...................................................................... 67 
4.5 
Definition of New Lesions ............................................................................................ 67 
4.6 
Tumor Response Using Immune-Related Response Criteria (irRC) ............................ 68 
4.6.1 
Confirmation Scans ............................................................................................... 68 
4.6.2 
Calculation of Sum of Product of Diameters (SPD) for irRC (irSPD) .................. 68 
4.6.3 
Impact of New Lesions on irRC ............................................................................ 68 
References: ...................................................................................................................... 69 
APPENDIX 5 – irAE Gastrointestinal Management Algorithm ................................................... 70 
APPENDIX 6 – irAE Hepatic Management Algorithm ................................................................ 71 
APPENDIX 7 – irAE Endocrine Algorithm.................................................................................. 72 
APPENDIX 8 – Novartis SAE fax cover sheets ........................................................................... 73 
  
 
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MCC 17439 – version 6-  December 21, 2015 
1 
INTRODUCTION AND STUDY RATIONALE  
1.1 
Study Rationale 
 
1.1.1 
Rationale for Subject Population Selection for the Study 
Since 1950, the global incidence of malignant melanoma has risen 690% while mortality rate 
increased by 165%. Even with the recent decline in the incidence of several cancers, the 
incidence of malignant melanoma is continuing to rise.1 While overall survival has improved 
for early stage tumors because of early detection and improved surgical treatment, recurrent 
and/or metastatic malignant melanoma remains largely a fatal disease. High-dose interferon 
alfa-2b (IFN) is currently approved by US Food and Drug Administration (FDA) for use as 
adjuvant therapy in patients with high risk of relapse. Treatment with high-dose IFN is, 
however, associated with only 10% improvement in recurrence-free survival, 0-10% 
improvement in overall survival and very significant toxicities that limit compliance with its 
use.2,3,4 
Dacarbazine, an FDA and EU approved chemotherapeutic agent for metastatic 
melanoma, provides an objective tumor response in only 5% to 20% of patients. These 
responses are short-lived (median duration of response = 6 months), and there is no 
associated increase in survival.5 High-dose IL-2 therapy is also approved for use in the 
metastatic setting. However, significant toxicity limits its clinical utility. Fotemustine, with an 
overall response rate of 15%, 6 months median duration of response and 2 months median 
time to progression, is approved in parts of EU for use in patients with metastatic melanoma.6 
Over the last 30 years many chemotherapeutic drugs, including the aggressive Dartmouth 
combination regimen (dacarbazine, cisplatin, carmustine, and tamoxifen)7 and newer drugs 
such as temozolomide,8 have been explored but have not resulted in significant improvement 
in survival when compared to dacarbazine. In fact, only one agent to date has been shown to 
extend survival in metastatic disease, the CTLA-4 abrogating antibody ipilimumab. In two 
phase III randomized trials, one in previously treated disease, and one in untreated stage IV 
melanoma, ipilimumab prolonged survival compared to either a vaccine alone cohort in pre-
treated patients, or with chemotherapy compared to chemotherapy alone in untreated patients 
9, 10. Malignant melanoma continues represent a considerable unmet medical need based on 
the significant but moderate efficacy and moderately severe toxicities of ipilimumab alone 
and the rising incidence of the melanoma in the world-wide.  
 
Molecular profiling studies in melanoma subjects have demonstrated that tumors in 40 to 
60% of subjects harbor activating mutations in BRAF. The V600E mutation is most common 
and accounts for greater that 80% of all mutations seen in BRAF.11-13 Suppression of 
activating BRAF mutations in human melanoma cells results in inhibition of the MAPK/ERK 
cascade causing growth arrest and promoting apoptosis.14,15 These and several other 
preclinical studies supporting an important role of MAPK signaling in melanoma have 
provided a strong scientific rationale for RAF as an important target in melanoma. Several 
selective RAF and MEK small molecule inhibitors are being tested at present in Phase 1 and 
Phase 2 clinical trials. Among these, R05185426 (PLX4032, Vemurafenib), a selective 
inhibitor of V600E mutant B-RAF kinase, has already demonstrated significant antitumor 
activity and high response rates in B-RAF V600E mutation positive melanoma subjects in 
Phase 1 and Phase 2 studies.16 At ASCO 2011, the first results of a randomized phase III trial 
of vemurafenib compared with Dacabazine showed that both overall survival and relapse-free 
survival were significantly prolonged in the vemurafenib group compared to the  
chemotherapy control arm17, 18 These observations have established B-RAF inhibition as a 
 
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MCC 17439 – version 6-  December 21, 2015 
legitimate therapeutic target in melanoma, but there are still significant unmet needs in 
unresectable melanoma, since most patients treated with vemurafenib will ultimately 
progress within 12 months, and at least 50% of all stage IV melanoma patients will have no 
chance to benefit from a B-RAF inhibitor.  
As is outlined in Section 1.4.1 below, panobinostat is a potent and selective inhibitor of 
histone deacetylase (HDAC)19-24. Pre-clinical data from 
 laboratory 
at Moffitt indicate that HDAC inhibitors including LHB589 have unexpected activity as 
immunomodulatory agents, with impact on the in vitro activity of antigen presenting cells, 
decreased immune-inhibiting cytokines from tumor cell lines, and decreased immune 
inhibition of effector T cells. Additional work in his laboratory has shown that in in vivo 
animal models of the poorly immunogenic B16 melanoma, addition of panobinostat can 
augment the clinical benefit of ipilimumab.  Data from other laboratories, including 
 
 showed that the addition of a pan-HDAC inhibitor (LAQ824) 
augmented the anti-tumor activity of adoptively transferred cytolytic T cells that were 
melanoma antigen-specific25 Further work using panobinostat in vitro has shown that 
inhibition of STAT3, changes in CCL22 that allow for Th1 polarization, and decreases in IL-
6 and other immunosuppressive cytokines may have a beneficial effect upon the use of 
immune modulators like ipilimumab when used in melanoma10. Taken together, these data 
indicate that testing whether an HDAC inhibitor like panobinostat adds to the immune and 
clinical effects of ipilimumab in patients with melanoma is warranted.  
 
Malignant melanoma is also an immune responsive disease. The earliest evidence provided 
by epidemiological observations that immunosuppressed patients have an increased incidence 
of melanoma, and in some (<1%) immunocompetent patients the primary melanoma lesions 
spontaneously regressed. Infiltration of melanoma lesions by T lymphocytes has been shown 
to be associated with a better clinical prognosis.26 Advances in immunology and oncology 
have revealed a dynamic interplay between host and tumor, suggesting that the ability of the 
tumor to evade the immune response can be an important determinant of the clinical course 
of the disease.20 Immunologic interventions to treat cancer can potentially be achieved 
through the induction of an immune response (active immunotherapy), administration of 
antibodies (passive immunotherapy), and/or stimulation of effector cells with cytokines or 
antibodies (immunostimulation). These approaches have resulted in the therapeutic use of 
immune- modulating agents such as IFN-α and IL-2 for the treatment of melanoma. In 
addition to a direct cytotoxic effect, IFN-α has also been demonstrated to stimulate natural 
killer (NK) cell activity and to regulate the expression of histocompatibility antigens or 
tumor- associated antigens.27 Similarly, IL-2 modulates the immune system by stimulating 
the growth and activity of T lymphocytes, human lymphocyte antigen (HLA)-restricted or - 
non-restricted cytotoxic T cells and induces the production of many cytokines, such as tumor 
necrosis factor (TNF), IFN-γ and IL-1.28  Ipilimumab, an antibody that abrogates the 
regulatory activity of cytotoxic-T lymphocyte antigen-4 (CTLA-4) on T cells and augments T 
cell proliferation, lytic activity and secretion of IL-2, has been shown to have anti-tumor 
activity in melanoma, renal cell cancer and other histologies 29-32. 
 
Ipilimumab has been tested extensively at doses of 3 mg/kg given as induction treatment four 
times over 12 weeks, or at 10 mg/kg given as induction therapy over 12 weeks, followed by 
maintenance therapy every 12 weeks until progression or relapse in patients with metastatic 
melanoma 33-34. The results of a phase III randomized trial of ipilimumab alone at 3 mg/kg or 
with a peptide vaccine compared with vaccine alone have been described, showing that 
 
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MCC 17439 – version 6-  December 21, 2015 
ipilimumab significantly prolongs survival in previously treated patients with advanced 
melanoma compared to the control arm.35 The median OS for patients receiving ipilimumab 
alone or with a peptide vaccine was 10.1 and 10.0 months, respectively, compared with 6.4 
months for the vaccine-alone control arm (P = .003 and P < .001, and hazard ratios of 0.66 
and 0.68, compared with vaccine alone). In that trial, the rate of grades 3-4 dose limiting side 
effects was 8.1%, with the majority of events being immune related adverse events (irAEs) 
related to the immune mechanism of action of ipilimumab.  Predominant events were skin 
related, colitis, hypophysitis and hepatitis. Virtually all dose limiting and other toxicities 
were reversible with the use of systemic steroids or in rare cases the TNF blocking antibody 
Infliximab.  Recently, the results of a large placebo-controlled phase III study in 502 patients 
treated with first-line DTIC with or without ipilimumab (10 mg/kg) were presented and 
published10. In that trial, survival was prolonged in the ipilimumab+DTIC containing arm 
compared to chemotherapy alone with p=0.0009 and a hazard ratio of 0.72 favoring 
ipilimumab+DTIC. Median survivals in that trial were 11.1 months for the ipilimumab arm 
versus 9.1 months for the control chemotherapy cohort. The safety data from that first-line 
trial confirmed that incidence of irAEs was indeed dose related but also determined by the 
ipilimumab partner, since in that trial grades 3-4 colitis was uncommon, at less than 6%, 
grades 3-4 hypophysitis was not seen, but elevated ALT/AST was quite common, observed 
in 18-21% of patients in the ipilimumab+DTIC cohort. Of note is that grades 3-4 elevation of 
ALT/AST has been seen at a rate of 2% or less in trials of ipilimumab at 3 or 10 mg/kg alone. 
Nonetheless, ipilimumab at 10 mg/kg was felt to be well tolerated with DTIC, and when 
tested alone, dose limiting irAEs were observed in approximately 20% of patients33-34. As in 
the second line trial at 3 mg/kg described above, at a dose of 10 mg/kg, virtually all 
ipilimumab associated irAEs were rapidly reversible with systemic steroids and rarely the use 
of TNF-blocking antibody infliximab. No treatment related deaths were observed in the 
ipilimumab + DTIC group. Two additional trials provide further support of the likelihood that 
ipilimumab at 3 mg/kg will be well tolerated with another immune modulator In a trial of 
high dose interleukin 2 and ipilimumab, the drugs were given at a dose of 720,000 IU/kg and 
3 mg/kg respectively repetitively36. The overall irAE rate of 14% was similar to that for 
ipilimumab alone at 3 mg/kg, and no treatment related deaths were reported, but a 22% ORR 
was described. Tarhini et al described follow-up data of from 36 patients in a trial conducted 
with the other CTLA-4 antibody from Pfizer, tremelimumab at 15 mg/kg, administered 
concurrently with high dose interferon alpha 2b37. In that trial, grade 3-4 dose limiting colitis 
was seen in 14% of patients, and grade 3-4 ALT-AST in 11%, not different than that seen 
with tremelimumab alone at that dose. These data suggest that ipilimumab at doses of 3 
mg/kg will be well tolerated, and that given the collective expertise of the principal and co-
investigators of this trial with the drug, the risk of significant and dose limiting side effects 
with the combination of ipilimumab and LBH589 will be minimized.  
  
Considered together, the observations summarized above suggest that a therapeutic regimen 
combining a HDAC inhibiting agent capable of immune modulation with an immune-
stimulating agent designed to potentiate the host antitumor response would be a rational, 
novel and well tolerated approach for the treatment of melanoma. It is likely that a HDAC 
inhibitor such as panobinostat could potentiate the antitumor immune response induced by 
ipilimumab by virtue of inducing important immune stimulating cytokines, decreasing levels 
of immune suppressive cytokines, increasing APC’s function and enhancingT-cell responses 
by epigenetic modulation of critical transcription factors (ie, EOMES). A careful phase I dose 
escalating trial is planned to evaluate biologic endpoints as well as the toxicity of the 
combination regimen. 
 
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1.2 
Research Hypothesis 
The purpose of this study is to evaluate the safety profile, tolerability, and immunoregulatory 
(pharmacodynamic; PD) activity of panobinostat administered in combination with 
ipilimumab (anti-CTLA4 antibody) to subjects with unresectable Stage III or Stage IV 
melanoma. We will test the hypothesis that panobinostat administered in combination with 
ipilimumab will be well tolerated and that the addition of panobinostat will augment the 
clinical efficacy of ipilimumab.  
 
1.3 
Objectives 
Primary Objective: 
• 
To define the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated 
dose (MTD) and recommended Phase 2 dose (RP2D) of panobinostat administered in 
combination with ipilimumab in subjects with unresectable Stage III or Stage IV melanoma 
 
Secondary Objectives: 
• To describe the preliminary anti-tumor activity of panobinostat administered in combination 
with ipilimumab to subjects with unresectable Stage III or Stage IV melanoma 
• To evaluate the pharmacodynamic (PD) effect of the combination regimen on biomarkers in 
peripheral blood samples and tumor biopsy specimens 
 
Exploratory Objectives: 
• To explore potential relationships between panobinostat exposure, biomarker measures, 
anti-tumor activity, and adverse event, for each combination dose regimen 
 
1.4 
Background 
 
1.4.1 
Summary of Results from Panobinostat Investigational Program  
 
Panobinostat (LBH589) belongs to a structurally novel cinnamic hydroxamic acid class of 
compounds and is a pan-inhibitor of Class I, II and IV histone deacetylases (HDACs). 
HDACs are involved in the deacetylation of histone and non-histone cellular proteins, 
targeting lysine groups on chromatin and transcription factors and various non-histone 
proteins such as p53, tubulin, heat shock protein 90 (Hsp90), and retinoblastoma protein 
(Rb). In addition to modulation of the acetylation state and function of histones, treatment of 
tumor cells with Panobinostat also resulted in increased acetylation of cytoplasmic proteins, 
including Hsp90, a target of HDAC6 and a major chaperone protein required for the 
stabilization of many key proteins implicated in cancer development and growth onco-
proteins. Panobinostat-induced acetylation of Hsp90 inhibited the protein-stabilizing function 
of Hsp90 and led to the destabilization and resulting degradation of anti-tumor targets, such 
as break point cluster region-abelson (BCR-abl, HER2/neu, estrogen receptor, androgen 
receptor, and anti- apoptotic proteins such as phospho-AKT, JAK-2 V617F, pJAK-2. 
Consequently, cells which exhibited high in vitro sensitivity to Panobinostat include those 
cultured from tumors known to be driven by the aforementioned onco-proteins. Panobinostat 
treatment of the HER+-driven BT474 breast cancer cell line resulted in increased acetylation 
 
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of Hsp90 and depletion of Hsp90 client onco-proteins. As a further illustration of the effect of 
Panobinostat on Hsp90 client proteins, Panobinostat treatment of CML cell lines or primary 
blasts cells derived from patients in CML blast crisis resulted in the degradation of wild type 
and mutant BCR-abl, including the T3151 BCR-abl mutant resistant to inhibition by all 
tyrosine kinase inhibitors (TKIs) currently approved for the treatment of CML. Consistent 
with its pan-HDAC inhibition in HL (Hodgkin’s lymphoma) cell lines, Panobinostat 
treatment resulted in effects on levels of JAK/STAT signaling proteins in all tested HL cell 
lines. HL is a disease model characterized by aberrant activation of signaling pathways, 
including constitutive activation of several components of the JAK/STAT pathway. 
Panobinostat treatment increased the expression of STAT1 and decreased the expression of 
both total STAT6 and activated phospho-STAT6; both effects are known to be interrelated 
and to correlate with tumor cell death. These results indicated that Panobinostat modulated 
the JAK/STAT pathway in a manner that was consistent with reversing effects associated 
with HL cell survival leading to apoptosis. Panobinostat has shown antitumor activity in 
preclinical models and cancer patients and has been formulated as an oral capsule and a 
solution for intravenous (i.v.) injection. Both the oral and i.v. formulations are currently 
being investigated in Phase IB/II studies in advanced solid tumors and hematological 
malignancies. Two Phase III studies with oral Panobinostat are ongoing in relapsed/refractory 
multiple myeloma (MM) and in post-transplant Hodgkin’s lymphoma (HL) patients in 
complete remission who are at high risk for relapse. 
 
1.4.1.1 
Preclinical pharmacology 
The drug was devised through iterative design and combinatorial approaches, and has shown 
inhibitory activity on purified total cellular HDAC and on most HDAC isoforms in 
nanomolar concentrations. It induced expression of cell-cycle control genes including 
CDKNIA (p21) and inhibited proliferation of a variety of tumor cell lines at low nanomolar 
concentrations. panobinostatt has demonstrated differential toxicity for tumor cells versus 
normal cells and has shown anti-tumor activity in cultured tumor cells which was associated 
with persistent HDAC inhibition, including melanoma cell lines.  The drug exhibited 
differential antiproliferative activity against a broad range of solid tumors cell lines and high 
sensitivity in lymphomas and hematologic malignancies cell lines, including acute myeloid 
leukemia (AML) and MM, and induced consistent tumor growth control in various tumor-
bearing xenografted mice and increased histone-H3 and -H4 acetylation in excised tumors. 
Panobinostat has shown synergistic or additive anti-tumor effects in combination with other 
anti-cancer agents such as trastuzumab, docetaxel, bortezomib or standard cytotoxic agents 
e.g., doxorubicin, fludarabine, Ara-C in murine xenograft and human in vitro models. 
 
1.4.1.2 
Animal pharmacokinetics and drug metabolism 
The absolute oral bioavailability of panobinostat is  ~50% in dogs, ~6 to 22% in rat, and 
2.4% in rabbits. It has moderate plasma protein binding that is independent of plasma 
concentrations. Its in vivo metabolism in dogs, rabbits and rats involves biotransformation 
reactions including reduction, oxidation, hydrolysis, with glucuronidation found only in rats. 
Panobinostat is a potent inhibitor of CYP2D6 in vitro, but weak inhibitor in vivo (clinical 
increase of dextromethorphan AUC of 1.6-fold).  It shows a weak time-dependent inhibition 
of CYP3A in vitro. Based upon drug-interaction modeling, Panobiostat is not expected to 
clinically interact with sensitive CYP3A substrates 
 
CYP3A4 appears to be the main enzyme involved in the oxidative metabolism of 
 
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panobinostat, (70-98% in human liver microsomes). Clinically, metabolism by CYP3A 
contributes to only ~40% of total panobinostat clearance as determined from the magnitude 
of drug interaction elicited with ketoconazole. 
 
1.4.1.3 
Non-clinical safety and toxicology 
Panobinostat has shown genotoxic potential in bacterial and eukaryotic systems. It has a 
preclinical signal for QT prolongation based on in vitro electrophysiological 
investigations and in vivo studies using telemeterized dogs. In the oral repeated doses 
toxicology studies, the primary target organs were identified as the erythropoietic, 
myelopoietic, and lymphatic system. Other secondary target organs included the 
gastrointestinal (GI) tract, reproductive system, thyroid and bone. Evidence of reversibility 
was observed for all white blood cells. 
 
Oral administration of panobinostat to rats and rabbits is associated with embryo-fetal 
toxicity (increased resorptions/decreased live litters). Although no major malformations were 
observed, the incidence of fetal skeletal variations and anomalies was increased. Based upon 
the results of preclinical studies, hematology parameters, thyroid function and cardiac 
function assessments have been included in clinical trials.  Panobinostat poses a reproductive 
risk to men and women of child bearing potential; therefore use of adequate birth control 
methods is required while a patient is on drug and for 12 weeks after the last dose. 
 
1.4.1.4 
Human pharmacokinetics and Safety 
In humans, panobinostat exhibits a linear PK profile following i.v. administration. 
panobinostat exposure is nearly dose- proportional at doses below 60 mg following oral 
administration; inter-patient variability in exposure (AUC) is 60% with oral and 40% with 
i.v. panobinostat (coefficient of variability [CV]).  The drug has a rapid oral absorption Tmax 
= 1 hour. Absolute bioavailability is 30% and elimination t1/2 is approximately 15 hours. 
 
The clinical development of panobinostat has been conducted with both an i.v. and oral 
formulation 19-24 The major dose-limiting-toxicity (DLT) for both formulations administered 
as a single agent is reversible thrombocytopenia. For the i.v. formulation, a weekly i.v. 
dosing scheme (Day 1, Day 8 every 21 days) is currently used in clinical studies with 
thrombocytopenia being managed by dose and schedule adjustment. For the oral formulation, 
a pooled analysis of data from phase I/II studies indicates that thrombocytopenia is the most 
common lab abnormality of any grade and of Grade 3-4 in patients treated with the three-
times-a-week (TIW), every week (QW) and every-other-week (QOW) schedules. The median 
time to Grade 3 thrombocytopenia appears to be shorter with the QW dosing as compared 
with the QOW dosing. The magnitude of platelet count decline is dose-dependent and related 
to the baseline platelet count. The median time to recovery from severe thrombocytopenia, 
Grade 3-4 to Grade 2 or below, is approximately 8 days for doses up to 40 mg in solid tumors 
and lymphomas. The median time to recovery from severe thrombocytopenia is much longer 
(up to approximately 74 days) for doses up to 60 mg used in hematologic malignancies. 
Preliminary evidence in patients with solid tumors and lymphomas suggests that switching 
from the QW to the QOW schedule may be more effective than other dose modifications for 
reducing the recurrence of thrombocytopenic events 
 
QT prolongation, a known class effect of HDAC inhibitors, appears to be formulation, 
dose and schedule dependent. For the i.v. formulation, QTcF prolongation of clinical 
relevance (Grade ≥3 with absolute increase >500 msec) was seen in 4/15 patients (26.7%) 
 
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treated with panobinostat daily x 7, in 2/29 patients (6.8%) treated with the daily x 3 schedule 
(1 Grade 3 and 1 Grade 4 torsade de pointes) and in 2/56 (3.6%) patients treated with the 
weekly dosing schemes. With the “intermittent” oral dosing (TIW QW and TIW QOW) used 
in clinical trials, QTcF >500 msec is uncommon (6/635 patients, 0.9%) and noted only with 
the oral QW schedule. The mean QTc changes from baseline across all oral doses and 
schedules have been limited to <10 msec and observed during the first week of cycle 1 
treatment. These changes did not coincide with the maximum concentration/time profile of 
the drug in plasma. No torsade de pointes has been reported in clinical trials with intermittent 
i.v. or oral dosing regimens 
 
Asymptomatic T-wave abnormalities including inverted T-waves, flat T-waves, and 
biphasic T-waves are the most common ECG abnormalities reported to date with 
panobinostat. Asymptomatic sinus tachycardia has also been noted in approximately 40% of 
patients who received i.v. or oral panobinostat 
 
Other common toxicities included fatigue (dose-related, but Grade 3-4 limited with 
both oral schedules), nausea, vomiting and diarrhea (more common with oral, and mostly 
Grade 1-2, regardless of the schedule; manageable with loperamide). Based on these 
preclinical and clinical observations, the safety and efficacy of panobinostat as a single agent 
and in combination with other chemotherapeutic agents is being explored in multiple Phase 
IB, II and III studies in patients with solid tumors and hematologic malignancies.  
 
1.4.2 
Summary of Results from Ipilimumab Investigational Program 
Enhancement of the magnitude and potency of tumor antigen-specific adaptive cellular 
responses by T cells continues to be a major goal for cancer immumotherapy. Full activation 
of naive T cells requires not only stimulation of antigen receptor by peptide/major 
histocompatibility complexes, but also by costimulatory signals. 29 These signals are provided 
by the engagement of CD28, which is constitutively expressed on T- cell surface, with CD80 
and CD86 molecules which are present on antigen presenting cells (APC). CD28-B7 
costimulatory signals are critical for the induction of T-cell proliferation, cytokine secretion, 
and effector functions which ultimately translate into clinical effects.30 CTLA-4 is an 
activation-induced T-cell surface molecule that binds CD80 and CD86with greater avidity 
than CD28. CTLA-4 ligation down regulates T-cell responses, which results in an abrogation 
of the clinical effects provided by T-cell activation.32 Blockade of CTLA-4/B7 interactions 
results in an increase in T-cell activation. 
 
1.4.2.1 
Nonclinical Pharmacology 
Ipilimumab is a fully human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody 
(mAb). In vitro studies were performed with ipilimumab to demonstrate that it is specific for 
CTLA-4, actively inhibits CTLA-4 interactions with CD80 and CD86, does not show any 
cross-reactivity with human CD80, CD86 negative cell lines, and stains the appropriate cells 
without non-specific cross-reactivity in normal human tissues, as demonstrated by 
immunohistochemistry. Ipilimumab does cross-react with CTLA-4 in non-human primates 
including cynomolgus monkeys, but the half life of ipilimumab is shortened by species-level 
differences in immunogenicity of the product protein. Ipilimumab was originally produced 
and purified from a hybridoma clone. Subsequently, a transfectoma (Chinese Hamster Ovary 
[CHO] cell) has been generated that is capable of producing more ipilimumab on a per cell 
basis than the hybridoma. Material from the transfectoma will be utilized in this and future 
ipilimumab clinical studies. Biochemical, immunologic and in vivo preclinical primate 
 
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assessments demonstrated similarity between hybridoma and transfectoma derived 
ipilimumab. Please see the current version of the Investigator Brochure.26 
 
1.4.2.2 
Clinical Safety 
Safety data are available for more than 2900 subjects treated in 25 completed clinical trials in 
multiple tumor types at a range of ipilimumab doses between 0.3 mg/kg and 20 mg/kg 31-34. 
Most experience with ipilimumab exists at the 3 mg/kg and 10 mg/kg dose levels. Subjects 
who received ipilimumab at 3 mg/kg were treated in clinical trials conducted early in the 
development program and received either a single or multiple injections. Intra-subject dose 
escalation indicated that subjects with no response at 3 mg/kg dose level may respond to 9 
mg/kg. Ipilimumab doses of up to 10 mg/kg are currently being investigated for the treatment 
of melanoma and other tumor types. Nonetheless, in March 2011, ipilimumab at 3 mg/kg for 
4 induction doses was approved by the FDA for metastatic melanoma. Drug-related adverse 
events (AE) were reported in studies with ipilimumab as monotherapy as well as in 
combination with vaccines, cytokines or chemotherapy. The AE profile of ipilimumab is 
relatively well characterized. Among subjects who received ipilimumab at 10 mg/kg (N = 
658) treatment-related AEs were reported in 85.3% (561/658) of subjects. AEs of grade 3 or 
higher were reported in 31.2% (205/658) of subjects. Most frequently reported treatment-
related AEs of any grade (reported in ≥ 10% of subjects who received ipilimumab at 10 
mg/kg) included diarrhea, fatigue, rash, pruritus, nausea, pyrexia, vomiting, and colitis. 
Treatment-related AEs associated with the use of ipilimumab generally tend to be immune-
mediated effects. These AEs, termed immune-related adverse events (irAEs) presumably 
represent the impact of CTLA-4 inhibition and immune modulation on normal tissue 
function. Drug-related Grade 3 or 4 SAEs in subjects who received ipilimumab include: 
rash/desquamation, pruritus, uveitis, speech impairment, abdominal pain, diarrhea/colitis, 
nausea/vomiting, transaminase elevation, adrenal insufficiency, panhypopituitarism and atrial 
fibrillation. Some of these events, such as rash/desquamation, pruritus, uveitis, 
diarrhea/colitis, transaminase elevation, adrenal insufficiency and panhypopituitarism, may 
represent drug induced irAEs. Please refer to the Package Insert (PI) for the latest update on 
SAEs.29 
 
As of 30 Jun 2009, study-drug related deaths based on investigator’s assessment were 
reported in approximately 1% (35/3800) of subjects treated with ipilimumab. Eleven of 35 
study-drug related deaths were reported for subjects known to have received ipilimumab at 
10 mg/kg multiple doses; 17 of the 35 related deaths were reported on studies that are 
ongoing and remain blinded to treatment. While a causal role of ipilimumab in these 35 
deaths could not be ruled out, confounding factors were identified in most of these cases. 
 
Immune-Related Adverse Events (irAEs) 
An immune-related adverse event (irAE) is defined as any adverse event associated with drug 
exposure and consistent with an immune-mediated event. Disease progression, infections and 
other etiologic causes are ruled out or deemed unlikely as contributing to the event. 
Supportive data, such as autoimmune serology tests or biopsies, are helpful but 
not necessary to deem an event an irAE. Events of unclear etiology which were plausibly 
“immune mediated” have been conservatively categorized as irAEs even if serologic or 
histopathology data are absent. These irAEs likely reflect a loss of tolerance to some self 
antigens or an unchecked immune response to gut or skin flora. Some breakthrough of 
immunity may be inseparably linked to the clinical antitumor activity of ipilimumab. 
 
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Among the 658 subjects who received ipilimumab at 10 mg/kg, 73.4% (483/658) developed 
any grade irAEs which predominately involved the GI tract, endocrine glands, liver, or skin. 
GI irAEs of any grade were reported for 40.0% (263/658) of subjects, and grade 3-4 GI irAEs 
were reported for 12.6% (83/658) of subjects. Inflammatory hepatotoxicity of any grade was 
reported for 9.0% (59/658) of subjects, and grade 3-4 inflammatory hepatotoxicity was 
reported for 6.4% (42/658) of subjects. Endocrinopathy of any grade was reported for 7.6% 
(50/658) of subjects, and grade 3-4 endocrinopathy was reported for 2.4% (16/658) of 
subjects. With few exceptions these irAEs were clinically manageable and reversible with 
supportive care or corticosteroids. In responding subjects, addition of corticosteroids does not 
appear to have a temporal relationship to change in objective tumor response. Immune-
related AEs associated with ipilimumab appear to be dose dependent. In the dose-ranging 
study, CA184022, overall incidence of irAEs increased with increasing ipilimumab doses of 
0.3 to 10 mg/kg. Comparison of the 3 and 10 mg/kg dose groups also showed an increased 
overall frequency of grade 3-4 irAEs for the higher dose group (the difference was 18.4%). 
The overall safety profile for the 10 mg/kg ipilimumab was consistent with that of the 3 
mg/kg ipilimumab. Please refer to the most updated PI. 29 
 
1.4.2.3 
Clinical Efficacy 
Treatment with ipilimumab has demonstrated clinically important and durable tumor 
responses in several malignancies including melanoma, prostate cancer, and renal cell 
carcinoma. The most extensively studied tumor type has been malignant melanoma. Early 
results show that ipilimumab is active in subjects with Stage IV malignant melanoma. The 
objective responses with ipilimumab have been observed across a spectrum of doses and 
schedules. Based on a preliminary analysis for study MDX010-15 involving ipilimumab 10 
mg/kg multiple doses, approximately 34% of subjects (N = 23) were progression-free at 6 
months and about 17% were progression-free at 1 year. In comparison, for study MDX010-
08 involving ipilimumab 3 mg/kg multiple doses, about 11% subjects (N = 37) had 
progression-free at 6 months and about 6% at 1 year.  
 
The results of a phase III randomized trial of ipilimumab alone at 3 mg/kg or with a peptide 
vaccine compared with vaccine alone have been described, showing that ipilimumab 
significantly prolongs survival in previously treated patients with advanced melanoma 
compared to the control arm.35 The median OS for patients receiving ipilimumab alone or 
with a peptide vaccine was 10.1 and 10.0 months, respectively, compared with 6.4 months 
for the vaccine-alone control arm (P = .003 and P < .001, and hazard ratios of 0.66 and 0.68, 
compared with vaccine alone). In that trial, the rate of grades 3-4 dose limiting side effects 
was 8.1%, with the majority of events being immune related adverse events (irAEs) related to 
the immune mechanism of action of ipilimumab.  Predominant events were skin related, 
colitis, hypophysitis and hepatitis. Virtually all dose limiting and other toxicities were 
reversible with the use of systemic steroids or in rare cases the TNF blocking antibody 
Infliximab.  Recently, the results of a large placebo-controlled phase III study in 502 patients 
treated with first-line DTIC with or without ipilimumab (10 mg/kg) were presented and 
published10. In that trial, survival was prolonged in the ipilimumab+DTIC containing arm 
compared to chemotherapy alone with p=0.0009 and a hazard ratio of 0.72 favoring 
ipilimumab+DTIC. Median survivals in that trial were 11.1 months for the ipilimumab arm 
versus 9.1 months for the control chemotherapy cohort. The results of these two trials led to 
the approval of ipilimumab for metastatic melanoma in March, 2011. 
 
 
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MCC 17439 – version 6-  December 21, 2015 
Consistent with the known mechanism of action of ipilimumab the reduction in tumor burden 
in melanoma studies was characterized by novel patterns of measurable clinical effect. In 
addition to objective response as measured by RECIST 1.1, novel patterns of clinical activity, 
which are related to the immunological mechanism of action of ipilimumab, were reported. 
These patterns were characterized by overall reductions from baseline in total tumor burden 
after the appearance of new lesions and/or after an initial tumor burden increase. 
 
1.4.3 
Rationale for Starting Doses of Panobinostat and Ipilimumab 
Based on data from the nonclinical pharmacology studies and monotherapy panobinostat 
studies the TIW dose regimen is hypothesized to result in target inhibition of HDAC activity 
while maintaining an acceptable safety profile. Therefore, the TIW dose regimen of 
PANOBINOSTAT has been selected for this study. In the ongoing monotherapy study, the 
10 and 20 mg TIW dose cohorts have demonstrated adequate safety and tolerability. In this 
study, PANOBINOSTAT will be administered as a formulated capsule that has been used in 
the clinic. The major toxicities of PANOBINOSTAT, being thrombocytopenia and cardiac in 
nature, do not overlap with the major known side effects of ipilimumab. Both 3 and 10 mg/kg 
doses of ipilimumab have been associated with anti-tumor activity in melanoma subjects. 
Based on the potential for better tolerability, the lower, 3 mg/kg, dose has been selected as 
the starting dose of ipilimumab for this study. 
 
1.4.4 
Rationale for Dose Escalation Phase I Design 
The 3+3 design that is commonly used in Phase I oncology trials, though widely accepted 
and used mainly due to ease of implementation, has known limitations. These include a lack 
of statistical basis for dose escalation decisions and for determination of the MTD, i.e. the 
MTD is not based on a target toxicity probability, it typically underestimates the true MTD, 
and may allow patients to be treated at suboptimal doses. Prior information on the adverse 
event profile of ipilimumab at the higher studied dose of 10mg/kg based on 658 treated 
subjects reported a 31.2% toxicity rate for drug-related adverse events of grade 3 or above.26 
In addition previous data on panobinostat indicate a less than 5% toxicity rate for drug-
related adverse events of grade 3 or above.28 Whereas results from nonclinical studies suggest 
that synergistic/additive antitumor activity from combining ipilimumab with panobinostat 
may be seen in the clinic, potential benefit versus risks with this combination have not been 
evaluated in humans. In this first clinical study with the combination, therefore, it is 
reasonable to assume that the maximum acceptable ≥ Grade 3 toxicity rate at the MTD of the 
combination should not exceed the Grade 3 toxicity rate for ipilimumab (combination partner 
with a higher Grade 3 toxicity rate when administered as monotherapy). The target toxicity 
and the toxicity interval at the MTD will be 18% and 17-19%, respectively, and will be 
consistent with keeping the ipilimumab dose at 3 mg/kg for this dose escalation trial. These 
proposed target toxicity rates, with the tight interval is also consistent with the general 
principles of the widely used 3+3 dose escalation design in oncology studies. Based on the 
above, and the need to better monitor ongoing toxicities due to the potential risk of combined 
side effect, the modified TPI (mTPI) design40 which uses Bayes rule under decision theoretic 
framework, was selected as an appropriate design for this study. The design provides more 
confidence in estimating the toxicity rate at each dose, selects the MTD based on a target 
toxicity probability, and it correctly identifies the true MTD more often than the 3+3 design, 
based on simulation results. The mTPI was selected among other Phase I oncology designs 
including Bayesian designs such as CRM, due to additional advantages of simplicity of 
 
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MCC 17439 – version 6-  December 21, 2015 
implementation and treating fewer subjects at suboptimal or at toxic doses. 
 
1.4.5 
Rationale for use of Immune-related Response Criteria (irRC) to Guide Clinical 
Care and Assessment of Clinical Activity 
In prior ipilimumab clinical studies, particularly those in metastatic melanoma, clinical 
efficacy appears to be characterized by objective tumor response (CR and PR), durable stable 
disease (commonly lasting 6 or more months in subjects receiving 10 mg/kg ipilimumab), 
and stable disease evolving to objective response after more than a year of follow-up in the 
absence of alternative anti-cancer therapy. In addition, melanoma subjects receiving 
ipilimumab who are found to have new lesions at the first follow-up tumor assessment and 
who are therefore scored as progressors by the mWHO or RECIST criteria have been 
observed to have stable or decreasing tumor burden in spite of the presence of new lesions. 
Subjects with such “mixed responses” have been reported to go on to continued reduction in 
tumor burden in the absence of alternative anti-cancer therapy and objective tumor response 
by any measure. 
The irRC were developed to provide a guide for clinical care of subjects on immunotherapy. 
Subjects with stable (irSD) or significantly decreasing (irPR) tumor burden despite the 
presence of new lesions remain on study and continue to receive study drug. Subjects with 
increasing tumor burden (irPD) are declared progressors and taken off study drug. To account 
for the various spectra of patterns of new lesions, measurable new lesions are added to the 
calculation of tumor burden (e.g. added to the SPD of the index lesions). Thus, subjects with 
many large new lesions will be scored as irPD even if the index lesions are stable or 
decreasing. 
 
1.4.6 
Rationale for use of Blood and Tumor Tissue Biomarkers 
Previous ipilimumab studies explored in their main study design a variety of potential 
biomarkers in melanoma patients. Results from studies CA184004 and CA184007 suggested 
the possible biomarkers listed below for further research: 
• An increase in peripheral-blood Absolute Lymphocyte Count (ALC) was associated with 
benefit (Best Overall Response of Complete Response, Partial Response, or prolonged Stable 
Disease (SD), i.e. SD lasting at least 24 weeks from first dose) and occurred in a dose-
dependent fashion favoring 10 mg/kg ipilimumab. In addition to change in ALC over time, 
ALC value just prior to a third dose of ipilimumab also was associated with benefit. 
 
We will also evaluate FOXP3 and IDO tumor tissue expression at baseline as predictive of 
clinical benefit, as well as flow cytometry of CD4 and CD8 T cells for Ki67, EOMES and 
ICOS, predictive markers that have been found to be associated with benefit using 
ipilimumab.  Serum cytokine assays with a multiplex analysis for IL-6, IL-10 and gamma 
interferon will be conducted, as well as T cell intracellular staining for those cytokines and 
assessment of allo MLR reactivity as a marker of T cell integrity.  
 
A mean increase in the percentage of activated (HLA-DR+), CD4+ and CD8+ T cells and 
central memory (CD45-RO and CCR9+) T-cells and a mean decrease in percent of naive 
CD4+ and CD8+ T-cells in Week 4 and Week 12 post-ipilimumab treatment samples has 
been observed in several studies. Based on these results, a biomarker plan is included in this 
trial which allows sample collection for biomarker analyses to determine the effects of 
PANOBINOSTAT on the immune-regulatory effects of ipilimumab treatment. Subjects will 
 
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be asked to give blood samples, serum and/or tumor tissue samples for predictive, 
pharmacodynamic and exploratory biomarker research.  
  
1.5 
Overall Risk/Benefit Assessment 
Pan-HDIs have been shown to have antitumor activity both in vitro and in vivo. In 
addition to inducing cell cycle arrest and apoptosis of tumor cells, these compounds are also 
endowed with immunoregulatory properties. For instance, the pan-HDI TSA has been shown 
to up-regulate MHC and costimulatory molecules on melanoma cells, making them more 
susceptible to attack by IFN-γ secreting T-cells. In addition, Vo et al. have demonstrated that 
in vivo treatment of melanoma bearing mice with the hydroxamic acid analogue pan-HDI 
LAQ824, significantly augment the anti-melanoma activity of adoptively transferred antigen-
specific T-cells25. Furthermore, studies in our lab have shown that LAQ824 inhibits the 
production of IL-10 in APCs rendering these cells more inflammatory and capable of 
effectively prime naïve antigen-specific CD4+ T-cells and able of restoring the 
responsiveness of tolerant T-cells (Wang et al. J Immunol. 186(7): 3986-96, 2011  
 
Panobinostat (LBH589) which is a potent cinnamic hydroxamic acid analog 
deacetylase inhibitor, induces apoptosis in multiple tumor cell lines in vitro at nanomolar 
concentrations. Panobinostat belongs to the same family of hydroxamic acid derivatives than 
LAQ824, but has the following advantages: (i) It is an oral agent, (ii) Clinical studies in 
humans have shown that panobinostat has a better safety profile than LAQ824 (which was 
removed from further clinical development due to cardiac toxicity) and, (iii) LBH displays 
more potent HDAC inhibition than LAQ824 both in vitro and in vivo.  Indeed, recent studies 
in our lab have confirmed that LBH589 is more potent than LAQ824 in inhibiting the 
proliferation of B16 melanoma cells in vitro (Fig. 1A).  Of note, panobinostat-treated B16 
cells are rendered immunogenic due to their enhanced expression of MHC class I and II 
molecules and the costimulatory molecule CD40 (Fig. 1B). In addition to its effect upon 
melanoma cells, panobinostat also influences the inflammatory status of APCs since 
treatment of these cells resulted in a dose-dependent inhibition of IL-10 that is accompanied 
by increased production of the pro-inflammatory cytokine IL-12 (Fig. 1C). These 
inflammatory APCs are in turn, better activators of naïve antigen-specific CD4+ T-cells in 
vitro (Fig. 1D).  
 
 
 
 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
 
 
 
 
 
 
The results above with LBH589 have been recently extended into human melanoma studies. 
First, in vitro treatment of several human melanoma cells, including BRAF WT (SKMEL21), 
BRAF mutants (WM983A, WM35 and WM164) or melanoma cells with constitutively 
activated STAT3 (WM793), with nanomolar doses of LBH589 resulted in a dose dependent 
inhibition in cell growth (Fig. 2A). Cell lines WM983, SKMEL21 and WM793 were the 
most sensitive to LBH589. Of note, normal melanocytes (HEMn-LP) were not affected by 
LBH589 at all the doses evaluated. Second, exposure of human melanoma cells to LBH589 
resulted in cell cycle arrest in G1 (Fig. 2B) and induction of apoptosis (Fig. 2C) as 
demonstrated by increased cleaved PARP in LBH589-treated WM793 and WM983A cells. 
Third, treatment with LBH589 resulted in increased expression of MHC class I and the 
costimulatory molecules CD80, CD86 and CD40 in WM983A human melanoma cells 
(Fig.2D).  
 
 
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MCC 17439 – version 6-  December 21, 2015 
 
 
 
 
 
 
 
 
 
 
The immunomodulatory effects of panobinostat upon melanoma cells, APCs and T cells 
together with the demonstration by others that panobinostat inhibits STAT3, a transcriptional 
activator of IL-10, and induces changes in CCL22 that allow for Th1 polarization points to 
this HDI as a novel immune adjuvant with the potential to enhance the therapeutic efficacy of 
immune stimulating agents like anti-CTLA4 antibodies for the treatment of melanoma. 
Indeed, we recently treated B16 melanoma bearing mice with anti-CTLA4 antibodies alone, 
LBH589 alone or a combination thereof. The therapeutic regimen combining panobinostat 
and CTLA4 blockade significantly delayed melanoma growth in vivo as compared to either 
agent alone shown in Fig 1E.  
 
Currently available treatment options for advanced melanoma including Ipilimumab and 
Vemurafenib, as well as high-dose interleukin-2, produce a spectrum of significant toxicities 
while providing meaningful clinical benefit. Demonstration of significant clinical responses 
and prolonged overall survival in subjects with advanced melanoma with the mutant selective 
inhibitor vemurafenib (PLX4032) has provided clinical validation for mutated B-RAF as a 
therapeutic target in this tumor type. Duration of response with this agent as monotherapy, 
however, appears to be limited. Ipilimumab is a potent immunomodulatory agent that has 
already demonstrated durable clinical benefit and benefit in overall survival in subjects with 
advanced melanoma. When considered together with the data on observed 
additive/synergistic anti-tumor activity and promotion of its immune effects in nonclinical 
studies and their distinct mechanisms of action, administration of panobinostat in 
combination with ipilimumab can provide a novel treatment regimen that could have the 
potential to provide significant sustained clinical benefit in this subject population. Potential 
benefits from this combination, therefore, outweigh the potential risks for toxicity. 
Assessment of safety and tolerability of panobinostat has been addressed in a monotherapy 
Figure 2. Effects of LBH589 in human melanoma cells. (A) Human melanoma cells were treated with the 
indicated concentrations of LBH589 for 48 hours and subject to an MTS cell proliferation assay. (B) Cell cycle 
analysis of fixed WM793 and WM983A human melanoma cells stained with propidium iodine. (C) LBH589 
induced apoptosis of WM793 and WM983A as determined by cleaved PARP (D)WM983A cellswere treated with 
LBH for 48 hours and the expression of MHC class I, CD40, CD80 and CD86 were determined by flow cytometry 
using specific antibodies.  
 
 
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MCC 17439 – version 6-  December 21, 2015 
study. In this study, panobinostat monotherapy has been administered to over 50 subjects, 
and continues to exhibit an acceptable tolerability profile that supports its further exploration. 
There is also preliminary evidence of clinical activity by way of subjects with advanced 
cancer continuing with panobinostat administration for prolonged periods of time. Principal 
AEs related to panobinostat administration in the clinic have comprised of constitutional 
symptoms including fatigue, nausea, diarrhea, vomiting, anorexia, skin rash and decreased 
appetite. These events are easily monitored by protocol defined clinical assessments 
(scheduled physical examinations, repeated vital sign measurements, and clinical laboratory 
assessments) and/or can be managed by supportive measures in conjunction with protocol-
specified dose modifications. No eye disorders associated with changes in the retina or the 
optic nerve have been reported in the clinic to date, as was observed among individual 
animals at high doses in the nonclinical studies. Given the superficial nature of these lesions, 
this finding is not considered prohibitive to continued evaluation of panobinostat in the clinic. 
The most common adverse events with ipilimumab are inflammatory in nature, presumably 
related to the immune-based mechanism of action, correlated with clinical activity and nearly 
always reversible with medical management. The most frequently reported drug-related 
adverse events include diarrhea, colitis, endocrinopathies, hepatitis, and rash. There is 
potential for overlapping GI toxicity with the combination. Appropriate monitoring plan and 
guidance on early intervention and management of these events, as well as dose modification 
guidelines have been included in the protocol. In order to minimize the overall risks to 
participating subjects, this protocol has inclusion-exclusion criteria appropriate to the 
population and proposed dosing regimens, exclusionary screening tests, and specific follow-
up safety assessments. Based on the potential adverse event profile, appropriate clinical, 
laboratory, and management algorithms have been incorporated into the protocol. The 
adverse events (AEs) and serious adverse events (SAEs) will be reviewed on an ongoing 
basis by the PI and the clinical research team and will be reviewed periodically with an 
independent DMC to look for trends and any safety issues. Since both PANOBINOSTAT 
and ipilimumab are experimental agents, it is possible that unforeseen, unknown, or 
unanticipated reactions can occur during the study. 
 
2 
ETHICAL CONSIDERATIONS  
2.1 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by 
the International Conference on Harmonisation (ICH) and in accordance with the ethical 
principles underlying European Union Directive 2001/20/EC and the United States Code of 
Federal Regulations, Title 21, Part 50 (21CFR50). The study will be conducted in compliance 
with the protocol. The protocol and any amendments and the subject informed consent will 
receive Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approval/favorable opinion prior to initiation of the study.  
 
Study personnel involved in conducting this study will be qualified by education, training, 
and experience to perform their respective task(s). This study will not use the services of 
study personnel where sanctions have been invoked or where there has been scientific 
misconduct or fraud (eg, loss of medical licensure, debarment). 
 
 
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MCC 17439 – version 6-  December 21, 2015 
2.2 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, written and dated approval from the IRB/IEC will be obtained for the 
protocol, consent form, subject recruitment materials/process (eg, advertisements), and any 
other written information to be provided to subjects. The investigator will also provide the 
IRB/IEC with a copy of the Investigator Brochure or product labeling information and any 
updates. 
The investigator or sponsor will provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments and administrative letters) according 
to regulatory requirements or institution procedures. 
 
2.3 
Informed Consent 
Investigators will ensure that subjects, or, in those situations where consent cannot be given 
by subjects, their legally acceptable representatives, are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. The informed consent form will adhere to the ethical principles that 
have their origin in the Declaration of Helsinki. 
 
3 
INVESTIGATIONAL PLAN  
3.1 
Study Design and Duration 
This is a Phase 1 open label study of panobinostat administered in combination with 
ipilimumab. Subjects with unresectable Stage III or Stage IV melanoma who meet the 
eligibility criteria will undergo screening evaluations within 28 days prior to initiation of 
study therapy.  The study will consist of a dose escalation assessment of the safety and 
tolerability of oral panobinostat administered concurrently in combination with ipilimumab. 
Treatment will be divided into induction with ipilimumab and panobinostat and a 
maintenance phase with panobinostat alone consistent with the general principles of 
ipilimumab therapy. It is anticipated that this evaluation will enable selection of the RP2D of 
this combination for further clinical testing. A study schematic is presented below: 
 
Each treatment cycle will be 42 days (6 weeks) during the induction phase, and 84 days (12 
weeks) during the maintenance phase. Panobinostat will be administered orally TIW on Days 
1-42 of each 42 day treatment cycle. Ipilimumab will be administered intravenously (IV) 
once every 3 weeks on Days 1 and 22 of each treatment cycle. The induction phase will last 
for up to 2 treatment cycles. During the maintenance phase, panobinostat will be 
administered orally TIW on Days 1-84 of each 84 day treatment cycle. Subjects will continue 
maintenance panobinostat treatment with their designated combination dose regimen until 
progression of disease, discontinuation due to toxicity, withdrawal of consent or any other 
reason as specified in Section 3.4. 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
Table 3.1 Dose Escalation regimen for Panobinostat and Ipilimumab 
 
Dose Cohort 
Panobinostat Dose 
Ipilimumab Dose 
1 
5 mg po TIW 
3 mg/kg 
2 
10 mg po TIW 
3 mg/kg 
3 
               15 mg po TIW 
3 mg/kg 
4 
20 mg po TIW 
3 mg/kg 
-1 
5 mg po TIW 
1 mg/kg 
 
Dose escalation: Subjects will be enrolled in successive cohorts of 3. An initial cohort of 3 
subjects will be enrolled at the given dose level, and additional cohorts of 3 subjects may be 
added to the same dose level (e.g. increasing the total number of enrolled subjects from 3 to 
6, 9 or 12) based on a modified version of a toxicity probability interval (TPI) design 
introduced by Ji et al.40 The modified TPI (mTPI) design uses Bayes rule in a decision 
theoretic framework to determine the MTD based on a target toxicity (eg, dose limiting 
toxicity; DLT) probability pT. A fixed number of subjects, 36, will be used during this dose 
escalation study. As the dose escalation proceeds under this design, the number of subjects 
enrolled at a given dose level depends on the number of the toxicities observed at that dose 
such that multiple cohorts of 3 subjects each may be enrolled to enable a dose escalation 
decision. The MTD is selected at the end of dose escalation as the dose with an observed 
toxicity rate closest to the pre-specified target toxicity probability PT. In this study, an 18% 
target toxicity (PT) is used. Background rationale as basis for selection of this target toxicity 
has been previously outlined in Section 1.4.6.  Dose escalation will evaluate panobinostat at 
doses ranging from 5 to 20 mg TIW administered in combination with ipilimumab at a dose 
of 3 mg/kg. The first cohort will receive panobinostat orally at a dose of 5 mg PO TIW; 
ipilimumab will be administered IV at a dose of 3 mg/kg. Enrollment of successive cohorts of 
subjects will proceed with administration of escalating doses of panobinostat in combination 
with ipilimumab. Additional dose levels of panobinostat beyond the 20 mg PO TIW dose 
cohort may be added if appropriate based on the safety and tolerability profile of the 
combination, and after consultation and agreement between Investigators and Novartis. It is 
expected that all subsequent dose levels of panobinostat will be no more than 33% higher 
than the preceding dose. If the first dose cohort is demonstrated to have unacceptable 
toxicity, dose level -1 will be instituted with 5 mg PO TIW of panobinostat and ipilimumab 
at 1 mg/kg.  
 
There will be no intra-subject dose escalation. Decisions regarding dose escalation 
between cohorts will be guided by the incidence of drug-related dose limiting toxicities 
(DLTs) occurring within 84 days (12 weeks; through Day 42 of induction cycle 2) of 
initiation of study therapy. If three patients complete their 84 day period  of treatment without 
DLT, then at least three additional patients must exceed 9 weeks without MTD being reached 
to be able to dose escalate. This DLT observation interval is based upon inclusion of the 
known median times to onset of common immune-related adverse events attributed to 
ipilimumab (see Section 4.3.5.1) and allows for a substantial amount of time for unexpected 
toxicities with the combined administration of panobinostat and ipilimumab to emerge. 
Subjects who do not complete the DLT observation period for reasons other than drug-related 
toxicity will be replaced. One of the following five decisions will be made at the end of the 
DLT period for each cohort of 3 subjects based on the number of DLT’s observed: 
 
 
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MCC 17439 – version 6-  December 21, 2015 
S: stay at the same dose and enroll a cohort of 3 more subjects at that dose 
E: escalate to the next higher dose by enrolling 3 more subjects 
D: de-escalate to the lower dose, and enroll 3 more subjects at the lower dose, or 
DU: declare the current dose as unacceptable and unsafe, de-escalate to the lower dose, and 
enroll 3 more subjects at the lower dose 
C: Study completed and dose is declared to be the MTD 
Decisions S or E are allowed by the design if determined that the corresponding doses are 
safe based on the target toxicity. Decisions D or U are based on evidence of exceeding 
predetermined toxicity. With a target toxicity rate of 18%, allowing any dose with estimated 
PT in the (17%, 19%) interval to be selected as the MTD in this study, and with a maximum 
fixed total of 36 subjects at the dose escalation phase in each arm, the algorithm for dose 
escalation decisions based on possible total number of subjects at each dose cohort is 
described in Table 3.2 below. 
 
Table 3.2 Dose Escalation Algorithm for each arm: modified TPI design 
 
Dose Escalation: This is a Phase I dose escalation trial and the sample size at each dose depends 
on the observed toxicity, and a total of 36 subjects at the dose-escalation phase allows sufficient 
number of subjects if needed, e.g. more than 6 subjects if dose-limiting toxicities are observed 
among 2 of 6 subjects, to better estimate the toxicity rates per dose, and more accurately 
determine the MTD. Cohorts of 3 subjects with possible expansions to 6, 9, or 12 subjects will be 
treated at each suggested dose level until MTD is defined. 
 
In this protocol, we will be using a new phase I trial approach (Table 3.2), modified from a design 
from Ji et al43.  This approach provides a broader phase I experience than the traditional 3+3 
design, thus allowing for a more robust choice of an MTD.  While setting the target toxicity rate 
at 18%, this design allows further examination of a dose when 2 DLTs occur among 6 patients, 
while still keeping the observed toxicity at the MTD well managed (it is below 26% for sample 
sizes ≥ 9).  Moreover the MTD will exploit the isotonic nature of dose escalation in determination 
of the MTD.   
 
Table 3.2 Decision Rules on dose escalation based on number of DLTs**  
N*       Observed DLTs per cohort and treatment decisions 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
3 
 
E 
 
S 
 
DU  
DU - 
- 
- 
- 
- 
- 
6 
 
E 
 
E 
  
S 
 
DU  
DU  
DU  
DU 
9 
 
E 
 
E 
 
S 
 
D 
 
DU  
DU  
DU 
12 
 
E 
 
E 
 
E 
 
C 
 
DU  
DU  
DU 
N* =number of subjects treated at a given dose level 
S: stay at the same dose and enroll a cohort of 3 more subjects at that dose 
E: escalate to the next higher dose by enrolling 3 more subjects 
D: de-escalate to the lower dose, and enroll 3 more subjects at the lower dose, or 
DU: declare the current dose as unacceptable and unsafe, de-escalate to the lower dose, and enroll 
3 more subjects at the lower dose 
C: Study completed and dose is declared to be the MTD 
**for MTD target toxicity pT=18%, and allowing any dose with pT in (17%, 19%) to be selected  
The modifications involve escalating the dose whenever the observed toxicity rate is below 17% 
and using the N-1st patient to define the change when the toxicity rate exceeds 19% and N ≥ 9 to 
account for the fact that the design is being used in cohorts of 3 rather than continuously as 
 
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MCC 17439 – version 6-  December 21, 2015 
designed by Ji et al43. 
 
Based on the above design, escalation to the next higher dose level can occur if DLT’s are 
observed in 0 of 3 or 6 subjects, in up to 1 of 6 subjects, in up to 2 of 12 subjects, and so on. 
If DLTs are observed in a greater number of subjects and escalation is not yet permitted, 
additional subjects in cohorts of 3 will be enrolled at the same dose in order to better estimate 
the true DLT rate at that dose until either escalation is allowed, the dose is deemed 
unacceptable and should not be used, or de-escalation is recommended, based on Table 3.2.  
All available clinical and laboratory data, and the nature, time of onset and time to resolution 
of DLTs observed during dose escalation will be reviewed to determine whether an alternate 
dose schedule should be examined after consultation between the Principal Investigator and 
the Data Monitoring Committee (DMC) if needed. If agreed upon, the alternate schedule will 
be identified by a protocol amendment and the MTD determined for the revised dose 
schedule. 
 
This phase I study design has tended to be applied to a fixed sample size of 30.  Due to the 
increased complexity of this combination-dose trial, we have chosen a sample size of 36. 
 
3.2 
Study Population 
The study population consists of ipilimumab naïve subjects with unresectable Stage III or 
Stage IV melanoma who satisfy the inclusion and exclusion criteria. 
For entry into the study, the following criteria MUST be met. No exceptions will be granted. 
 
3.2.1 
Inclusion Criteria 
1) 
Signed Written Informed Consent 
The signed informed consent form prior to the performance of any study related procedures 
that are not considered part of standard of care. 
 
2) 
Target Population 
a) 
Subjects who are 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 (eg, chemotherapy, biologic or targeted therapy or IL-2).  
b) 
Histologic or cytologic confirmation of stage III or stage IV melanoma 
c) 
Measurable disease at baseline as assessed by CT and/or MRI 
d) 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
e) 
Screening laboratory values must meet the following criteria  
i)  
WBCs                  ≥ 2000/µL 
ii) 
Neutrophils          ≥ 1500/µL 
iii) 
Platelets                ≥ 100 x 10³/µL 
iv) 
Hemoglobin         ≥ 9.0 g/dL 
v) 
Creatinine Serum creatinine ≤ 1.5 x ULN or creatinine clearance > 40 
mL/minute (using Cockcroft/Gault formula) 
vi) 
AST                      ≤ 3 x ULN  
vii) 
ALT                      ≤ 3 x ULN  
viii) 
Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome who 
must have total bilirubin < 3.0 mg/dL) 
 
 
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MCC 17439 – version 6-  December 21, 2015 
 
3) 
Age and Reproductive Status 
Men and women ≥ 18 years old 
a) 
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. See Section 3.3.3 for the definition of WOCBP. 
b) 
Women must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) within 72 hours prior to the start of investigational product. 
 
3.2.2 
Exclusion Criteria 
 
1) 
Target Disease Exceptions 
a) Subjects with known or suspected brain metastasis, or brain as the only site of disease are 
excluded with the following exceptions. 
i) 
Subjects with 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) will be allowed. 
b) Subjects with a 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. 
 
2) 
Medical History and Concurrent Diseases 
a) 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. 
b) Known human immunodeficiency virus (HIV), active hepatitis A, or hepatitis B or C 
infection. 
c) History of any hepatitis (eg, alcohol or non-alcohol steatohepatitis (NASH), drug- 
related, autoimmune) 
d) Evidence of active infection that requires anti-bacterial, anti-viral, or anti-fungal 
therapy ≤ 7 days prior to initiation of study drug therapy 
e) History of acute diverticulitis, or current chronic diarrhea 
f) Active peptic ulcer disease even if asymptomatic  
g) History of adrenal insufficiency (including subjects using replacement therapy)  
h) Prior organ allograft or allogenic bone marrow transplantation 
i) Uncontrolled or significant cardiovascular disease including, but not limited to, any 
of the following: 
i. Myocardial infarction within the past 6 months  
ii.  Uncontrolled angina within the past 6 months  
iii)  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. 
iv)  Baseline QTc interval greater than 500 milliseconds 
j) Baseline toxicities from prior anti-cancer treatments > Grade 1. 
k) Inability to be venipunctured and/or tolerate venous access. 
l) Any major surgery within 4 weeks or a diagnostic procedure (eg incision, needle 
 
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MCC 17439 – version 6-  December 21, 2015 
biopsy) within 1 day of study drug administration. 
m) Any current or recent (within 3 months) gastrointestinal disease that could potentially 
impact the ability to swallow and/or absorb study drug (ie, gastrointestinal surgery, 
malabsorption syndrome). 
n) Diabetes mellitus uncontrolled by medication. 
o) Known drug or alcohol abuse. 
p) 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. 
 
3) 
Allergies and Adverse Drug Reaction 
a) History of allergy to components of ipilimumab or panobinostat, or known allergy to other 
antibody therapies. 
 
4) 
Sex and Reproductive Status 
a) 
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. 
b) 
Women who are pregnant or breastfeeding. 
c)       Women with a positive pregnancy test on enrollment or prior to investigational product 
administration. 
d)      Sexually active fertile men not using effective birth control if their partners are 
WOCBP. 
 
5) 
Prohibited Prior Treatments and/or Therapies 
a) 
Exposure to any investigational drug within 4 weeks of study drug administration.  
b) Any anti-cancer therapy (eg, chemotherapy, biologics, radiotherapy, or hormonal 
treatment) within 4 weeks or at least 5 half-lives (whichever is longer) of study drug 
administration. 
c) Prior therapy with an anti-CTLA4 antibody or an HDAC inhibitor 
d) Concurrent chemotherapy, hormonal therapy, immunotherapy regimens, or radiation 
therapy, standard or investigational. 
 
6) 
Other Exclusion Criteria 
a) 
Prisoners or subjects who are involuntarily incarcerated 
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness 
 
3.2.3 
Women of Childbearing Potential 
Women of childbearing potential include any female who has experienced menarche and who 
has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as: 
• Amenorrhea ≥ 12 consecutive months without another cause and a documented serum 
follicle stimulating hormone (FSH) level >35 mIU/mL 
• Women with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL 
 
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MCC 17439 – version 6-  December 21, 2015 
• 
Women on hormone replacement therapy (HRT) 
 
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, 
skin patches, or implanted or injectable products), or mechanical products such as an 
intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent 
pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) 
should be considered to be of childbearing potential. 
 
3.3 
Concomitant Treatments 
Medications taken within 4 weeks prior to study drug administration and while on study 
treatment must be recorded. 
 
3.3.1 
Prohibited and/or Restricted Concomitant Treatments 
Restrictions on medications taken prior to enrollment in the study are described above in 
Section 3.3.2. Use of prescription and over-the counter medications (except medications from 
categories outlined below) is permitted at the discretion of the Investigator and must be 
recorded. 
Concurrent use of the following medications or drug classes while on study therapy is 
prohibited. In the setting where eligible subjects are already taking these therapies, they 
should be switched to and stabilized on alternative medications as clinically indicated, and a 
minimum wash out interval of 5 half-lives of the prohibited medications should be allowed 
prior to initiation of study therapy. 
1) Systemic or inhalational corticosteriods. Ocular use of corticosteriods is permitted as is the 
transient use of topical corticosteriods over a limited surface area. Replacement 
corticosteroids may be used up to the equivalent of 10 mg of prednisone daily. 
2) Other immunosuppressive agents  
 
3.3.2 
Other Restrictions and Precautions 
Panobinostat may also interact with and inhibit the metabolizing enzyme cytochrome P450 
3A4. Therefore, strong inducers, inhibitors, or substrates of CYP3A4, should be used with 
caution during the study. Investigators are encouraged to consult the sponsor prior to the use 
of strong modulators of CYP450 activity. Appendix 2 provides examples of drugs in this 
category. 
 
3.4 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue investigational products (and noninvestigational product at the 
discretion of the investigator) for any of the following reasons: 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• 
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, 
in the opinion of the investigator, indicates that continued participation in the study is not in 
the best interest of the subject 
• 
Pregnancy (see Section 6.4) 
• 
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious disease) illness 
• 
Subject’s inability to comply with the protocol  
 
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MCC 17439 – version 6-  December 21, 2015 
•       Toxicity requiring discontinuation as outlined in the Guidelines for Dose 
Modification (Section 4.3.5) 
 
All subjects who discontinue should comply with protocol specified follow-up procedures as 
outlined in Section 5. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness). 
If a subject was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate case report form (CRF) page. 
 
4 
TREATMENTS 
All protocol-specified investigational and non-investigational products are considered study 
drug. 
 
4.1 
Study Treatments 
Study drug therapy will be divided into induction and maintenance phases. For the purpose of 
managing study visits and procedures, a treatment cycle will be defined as 42 days during the 
induction phase, and as 84 days during the maintenance phase. 
 
4.1.1 
Investigational Product 
The investigational product should be stored in a secure area according to local regulations. It 
is the responsibility of the investigator to ensure that investigational product is only 
dispensed to study subjects. The investigational product must be dispensed only from official 
study sites by authorized personnel according to local regulations. In this protocol, 
investigational product(s) is/are: Panobinostat 5 mg, 10 mg, 15 mg and 20 mg capsules and 
Ipilimumab. 
 
4.1.1.1 
Ipilimumab (BMS-734016) 
Study drug is to be administered and prepared according to the package insert as described 
below. 
 
Preparation of Solution 
• 
Allow the vials to stand at room temperature for approximately 5 minutes prior to 
preparation of infusion. 
• 
Withdraw the required volume of YERVOY and transfer into an intravenous bag. 
• 
Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to 
prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 
mg/mL. Mix diluted solution by gentle inversion. 
• 
Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 
36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F). 
• 
Discard partially used vials or empty vials of YERVOY. 
 
Administration Instructions 
 
32 


MCC 17439 – version 6-  December 21, 2015 
• 
Do not mix YERVOY with, or administer as an infusion with, other medicinal 
products. 
• 
Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP after each dose. 
• 
Administer diluted solution over 90 minutes through an intravenous line containing a 
sterile, non-pyrogenic, low-protein-binding in-line filter. 
 
Dose, Volume and Rate Calculations 
Total dose should be calculated as follows: 
Subject body weight in kg x 3 mg = total dose, mg 
Total infusion volume should be calculated as follows: Total dose in mg divided by 5 mg/mL 
= infusion volume, mL 
 
Rate of infusion should be calculated as follows: Infusion volume in mL divided by 90 
minutes = rate of infusion, mL/min 
 
For example, a subject weighing 114 kg (250 lb) and designated to receive ipilimumab at a 
dose of 3 mg/kg would be administered 342 mg of ipilimumab (114 kg x 3 mg/kg = 342 mg) 
with an infusion volume of 70 mL (342 mg divided by 5 mg/mL = 70 mL) at a rate of 
approximately 0.77 mL/min (70 mL divided by 90 minutes) in 90 minutes. 
 
Ipilimumab (BMS-734016) Injection (5 mg/ml), must be stored refrigerated (2 - 8°C) with 
protection from light. Ipilimumab may be stored (5 mg/ml) in DEHP free IV infusion bags 
for up to 24 hours at room temperature or refrigerated (2°C - 8°C). This would include any 
time in transit and the total time for infusion. Drug must be completely delivered to the 
subject within 24 hours of preparation. 
 
4.1.1.2 
PANOBINOSTAT (LBH-589) 
The drug product will be provided by Novartis and is an immediate-release solid oral dosage 
form capsule. The hard gelatin capsules contain the active substance Panobinostat lactate salt 
at dosage strengths of 5 mg, 10 mg, 15 mg and 20 mg as anhydrous free base. The inactive 
ingredients are: mannitol, microcrystalline cellulose, pregelatinized starch and magnesium 
stearate. An aqueous granulation and blending process produces the capsule content. The 5 
mg, 10 mg, 15 mg, and 20 mg capsules are packaged in high-density polyethylene (HDPE) 
bottles with an induction seal and plastic CR closure. The current storage condition for all 
capsules strengths is: Do not store above 25°C. The retest date for the capsule formulations 
will be assigned based on available stability data.   
 
4.1.2 
Handling and Dispensing 
The investigational pharmacist will ensure that the study drug is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by the 
package insert. If concerns regarding the quality or appearance of the study drug arise, do not 
dispense the study drug and contact the sponsor immediately. 
 
Panobinostat 5 mg, 10 mg, 15 mg and 20 mg capsules must be stored below 25°C, in very 
tight packaging with water permeation <0.5 mg/day/liter, protected from light. Ipilimumab 
 
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MCC 17439 – version 6-  December 21, 2015 
(BMS-734016) Injection (5 mg/ml), must be stored refrigerated (2 - 8°C) with protection 
from light. Ipilimumab may be stored (5 mg/ml) in DEHP free IV infusion bags for up to 24 
hours at room temperature or refrigerated (2°C - 8°C). This would include any time in transit 
and the total time for infusion. Drug must be completely delivered to the subject within 24 
hours of preparation. 
 
4.2 
Method of Assigning Subject Identification 
This is an open-label study. All enrolled subjects will be assigned a subject number, starting 
with 00001. After it has been determined that the subject meets all eligibility criteria, the 
investigator (or designee) will register the subject by following the enrollment procedures 
established at Moffitt. The following information is required for registration: 
• 
Date of birth  
•       Gender  
•       Diagnosis  
• 
Date of informed consent  
• 
Planned date of 1st dose 
The subject number will be assigned once the subject signs informed consent. Subject 
numbers will be assigned in the order of enrollment within 3 days prior to Day 1 of Cycle 1 
dosing. Subjects who do not complete the DLT observation period for reasons other than 
drug- related toxicity will be replaced. Replacement subjects will receive the same treatment 
but will be assigned a new subject number. 
 
4.3 
Selection and Timing of Dose for Each Subject 
As described under Study Design (Section 3.1), panobinostat will be administered orally 
concurrently in combination with intravenous ipilimumab. For each arm, treatment will be 
divided into induction and maintenance phases. 
 
4.3.1 
Study Treatments During Dose Escalation 
Subjects will be enrolled in successive cohorts of 3. An initial cohort of 3 subjects will be 
enrolled at a given dose level, and additional cohorts of at least 3 subjects will be added 
based on the design as outlined in Section 3.1. The first cohort will receive panobinostat 
orally at a dose of 5 mg PO TIW; ipilimumab will be administered IV at 3 mg/kg. 
Subsequent dose levels of panobinostat and ipilimumab will be increased according to the 
schedule in Table 4.1. 
(20%, 30%) to be selected 
Table 4.1 Dose Escalation regimen for Panobinostat and Ipilimumab 
 
Dose Cohort 
Panobinostat Dose 
Ipilimumab Dose 
1 
5 mg po TIW 
3 mg/kg 
2 
10 mg po TIW 
3 mg/kg 
3 
               15 mg po TIW 
3 mg/kg 
4 
20 mg po TIW 
3 mg/kg 
-1 
5 mg po TIW 
1 mg/kg 
 
Additional dose levels of panobinostat beyond the 20 mg PO TIW dose cohort may be added 
as appropriate, although it is expected that all subsequent doses will be no more than 33% 
 
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MCC 17439 – version 6-  December 21, 2015 
higher than the preceding dose (eg, from 20 mg PO TIW to 25 mg PO TIW). Start of 
induction cycle 1, Day 1 for the first 3 subjects should be separated by at least 1 day. During 
the DLT observation (within 84 days of initiation of study therapy), subjects, who for reasons 
other than study-drug related toxicity, either miss 1 or more of their scheduled doses of 
ipilimumab, or miss more than 10% of their scheduled Q12 hour doses of panobinostat, or do 
not complete the first induction cycle, will not be considered evaluable for safety for the 
purposes of dose escalation and will be replaced. 
 
4.3.2 
Administration of ipilimumab 
Ipilimumab is to be administered as an IV infusion with a 1.2 μm in-line filter (see current 
version of Investigator’s Brochure), using a volumetric pump, at the 3 mg/kg dose, and at an 
appropriate rate to complete the infusion in 90 minutes with a 10 cc normal saline flush at the 
end. Additional details on ipilimumab dose are outlined above in Section 4.1.1.1. 
Refer to Section 4.3.8.1 regarding management of infusion reactions. 
 
4.3.3 
Dose Limiting Toxicity 
For the purpose of guiding dose escalation decision making, hematologic and non- 
hematologic (hepatic versus non-hepatic) DLT will be defined separately and will be 
determined based on the incidence, severity, and duration of study drug-related AEs 
occurring within 84 days (12 weeks; through Day 42 of induction cycle 2) of initiation of 
study therapy. Using these features, the severity of AEs will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. For the purposes 
of subject management, DLTs will lead to dose modification regardless of the cycle in which 
a DLT occurs (see Section 4.3.8 for specific guidelines). 
 
4.3.3.1 
Definition of non hematologic dose-limiting toxicity 
Non-hematologic dose-limiting toxicity (DLT) will be defined as follows: 
A: Hepatic Non-Hematologic DLT 
Any one of the following events will be considered a hepatic DLT (irrespective of whether it 
is considered to be an irAE): 
Isolated Grade 4 AST/ALT 
Isolated Grade 3 AST/ALT that fails to return to Grade 1 or less within 5 days  
Isolated Total Bilirubin ≥ Grade 3 with AST or  
ALT > 3 x ULN and concurrent total bilirubin > 2 x ULN 
B: Non-Hepatic Non-Hematologic DLT 
Any Grade 3 or greater non-hepatic non-hematologic toxicity will be considered as a dose-
limiting toxicity with the following specific exceptions: 
• Grade 3 electrolyte abnormalities that are not complicated by associated clinical adverse 
experiences, last less than 48 hours and either resolve spontaneously or respond to 
conventional medical intervention. 
• Grade 3 nausea or vomiting that lasts less than 48 hours, and either resolves spontaneously 
or responds to conventional medical intervention. 
• Isolated Grade 3 elevation of amylase or lipase not associated with clinical or radiographic 
evidence of pancreatitis. 
• Isolated Grade 3 fever that lasts ≤ 3 days and is not associated with hemodynamic 
compromise (ie hypotension, clinical or laboratory evidence of impaired end-organ 
 
35 


MCC 17439 – version 6-  December 21, 2015 
perfusion). 
 
Criteria for Non-Hematologic DLT in Context of Immune-Related AEs and Infusion 
Reactions: 
A constellation of immune-related adverse events  (irAEs) have been observed in patients 
treated with ipilimumab monotherapy. Similarly, as has been seen with a broad range of 
therapeutic antibodies, infusion reactions have been observed among patients treated with 
ipilimumab. Based on broad clinical experience with ipilimumab, a unique set of criteria 
have been developed to define and manage dose-limiting toxicities in the context of irAEs 
and/or infusion reactions and are outlined below. 
 
C: Immune-related Adverse Experiences (irAEs) and DLT 
Definition of DLT in the context of irAEs will consider the incidence, severity, time of onset, 
duration and time to resolution for the specific irAE in the context of existing experience 
with ipilimumab. All Grade 3 or greater immune related AEs will be considered as potential 
DLTs. An independent DMC will be utilized to advise on aggregate safety data from this 
study and more specifically to review all Grade 3 or greater irAEs. Immune related AEs 
among patients treated with ipilimumab have clustered among skin, gastrointestinal, 
endocrine and liver-related events as follows: 
Skin: alopecia, dry skin, hyperhidrosis, night sweats, pruritus, rash/desquamation, toxic 
epidermal necrolysis, urticaria, and vitiligo. 
Gastrointestinal: abdominal discomfort or pain, anal ulcer, colitis (including ulcerative, 
haemorrhagic, ischaemic, and megacolon), constipation, cramping, diarrhea (including 
haemorrhagic), diverticulitis/diverticulum, duodenitis, dyspepsia, dysphagia, enteritis, 
esophagitis, gastritis (including erosive), gastrointestinal haemorrhage (including rectal), 
hematochezia, ileitis, ileus, intestinal obstruction, intestinal perforation (including small and 
large intestines), melena, nausea, pancreatitis, peritonitis, stomatitis (including aphthous), 
vomiting, vasculitis gastrointestinal. 
Endocrine: adrenal insufficiency (including Addison’s disease), glucose tolerance impaired, 
hyperthyroidism hypogonadism, hypophysitis/hypopituitarism (autoimmune), 
hypothyroidism, pituitary enlargement, thyroiditis (autoimmune). 
Liver: hepatitis, jaundice 
 
Dose-limiting immune-related AEs will be defined as the follows: 
• 
Any Grade 2 or greater eye pain or reduction in visual acuity that does not respond to 
topical therapy and does not improve to Grade 1 severity within 2 weeks of the initiation of 
topical therapy or any Grade 2 or greater eye pain or reduction in visual acuity that requires 
systemic treatment. 
• 
Any other Grade 3 or greater irAE: 
 
D: Infusion Reaction and DLT 
Grade 3 or Grade 4 infusion reactions will also be considered as dose-limiting events. 
 
4.3.3.2 
Definition of hematologic DLT 
Hematologic DLT will be defined as follows:  
• Grade 4 neutropenia ≥ 7 days in duration 
• Grade 4 thrombocytopenia, or any Grade 3 thrombocytopenia associated with clinically-
significant bleeding 
 
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MCC 17439 – version 6-  December 21, 2015 
• Grade ≥ 3 febrile neutropenia  
• Grade ≥ 3 hemolysis 
 
4.3.4 
Duration of Treatment 
Subjects may remain on study therapy until progressive disease as determined by immune-
related response criteria (irRC), withdrawal due to toxicity, withdrawal of consent, or at the 
discretion of the investigator. 
 
4.3.5 
Intra-subject Dose Escalation 
Intrasubject dose escalation for panobinostat or ipilimumab is not permitted in order to allow 
better evaluation of extended safety and efficacy at individual levels. 
 
4.3.6 
Guidelines for Dose Modification 
Patients who have not experienced a dose-limiting toxicity may continue on therapy if, in the 
opinion of the investigator, they are experiencing clinical benefit (i.e. stable disease or 
objective response as determined by irRC). For patients who experience a dose-limiting 
hematologic or non-hematologic toxicity, therapy should be held/deferred pending resolution 
of the toxicity. 
 
Panobinostat/Ipilimumab Dose Modification Guidelines for Non-hematologic and 
Hematologic Events Other Than Infusion Reactions: 
• 
Patients who experience hepatic non-hematologic DLT irrespective of irAE or any 
Grade 3 or greater irAE will be removed from study with no further dose reduction. 
• 
For patients who experience a first episode of non-hepatic non-hematologic DLT or a 
first episode of hematologic DLT, therapy may be reinitiated at the next lowest 
panobinostat/ipilimumab dose level as specified below in Table 4.3 if the event has resolved 
to less than or equal to Grade 1 in severity at the time the next cycle is due. 
• 
For patients who experience a second episode of either hematologic or non-hepatic 
non-hematologic DLT, a second dose reduction may be performed as specified below for the 
successive cycle if the second dose-limiting event is distinct in nature from the first event and 
the event has resolved to less than or equal to Grade 1 in severity at the time the next cycle is 
due. 
• 
In the event of a DLT, successive cycles of therapy may be delayed up to 14 days 
pending resolution of the toxicity to grade 1 or less in severity. Patients on dose level #1 will 
not be dose reduced in the event of DLT. Patients on dose level #2 will be allowed a 
maximum of 1 dose reduction, with the second occurrence of DLT necessitating removal 
from study. 
• 
Any patient who develops significant irreversible (i.e. more than 2 weeks after the last 
dose of study drug) organ dysfunction (i.e., Grade IV non-hepatic non- hematologic toxicity) 
or anaphylaxis considered to be related to study drug will also be removed from study with 
no further dose reduction. 
• 
All cardiac events should be treated as per the local standard of care and referred to 
a specialist if clinically indicated.  The readings of ECGs will use the Fridericia 
correction: QTcF.  Any final decisions concerning dose modifications or permanently 
discontinuing the patient from study drug due to QTcF prolongation will be based on the 
 
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MCC 17439 – version 6-  December 21, 2015 
assessment of the principal investigator.  If a patient cannot be dosed due to prolonged 
QTcF for more than 7 days since last dose, patient should be discontinued from study. 
Table 4.2 Criteria for dosing delays, dose-reductions, and re-initiation of treatment due to 
study drug-related QTcF abnormalities 
ECGs to be 
performed at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy (including 
intended day of dosing) 
Cycle 1 Day 1 dose modification criteria: 
Pre-dose on  
cycle 1, day 1 
3 ECGs separated 
by at least 5 
minutes, obtained 
prior to panobinostat 
dosing 
Average QTcF > 450 
msec 
 
Check and correct the patient’s serum 
potassium, magnesium, calcium and 
phosphorus immediately, as well as evaluate 
con-meds. 
Repeat 3 pre-dose ECGs. 
If the 3 pre-dose ECGs: 
Do not meet criteria again, discontinue patient 
from study. 
Do meet criteria for dosing; administer study 
drug treatment.  
 
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MCC 17439 – version 6-  December 21, 2015 
ECGs to be 
performed at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy (including 
intended day of dosing) 
Cycle 1 Day 5 dose modification criteria 
Pre-dose on  
cycle 1, day 5: 
3 ECGs separated 
by at least 5 
minutes, obtained 
prior to panobinostat 
dosing 
 
Average QTcF: 
≥ 480 msec to < 500 
msec 
OR 
> 60 msec increase 
from baseline average 
Check and correct the patient’s serum 
potassium, magnesium, calcium and 
phosphorus immediately, as well as evaluate 
con-meds. 
Notify Sponsor and transmit to ERT 
immediately for prompt review. 
Repeat 3 pre-dose ECGs. 
If the 3 pre-dose ECGs: 
Do meet criteria for dosing; administer study 
drug treatment. 
Do not meet criteria again, delay dose until the 
next scheduled time point and repeat 3 pre-
dose ECGs. 
If the repeat 3 pre-dose ECGs: 
Do not meet pre-dose ECG criteria again, 
discontinue patient from study. 
Do meet pre-dose ECG criteria for dosing and 
QT prolongation is determined to be related to 
study drug, resume study drug treatment with a 
dose reduction of one dose level. If however, it 
was determined that the QT prolongation was 
secondary to electrolyte abnormalities or con-
meds, continue at the same dose level. Repeat 
ECGs - pre-dose (x3) on the next scheduled 
dosing day. 
Average QTcF ≥ 500 
msec 
Check and correct the patient’s serum 
potassium, magnesium, calcium and 
phosphorus immediately, as well as evaluate 
con-meds. 
Notify Sponsor and transmit to ERT 
immediately for prompt review. 
Discontinue patient from study therapy 
If however, it was determined that the QT 
prolongation was secondary to electrolyte 
abnormalities or con-meds: omit dose. On the 
next scheduled dosing day continue at the 
same dose level. Repeat ECGs - pre-dose 
(x3), 3-hours post-dose (x3), on the next 
scheduled dosing day. 
 
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MCC 17439 – version 6-  December 21, 2015 
ECGs to be 
performed at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy (including 
intended day of dosing) 
Cycle 2 and beyond dose modification criteria: 
If required: 
Pre-dose on  
day 1 of each cycle 
3 ECGs separated 
by at least 5 
minutes, obtained 
prior to panobinostat 
dosing: 
Average QTcF > 480 
msec 
Check and correct the patient’s serum 
potassium, magnesium, calcium and 
phosphorus immediately, as well as evaluate 
con-meds. 
If abnormality noted: 
Repeat 3 pre-dose ECGs. 
If the 3 pre-dose ECGs: 
Do not meet criteria again, discontinue patient 
from the study. 
Do meet criteria for dosing; administer study 
drug treatment 
If, however, it was determined that the QT 
prolongation was secondary to electrolyte 
abnormalities or con-meds: 
Omit dose. On the next scheduled dosing day, 
continue at the same dose level. Repeat ECGs 
pre-dose (x3) on the next scheduled dosing 
day. 
Average QTcF ≥ 500 
msec 
Check and correct the patient’s serum 
potassium, magnesium, calcium and 
phosphorus immediately. 
Discontinue patient from study therapy 
If however, it was determined that the QT 
prolongation was secondary to electrolyte 
abnormalities or con-meds: omit dose. On the 
next scheduled dosing day continue at the 
same dose level. Repeat ECGs - pre-dose (x3)  
on the next scheduled dosing day. 
 
In the setting where dose modifications are required, doses of PANOBINOSTAT and 
ipilimumab will be reduced to doses for the cohort immediately preceding the current dose 
level. Dose modifications are provided in Table 4.3 
Table 4.3  Dose Modification Guidelines for Panobinostat and Ipilimumab 
Cohort 
Ipilimumab Dose 
Panobinostat Dose  
Dose Modification #1  Dose Modification #2 
1 
3 mg/kg 
1 mg/kg 
Off Study 
5 mg 
5 mg 
 
2 
3 mg/kg 
3 mg/kg 
Off Study 
10 mg 
5 mg 
 
3 
3 mg/kg 
3 mg/kg 
3 mg/kg 
15 mg 
10 mg 
5 mg 
4 
3 mg/kg 
3 mg/kg 
3 mg/kg 
20 mg 
15 mg 
10 mg 
-1 
1 mg/kg 
Off Study 
Off Study 
5 mg 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
 
 
4.3.7 
Supportive Care Guidelines 
4.3.7.1 
Guidelines For Infusion Reactions 
Ipilimumab may induce infusion or hypersensitivity reactions. These reactions may manifest 
with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo or hypertension, 
bronchospasm, or other symptoms. Infusion reactions should be graded according to 
Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0) guidelines. The 
Sponsor will be responsible for the appropriate notification of Study Investigators and the 
DMC of ≥ Grade 3 infusion reactions. Treatment recommendations and dose modification 
guidelines are provided below. Supportive care guidelines may be modified based on clinical 
judgment, local treatment standards and guidelines, and/or specific symptoms, as appropriate: 
For Grade 1 symptoms: Mild reactions (localized cutaneous reactions including mild pruritus, 
flushing, rash), 
• 
Decrease the rate of ipilimumab infusion until recovery from symptoms. 
• 
Remain at bedside and monitor subject until resolution of symptoms. 
• 
Diphenhydramine 50 mg, may be administered at the discretion of the treating 
physician. 
• 
When symptoms resolve, restart the infusion at the original infusion rate 
• 
Institute additional treatment as clinically indicated. 
If a subject has a Grade 1 infusion reaction with ipilimumab, prophylactic preinfusion 
medications should be given prior to all subsequent ipilimumab infusions. The following 
prophylactic preinfusion medications are recommended in this setting to administered at least 
30 minutes prior to ipilimumab administration; 
• 
diphenhydramine 50 mg (or equivalent) and/or • acetaminophen 325 to 1000 mg 
For Grade 2 symptoms: Moderate reactions [ie, any symptom not listed above (mild 
symptoms) or below (severe symptoms) such as generalized pruritus, flushing, rash, dyspnea, 
hypotension with systolic blood pressure > 80 mm Hg], require infusion interruption but 
respond promptly to symptomatic treatment [eg, antihistamines, non- steroidal anti 
inflammatory drugs, narcotics, corticosteroids, i.v. fluids]; prophylactic preinfusion 
medications indicated for ≤ 24 hours. 
• 
Discontinue the study drug infusion.  
• 
Begin an i.v. infusion of normal saline, and treat the subject with diphenhydramine 50 
mg i.v. (or equivalent) and/or acetaminophen 325 to 1000 mg. • 
Remain at bedside and 
monitor subject until resolution of symptoms. • Corticosteroid therapy may be administered 
at the discretion of the treating physician. 
• 
When symptoms resolve, restart the infusion at 50% of the original infusion rate; if no 
further complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate. 
• 
Monitor subject closely. If symptoms recur, immediately discontinue the infusion; no 
further study drug will be administered at that visit. Administer diphenhydramine 50 mg i.v., 
and remain at bedside and monitor the subject until resolution of symptoms. 
If a subject has a Grade 2 infusion reaction with ipilimumab, prophylactic preinfusion 
medications should be given prior to all subsequent ipilimumab infusions. The following 
prophylactic preinfusion medications are recommended in this setting to administered at least 
30 minutes prior to ipilimumab administration; 
• 
diphenhydramine 50 mg (or equivalent) and/or 
 
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MCC 17439 – version 6-  December 21, 2015 
• 
acetaminophen 325 to 1000 mg 
• 
If considered necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may 
be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction [eg, bronchospasm, generalized urticaria, 
systolic blood pressure ≤ 80 mm Hg, or angioedema], Grade 3: prolonged [ie, requiring 6 or 
more hours to respond to symptomatic medication and/or discontinuation of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for other 
clinical sequelae [eg, renal impairment, pulmonary infiltrates]. Grade 4: life-threatening; 
pressor or ventilatory support indicated). 
•        Immediately discontinue the study drug infusion. No further study drug will be given  
•        Begin an i.v. infusion of normal saline, and treat as follows: bronchodilators, 
epinephrine 0.2 to 1.0 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 
mg of a 1:10,000 solution injected slowly for i.v. administration, and/or diphenhydramine 50 
mg i.v. with methylprednisolone 100 mg i.v. (or equivalent), as needed. 
• 
Remain at bedside and monitor subject until recovery from symptoms. Subject should 
be monitored until the Investigator is comfortable that the symptoms will not recur. 
• 
The amount of study drug infused must be recorded on the case report form (CRF). 
• 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized 
or generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine, or corticosteroids). In addition, Investigators should also follow their 
institutional guidelines for the treatment of anaphylaxis. 
4.3.7.2 
Guidelines for Management of Gastrointestinal AEs and 
 
Endocrinopathies 
Immune-related adverse events are well described with the use of ipilimumab. All subjects 
who receive treatment on this study should be closely monitored for any signs related to 
gastrointestinal or endocrine systems and aggressively managed at the first onset of clinical 
symptoms. A high index of suspicion for immune-mediated colitis should be maintained in 
subjects who present with diarrhea or other abdominal symptoms. Prompt initiation of 
appropriate therapy, including early administration of steroids should be instituted as 
consistent with the guidelines on management of diarrhea within the ipilimumab program 
(see Appendices 5-8). Specific algorithms for the management of immune-related AEs, 
diarrhea, hepatotoxicity, and endocrinopathies have been developed within the ipilimumab 
clinical program and are provided for reference in Appendices 5-8. 
 
4.4 
Blinding/Unblinding 
This is an open label study. Blinding will not be utilized. 
 
4.5 
Destruction and Return of Study Drug 
 
4.5.1 
Destruction of Study Drug 
If study drug panobinostat sourced by the investigator by Novartis are to be destroyed on site, 
it is the investigator’s responsibility to ensure that arrangements have been made for the 
disposal, procedures for proper disposal have been established according to applicable 
regulations, guidelines and institutional procedures, and appropriate records documented.  
 
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MCC 17439 – version 6-  December 21, 2015 
 
5 
STUDY ASSESSMENTS AND PROCEDURES  
5.1 
Flow Chart/Time and Events Schedule 
 
Table 5.11  Screening Days -28 to -1 
Procedure 
Screening Visits 
Notes 
Eligibility Assessment 
X 
 
Informed Consent 
X 
 
Eligibility Criteria 
X 
 
History 
X 
 
Pathology review 
X 
 
Physical examination 
X 
 
Vital Signs 
X 
 
Height and Weight 
X 
 
Performance Status 
X 
 
ECG 
X 
Single 12-lead ECG or triplicate if 
planned to be used as baseline (Induction 
Cycle 1 Day 1) 
Chem panel, CBC 
X 
 
Free T4, TSH, ACTH, 
Cortisol 
X 
 
Liver and HIV serologies 
X 
HIV, HepBsAg, Hep C ab 
PT/PTT 
X 
 
Pregnancy test 
X 
Serum 
Urinalysis 
X 
 
Ophthalmologic exam 
X 
With slit lamp as a baseline 
Tumor assessment 
X 
CT C-A-P with contrast, and unless 
contraindicated, MRI brain with 
gadolinium 
Tumor Biopsy 
X 
Voluntary 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
Table 5.12  During Treatment, Day 1 onward 
Study Cycle 
 
Induction Cycle 
Maintenance 
Cycle 
End of 
Treatment 
Follow-
up 
Notes 
Cycle # 
1 
2 
Each Cycle 
 
 
 
Day of Cycle1 
1 
5 
22 35 
1 
22 
 
Safety Assessments 
Physical exam 
X2 
 
X 
 
X 
X 
X 
X 
X 
 
Ophthalmology 
Exam 
X 
 
 
 
 
 
 
 
 
Baseline only 
Vital Signs 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Weight 
X 
 
X 
 
X 
X 
X 
X 
X 
 
PS 
X2 
 
X 
 
X 
X 
X 
X 
X 
 
ECG 
X2, 3 X3 
 
 
X 
 
X 
X 
 
Triplicate 12-lead
for Induction 
Cycle 1 Day 1 & 
Day 5; single 12-
lead ECG 
otherwise 
Chem Panel, 
CBC 
X2 
 
X 
 
X 
X 
X 
X 
X 
 
PT/PTT 
X2 
 
 
 
 
 
 
 
 
 
T4, TSH 
X2 
 
X 
 
X 
X 
X 
 
 
 
Serum Preg 
X2 
 
 
 
 
 
X 
 
 
 
Urinalysis 
X2 
 
 
 
X 
 
X 
 
 
 
SAE 
Monitoring 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Ipilimumab 
X 
 
X 
 
X 
X 
 
 
 
 
Panobinostat 
X 
 
X 
 
X 
X 
X5 
 
 
 
Disease 
Assessment 
 
 
 
 
X 
 
X 
X 
X 
 
PD Blood 
X 
 
X 
 
X 
X 
X 
X 
 
 
Tumor bx 
 
 
 
X4 
 
 
 
 
 
 
1  All study visits may be scheduled +/- 3 days from planned visit date. 
2  These tests will not be repeated on Cycle 1 Day 1 of the initial treatment period if completed for 
screening less than 72 hours (3 days) before the first dose of the study drugs. 
3  Triplicate ECGs at least 5 minutes apart will be done pre-dose on C1 D1 & C1 D5. 
4 Biopsy to be done between Days 35 and 42. 
5 Panobinostat will continue to be administered thrice weekly during the maintenance cycles. 
6. Patients will continue to be followed for PFS and OS. 
 
5.2 
Study Materials 
The Moffitt Cancer Center provide all of the required equipment for safe drug administration 
including all therapies as well as equipment for proper storage of study documentation, 
storage of clinical supplies, and processing of laboratory samples. The site will provide 
medications required for standard treatments. A current and fully- stocked advanced cardiac 
life support (ACLS) cart including resuscitation equipment and other agents to treat 
anaphylaxis (see Section 4.3.4) will be immediately available on the premises. The site will 
provide all materials required for accurate source documentation of study activities. 
 
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MCC 17439 – version 6-  December 21, 2015 
Case report forms (electronic or hard copy) will be provided by the Moffitt Clinical Trials 
Office. Novartis will provide panobinostat and ipilimumab will be from commercial stock.  
 
5.3 
Safety Assessments 
All subjects who receive at least one dose of panobinostat and or Ipilimumab will be 
evaluated for safety parameters. Additionally, any occurrence of an SAE from time of 
consent until 90 days post discontinuation of study drug dosing will be documented. Safety 
will be evaluated for all treated subjects using the NCI CTCAE version 4.0. Safety 
assessments will be based on medical review of AE reports and the results of vital sign 
measurements, physical examinations and clinical laboratory tests. The incidence of AEs will 
be tabulated and reviewed for potential significance and clinical importance. The schedule or 
required visits, tests, procedures and assessments are described in the Procedural Outline 
Tables. In limited instances, scheduled evaluations can occur outside of this time frame but 
only within the windows noted. Please see the Procedural Outline Tables for a 
comprehensive list of assessments/procedures (Section 5.1). If the screening evaluation 
(physical exam, physical measurements, ECOG status and laboratory tests) is conducted 
within the 72 hour window of the first dose of panobinostat, then a single evaluation for these 
assessments may count for screening and pre-dose evaluation. If a subject has a delay in 
study drug administration for any reason, then assessments, laboratory tests and scans will be 
correspondingly delayed. 
A screening 12-lead ECG will be performed to assess study eligibility. Additional 12-
lead ECGs will be performed at a minimum at scheduled time points as indicated in 
Table 5.12. For all patients, a minimum of 3 sequential 12-lead ECGs, separated by at 
least 5 minutes, must be performed on cycle 1 day 1 prior to the first administration of 
oral panobinostat or within 72 hours prior to that day in order to get an accurate baseline 
QTcF calculation. Additionally, triplicate ECGs will be performed on cycle 1 day 5. The 
recommended dose modifications due to QTc interval prolongation are outlined in 
section 4.3.6. 
5.3.1 
Laboratory Test Assessments 
A local laboratory will perform the analysis and will provide reference ranges for these tests. 
Results of clinical laboratory tests should be available for review prior to dosing on Day 1 of 
each treatment cycle. For other visit days, laboratory tests results should be reviewed within 
24 hours of the visit. With the exception of laboratory assessments prior to the first dose of 
panobinostat/Ipilimumab, all laboratory tests can be performed within 24 hours prior to the 
scheduled visits. Laboratory assessments prior to the first dose of panobinostat/Ipilimumab 
may be performed up to 72 hours prior to the scheduled visits. 
 
The following clinical laboratory tests will be performed: 
Hematology 
Hemoglobin Hematocrit Total leukocyte count, including differential Platelet count 
Serum Chemistry 
Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Total bilirubin Direct 
bilirubin, if total bilirubin > ULN Alkaline phosphatase 
Lactate dehydrogenase (LDH) Creatinine Blood Urea Nitrogen (BUN) or Urea Amylase 
Lipase 
 
 
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MCC 17439 – version 6-  December 21, 2015 
Serology 
Uric Acid Glucose Total Protein Albumin Sodium Potassium Chloride Calcium Phosphorus 
Magnesium Bicarbonate; HepB, HepC, HIV (at screening only) 
Other Assays 
T4/TSH 
Urinalysis 
Protein Glucose Blood Leukocyte esterase Microscopic examination of the sediment if blood, 
protein or leukocyte esterase are positive on the dipstick 
Coagulation Profile 
PT/INR aPTT  
Other Analyses 
Pregnancy test (WOCBP only) FSH (if needed to document post-menopausal status as 
defined in Section 3.3.3) 
 
At the investigator’s discretion, laboratory tests may be repeated if clinically significant. 
If the units of a test result differ from those printed on the CRF, the recorded laboratory 
values must specify the correct units. Any abnormal laboratory test result considered 
clinically significant by the investigator must be recorded on the appropriate AE page of the 
CRF (see Section 6.2 Laboratory Test Abnormalities). 
 
5.4 
Efficacy Assessments 
In this study, immune-related Response Criteria (irRC; see Appendix 4) will be used to 
assess subject response to study treatment and guide clinical care. However, response- based 
assessments in this study will be captured using both modified irRC and RECIST 1.1. The 
investigator will determine the irRC response at each tumor assessment. The RECIST 1.1 
response for the patient will be calculated from the tumor assessment data by the Sponsor and 
will be used for reporting purposes. The RECIST 1.1 criteria will be used to determine 
subjects’ best overall response (BOR), and for statistical analysis of efficacy in this study. 
Assessments of tumor status will be made during screening and then at 6 and 12 weeks and 
then every 12 weeks thereafter.  The irRC represent modifications of the modified WHO 
criteria reflecting the clinical experience with ipilimumab in the completed and/or ongoing 
clinical studies in which objective and durable responses (as per mWHO) were observed in 
subjects following progression and without intervening alternative anti-cancer therapy. As 
such, the irRC are designed to capture clinical activity of ipilimumab immunotherapy that 
may not be adequately addressed by the RECIST 1.1 criteria and will only be used for patient 
management decisions, not formal efficacy reporting. 
 
 
 
 
 
 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
 
 
6 
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of investigational product, whether or not considered related to the 
investigational product. Adverse events can be spontaneously reported or elicited during 
open-ended questioning, examination, or evaluation of a subject. (In order to prevent 
reporting bias, subjects should not be questioned regarding the specific occurrence of one or 
more AEs.) 
 
6.1 
Serious Adverse Events 
A serious AE (SAE) is any untoward medical occurrence that at any dose:  
• 
results in death 
• 
is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
•        is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon appropriate 
medical and scientific judgment, may jeopardize the subject or may require intervention [eg, 
medical, surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) 
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE. Although pregnancy, overdose 
and cancer are not always serious by regulatory definition, these events must be handled as 
SAEs for data transmission purposes (See Section 6.1.1 for reporting pregnancies). 
 
NOTE: The following hospitalizations are not considered SAEs: 
− 
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered "important medical event" or event life 
threatening) 
− 
elective surgery, planned prior to signing consent 
− 
admissions as per protocol for a planned medical/surgical procedure 
−       routine health assessment requiring admission for baseline/trending of health status   
(eg, routine colonoscopy) 
− 
medical/surgical admission for purpose other than remedying ill health state and was 
 
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MCC 17439 – version 6-  December 21, 2015 
planned prior to entry into the study. Appropriate documentation is required in these cases 
−       admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
 
6.1.1 
Serious Adverse Event Collection and Reporting 
Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. SAEs (except those events considered secondary or related to 
disease progression) should be followed to resolution or stabilization. Follow-up is also 
required for SAEs that cause interruption or discontinuation of study drug, or those that are 
present at the end of study treatment as appropriate. The investigator should collect any SAE 
occurring after these time periods that is believed to be related to study drug or protocol-
specified procedure. An SAE report should be completed for any event where doubt exists 
regarding its status of seriousness. If the investigator believes that an SAE is not related to 
study drug, but is potentially related to the conditions of the study (such as withdrawal of 
previous therapy, or a complication of a study procedure), the relationship should be 
specified in the narrative section of the SAE Report Form.  
Any event that is both serious and unexpected must be reported to the FDA as soon as 
possible and, in no event, later than 7 days (death or life-threatening event) or 15 days (all 
other SAEs) after the investigator’s or institutions  initial receipt of the information. SAEs 
may be reportable to the FDA for both FDA-approved (post-market) drugs as well as 
investigational agents.   
For an event to be reportable to the FDA, it must meet both of the following requirements as 
determined by the principal investigator of the study: 
1. The event is possibly, probably or definitely related to the agent  
2. The event is unexpected (i.e., not listed in the protocol, investigational brochure, 
or informed consent) 
SAEs may be reportable to the FDA for both FDA-approved (post-market) drugs as well as 
investigational agents.   
 
Reporting events for an APPROVED, POST-MARKET AGENT: 
The current MedWatch mandatory reporting form FDA 3500A can be found on the FDA 
website:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
Use: Form FDA 3500A - Mandatory Reporting 
Complete the MedWatch report and mail it to the appropriate address below: 
For Drugs:  
Central Document Room 
Center for Drug Evaluation and Research 
Food and Drug Administration 
5901-B Ammendale Road 
Beltsville, MD 20705-1266 
 
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MCC 17439 – version 6-  December 21, 2015 
For Biologics, including Human Cells, Tissues, and Cellular and Tissue-Based 
Products (HCT/Ps):  
Center for Biologics Evaluation and Research 
OBE Division of Epidemiology, (HFM-220) 
Food and Drug Administration 
1401 Rockville Pike 
Rockville, MD 20852-1448 
 
To report an event for an INVESTIGATIONAL AGENT under investigational new 
drug applications: 
Send a narrative of the event with circumstances, IND number, and why it is related and 
unexpected to the H. Lee Moffitt Cancer Center Regulatory Affairs IND Office..  A 
MedWatch report for the event would suffice. These events should not be reported or sent 
directly to the FDA by the study coordinator. The Regulatory Affairs IND Office at Moffitt 
Cancer Center will submit the reportable event as an IND safety report to the FDA on behalf 
of the principal investigator. 
 
If the principal investigator determines that the event could be possibly related and 
unexpected to both the post-market agent and the investigational agent, then the following 
should be done: 
• 
Submit the MedWatch report to the appropriate post-market address at the FDA as 
written above.   
• 
Send the MedWatch report to regulatory affairs. The office will submit and IND 
safety report on the behalf of the principal investigator.   
 
Reporting SAEs to Novartis 
In addition to the reporting guidelines above, all SAEs, regardless of causality, should be 
reported to Novartis within 24 hours of becoming aware of the event. SAEs may be 
submitted in any format, using the fax cover sheets in Appendix 8. 
 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to FDA using the 
same procedure used for transmitting the initial SAE report. All SAEs should be followed to 
resolution or stabilization. 
 
6.2 
Nonserious Adverse Events 
A nonserious adverse event is an AE not classified as serious.  
 
6.2.1 
Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin at initiation of study drug and 
continue through the day 90 follow-up visit with no new nonserious adverse events being 
reported past the end of treatment visit unless  believed to be related to study drug. Post the 
EOT visit any ongoing AE’s should be followed to resolution or stabilization, through the 
 
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MCC 17439 – version 6-  December 21, 2015 
day 90 follow-up, or reported as SAE’s if they become serious (see Sections 6.1.1). 
Nonserious AE information should also be collected from the start of a placebo lead-in period 
or other observational period intended to establish a baseline status for the subjects. Follow-
up is also required for nonserious AEs that cause interruption or discontinuation of study 
drug, or those that are present at the end of study treatment as appropriate. Completion of 
supplemental CRFs may be requested for AEs and/or laboratory abnormalities that are 
reported/identified during the course of the study. 
 
6.3 
Laboratory Test Abnormalities 
The following laboratory abnormalities should be captured as appropriate: 
• 
Any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
Any laboratory abnormality that required the subject to have study drug discontinued 
or interrupted 
• 
Any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
It is expected that wherever possible, the clinical, rather than the laboratory term would be 
used by the reporting investigator (eg, anemia versus low hemoglobin value). 
 
6.4 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject or a female partner of a male study participant is pregnant or may have been 
pregnant at the time of investigational product exposure, including during at least 6 half-lives 
after product administration, the investigational product will be permanently discontinued for 
the female study participant in an appropriate manner (eg, dose tapering if necessary for 
subject safety). Protocol-required procedures for study discontinuation and follow-up must be 
performed on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other 
appropriate pregnancy follow-up procedures should be considered if indicated. Follow-up 
information regarding the course of the pregnancy, including perinatal and neonatal outcome 
and, where applicable, offspring information must be reported. Any pregnancy that occurs in 
a female partner of a male study participant should be reported to the IRB.  
 
6.5 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as SAEs (see Section 6.1.1 for reporting details). 
 
6.6 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious 
AE, as appropriate, and reported accordingly. 
 
 
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MCC 17439 – version 6-  December 21, 2015 
7 
DATA MONITORING COMMITTEE  
To provide independent oversight for safety, study conduct and risk-benefit-ratio, an 
independent DMC made up of Moffitt faculty from the SPORE IAC and a patient advocate 
will provide oversight to this combination study of panobinostat with ipilimumab in subjects 
with melanoma. This committee will strictly serve in an advisory capacity to the study team. 
The committee will periodically review aggregate data from the study, specifically review all 
cases of Grade 3 or greater irAEs and will advise the study team regarding subject 
management, continuation, modification or discontinuation of dose regimens as appropriate. 
A charter detailing the activities of this DMC is available. 
 
8 
STATISTICAL CONSIDERATIONS  
8.1 
Sample Size Determination 
 
Dose Escalation: This is a Phase I dose escalation trial and the sample size at each dose 
depends on the observed toxicity; however a total of 36 subjects for the dose-escalation study 
allows sufficient number of subjects if needed, e.g. more than 6 subjects if dose-limiting 
toxicities are observed among 2 of 6 subjects, to better estimate the toxicity rates per dose, 
and more accurately determine the MTD. Cohorts of 3 subjects with expansions to 6, or 
possibly even 9 or 12 subjects will be treated at each suggested dose level until MTD is 
determined. 
 
In this protocol, we will be using a new phase I trial approach (Table 8.1), modified from a 
design from Ji et al43.  This approach provides a broader phase I experience than the 
traditional 3+3 design, thus allowing for a more robust choice of an MTD.  While setting the 
target toxicity rate at 18%, this design allows further examination of a dose when 2 DLTs 
occur among 6 patients, while still keeping the observed toxicity at the MTD well managed 
(it is below 26% for sample sizes ≥ 9).  The trials will 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 DLTs.  If, at any time, one de-escalates 
to a dose which has already accrued 12 patients, the study will be terminated and that dose 
declared to be the MTD.  The MTD is obtained at 33 patients if 9 or 12 patients have been 
accrued at the current dose and the dose is acceptable (E, S or C).  Otherwise, if the current 
dose has ≤1 of 3, or ≤2 of 6 DLTs, then three more patients will be accrued at that dose – if at 
most 1 of 6, or 2 of 9 have DLTs, that dose is the MTD.   
 
Table 8.1 Decision Rules on dose escalation based on number of DLTs**  
N*       Observed DLTs per cohort and treatment decisions 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
3 
 
E 
 
S 
 
DU  
DU - 
- 
- 
- 
- 
- 
6 
 
E 
 
E 
  
S 
 
DU  
DU  
DU  
DU 
9 
 
E 
 
E 
 
S 
 
D 
 
DU  
DU  
DU 
12 
 
E 
 
E 
 
E 
 
C 
 
DU  
DU  
DU 
N* =number of subjects treated at a given dose level 
S: stay at the same dose and enroll a cohort of 3 more subjects at that dose 
E: escalate to the next higher dose by enrolling 3 more subjects 
 
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MCC 17439 – version 6-  December 21, 2015 
D: de-escalate to the lower dose, and enroll 3 more subjects at the lower dose, or 
DU: declare the current dose as unacceptable and unsafe, de-escalate to the lower dose, and 
enroll 3 more subjects at the lower dose 
C: Study completed and dose is declared to be the MTD 
**for MTD target toxicity pT=18%, and allowing any dose with pT in (17%, 19%) to be 
selected  
The modifications involve escalating the dose whenever the observed toxicity rate is below 
17% and using the N-1st patient to define the change when the toxicity rate exceeds 19% and 
N ≥ 9 to account for the fact that the design is being used in cohorts of 3 rather than 
continuously as designed by Ji et al43. 
 
8.2 
Endpoint Definitions 
8.2.1 Safety Endpoints 
All subjects 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. 
Single 12-lead ECGs will be collected at screening, prior to dosing on Day 1 of each 
treatment cycle and at the end of treatmentvisit. 
Adverse events will be categorized using the most current version of MedDRA and adverse 
events and laboratory tests will be graded using National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0. Immune-related adverse 
experiences (irAEs) among treated subjects will be specifically assessed as well. 
 
8.2.2 
Efficacy Endpoints 
8.2.2.1 
Efficacy Endpoints based on RECIST 1.1 
The best overall response (BOR), computed for all treated subjects, is defined as the best 
response designation over the study as a whole, recorded between the dates of first dose until 
the last tumor assessment prior to subsequent therapy. 
Objective Response Rate (ORR) is defined as the total number of subjects whose best 
response outcome is a complete response (CR) or partial response (PR) divided by the total 
number of evaluable subjects. 
Disease Control Rate (DCR) is defined as the total number of subjects whose best response 
outcome is a complete response (CR) or partial response (PR), or stable disease divided by 
the total number of evaluable subjects. 
Prolonged Disease Control Rate (PDCR) is defined as the total number of subjects whose 
best response outcome is a complete response (CR) or partial response (PR), or stable disease 
lasting at least 12 weeks, divided by the total number of evaluable subjects. 
Progression Free Survival (PFS): is defined for each subject 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. Subjects who do not have any tumor assessment on treatment will be censored 
on the day of the first dose. 
Duration of Overall Response: will be computed for all subjects whose best response is 
either a PR or CR and is calculated from the time the measurement criteria are met for PR or 
CR, whichever is recorded first, until the date of documented progressive disease or death. 
 
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Duration of Disease Control: will be computed for the subjects who had BOR outcome of 
CR, PR, or Stable Disease and is calculated from the beginning of treatment until the time of 
documented disease progression. 
 
8.2.2.2 
Efficacy Endpoints based on Immune Related Criteria (irCR) 
Immune Related Best Overall Response (irBOR) is the best irRC designation over the 
study as a whole, recorded between the date of first dose until the last tumor assessment prior 
to subsequent therapy (except for local palliative radiotherapy for painful bone lesions) for 
the individual subject in the study. irCR or irPR determinations included in the irBOR 
assessment must be confirmed by a second (confirmatory) evaluation meeting the criteria for 
response and performed no less than 4 weeks after the criteria for response are first met. 
Immune-related Response Rate (irRR) is defined as the proportion of response evaluable 
subjects whose irBOR outcome is irPR, irCR. 
Immune-related Disease Control Rate (irDCR) is defined as the proportion of the response 
evaluable subjects whose irBOR outcome is irPR, irCR, or irSD. 
Immune-related Prolonged Disease Control Rate (irPDCR) is defined as the proportion of 
the response evaluable subjects whose irBOR outcome is irPR, irCR, or irSD, with stable 
disease lasting at least 12 weeks. 
Immune-related Progression-Free Survival (irPFS) is defined as the time between the first 
dosing date and the date of irPD or death, whichever occurs first. For subjects with no 
recorded post-baseline tumor assessment, irPFS will be censored at the day of first dose. A 
subject who dies without reported irPD will be considered to have progressed on the date of 
death. For those who remain alive and have no irPD, irPFS will be censored on the date of 
last evaluable tumor assessment. Subjects who do not have any tumor assessment on 
treatment will be censored on the day of the first dose. 
Duration of Immune Related Overall Response: will be computed for all subjects whose 
irBOR outcome is either an irPR or irCR and is calculated from the time the measurement 
criteria are met for irPR or irCR, whichever is recorded first, until the date of documented 
progressive disease or death by irRC. 
Duration of Immune Related Disease Control: will be computed for the subjects who had 
irBOR outcome of irCR, irPR, or ir Stable Disease and is calculated from the beginning of 
treatment until the time of documented disease progression by irRC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
 
 
8.3 
Analyses 
8.3.1 
Demographics and Baseline Characteristics 
Frequency distributions of gender and race will be tabulated by dose. Summary statistics for 
age, body weight, height, and Body Mass Index (BMI) will be tabulated by dose. 
8.3.2 
Efficacy Analyses 
Listings of tumor measurements will be provided by subject and study day in each arm. 
Individual subject’s best overall response (BOR) and progression free survival (PFS) will be 
listed based on RECIST 1.1 (dose escalation and cohort expansion). To describe the anti-
tumor activity of panobinostat administered in combination with ipilimumab, Objective 
Response Rate (ORR) as well as prolonged disease control rate by RECIST 1.1 (PDCR) will 
be similarly summarized. Objective Response (OR) is defined as BOR outcome of CR or PR 
by RECIST 1.1. Disease Control (DC) defined as BOR outcome of CR, PR, or Stable 
Disease by RECIST 1.1. Prolonged disease control is defined as disease control with stable 
disease of at least 12months. Duration of response and duration of disease control will also be 
calculated for the subjects with such outcome, based on both efficacy criteria. Median PFS, 
Duration of Response, and Duration of Disease Control will be estimated by Kaplan-Meier 
method and with 95% confidence intervals, at the MTD based on both response criteria. 
Kaplan Meier plots will be provided for all time-to-event variables at the MTD, based on 
both response criteria. We will also fit the survival function using a parametric survival 
approach, as this approach provides a more accurate estimate of the median PFS Additional 
assessments, e.g. sensitivity analyses may be performed to characterize clinical activity. The 
relationship between panobinostat exposure/dose and clinical efficacy (e.g. tumor response 
based on RECIST 1.1 criteria) may be explored graphically and appropriate model may be 
fit. 
 
 
8.3.3 
Safety Analyses 
All recorded adverse events will be listed and tabulated by system organ class, preferred 
term, and dose and coded according to the most current version of MedDRA. The incidence 
of adverse events will be tabulated and reviewed for potential significance and clinical 
importance. Vital signs and clinical laboratory test results will be listed and summarized by 
and dose. Any significant physical examination findings and results of clinical laboratory 
tests will be listed. ECG listings will be evaluated by the investigator and abnormalities, if 
present, will be listed. A separate listing and summary of all immune-related adverse events 
(irAE) and inflammatory events regardless of causality (IERC) will be provided. In addition, 
the irAE rate will be estimated and a 90% confidence interval will be constructed for the 
irAE and the grade 3-4 GI irAE rate in each arm, based on the Clopper-Pearson method. The 
relationship between panobinostat exposure/dose and adverse event may be explored 
graphically and appropriate model may be fit. 
 
8.3.4 
Biomarker Analyses 
 
 
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MCC 17439 – version 6-  December 21, 2015 
Pharmacodynamic analyses will examine the patterns of change in ALC over time, and how 
these patterns might differ between treatment arms. Predictive analyses will examine 
potential relationships between ALC and measures of response such as PFS or irPFS. The 
mean rate of change in ALC over time and corresponding two-sided 95% CIs will be 
estimated using an extended linear model, fit by restricted maximum likelihood (REML). The 
model will have fixed effects of treatment and time since first dose. Predictive analyses will 
assess the relationship between PFS / irPFS and rate of change in ALC over time (ALC 
slope). Summary statistics for peripheral blood biomarkers of immunoregulatory activity 
such as, but not limited to T-cell subpopulation counts, serum cytokines, and their 
corresponding changes (or percent changes) from baseline will be tabulated by planned study 
day and dose in each arm, to assess pharmacodynamic effects. In addition, the time course of 
biomarker measures will be investigated graphically; if there is indication of meaningful 
pattern across time, further analysis (eg, by linear mixed models) may be performed to 
characterize the relationship. Possible associations between changes in biomarker measures 
of interest and panobinostat exposure will be explored graphically. Summary statistics for 
measures and changes from baseline of tumor-based markers including T-cell (CD4, CD8, 
CD45, FoxP3) and apoptosis markers (IDO and granzyme B) will be tabulated by study visit 
for each arm. Results from mRNA expression profiles pre- and on-treatment, in peripheral 
blood and fresh tumor biopsies and from T cell phenotype analysis on baseline samples will 
be tabulated, and possible associations with clinical outcome (e.g. tumor response) will be 
explored based on data availability. Associations between biomarkers and efficacy measures 
will be analyzed in all response-evaluable subjects. Methods such as, but not limited to, 
logistic regression will be used to explore possible associations between biomarker measures 
from peripheral blood or tumor markers and clinical outcome, e.g. tumor response, based on 
both RECIST 1.1 and irRC criteria. 
 
9 
STUDY MANAGEMENT  
9.1 
Compliance with the Protocol and Protocol Revisions 
The study shall be conducted as described in this protocol. The investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment. Any significant deviation 
must be documented in the CRF. If a deviation or change to a protocol is implemented to 
eliminate an immediate hazard(s) prior to obtaining IRB/IEC approval/favorable opinion, as 
soon as possible the deviation or change will be submitted to: IRB/IEC for review and 
approval/favorable opinion. Documentation of approval signed by the chairperson or 
designee of the IRB(s)/IEC(s) will be sent to Novartis. If an amendment substantially alters 
the study design or increases the potential risk to the subject: (1) the consent form must be 
revised and submitted to the IRB(s)/IEC(s) for review and approval/favorable opinion; (2) the 
revised form must be used to obtain consent from subjects currently enrolled in the study if 
they are affected by the amendment; and (3) the new form must be used to obtain consent 
from new subjects prior to enrollment. If the revision is an administrative letter, investigators 
must inform their IRB(s)/IEC(s). 
 
9.2 
Monitoring 
This study will be monitored internally by the Moffitt Cancer Center Monitoring Core. 
 
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MCC 17439 – version 6-  December 21, 2015 
Representatives of Novartis will be allowed to visit the study site periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the investigator, and 
verify that the facilities remain acceptable. The investigator must notify Novartis promptly of 
any inspections scheduled by regulatory authorities, and promptly forward copies of 
inspection reports to Novartis. 
 
9.3 
Records 
9.3.1 
Records Retention 
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by the sponsor, whichever is longer. The investigator must contact Novartis prior to 
destroying any records associated with the study. If the investigator withdraws from the study 
(eg, relocation, retirement), the records shall be transferred to a mutually agreed upon 
designee (eg, another investigator, IRB).  
 
9.3.2 
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (panobinostat supplied by Novartis) is maintained at the study site. 
Records or logs must comply with applicable regulations and guidelines and should include: 
• 
amount received and placed in storage area 
• 
amount currently in storage area 
• 
label ID number or batch number 
• amount dispensed to and returned by each subject, including unique subject identifiers 
• 
amount transferred to another area/site for dispensing or storage • non-study 
disposition (eg, lost, wasted) • amount destroyed at study site, if applicable • amount 
returned to the sponsor 
• 
retain samples for bioavailability/bioequivalence, if applicable • dates and initials of 
person responsible for Investigational Product (IP) 
dispensing/accountability, as per the Delegation of Authority Form. 
The sponsor will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements. 
9.3.3 
Case Report Forms 
An investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated or entered as a control in the investigation. Data reported on the CRF that 
are derived from source documents must be consistent with the source documents or the 
discrepancies must be explained. The confidentiality of records that could identify subjects 
must be protected, respecting the privacy and confidentiality rules in accordance with the 
applicable regulatory requirement(s). The investigator will maintain a signature sheet to 
document signatures and initials of all persons authorized to make entries and/or corrections 
on CRFs. The completed CRF, including any paper SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by a qualified physician who is an investigator or sub- 
investigator.  
 
 
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MCC 17439 – version 6-  December 21, 2015 
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10. Robert, C.,Thomas, L., Bodarenko, I, O’Day, S et al Ipilimumab plus Dacarbazine for 
Previously Untreated Metastatic Melanoma New Engl J Med 2011 364 2517-2526 
 
11. Brose MS et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer 
Research 62:6997-7000;2002. 
 
12. Zhang DZ et al. Clinical significance of BRAF mutations in metastatic melanoma. Journal of 
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16. Sosman J, Kim K, Schuchter L, et al. An open-label, multicenter phase II study of continuous 
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Cancer Res. 2009 Nov 15;69(22):8693-9 
 
26. Clemente, C.G., et al., Prognostic value of tumor infiltrating lymphocytes in the vertical 
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27. Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the 
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30. Lenschow D.J., et al., CD28/B7 system of T cell costimulation. Ann Rev Immunol, 1996. 14: 
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32. Krummel MF, Sullivan TJ, Allison JP. Supraantigen responses and costimulation: CD28 and 
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33. Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab 
monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, 
multicentre, phase 2, dose-ranging study. Lancet Oncol.11:155-64. 
 
34. O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, et al. 
Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a 
multicenter single-arm phase II study. Ann Oncol.21:1712-7. 
 
35. Hodi, S., O’Day, S., McDermott, M.J., Weber, R.W., et al Improved Survival with 
Ipilimumab in Patients with Metastatic Melanoma  New Engl J Med 2010 363: 711-723  
 
36. Maker AV, Phan GQ, Attia P, Yang JC, et al Tumor regression and autoimmunity in patients 
treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II 
study. Ann Surg Oncol. 2005 Dec;12(12):1005-16 
 
37. A. A. Tarhini, S. J. Moschos, H. Tawbi, Y. Shuai,  et al Phase II evaluation of tremelimumab 
(Treme) combined with high-dose interferon alpha-2b (HDI) for metastatic melanoma J Clin 
Oncol 28:15s, 2010 (suppl; abstr 8524) 
 
38. Swan KA et al. Involvement of p21as distinguishes positive and negative selection in 
thymocytes. EMBO Journal 1995. 14:276-285. 
 
39. Tsukamoto H et al. B-Raf mediated signaling pathway regulates T cell development. 
European Journal of Immunology 2008.38:518-527. 
 
 
40. Willoughby JE et al. Raf signaling but not the ERK effector SAP-1 is required for regulatory 
T cell development. Journal of Immunology 2007.179:6836-6844. 
 
41. Theil G, Ekici M, Rossler OG. Regulation of cellular proliferation, differentiation and cell 
death by activated Raf. Cell Communication and Signaling 2009. 7:8. 
 
42. Malik NM, Gilroy DW, Kabouridis PS. Regulation of growth and survival of activated T cells 
by cell-transducing inhibitors of Ras. FEBS Letters 2009.583:61-69. 
 
43.Ji YA, Liu P, Li YS, Bekele BN.  A modified toxicity probability interval method for dose-
finding trials,  Clinical Trials 7(6):653-663, 2010. 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
APPENDIX 1 – ECOG PERFORMANCE STATUS 
 
ECOG PERFORMANCE STATUS 
Performance Status Criteria 
ECOG (Zubrod) 
Score 
Description 
0 
Fully active; able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous 
activity but ambulatory and 
able to carry on normal activity; minor symptoms of disease 
2 
Ambulatory and capable of all self care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
3 
Capable of only limited self care; confined to bed or chair more 
than 50% of waking hours. 
4 
Completely disabled; cannot carry on any self care; totally 
confined to bed or chair. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
APPENDIX 2 – CYP3A4 INHIBITORS, INDUCERS, AND 
SUBSTRATES 
 
CYP3A4 INHIBITORS, INDUCERS, AND SUBSTRATES 
The following list describes medications and foods which are common inhibitors, inducers, 
or substrates of CYP3A4. These medications should be used with caution during this study. 
This list should not be considered all inclusive. Consult individual drug labels for specific 
information on a compound’s propensity to inhibit CYP3A4. 
 
STRONG CYP3A4 INHIBITORS 
atazanavir indinavir nelfinavir ritonavir saquinavir clarithromycin itraconazole ketoconazole 
 
STRONG CYP3A4 INDUCERS 
rifampin carbamazepine phenytoin phenobarbital St. John’s wort 
mibefradil nefazodone telithromycin cyclosporin troleandomycin verapamil grape fruit 
seville orange 
 
CYP3A4 SUBSTRATES WITH NARROW THERAPEUTIC INDEX 
alfentanil astemizole cisapride cyclosporine diergotamine ergotamine 
Revised Protocol No.: 01 Date: 30-Sep-2010 
fentanyl pimozide quinidine sirolimus tacrolimus terfenadine 
 
OTHER CYP3A4 SUBSTRATES, INHIBITORS AND INDUCERS CYP3A4 
SUBTRATES 
Macrolide antibiotics: clarithromycin erythromycin NOT azithromycin telithromycin 
Anti-arrhythmics: quinidine Benzodiazepines: alprazolam diazepam midazolam triazolam 
Immune Modulators: cyclosporine tacrolimus (FK506) 
HIV Protease Inhibitors: indinavir ritonavir saquinavir 
Prokinetic: cisapride 
Antihistamines: astemizole chlorpheniramine 
Calcium Channel Blockers: amlodipine diltiazem felodipine 
nifedipine nisoldipine nitrendipine verapamil 
HMG CoA Reductase Inhibitors: atorvastatin cerivastatin lovastatin 
NOT pravastatin simvastatin 
Others: aripiprazole buspirone gleevec haloperidol (in part) methadone pimozide 
quinine NOT rosuvastatin sildenafil tamoxifen trazodone vincristine 
 
CYP3A4 INHIBITORS 
amiodarone NOT azithromycin cimetidine 
 
CYP3A4 INDUCERS 
HIV Antivirals: efavirenz nevirapine 
diltiazem erythromycin fluvoxamine 
Others: barbiturates glucocorticoids modafinil troglitazone rifabutin 
 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
APPENDIX 3 – RECIST 1.1 CRITERIA 
 
RECIST 1.1 CRITERIA 
• 
Only patients with measurable disease at baseline should be included in protocols 
where objective tumor response is the primary endpoint. 
− Measurable disease: the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
− 
Measurable lesions: lesions that can be accurately measured in 2 perpendicular 
diameters with at least one diameter ≥ 20 mm using conventional techniques or ≥ 10 mm 
with spiral CT scan using a 5 mm contiguous reconstruction algorithm. 
− Non-measurable lesions: all other lesions, including small lesions (longest diameter < 20 
mm with conventional techniques or < 10 mm with spiral CT scan), i.e., bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonitis, cystic lesions, and also abdominal masses that are not 
confirmed and followed by imaging techniques. 
• 
All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. All lesion measurements must be recorded in millimetres (or decimal fractions of 
centimetres). 
• 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than approximately 30 days before the beginning of the treatment. 
• The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
• 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
Methods of measurement 
• 
CT and MRI are the best currently available and reproducible methods to measure 
index lesions selected for response assessment. Conventional CT and MRI should be 
performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be 
performed using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the 
chest, abdomen and pelvis. Head and neck tumors and those of extremities usually require 
specific protocols. 
• 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not 
yet been fully and widely validated. Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers. 
Therefore, the utilization of such techniques for objective tumor response should be restricted 
to validation purposes in specialized centers. However, such techniques can be useful in 
confirming complete pathological response when biopsies are obtained. 
• 
Tumor markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response when all lesions have disappeared. 
• 
Cytology and histology can be used to differentiate between PR and CR in rare cases 
(e.g., after treatment to differentiate between residual benign lesions and residual malignant 
lesions in tumor types such as germ cell tumors). 
Baseline documentation of “index” and “non-index” lesions 
• 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in 
total, representative of all involved organs should be identified as index lesions and recorded 
 
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MCC 17439 – version 6-  December 21, 2015 
and measured at baseline. 
• 
Index lesions should be selected on the basis of their size (lesions with the longest 
diameter and perpendicular diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). 
• 
A sum of the longest diameters for all index lesions will be calculated and reported as 
the baseline sum. The baseline sum will be used as reference by which to characterize the 
objective tumor. 
• 
All other lesions (or sites of disease) should be identified as non-index lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up. 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started). In general, the patient’s best response 
assignment will depend of the achievement of both measurements and confirmation criteria. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
• 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm 
the complete response status. 
Confirmation 
• 
The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed. In cases where confirmation of response is not feasible, it should be 
made clear when reporting the outcome of such studies that the responses are not confirmed. 
• To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after 
the criteria for response are first met. Longer intervals as determined by the study protocol 
may also be appropriate. 
• 
In the case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in 
the study protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
APPENDIX 4 – IMMUNE RELATED RESPONSE CRITERIA 
 
Immune Related Response Criteria  
4.1 
Tumor Assessments 
The immune-related Response Criteria (irRC) is a further refinement of the mWHO criteria 
to better capture tumor responses in subjects on immunotherapy. The irRC was 
developed/implemented to address the difference in the natural history of the clinical 
responses observed in subjects treated with immunotherapy agents which differs from those 
seen in subjects on other classes of anti-cancer agents.  
 
Differences of response patterns between cytotoxic and immune therapies are now 
recognized by the scientific community1 as well as by Regulatory Authorities2. These 
differences have been characterized by Wolchok3 et al after a post hoc analysis of the 
radiological responses that were observed during the Phase 2 studies performed in melanoma: 
• The appearance of measurable antitumor activity may take longer for immune therapies 
than for cytotoxic therapies; 
• 
Responses to immune therapies may occur after conventional PD; •
 
Discontinuation of immune therapy may not be appropriate in some cases, unless PD 
is confirmed (as is usually done for response); 
• 
Allowance for “clinically insignificant” PD (eg, small new lesions in the presence of 
other responsive lesions) is recommended; 
• 
Durable SD may represent antitumor activity. 
These observations lead to the development or immune-related Response Criteria extensively 
described by Wolchok et al3, used to define efficacy endpoints in more recent ipilimumab 
studies. 
4.2 
Radiological Assessment of Tumor Lesions 
4.2.1 
CT/MRI 
CT/MRI imaging of the chest and abdomen is required at Screening and at each tumor 
assessment (TA), regardless of the location of known metastases. In addition, CT/MRI scans 
must be obtained of anatomic regions not covered by the chest and abdomen scans in subjects 
where there is clinical suspicion of deep soft tissue metastases (eg, lesions in the thigh). Such 
additional CT/MRIs will be required at Screening only when deep soft tissue disease is 
known/suspected and must be consistently repeated at all TAs if a deep soft tissue lesion is 
identified during Screening. The same imaging modality must be used at all TAs. 
Brain scans are required at Screening to rule out CNS metastases. Brain scans to be repeated 
as clinically indicated. Contrast enhanced CTs are preferred, MRIs are a second choice. 
Similar methods of TA and similar techniques must be used to characterize each identified 
and reported lesion at Screening and all subsequent tumor assessments. Imaging-based 
evaluation is preferred to clinical examination. Helical (spiral) CT scans of the chest and 
abdomen are preferred. If not available, conventional (non helical, non- spiral CT) should be 
used; however, a measurable lesion must not have the longest diameter smaller than 20 mm. 
IV contrast should be used for all CT scans; if IV contrast is contraindicated, oral contrast 
maybe used, or MRI should be used at the Screening exam and at all TA time points. 
Subjects who develop contrast allergy after study enrollment must be followed by MRI for 
subsequent tumor measurements. 
 
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A reference measurement ruler must be printed on every image for scale determination. 
Sections should be contiguous, similarly sized and consistent from visit-to-visit. Section 
thickness must be based on institutional standards (e.g, from 5 to 8 mm, 10 mm cuts are 
not recommended). Chest x-rays and ultrasound are not acceptable methods to measure 
disease. 
4.2.2 
Bone Scans 
Assessment of irPD is never based only on a new lesion(s) found on bone scans. However, if 
bone lesions are identified at any time during the study, additional imaging studies of the 
lesion(s) must be performed to confirm the malignant nature of the new findings on the bone 
scan. If an abnormal bone scan was observed at any time point throughout the study, a new 
bone scan must be performed prior to the confirmation of a complete response (eg, the 
remaining metastastic lesions must have resolved). In case of new lesions such as pleural 
effusion, cytology must be performed to identify and confirm malignancy. Skin and soft 
tissue lesions will be captured as non-measurable lesions through physical examination only. 
4.3 
Definition of Measurable / Non-Measurable Lesions 
• 
Measurable lesions are lesions that can be accurately measured in 2 perpendicular 
diameters, with at least one diameter ≥ 20 mm and the other dimension ≥ 10 mm (10 mm x 
10 mm for spiral CT with cuts of 5 mm). The area will be defined as the product of the 
largest diameter with its perpendicular. 
• 
Non-measurable (evaluable) lesions are all other lesions, including unidimensional 
measurable disease and small lesions (lesions without at least one diameter ≥ 20 mm), and 
any of the following: lesions occurring in a previously irradiated area (unless they are 
documented as new lesions since the completion of radiation therapy), bone lesions, 
leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitis cutis/pulmonis, 
abdominal masses that are not pathologically/cytologically confirmed and followed by 
imaging techniques and cystic lesions. 
4.4 
Definition of Index / Non-Index Lesions 
Measurable lesions, up to a maximum of five lesions per organ and ten lesions in total, 
must be identified as index lesions to be measured and recorded on the CRF at Screening. 
The index lesions should be representative of all involved organs. In addition, index lesions 
must be selected based on their size (eg, lesions with the longest diameters), their suitability 
for accurate repeat assessment by imaging techniques, and how representative they are of the 
subject’s tumor burden. At Screening, a Sum of the Products of Diameters 
 (SPD) for all index lesions will be calculated and considered the baseline SPD. The baseline 
sum will be used as the reference point to determine the objective tumor response of the 
index lesions at TA. 
Measurable lesions, other than index lesions, and all sites of non-measurable disease, will be 
identified as non-index lesions. Non-index lesions will be recorded on the CRF and will be 
evaluated at the same assessment time points as the index lesions. In subsequent assessments, 
non-index lesions will be recorded as complete response, stable or progression. 
All measurable and non-measurable lesions should be assessed at Screening and at the 
defined TA time points. Extra assessments may be performed, as clinically indicated, if there 
is a suspicion of progression. The Investigator will base response to treatment using the irRC. 
4.5 
Definition of New Lesions 
New lesions (both measurable and non-measurable) will be recorded on the appropriate CRF 
 
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for any tumor assessment. The appearance of up to 10 new lesions should be recorded. Once 
a new lesion has been identified ir should be reassessed at each subsequent TA time point 
using the same imaging modality. If meaurable, the dimensions of the new lesions should be 
recorded on the CRF, as they will be used to calculate the irSPD. 
4.6 
Tumor Response Using Immune-Related Response Criteria 
(irRC) 
4.6.1 
Confirmation Scans 
Any subject who develops an objective tumor response (irCR or irPR) is recommended to 
undergo confirmatory scans no less than 4 weeks since the prior scan in order to verify the 
reliability of the radiologic finding. 
It is also recommended that any subject that develops ir-progressive disease (irPD) also 
undergo confirmatory scans no less than 4 weeks since the prior scan to verify the reliability 
of the radiologic finding before discontinuation of all study treatment. 
4.6.2 
Calculation of Sum of Product of Diameters (SPD) for irRC (irSPD) 
SPD is an estimation of tumor burden. The two greatest perpendicular diameters are used to 
estimate the size of each tumor lesion. The SPD is calculated as the sum of the product of the 
diameters for index tumor lesions. Several variations of the SPD are identified for the 
purpose of classification of tumor responses. 
SPD at Baseline: The sum of the product of the diameters for all index lesions identified at 
baseline prior to treatment on Day 1. Immune-related SPD (irSPD) at baseline is the same as 
SPD. 
SPD at TA: For every on-study TA collected, per protocol Section 5.1 or as clinically 
indicated, the SPD at TA will be calculated using tumor imaging scans. An index lesion and 
all new measurable lesions that have emerged after baseline will contribute to SPD at TA. 
Therefore, the SPD at TA using the irRC for progressive disease incorporates the 
contribution of new measurable lesions. Each net percentage change in tumor burden per 
assessment using irRC accounts for the size and growth kinetics of both old and new lesions 
as they appear. 
SPD at Nadir: For tumors that are assessed more than one time after baseline, the lowest 
value of the SPD (SPD Baseline or SPD at TA) is used to classify progression at subsequent 
TAs for each subject. 
4.6.3 
Impact of New Lesions on irRC 
New lesions alone do not qualify as progressive disease. However their contribution to total 
tumor burden is included in the SPD which in turn feeds into the irRC for tumor response. 
Therefore, new non-measurable lesions will not discontinue any subject from the study. 
Definition of Best Overall Response using irRC (irBOR) will be based on the following 
criteria: 
• Immune-related Complete Response (irCR): Complete disappearance of all tumor lesions 
(index and non-index together with no new measurable/unmeasurable lesions) for at least 4 
weeks from the date of documentation of irCR. 
• 
Immune-related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all index lesions is measured and captured as the SPD baseline. At 
each subsequent TA, the sum of the products of the two largest perpendicular diameters of all 
index lesions and of new measurable lesions are added together to provide the Immune 
Response Sum of the Product of the Diameters (irSPD). A decrease, relative to baseline of 
 
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the irSPD of 50% or greater is considered an irPR. This must be confirmed no less than 4 
weeks from the first irPR. 
• 
Immune-related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
immune complete response or immune partial response, in the absence of progressive 
disease. 
• 
Immune-related Progressive Disease (irPD): It is recommended in difficult cases to 
confirm PD at the following TA. Any of the following will constitute progressive disease: 
− 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. 
References: 
1 Guidance for Industry. Clinical Consideration for Therapeutic Vaccines. Draft guidance. 
FDA. 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformatio 
n/Guidances/Vaccines/ucm182443.htm. Accessed 12-03-09. 
2. A clinical development paradigm for cancer vaccines and related biologics. Hoos A, 
Parmiani G, Hege K, Sznol M, Loibner H, Eggermont A, Urba W, Blumenstein B, Sacks N, 
Keilholz U, Nichol G; Cancer Vaccine Clinical Trial Working Group. J Immunother. 2007 
Jan;30(1):1-15. Review. 
3. Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune- 
Related Response Criteria.Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, 
Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS. Clin Cancer Res. 2009 
Dec 1;15(23):7412-7420. Epub 2009 Nov 24. 
 
 
 
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APPENDIX 5 – IRAE GASTROINTESTINAL MANAGEMENT ALGORITHM 
 
 
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MCC 17439 – version 6-  December 21, 2015 
APPENDIX 6 – IRAE HEPATIC MANAGEMENT ALGORITHM 
 
 
 
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MCC 17439 – version 6-  December 21, 2015 
APPENDIX 7 – IRAE ENDOCRINE ALGORITHM 
 
 
 
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APPENDIX 8 – NOVARTIS SAE FAX COVER SHEETS 
 
 
73 


 
 
Interventional Clinical Trial SAE Fax Cover Sheet 
 
 
 
 
 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
 
Relationship between study treatment and event(s) is: 
 
Suspected/Unknown 
 
 
  
 
 
 
 
Version 2.0 3Aug11 


 
 
Interventional Clinical Trial SAE Fax Cover Sheet 
 
 
 
 
 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
 
Relationship between study treatment and event(s) is: 
 
Not Suspected 
 
 
 
 
 
 
 
Version 2.0 3Aug11