Conditions: Hematologic Neoplasms
Keywords: Hematologic Neoplasms, LBH589, Panobinostat,
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
The study allowed continued use of single agent panobinostat in patients who were on single agent panobinostat treatment in a Novartis-sponsored study which had met its endpoint and were benefiting from the treatment as judged by the investigator.

Detailed description:
This was a multi-center open label study to provide continued use of single agent oral panobinostat to patients treated in a Novartis-sponsored study (parent study) which had met its endpoint and were benefiting from continuation of the treatment with single-agent panobinostat as judged by the investigator. Patients from multiple parent studies were transferred over to this protocol and continued to receive single agent panobinostat at the last assigned dose and regimen of the parent protocol. There was no screening period, and patients had to visit the study center at least on a quarterly basis. During these visits limited information on study treatment and occurrence of SAEs was collected for the clinical database. SAEs were only reported to the Novartis safety database. Other assessments and possibly more frequent visits occurred as per standard of care at the site. Patients continued treatment until they were no longer benefiting from panobinostat treatment, developed unacceptable toxicities, withdrew consent, were non-compliant with the protocol, the investigator believed it was no longer in the best interest to continue, the patient died, or for other administrative reasons. An end of treatment visit and a safety follow-up for 30 days after the last dose was performed. The study was expected to remain open for 5 years or until such time that enrolled patients no longer needed treatment with panobinostat, whichever came earlier.

Arms:
arm 1: 10 to 40mg/day TIW QoW (3 times/week every other week) as per parent protocol design

Interventions: intervention 1: Panobinostat
Intervention descriptions: intervention 1: Panobinostat was provided as 5, 10 and 20 mg hard gelatin capsules to be taken orally. Patients started on dose from parent protocol and dose modifications were at the discretion of the investigator based on guidance provided in the protocol and IB.

Protocol document:
Prot_000.pdf: 
Clinical Development
LBH589 (Panobinostat)
Protocol CLBH589B2402B / NCT01802879
An open-label multi-center single agent panobinostat roll-
over protocol for patients who have completed a previous 
Novartis-sponsored panobinostat study and are judged by 
the investigator to benefit from continued single agent 
panobinostat treatment
Authors
Document type
Amended Protocol Version
EUDRACT number
2012-005252-41
Version number
01 (Clean)
Development phase
II
Document status
Final
Release date
11-Mar-2016
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 19-Nov-2015


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................5
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................8
Amendment 01 ....................................................................................................................9
Protocol summary:.............................................................................................................12
1
Background........................................................................................................................14
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............14
1.2
Introduction to investigational treatment(s) and other study treatment(s).............15
1.2.1
Overview of panobinostat .....................................................................15
2
Rationale............................................................................................................................17
2.1
Study rationale and purpose...................................................................................17
2.2
Rationale for the study design ...............................................................................18
2.3
Rationale for dose and regimen selection..............................................................18
2.4
Rationale for choice of combination drugs............................................................18
2.5
Rationale for choice of comparators drugs............................................................18
2.6
Risks and benefits..................................................................................................18
3
Objectives and endpoints...................................................................................................19
4
Study design ......................................................................................................................21
4.1
Description of study design ...................................................................................21
4.2
Timing of interim analyses and design adaptations...............................................22
4.3
Definition of end of study......................................................................................22
4.4
Early study termination..........................................................................................22
5
Population..........................................................................................................................22
5.1
Patient population..................................................................................................22
5.2
Inclusion criteria ....................................................................................................22
5.3
Exclusion criteria...................................................................................................23
6
Treatment...........................................................................................................................24
6.1
Study treatment......................................................................................................24
6.1.1
Dosing regimen .....................................................................................24
6.1.2
Ancillary treatments..............................................................................25
6.1.3
Rescue medication ................................................................................25
6.1.4
Guidelines for continuation of treatment ..............................................25
6.1.5
Treatment duration................................................................................25


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6.1.6
Starting dose rationale...........................................................................25
6.2
Dose modifications ................................................................................................26
6.2.1
Non-Cardiac Toxicity Dose Modifications...........................................26
6.2.2
Thrombocytopenia ................................................................................26
6.2.3
Gastrointestinal toxicity ........................................................................27
6.2.4
Neutropenia...........................................................................................27
6.2.5
Follow-up for toxicities.........................................................................28
6.2.6
Dose modification of panobinostat for prolonged QTcF interval.........28
6.2.7
Suggested management of selected adverse events ..............................29
6.2.8
Follow up on potential drug-induced liver injury (DILI) cases ............30
6.3
Concomitant medications ......................................................................................31
6.3.1
Use of Bisphosphonates (or other concomitant agents)........................33
6.4
Patient numbering, treatment assignment or randomization .................................33
6.4.1
Patient numbering .................................................................................33
6.4.2
Treatment assignment or randomization...............................................33
6.4.3
Treatment blinding................................................................................33
6.5
Study drug preparation and dispensation...............................................................33
6.5.1
Study treatment packaging and labeling ...............................................33
6.5.2
Drug supply and storage........................................................................33
6.5.3
Study drug compliance and accountability ...........................................34
6.5.4
Disposal and destruction .......................................................................34
7
Visit schedule and assessments .........................................................................................34
7.1
Study flow and visit schedule................................................................................34
7.1.1
Molecular pre-screening........................................................................36
7.1.2
Screening...............................................................................................36
7.1.3
Treatment period ...................................................................................36
7.1.4
Pregnancy and assessment of fertility...................................................36
7.1.5
Discontinuation of study treatment .......................................................37
7.1.6
Withdrawal of consent ..........................................................................38
7.1.7
Follow up for safety evaluations...........................................................39
7.1.8
Lost to follow-up...................................................................................39
7.2
Assessment types...................................................................................................39
7.2.1
Efficacy assessments.............................................................................39
7.2.2
Other assessments .................................................................................39
7.2.3
Safety and tolerability assessments.......................................................39
7.2.4
Pharmacokinetics ..................................................................................39


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7.2.5
Resource utilization...............................................................................40
7.2.6
Patient reported outcomes.....................................................................40
8
Safety monitoring and reporting........................................................................................40
8.1
Adverse events.......................................................................................................40
8.1.1
Definitions and reporting ......................................................................40
8.1.2
Laboratory test abnormalities................................................................41
8.1.3
Adverse events of special interest.........................................................42
8.2
Serious adverse events...........................................................................................42
8.2.1
Definitions.............................................................................................42
8.2.2
Reporting...............................................................................................42
8.3
Emergency unblinding of treatment assignment ...................................................43
8.4
Pregnancies............................................................................................................44
8.5
Warnings and precautions......................................................................................44
8.6
Data Monitoring Committee..................................................................................44
8.7
Steering Committee ...............................................................................................44
9
Data collection and management.......................................................................................44
9.1
Data confidentiality ...............................................................................................44
9.2
Site monitoring ......................................................................................................45
9.3
Data collection.......................................................................................................45
9.4
Database management and quality control............................................................46
10 Statistical methods and data analysis ................................................................................46
10.1
Analysis sets ..........................................................................................................46
10.1.1
Full Analysis Set ...................................................................................46
10.1.2
Safety Set ..............................................................................................46
10.1.3
Dose-determining analysis set...............................................................46
10.2
Patient demographics/other baseline characteristics .............................................46
10.3
Treatments (study treatment, compliance) ............................................................46
10.4
Primary objective...................................................................................................46
10.4.1
Variable.................................................................................................47
10.4.2
Statistical hypothesis, model, and method of analysis..........................47
10.4.3
Handling of missing values/censoring/discontinuations.......................47
10.4.4
Supportive analyses...............................................................................47
10.5
Secondary objectives .............................................................................................47
10.5.1
Key secondary objective(s)...................................................................47
10.5.2
Other secondary efficacy objectives .....................................................47
10.5.3
Safety objectives ...................................................................................47


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10.6
Interim analysis......................................................................................................48
10.7
Sample size calculation..........................................................................................48
10.8
Power for analysis of key secondary variables......................................................48
11 Ethical considerations and administrative procedures ......................................................48
11.1
Regulatory and ethical compliance........................................................................48
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................48
11.3
Informed consent procedures.................................................................................48
11.4
Discontinuation of the study..................................................................................49
11.5
Publication of study protocol and results...............................................................49
11.6
Study documentation, record keeping and retention of documents.......................49
11.7
Confidentiality of study documents and patient records .......................................50
11.8
Audits and inspections...........................................................................................50
11.9
Financial disclosures..............................................................................................50
12 Protocol adherence ............................................................................................................51
12.1
Amendments to the protocol..................................................................................51
13 References (available upon request)..................................................................................52
14 Appendices ........................................................................................................................53
14.1
Concomitant medication........................................................................................53
14.1.1
Medications which are known to prolong the QT interval and/or
induce Torsades de pointes ventricular arrhythmia should be
avoided ..................................................................................................53
14.1.2
Medications which are known strong CYP3A4/5 inhibitors to be 
avoided ..................................................................................................54
14.1.3
Medications which are known CYP2D6 substrates to be used with
caution...................................................................................................55
List of figures
Figure 4-1
Study design..........................................................................................22


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List of tables
Table 3-1
Objectives and related endpoints ..........................................................20
Table 6-1
Dose and treatment schedule.................................................................24
Table 6-2
Thrombocytopenia dose modifications.................................................27
Table 6-3
Diarrhea dose modifications .................................................................27
Table 6-4
Neutropenia dose modifications............................................................27
Table 7-1
Visit evaluation schedule ......................................................................35
Table 14-1
Medications which are known to prolong the QT interval and/or 
induce Torsades de Pointes to be avoided.............................................53
Table 14-2
Medications which are known strong CYP3A4/5 inhibitors to be
used with caution...................................................................................55
Table 14-3
Medications which are known CYP2D6 substrates to be used with 
caution...................................................................................................56


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List of abbreviations
AE
Adverse Event
CRF
Case Report/Record Form
CRF
Case report/record form
CRO
Contract Research Organization
CRO
Contract Research Organization
CSR
Clinical study report
CTCL
Cutaneous T-cell lymphoma 
DACis
Deacetylase inhibitors
DDI
Drug-drug interaction
DS&E
Drug Safety and Epidemiology
EC
Ethics Committee
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EOT
End Of Treatment 
HDACs
Histone deacetylases
i.v.
Intravenous(ly)
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IIT
Investigator-Initiated Trial
IRB
Institutional Review Board
LBH589
Panobinostat
o.d.
Omnia die/once a day
OGD&GMA
Oncology Global Development & Global Medical Affairs
p.o.
Per os/by mouth/orally
QOW
Every other week
QW
Every week
s.a.
Single agent 
SAE
Serious Adverse Event
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TIW
Three-times-a-week


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Investigational drug
The study drug or treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This also 
includes approved drugs used outside of their indication/approved dosage, or 
that are tested in a fixed combination. Investigational treatment generally does 
not include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage
Other study treatment
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment
Parent Study
The original Novartis-sponsored, Oncology Global Development & Global 
Medical Affairs (OGD&GMA) study, where the patient was first enrolled and 
received treatment
Patient Number 
A unique identifying number assigned to each patient/subject who enrolls in 
the study
Roll-over study
A roll-over study allows patients from multiple parent studies spanning multiple 
indications to continue to be treated within one study after the completion of 
the parent study/ies
Study treatment
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination.


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Amendment 01 
Amendment rationale
The main purpose of the amendment is to change the primary endpoint to safety to better 
characterize the long-term safety of the compound.  In addition, the protocol has been 
amended to include the collection of all AEs (including non-serious AEs) and an investigator 
attestation of continued clinical benefit. 
This roll-over study has been opened since 24-Jun-2013 with 9 total patients enrolled and 3 
patients ongoing. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
The following changes have been implemented: 
Section 1.2.1.2: Updated clinical experience section to include the results from a multicentre 
phase III study in patients with relapsed or relapsed and refractory multiple myeloma and 
included title for section 1.2.1.2.1 (Clinical pharmacokinetics and pharmacodynamics).
Section 2.1: The purpose of the study has been updated to better characterize the long-term 
safety of s.a. oral panobinostat in patients who are on s.a. oral panobinostat treatment in a 
Novartis-sponsored study and are benefitting from the treatment as judged by the investigator. 
Section 2.2: The rationale for the study design has been updated to better characterize the 
long-term safety of s.a. oral panobinostat in patients being treated in a current Novartis-
sponsored study and who are benefitting from treatment with s.a. oral panobinostat. 
Section 2.4 and 2.5 added per new protocol template. 
Section 2.6: Risks and Benefits section added per the new protocol template. 
Table 3-1: Updated with revised study objectives.  The primary objective is to evaluate long 
term safety data. The secondary objective is to evaluate clinical benefit as assessed by the 
investigator.
Section 4.1: Updated to clarify that all adverse events and serious adverse events will be 
collected continuously throughout the study and to specify that at every quarterly visit, the 
investigator is required to confirm that the patient continues to have clinical benefit and may 
continue receiving study treatment. Updated to include study termination by sponsor as 
another possible criterion for discontinuation.
Section 5.3 Exclusion criterion #4 updated to clarify highly effective contraception methods
and duration of contraception use after stopping study treatment (i.e. 6 months for male 
participants and 3 months for females). Exclusion criterion #5 added to exclude sexually 
active males unless they use a condom during intercourse while taking study drug and for 6 
months after stopping treatment and should not father a child in this period. A condom is 
required to be used also by vasectomized men as well as during intercourse with a male 
partner in order to prevent delivery of the drug via semen


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Previous Section 6.1.5 (Dose escalation guidelines) re-located to section 6.2 per the new 
template.
Previous Section 6.1.6 (Treatment duration) updated to Section 6.1.5 was modified to specify 
that at every quarterly visit, the investigator is required to confirm that the patient continues to 
have clinical benefit and may continue receiving study treatment.
Section 6.2 and 6.2.1 added per the new protocol template. 
Section 6.3 added to include information for identifying potential drug-induced liver injury. 
Previous Section 6.2 (Concomitant medications) updated to Section 6.4 and Section 6.4.1 
added per the new protocol template. 
Section 6.4 updated to clarify that no other investigationl therapy should be given to patients 
and no anticancer agents other than the study medication (panobinostat) should be given to 
patients during the study. If such agents are required for a patient then the patient must first be 
withdrawn from the study. 
Sections 6.6, 6.6.1 and 6.6.2 added/updated per the new protocol template. 
Table 7-1: Updated to include investigator attestation of clinical benefit at every quarterly 
visit, collection of all adverse events, relevant medical history, monthly at home pregnancy 
testing for female patients of child bearing potential and the study evaluation completion 
eCRF page at the end of the 30 day safety follow up.
Section 7.1.3: Updated to specify that the investigator is required to confirm that the patient 
continues to have clinical benefit at every quarterly visit and may continue receiving study 
treatment.
Section 7.1.4: Updated to include information on pregnancy and assessment of fertility. 
Female patients of child bearing potential will now be required to perform monthly home 
urine pregnancy tests and complete a simple diary with the dates and the outcome of the home 
urinary test while on study treatment and during safety follow-up (30 days after the final dose 
of study medication). A pregnancy test (either with serum testing if routinely/locally available 
or urine pregnancy test) on female patients of child bearing potential is required at the final 
study visit.
Section 7.1.5, 7.1.6, 7.1.8 and 7.2.3 added per the new protocol template. 
Section 7.1.5: Updated to include the completion of the study evaluation completion eCRF 
page at the end of the 30 day safety follow up.
Section 7.1.5.1: Updated to include study termination by sponsor as another possible criterion
for discontinuation.
Section 7.1.7: Updated to include adverse events in safety follow up period. 
Section 7.2.1: Updated to include investigator attestation of clinical benefit at every quarterly 
visit. 
Section 8: Updated with new AE/SAE reporting process. 
Section 9.1 updated per the new protocol template. 


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Section 10: Updated statistical analysis section based on revised study objectives.
The protocol summary has also been updated to incorporate all the necessary changes 
described above.
All instances of Oncology Clinical Development & Medical Affairs (CD&MA) have been 
updated to Oncology Global Development & Global Medical Affairs (OGD&GMA).
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Protocol summary: 
Protocol number
CLBH589B2402B
Title
An open-label multi-center single agent panobinostat roll-over protocol for patients 
who have completed a previous Novartis-sponsored panobinostat study and are 
judged by the investigator to benefit from continued single agent panobinostat 
treatment
Brief title
Study to allow access to single agent panobinostat for patients who are on single 
agent panobinostat treatment in a Novartis-sponsored study and are benefiting 
from the treatment as judged by the investigator.
Sponsor and Clinical Phase
Novartis, II.
Investigation type
Drug.
Study type
Interventional.
Purpose and rationale
The purpose of this study is to better characterize the long-term safety of single 
agent panobinostat in patients who are on single agent panobinostat treatment in a 
Novartis-sponsored, Oncology Global Development & Global Medical Affairs 
(OGD&GMA) study and are benefiting from the treatment as judged by the 
investigator.
Primary Objective(s) and 
Key Secondary Objective
To evaluate long term safety data (SAEs and AEs)
Secondary Objectives
To evaluate clinical benefit as assessed by the investigator
Study design
This is a multi-center, open label study to better characterize the long-term safety
of patients being treated in current Novartis-sponsored Oncology OGD&GMA
studies and who are benefiting from treatment with single agent panobinostat. 
There will be no screening period for this study. Eligible patients are to be 
consented and can start their treatment with panobinostat as soon as they enter 
the study. All patients must report to the study site for their first visit at which time, 
a quarterly supply of panobinostat can be dispensed to the patient.
Patients must return to the study center on quarterly (every 12 +/- 2 weeks) basis 
for resupply of study medication at which time  drug dispensing and adverse event 
information will be collected. 
Patients will continue to be treated until they are no longer benefiting from 
panobinostat treatment, develop unacceptable toxicities, withdraw consent, are 
non-compliant to the protocol (i.e. pregnancy occurs, etc.), the investigator feels it 
is no longer in the patient’s best interest to continue panobinostat therapy or the 
patient dies, whichever comes first. 
A patient will reach the end of study when panobinostat treatment is permanently 
discontinued and the end of treatment visit has been performed. All patients must 
be followed up for safety evaluations for 30 days after the last dose of study 
treatment. Following this there are no further follow-up study visits.
The study is expected to remain open for 5 years or until such time that enrolled 
patients no longer need treatment with panobinostat, whichever comes earlier. 
Population
Male and female patients, who are currently enrolled in a Novartis-sponsored, 
Oncology OGD&GMA panobinostat study, are benefiting from treatment with single 
agent panobinostat and have fulfilled all their requirements in the parent study. All 
objectives of the parent study must have been reached, and the study must be in 
the process of being completed & reported. 
Inclusion criteria
Patient is currently enrolled in a Novartis-sponsored, Oncology Global 
Development & Global Medical Affairs study receiving single agent panobinostat 
and has fulfilled all their requirements in the parent study.
Patient is currently benefiting from the treatment with single agent panobinostat, as 
determined by the investigator. 
Patient has demonstrated willingness and compliance, as assessed by the 
investigator, with the parent study protocol requirements.


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Exclusion criteria
Patient has been permanently discontinued from panobinostat study treatment in 
the parent study due to unacceptable toxicity, non-compliance to study procedures, 
withdrawal of consent or any other reason.
Patient has participated in a Novartis sponsored combination trial where 
panobinostat was dispensed in combination with another study medication and is 
still receiving combination therapy. 
Investigational therapy
Panobinostat 5 mg, 10mg, 15mg and/or 20 mg capsules, dose and dose regimen 
depending on parent protocol
Efficacy assessments
At every quarterly visit, the investigator is required to confirm that the patient 
continues to have clinical benefit and may continue receiving study treatment.
Safety assessments
Adverse events and SAEs will be collected continuously moving forward. 
Other assessments
Not applicable.
Data analysis
Proportion of patients with clinical benefit as assessed by the investigator will be 
summarized at scheduled visits. The assessment of safety will be based mainly on 
the frequency of AEs and SAEs. As needed, safety information on patients from 
this protocol will link to the patient identifiers from the parent protocol.
Key words
Panobinostat roll-over study for continued use of panobinostat to patients receiving 
panobinostat in a Novartis-sponsored Oncology OGD&GMA study which has 
reached its objectives and who are benefiting from treatment with panobinostat.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Global changes in the epigenetic landscape are a hallmark of cancer (Jones et al 2007). Recent 
advancements in the rapidly evolving field of cancer epigenetics have shown extensive 
reprogramming of every component of the epigenetic machinery in cancer including DNA 
methylation, histone modifications, nucleosome positioning and non-coding RNAs, 
specifically microRNA expression (Boumber et al 2011). The reversible nature of epigenetic 
aberrations has led to the emergence of the promising field of epigenetic therapy, which is 
already making progress with the recent FDA approval of four epigenetic drugs for cancer 
treatment: two DNA methyltransferase inhibitors, azacitidine (Vidaza®) and decitabine 
(Dacogen®), followed by two histone deacetylase inhibitors (DACis), vorinostat (Zolinza®) 
and romidepsin (Istodax®). So far all four FDA approved epigenetic drugs have shown the 
greatest efficacy in hematopoietic malignancies, i.e. azacitidine and decitabine in 
myelodysplastic disorders and leukemia (Issa et al 2006; Kantarjian et al 2006; Issa 2007) and 
vorinostat and romidepsin in cutaneous T-cell lymphoma (CTCL) (Duvic et al 2007; Grant et 
al 2010). General features of responses observed with these agents have included the 
requirement for multiple cycles of therapy, a slow onset of response with some patients 
experiencing a long-lasting clinical benefit requiring prolonged treatment administration.
Similar observations have been made in clinical trials with other investigational DAC 
inhibitors, including panobinostat (Prince et al 2009; Duvic et al 2012; Younes et al 2012). In 
these cases the question has been raised on how to continue treatment of few patients beyond 
study completion and assure adequate monitoring and proper regulatory reporting of relevant 
safety information. In order to allow continued access to a given anticancer therapy to patients 
benefiting from their study treatment, a roll-over study design has been widely used. 
Currently there are 37 roll-over study protocols posted on clinicaltrials.gov for the treatment 
of patients with various malignancies (clinicaltrials.gov).
The purpose of this study is to allow continued use of oral panobinostat in patients who ar e 
currently receiving single agent (s.a) panobinostat treatment in a Novartis-sponsored, 
Oncology Global Development & Global Medical Affairs (OGD&GMA) study that has 
reached its objectives, are not progressing on the current study treatment as defined by the 
parent protocol and are benefiting from the treatment as judged by the investigator.
This roll-over study is designed to accept patients with various disease origins. Please refer to 
the parent protocol for the disease background information and rationale for use of 
panobinostat in their individual indications.


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1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of panobinostat
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). 
Panobinostat has shown antitumor activity in preclinical models and in cancer patients and 
has been formulated as an oral capsule and as a solution for intravenous (i.v.) injection. Both 
the i.v. and the oral formulations have been investigated in Phase IB/II studies in advanced 
solid tumors and hematological malignancies.
1.2.1.1
Non-clinical experience
Panobinostat has been developed as an anticancer agent based on its potential to act:

by exhibiting 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 multiple myeloma (MM).

by inducing consistent tumor growth control in various tumor-bearing xenografted mice 
and by increasing histone-H3 and -H4 acetylation in excised tumors.

by showing synergistic or additive anti-tumor effect in combination with other anti-cancer 
agents such as trastuzumab, docetaxel, bortezomib or standard cytotoxic agents e.g., 
doxorubicin, fludarabine, Ara-C.
The potent anticancer effects of panobinostat seen in experimental models may result from 
two distinct mechanisms of action, both related to pan-HDAC inhibition. Panobinostat was 
shown to affect epigenetic mechanisms of gene expression via inhibition of Class I HDACs, 
as shown by induction of histone acetylation and consequent induction of cell cycle control 
genes (i.e. p21) and to inhibit HDAC6 through abrogation of Hsp90 –mediated stabilization of 
client oncoproteins, resulting in their depletion and in reduced downstream oncogenic 
signaling (Atadja 2011). Although the pharmacodynamic effects of panobinostat on histone 
acetylation have been consistently seen in experimental models as well as in cancer patients, 
histone hyperacetylation does not seem to relate with therapeutic activity. Similar results have 
been reported for other HDAC inhibitors and thus clinical development of these agents has 
been broadly approached by targeting various hematologic and non-hematologic malignancies 
(Atadja 2009, Atadja 2011, Boumber et al 2011).
For the latest information on the pre-clinical pharmacology and toxicology of panobinostat, 
please refer to the current [Investigator Brochure].
1.2.1.2
Clinical experience
As of 31 December 2011, 35 clinical studies, including clinical pharmacology (CP), Phase I 
and Phase II trials, as well as two randomized Phase III studies have either been completed or 
are ongoing. Safety risks associated with panobinostat have been characterized in more than 


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2000 patients enrolled in the overall clinical development program. The majority of severe 
adverse events is hematologic (mainly thrombocytopenia), easily documented with routine 
hematology tests and manageable with conventional supportive care and dosing modifications. 
Common non-hematologic toxicities, including gastro-intestinal (GI) toxicity and fatigue, are 
mild to moderate in severity and generally reversible. They are manageable with dose 
adjustments. The most common ECG findings include post-baseline increase in frequency of 
sinus tachycardia, T-waves changes as well as depressed ST segment. They can be readily 
captured by conventional non-invasive cardiac monitoring (ECGs) and do not appear to be 
clinically significant. With the intermittent oral dosing schedules (three-times-a-week, weekly 
or every other week) used in current clinical trials, QTcF above 500 msec is uncommon 
(6/635 patients, 0.9%) and noted only with the weekly oral dosing regimen. No torsade de 
pointes has been reported in clinical trials with oral panobinostat.
The efficacy and safety of panobinostat in combination with bortezomib and dexamethasone 
were evaluated in a randomised, double-blind, placebo-controlled, multicentre phase III study 
in patients with relapsed or relapsed and refractory multiple myeloma who had received 1-3 
prior lines of therapies.
Patients received panobinostat (20 mg taken orally once a day, three times per week, on a 2 
weeks on and 1 week off dosing regimen), in combination with bortezomib (1.3 mg/m2 
injected intravenously) and dexamethasone (20 mg). Treatment was administered for a 
maximum of 16 cycles. A total of 768 patients were randomised to either the panobinostat + 
bortezomib + dexamethasone (n=387) or the placebo + bortezomib + dexamethasone (n=381) 
arm. Demographics and baseline disease characteristics were balanced and comparable 
between the study arms. 
The median PFS (95% CI) was 12.0 months (10.3, 12.9) and 8.1 months (7.6, 9.2), 
respectively. Out of the pre-specified subgroup of patients with prior treatment with 
bortezomib and an immunomodulatory agent (N=193), 76% of patients had received at least 
two prior regimens. The median PFS (95% CI) was 12.5 months (7.26, 14.03) in the 
panobinostat + bortezomib + dexamethasone arm and 4.7 months (3.71, 6.05) in the placebo + 
bortezomib + and dexamethasone arm [HR: 0.47 (0.31, 0.72)]. 
Regarding safety, the median duration of exposure in the study was 5.0 months. 15.7% of 
patients were exposed to study treatment for ≥48 weeks. The most common non-
haematological adverse reactions were diarrhoea, fatigue, nausea and vomiting. Treatment-
emergent haematological toxicities included thrombocytopenia, anaemia, neutropenia and 
lymphopenia. QTcF >480 and <500 msec was recorded in 1.3% of patients and change from 
baseline of >60 msec was observed in 0.8% of patients. No patient had an absolute 
QTcF >500 msec.
1.2.1.2.1 Clinical pharmacokinetics and pharmacodynamics
Single agent oral panobinostat is administered three-times-a-week (TIW) every-week (QW) or 
every-other-week (QOW). Following oral administration, panobinostat is rapidly absorbed 
with peak plasma concentrations reached within 1 hour; systemic clearance is 33 L/hour and 
central volume of distribution 25 liters. Half-life associated with the distribution, initial 
elimination and terminal elimination phase based on population parameterization are 0.15, 2.3 


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and 37 hours, respectively. Observed drug accumulation is approximately 1.14 fold with TIW 
schedule. This is consistent with an effective half-life of 15 hours. Absolute oral 
bioavailability is 21%.
The extent of binding to human plasma protein is moderate (89.6%) in vitro and independent 
of panobinostat concentration. Panobinostat can be administered without regard to food 
(Shapiro et al 2012).
Panobinostat is extensively metabolized in patients, with the parent compound accounting for 
6-9% of the drug-related exposure in plasma with the remainder accounted for by 
approximately 40 metabolites. Metabolites formed via the primary metabolic pathways were 
all inactive for DAC inhibitory activity in vitro.
CYP3A4 is the main oxidative metabolizing enzyme of panobinostat with minor involvement 
of CYP2D6 and CYP2C19. Drug-drug interaction (DDI) studies in cancer patients using 
standard drug probes have shown a weak interaction between panobinostat and a strong 
CYP3A inhibitor (ketoconazole) (Hamberg et al 2011) or between panobinostat and a 
sensitive CYP2D6 substrate (dextromethorphan). In both cases the systemic exposures of 
panobinostat in the presence of ketoconazole or the systemic exposure of dextromethorphan in 
the presence of panobinostat increased by 80% and 60%, respectively. Therefore co-
administration of a strong CYP3A inhibitor or of a sensitive CYP2D6 substrate with 
panobinostat is feasible when medically necessary with close monitoring. Based on the results 
of the ketoconazole DDI study, oxidative metabolism via CYP enzyme is a minor metabolic 
pathway of panobinostat, suggesting no relevant clinical PK interaction via CYP pathways.
Based on in vitro and clinical metabolic profile of panobinostat and in-silico prediction, co-
administration of panobinostat with a strong CYP3A4 inducer, rifampicin is expected to 
decrease panobinostat systemic exposure by 70% in patients. Co-administration of 
panobinostat with strong CYP3A inducers is to be avoided.
For further details, please refer to the current panobinostat [Investigator Brochure].
2
Rationale
2.1
Study rationale and purpose
In various clinical trials with single agent (s.a.) oral panobinostat, it was evident that some 
patients may benefit from prolonged treatment with this agent well beyond the study 
objectives have been attained (Prince et al 2009; Duvic et al 2012; Younes et al 2012). 
Recognizing that it is important to allow these patients to continue their therapy under a 
controlled, even if less frequent monitoring plan, this multi-center, open-label roll-over 
protocol has been designed to better characterize the long-term safety 
of s.a. oral 
panobinostat in patients being treated in a Novartis-sponsored, Oncology OGD&GMA study 
who are responding to treatment with this agent.
The purpose of this study is to better characterize the long-term safety of panobinostat in 
patients who are on s.a. panobinostat treatment in a Novartis-sponsored, Oncology 
OGD&GMA study that has reached its objectives, who are not progressing on the current 
study treatment as defined by the parent protocol and are benefiting from this treatment as 


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judged by the investigator. Parent studies eligible to participate in the roll-over study will be 
decided by Novartis. Investigator initiated trials (IITs) will not be included. The objectives of 
the parent study must have been reached and the parent study must be in the process of being 
completed and reported.
Patients enrolled in this study will continue to receive s.a. oral panobinostat until one of the 
following occurs: the patient is no longer benefiting from the treatment (e.g. the underlying 
disease is progressing), unacceptable toxicity develops, consent is withdrawn, non-compliance 
with the protocol, the investigator feels it is no longer in the patient’s best interest to continue 
therapy (e.g. pregnancy, etc.), or the patient’s death.
2.2
Rationale for the study design
This is a multi-center, open-label study to better characterize the long-term safety of s.a. oral 
panobinostat in patients being treated in a current Novartis-sponsored, Oncology OGD&GMA
study, who are benefiting from the treatment with oral panobinostat.
The design of this roll-over study is widely used in cancer clinical programs to allow access to 
an effective study treatment to those patients who are benefiting from this therapy well 
beyond trial objectives completion. The study protocol is also designed to gather long-term 
safety information in cancer patients who are eligible to transfer into this roll-over study. The 
well-known safety profile of panobinostat supports the rationale for a less frequent visit 
schedule more adapted to standard of care practice with monitoring focused on adverse events 
reporting. This will ensure not only adequate supervision of the patients’ well-being but also 
proper regulatory reporting of relevant safety information.
2.3
Rationale for dose and regimen selection
The dose/s and regimen/s provided in this roll-over study protocol are those defined in the 
parent protocols for each enrolled patient. Therefore, depending on the capsule strength/s used 
in the parent protocol, s.a. panobinostat will be provided as 5-mg and/or 20-mg hard gelatin 
capsules. At the time of transition to the roll-over study, the starting dose and regimen of oral 
panobinostat should be the same as the last assigned dose and regimen that were given in the 
parent study. Dosing modifications thereafter (following the starting dose) may be done at the 
discretion of the investigator based upon what is in the patient’s best interest.
2.4
Rationale for choice of combination drugs
Not applicable.
2.5
Rationale for choice of comparators drugs 
Not applicable. 
2.6
Risks and benefits 
Based on the last edition of the IB, the risk/benefit assessment of panobinostat (LBH589) is 
considered favorable and unchanged. The risks of single agent panobinostat are well 
characterized by a large safety database and no significant new safety signals have emerged 
since previous editions of this IB. This assessment serves as a basis for the safety monitoring 


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of panobinostat tested in combination with other cancer agents in ongoing clinical studies. As 
appropriate, monitoring of patients is required in the clinical development protocols and no 
protocol changes have been or are planned to be made. Management of adverse events 
remains confined to clinical monitoring per protocol and appropriate dose and schedule 
modifications with supportive care as clinically indicated.
Consistent with the safety profile from the extensive experience with panobinostat single 
agent studies, the major toxicities associated with the active combination of panobinostat with 
bortezomib and dexamethasone in MM patients involved the same adverse events noted 
during single agent treatment. However, the overlapping toxicity, primarily hematologic, GI 
and constitutional in nature was apparent with respect to frequency and severity due to the 
combination regimen. Cardiac toxicity was unremarkable. The known toxicities could be 
predicted and could be effectively managed with established clinical interventions. In the 
context of the significant clinical benefit panobinostat provides to MM patients with limited 
treatment options, its tolerability is considered acceptable.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To evaluate long term safety data (SAEs and 
AEs)
Frequency and severity of AEs/SAEs
Secondary
Refer to Section 10.5.2
To evaluate clinical benefit as assessed by the 
investigator
Proportion of patients with clinical benefit as 
assessed by the investigator at scheduled visits


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4
Study design
4.1
Description of study design
This is a multi-center, open-label study to better characterize the long-term safety of s.a. oral 
panobinostat to
in
patients being treated in current Novartis-sponsored, Oncology 
OGD&GMA study and who are benefiting from the treatment with s.a. oral panobinostat as 
determined by the guidelines of the parent protocol (for which the study objectives have been 
met) and based on the investigator’s clinical judgment.
This roll-over study will not include screening period as patients will transfer directly from
the parent study and commence with panobinostat as soon as they are consented and meet 
inclusion criteria of the roll-over protocol. All patients must report to the study site for their 
first visit and commence study participation. At that time, a quarterly (12 +/- 2 weeks) supply 
of oral panobinostat will be dispensed to the patient or as per local practice.
Patients must return to the study center on a quarterly (every 12 +/- 2 weeks) basis for 
resupply of study medication at which time limited drug dispensing information will be 
collected. Changes in dosing which might occur any time during the study treatment will be 
documented on the dose administration page.
Patients may return to the study center more frequently at the physicians’ discretion as 
clinically indicated or as per standard of care, however, these unscheduled visits will not be 
captured in the eCRF, but rather only in the source documents at the study center.
All adverse events and serious adverse events will be collected throughout the study. 
Patients entering the roll-over protocol should be followed at the investigator’s discretion for 
known and/or clinically notable AEs that occur on panobinostat treatment as described in the 
current version of the [Investigator Brochure].
Patients will continue to be treated in the roll-over protocol until they are no longer benefiting 
from the s.a. oral panobinostat treatment, develop unacceptable toxicities, withdraw consent, 
are non-compliant to the protocol, the investigator feels it is no longer in the patient’s best 
interest to continue s.a. oral panobinostat therapy, pregnancy occurs or the patient dies, or 
study is terminated by sponsor, whichever comes first. At every quarterly visit, the 
investigator is required to confirm that the patient continues to have clinical benefit and may 
continue receiving study treatment.
A patient will reach the end of the study treatment when s.a. oral panobinostat treatment is 
permanently discontinued. A 30-day safety follow-up after last dose of study drug should be 
conducted.
The study is expected to remain open for 5 years or until such time that enrolled patients no 
longer need treatment with panobinostat, whichever occurs earlier.


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Figure 4-1
Study design
4.2
Timing of interim analyses and design adaptations
No interim analyses are planned.
4.3
Definition of end of study
End of study is defined as either a 5 year duration or when all patients in this study have 
permanently discontinued panobinostat treatment and the end of treatment visit plus the 30-
day safety follow up have been performed for each patient (and no further follow-up is 
needed), whichever comes earlier.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1.3 The investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing IRBs and/or ECs of the 
early termination of the trial.
5
Population
5.1
Patient population
The study population is constituted of patients with various malignancies who participated in 
a Novartis-sponsored, Oncology OGD&GMA clinical trial for their specific indication and 
qualify to transfer to this roll-over protocol.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patient is currently enrolled in a Novartis-sponsored, Oncology OGD&GMA study 
receiving s.a. oral panobinostat and has fulfilled all their requirements in the parent study.
2. Patient is currently benefiting from the treatment with s.a. oral panobinostat as determined 
by the guidelines of the parent protocol and according to the Investigator’s clinical 
judgment.


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3. Patient has demonstrated compliance, as assessed by the investigator, with the parent 
study protocol requirements.
4. Willingness and ability to comply with scheduled visits, treatment plans and any other 
study procedures.
5. Written informed consent obtained prior to enrolling into the roll-over study.

If consent cannot be expressed in writing, it must be formally documented and 
witnessed, ideally via an independent trusted witness.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient has been permanently discontinued from s.a. oral panobinostat study treatment in 
the parent study due to unacceptable toxicity, withdrawal of consent, non-compliance to 
study procedures or any other reason (including progression of disease).
2. Patient has participated in a Novartis sponsored combination trial where panobinostat was 
dispensed in combination with another study medication and is still receiving combination 
therapy.
3. Patient is pregnant or nursing (lactating) at time of entry into the roll-over protocol. 
Pregnancy is defined as the state of a female after conception and until the termination of 
gestation, confirmed by a positive hCG laboratory test.
4. Women of child-bearing potential and male patients with sexual partner(s) of child-
bearing potential unwilling to use highly effective methods of contraception during dosing 
and for a specified duration (6 months for male participants and 3 months for females) 
after stopping study treatment.
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to enrolling). For female patients on the 
study the vasectomized male partner should be the sole partner for that patient.

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. Women using hormonal 
contraceptives should additionally use a barrier method of contraception. 
Note: In case of use of oral contraception, women should have been stable on the same pill 
for a minimum of 3 months before entering the roll-over protocol. 

Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 


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profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 

If a study patient becomes pregnant or suspects being pregnant during the study or 
within 30 days after the final dose of panobinostat, the Investigator/Study Doctor 
needs to be informed immediately and ongoing study treatment with panobinostat has 
to be stopped immediately.
5. Sexually active males unless they use a condom during intercourse while taking the drug 
during treatment and for 6 months after stopping treatment and should not father a child in 
this period. A condom is required to be used also by vasectomized men as well as during 
intercourse with a male partner in order to prevent delivery of the drug via semen.
6
Treatment
6.1
Study treatment
Study drug and investigational treatment refer to s.a. oral panobinostat (hereof defined as the 
study treatment).
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Strength
Dosing Regimen
Panobinostat
Capsule for oral use
5 mg, 10mg, 15mg and/or 
20 mg depending on 
parent protocol
Per parent protocol
The dose/s and regimen/s provided in this roll-over study protocol are those defined in the 
parent protocols for each enrolled patient, hence this may differ for patients enrolling from 
various studies.
Panobinostat will initially be provided as 5 mg and/or 20 mg hard gelatin capsules, depending 
on the strength/s used in the parent protocol. If the need arises at a later time, also 10mg 
and/or 15mg capsules might be used. The investigational treatment is to be stored in a secure 
locked area while under the responsibility of the investigator. Receipt and dispensing of 
investigational treatment must be recorded by an authorized person at the investigator’s site.
Patients will be instructed to take panobinostat orally with a glass of water, at the last assigned
dose and schedule received in the parent protocol, either consistently with food or consistently 
without food. The capsule should be swallowed as a whole and should not be chewed or 
crushed. Dietary habits at the time of enrolling in the study from the parent study should be 
kept as consistent as possible throughout the study.


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6.1.2
Ancillary treatments
Not applicable
6.1.3
Rescue medication
Not applicable
6.1.4
Guidelines for continuation of treatment 
The starting dose of oral panobinostat should be the same as the last assigned dose and 
schedule that was given in the parent study. Assigned dose is the dose as designated by 
investigator and does not include unintended changes or error in dosing in parent protocol.
Dose modification thereafter (following the starting dose) may be done at the discretion of the 
investigator based upon what is in the patient’s best interest.
In case patients do not tolerate the dosing schedule, dose adjustments are permitted in order to 
keep the patient on study drug. These dose adjustments may be delays in dosing and/or 
reductions in the dose being administered. Dosing should always be temporarily discontinued 
if the physician determines it is in the best interest of the patient. All dose modifications 
should be recorded in the source documents and on the Dosage Administration Record Form.
Patients receiving a reduced dose of panobinostat due to toxicity who are clearly benefiting 
from panobinostat and whose AE(s) remain grade < or = 1, which the patient believes is/are 
tolerable may at the discretion of the Investigator after agreement by the Sponsor return to the 
initial dosage in 5mg/increments. Dose re-escalation should be reviewed on a case basis and 
requires agreement between Sponsor and Investigator. No more than 2 dose reductions are 
permitted (i.e. the minimum dose patients may receive is 5 mg/day).
6.1.5
Treatment duration
Patients will continue to be treated until they are no longer benefiting from s.a. oral 
panobinostat, develop unacceptable toxicities, withdraw consent, are non-compliant with the 
protocol, the investigator feels it is no longer in the patient’s best interest to continue 
panobinostat therapy (e.g. disease progression, pregnancy, etc.) or the patient dies, whichever 
comes first. A patient will reach the end of the roll-over study when panobinostat is 
permanently discontinued. A 30-day safety follow-up should be conducted after the last dose 
of panobinostat. At every quarterly visit, the investigator is required to confirm that the patient 
continues to have clinical benefit and may continue receiving study treatment.  
The study is expected to remain open for 5 years or until such time that enrolled patients no 
longer need treatment with s.a. oral panobinostat, whichever occurs first. The study can be 
terminated at any time for any reason by Novartis.
6.1.6
Starting dose rationale
The starting dose of panobinostat should be the same as the last dose that was given in the 
parent study. After this, the dose of panobinostat is based on the investigator’s judgment.


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6.2
Dose modifications 
For patients who do not tolerate the specified dose, dose adjustments are permitted in order to 
allow the patient to continue treatment. The following guidelines should be applied.
If a patient requires a dose delay more than 28 days from the intended day of the next 
scheduled dose, the patient should be considered for discontinuation of treatment. If, however, 
the patient was clearly benefitting from treatment and the cause of the delay has resolved, the 
patient may be able to restart treatment after discussion with Novartis. This option should be 
used with the highest amount of caution keeping the safety of the patient in mind, and 
evaluating whether or not the benefit outweighs the risk. 
6.2.1
Non-Cardiac Toxicity Dose Modifications
Treatment dose and/or schedule modification may be required based on individual tolerability. 
Clinical judgment on how to continue the treatment should be exercised when a patient 
experiences adverse drug reactions. 
If a dose reduction is required, the dose of panobinostat should be reduced by decrements of 5 
mg (i.e. from 20 to 15 mg or from 15 to 10 mg). The dose should not be reduced below 10 mg 
daily and the same treatment schedule should be maintained. 
6.2.2
Thrombocytopenia 
If patients experience thrombocytopenia (TCP), panobinostat may need to be temporarily 
withheld and the subsequent dose may need to be reduced. In patients with Common 
Terminology Criteria for Adverse Events version 3.0 (CTCAE) grade 3 (<50x109/L, 
complicated by bleeding), or grade 4 (<25x109/L) thrombocytopenia, panobinostat therapy 
should be withheld and resumed at a reduced dose upon recovery to ≤ grade 2 (≥50x109/L). 
Discontinuation of treatment may be considered if thrombocytopenia does not improve 
despite the treatment modifications described above and/or the patient requires repeated 
platelet transfusions. 


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Table 6-2
Thrombocytopenia dose modifications
Thrombocytopenia grade on 
day of treatment 
Modification of panobinostat 
starting dose 
Panobinostat dose on 
recovery to ≤ grade 2 
thrombocytopenia (≥50 x 
109/L) 
Grade 3 with bleeding 
Platelets <50 x 109/L 
Omit dose 
Resume at reduced dose 
Grade 4 
Platelets <25 x 109/L
Omit dose 
Resume at reduced dose 
6.2.3
Gastrointestinal toxicity 
Gastrointestinal toxicity is very common in patients treated with panobinostat. Patients who 
experience diarrhea and nausea or vomiting may require temporary dose discontinuation or 
dose reduction. 
Table 6-3
Diarrhea dose modifications
Adverse drug 
reaction 
Grade on day of 
treatment 
Modification of 
panobinostat starting 
dose 
Panobinostat dose on 
recovery to ≤ grade 1 
Diarrhoea 
Grade 2 despite anti-
diarrheal medicinal 
product 
Omit dose 
Resume at the same 
dose 
Grade 3 despite anti-
diarrheal medicinal 
product 
Omit dose 
Resume at reduced 
dose 
Grade 4 despite anti-
diarrheal medicinal 
product 
Discontinue 
Discontinue 
At the first sign of abdominal cramping, loose stools, or onset of diarrhea, it is recommended 
that the patient be treated with anti-diarrheal medication (e.g. loperamide). Prophylactic anti-
emetics should be administered at the discretion of the physician and in accordance with local 
medical practice.
6.2.4
Neutropenia 
Neutropenia may require temporary or permanent dose reduction.
Table 6-4
Neutropenia dose modifications
Neutropenia grade on day of 
treatment 
Modification of panobinostat 
starting dose 
Panobinostat dose on 
recovery to grade 2 
neutropenia (<1.5-1.0 x 109/L) 
Grade 3 neutropenia (<1.0-0.5 x 
109/L) 
Omit dose 
Resume at same dose 
Grade 4 neutropenia (<0.5 x 
109/L) or febrile neutropenia 
(<1.0 x 109/L and fever ≥38.5°C) 
Omit dose 
Resume at reduced dose 


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In case of grade 3 or 4 neutropenia, physicians should consider the use of growth factors (e.g. 
G-CSF) according to local guidelines. Discontinuation of treatment may be considered if 
neutropenia does not improve despite the dose modifications and/or despite the addition of 
colony stimulating factor therapy according to local medical practice and treatment guidelines, 
and/or in case of severe secondary infections. 
6.2.5
Follow-up for toxicities
Patients who treatment is interrupted or permanently discontinued from study treatment due to 
an AE or abnormal laboratory value should be followed at least once a week during drug hold 
and be followed for 4 weeks, and subsequently at 4-week intervals, until resolution or 
stabilization of the event, whichever comes first. All patients will be followed for AEs and 
SAEs for 30 days following the last dose of panobinostat. 
6.2.6
Dose modification of panobinostat for prolonged QTcF interval
All cardiac events should be treated as per the local standard of care and referred to a 
cardiologist if clinically indicated. The central and/or local readings of ECGs will use the 
Fridericia correction for QTc interval assessment: QTcF. Any final decisions concerning 
panobinostat dose modifications or permanently discontinuing the patient from study 
treatment due to QTcF prolongation will be based on the assessment performed by the 
Investigator. 
In case of average QTcF > 450 ms pre-dose:

Assess the quality of the ECG recording and the QT value and repeat if needed

Do not initiate study treatment

Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before initiating study treatment. 

Review concomitant medication use for other causes for QT prolongation, and for drugs 
with the potential to increase the risk of drug exposure related QT prolongation (e.g 
concomitant use of strong CYP3A4 inhibitors)

Within 7 days, repeat triplicate pre-dose ECG if average QTcF > 450 ms, do not initiate 
study treatment

If average QTcF ≤ 450 ms, initiate study treatment.
In case of average QTcF > 480 ms, (or average QTcF prolongation >60 ms from baseline) any 
time after first dose of panobinostat until end of panobinostat treatment:

Assess the quality of the ECG recording and the QT value and repeat if needed.

Interrupt panobinostat treatment

Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment. 

Review concomitant medication use for other causes of QT prolongation, and for drugs 
with the potential to increase the risk of drug exposure related QT prolongation.

Check study drug dosing schedule and treatment compliance

Consider more frequent ECG monitoring (e.g. approximately every 2-3 hours between 2 
hours post treatment and 6 hours post treatment) until average QTcF is ≤ 480 ms)


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After confirming ECG reading at site, if average QTcF > 480 ms: 

Interrupt panobinostat treatment

Repeat ECG and confirm ECG diagnosis by a cardiologist 

If average QTcF confirmed > 480 ms:

Correct electrolytes, eliminate culprit concomitant treatments, and identify clinical 
conditions that could potentially prolong the QT 

Consult with a cardiologist (or qualified specialist)

Increase cardiac monitoring as indicated (e.g., perform approximately hourly ECGs at 
between 2h post dose of 6h post dose on the same day an average QTcF > 480 ms is 
reported and pre-dose and at 2h post dose and the next dosing days) until the average 
QTcF returns to ≤ 480 ms

After resolution within 7 days to ≤ 480 ms, consider re-introducing panobinostat treatment 
at the same or reduced dose, and increase ECG monitoring (e.g., pre-dose panobinostat 
and 2h post panobinostat) for the next treatments:

If average QTcF remains ≤ 480 ms, continue planned ECG monitoring during subsequent 
panobinostat treatment. 

If average QTcF recurs > 480 ms after re-introduction of panobinostat treatment or 
remains > 480 ms for more than 7 days prior to re-introduction, discontinue patient from 
study treatment. 

Please note that for unscheduled ECGs at any time during panobinostat treatment: 

If a single QTcF is > 480 ms, two additional ECGs should be performed. The three ECGs 
should be separated by 5-10 minutes. The average QTcF of those three ECGs should be 
calculated and used for determination of panobinostat dose modifications. 
6.2.7
Suggested management of selected adverse events
One of the most common adverse events associated with treatment with oral panobinostat is 
reversible thrombocytopenia; the degree of thrombocytopenia is dose-dependent. Other side 
effects include fatigue (dose-dependent), nausea, vomiting and diarrhea.
Diarrhea is especially problematic since, when more severe, can affect drug exposure and 
result in patient discontinuation. Diarrhea can be controlled with the following regimen which 
includes of the use of loperamide. 

Patient should be instructed to contact physician at the onset of diarrhea

Patient should be encouraged to maintain adequate oral hydration (at least 240 ml every 2 
hours) with the onset of diarrhea.

The patient should be instructed to have loperamide readily available and to begin 
treatment for diarrhea at the first episode of poorly formed or loose stools or the earliest 
onset of bowel movements more frequent than normally expected for the patient.

Loperamide 4 mg should be taken at the first loose stool or more frequent than usual 
bowel movements, followed by 2 mg as needed, no more frequently than every 4 hours, 
not to exceed a total of 16 mg in 24 hours. 


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
Patients with diarrhea ≥ grade 2 despite this loperamide regimen should interrupt 
treatment with panobinostat as described in Table 6-3.

If the above regimen is inadequate then additional evaluation and treatment should be 
pursued as medically indicated. 

Replacement i.v. fluids and electrolytes may be used as appropriate.

Additional treatment should be provided in accordance with institutional standard of care 
and/or local guidelines.

Premedication with loperamide is not recommended. 

The use of drugs with laxative properties should be avoided because of the potential for 
exacerbation of diarrhea. Patients should be advised to contact their physician to discuss 
any laxative use.
For orally administered panobinostat, no grade 4 QTc has been reported with “interrupted” 
dosing schedules. For oral dose of 20 mg or 60 mg given three times weekly, the incidence of 
grade 3 QTc prolongation ranges from <1% to 6%. The largest QTc change is seen 
approximately five days after the drug is given and does not correlate with drug serum levels. 
For detailed safety information as well as the list of adverse drug reactions (i.e. those AEs 
considered causally related to panobinostat), please refer to the latest panobinostat IB. 
6.2.8
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from 
the awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 


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1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.
6.3
Concomitant medications
All medications and significant non-drug therapies (including physical therapy and blood or 
platelet transfusions) administered at the time of entry into this rollover protocol through 30 
days after the last panobinostat dosing and the reasons for therapy use should be reported in 
the source documents at the study center. Medications include not only physician prescribed 
medications, but also all over-the-counter medications, vitamins, herbals and alternative 
therapies.
The following restrictions apply during the study:

No other investigationl therapy should be given to patients.

No anticancer agents other than the study medication (panobinostat) should be given to 
patients during the study. If such agents are required for a patient then the patient must 
first be withdrawn from the study.
The following recommendations should be followed for the use of medications that may 
affect or may be affected by panobinostat treatment:

For patients who require chronic anticoagulant therapy while on panobinostat therapy, low 
molecular weight heparin (LMWH) should be the preferred anticoagulant medication. In 
patients for whom low molecular weight heparin use is to be initiated, the degree of 
thrombocytopenia should be considered, coagulation parameters monitored, and dose of 
anti-coagulant adjusted accordingly.


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
Concomitant use of strong CYP3A4/5 inhibitors (including, but not limited to, 
ketoconazole, itraconazole, ritonavir, clarithromycin and telithromycin) should be avoided. 
If medically necessary, close clinical monitoring of signs and symptoms of panobinostat 
related AEs is recommended when long-term (≥ 1 week) concomitant administration of 
any strong CYP3A inhibitors occurs, as this may increase the exposure of panobinostat. 
Co-administration of panobinostat with a moderate or weak CYP3A inhibitor is allowed. 
Star fruit, pomegranates or pomegranate juice, grapefruit juice that are known to inhibit 
CYP3A should be avoided during treatment with panobinostat. In patients with hepatic 
impairment receiving concomitant medicinal products which are strong CYP3A4 
inhibitors, treatment with panobinostat should be avoided due to lack of experience and 
safety data in this patient population. 

In silico data showed that the systemic exposure of panobinostat may be decreased by 70% 
in the presence of strong CYP3A4 inducers (including, but not limited to, avasimibe, 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort). Even 
though no clinical data are available, panobinostat blood concentrations may be reduced
by CYP3A4 inducers. Concomitant use of strong CYP3A4 inducers should be avoided.

Concomitant use of medications which are known sensitive CYP2D6 substrates (including, 
but not limited to, tamoxifen, propafenone, risperidone, thoridazine) are to be used with 
caution. Patients should be carefully monitored for potential signs and symptoms of 
toxicity and may require dose titration or dose reduction of a sensitive CYP2D6 substrate 
which also has a narrow therapeutic window (e.g., the ratio of toxicity exposure is ≤ 2-fold 
higher than the efficacious or therapeutic exposure).

Granulocyte growth factors (G-CSF) or red blood cell transfusion may be used for severe 
neutropenia or for severe anemia, respectively, according to institutional guidelines.

Patients who were receiving recombinant erythropoietin or darbepoetin alfa prior to 
starting study drug may continue to receive their pre-study doses throughout the trial.

Palliative radiation therapy may be permitted, but the need for radiation therapy is usually 
indicative of disease progression.

Analgesics for tumor-related pain can be maintained during the study. However, an 
increase in analgesic use for control of tumor-related pain may indicate disease 
progression. If an increase in analgesic medication from study entry is required during the 
study, the patient should be evaluated for progression of disease.

Anti-emetic medications may be used at the discretion of the Investigator, but consider 
preferentially the use of metoclopramide. Prophylactic anti-emetics except those listed in 
Appendix 14.1 can be administered at the discretion of the Investigator. Intravenous 
dolasetron is contraindicated for preventing nausea and vomiting associated with cancer 
therapy based on FDA drug safety warning (communication dated 17-December-2010).

Concomitant use of anti-arrhythmic medicines (including, but not limited to, amiodarone, 
disopyramide, procainamide, quinidine, and sotalol) and other drugs known to prolong the 
QT interval (including, but not limited to, chloroquine, halofantrine, chlarithromycin, 
methadone, moxifloxacin, bepridil and pimozide) is not recommended.

DAC inhibitors (including valproic acid) for any clinical indication are to be avoided 
while on panobinostat treatment.


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For additional information regarding these and other medications please refer to Appendix 
14.1 and for detailed safety guidance, please refer to the Investigator’s Brochure.
6.3.1
Use of Bisphosphonates (or other concomitant agents)
Not applicable
6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled in the roll-over study and is retained as the primary identifier for 
the patient throughout his/her entire participation in the trial. The Patient No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential patient number suffixed to it, so that each subject is numbered uniquely across the 
entire database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Subject No. available to the investigator through the clinical trial database. 
Additionally, an eCRF will be completed that identifies the patient by gender, date of birth, 
previous (parent) study, site/center and patient number.
6.4.2
Treatment assignment or randomization
All consented patients who meet all the inclusion criteria and none of the exclusion criteria 
are eligible to receive panobinostat.
6.4.3
Treatment blinding
Not applicable
6.5
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF.
6.5.1
Study treatment packaging and labeling
Panobinostat for the roll-over study is provided as global open label supply, packed and 
labeled under the responsibility of Novartis Drug Supply Management. Study treatment labels 
will be in the local language and comply with the legal requirements of each country. They 
will include storage conditions for the drug but no information about the patient. Please note 
that clinical supplies of panobinostat will be labeled as “LBH589”. Should panobinostat 
become commercially available during the course of this study, drug may be sourced and 
labeled in-country and the locally-approved form and packaging will be used.
6.5.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 


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designated site personnel have access. Upon receipt, the panobinostat should be stored 
according to the instructions specified on the drug labels and in the current [Investigator’s 
Brochure].
6.5.3
Study drug compliance and accountability
6.5.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit.
6.5.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.5.3.3
Handling of other study treatment
Not applicable.
6.5.4
Disposal and destruction
The drug supply can only be destroyed once the study drug accountability check has been 
performed by the monitor. The supply of panobinostat can be destroyed at the local Novartis 
facility, Drug Supply group or third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. Patients must return to the study center at least on a quarterly (every 12 +/- 2 
weeks) basis for resupply of study medication. Patients may return to the study center more 
frequently at the physicians’ discretion as clinically indicated or as per standard of care; 
however, data from these visits will not be captured in the eCRF, but rather only in the source 
documents at the study center.
The table indicates in the “Category” column which assessments produce data to be entered in 
the database (D).


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Table 7-1
Visit evaluation schedule
Category
Protocol 
reference
section 
Enrollment
Quarterly (every 12 +/- 2 weeks) 
visits during treatment phase
End of treatment 
(EoT)
30 day safety
follow-up post 
last dose of study 
drug/End of 
Study
Visit Number
1
2
3
4
5
6
7
8
9+
777
501/778
Obtain informed consent
D
7.1.2
x
Parent Study History (e.g. subject’s 
previous study, site and patient number)
D
7.1.2.3
x
Demography (e.g. gender and date of 
birth)
D
7.1.2.3
x
Relevant medical history/current 
medical conditions
D
7.1.2.3
Inclusion/exclusion criteria
D
5.2 / 5.3
x
Adverse events and serious adverse 
events*
D
8.1.1 & 
8.2.2
continuous
x
s.a. oral panobinostat dosing 
administration 
D
7.1.3
x
continuous
Pregnancy testing
D, S
7.1.4
continuous
Confirmation of Clinical Benefit from 
Study Treatment
D
7.2.1
x
x
x
x
x
x
x
x
x
End of treatment
D
7.1.5
x
Study Evaluation Completion
D
7.1.5
x
*SAEs will be reported to the Novartis safety database within 24 hours of investigator or treating physician’s knowledge of the event from the time the 
patient signed informed consent until at least 30 days after the patient stopped study treatment (see Section 8).
Note: All other assessments are performed as per standard of care at the site and will not be captured in the CRF.


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7.1.1
Molecular pre-screening 
Not applicable.
7.1.2
Screening
At the enrollment visit, the patient will need to complete a written informed consent. There 
will be no screening period for this study. Once consented, patients will be evaluated for 
eligibility via the inclusion and exclusion criteria.
7.1.2.1
Eligibility screening
Not applicable.
7.1.2.2
Information to be collected on screening failures
Not applicable.
7.1.2.3
Patient demographics and other baseline characteristics
For patients that are eligible to participate in this roll-over study, the patients’ gender, date of 
birth, previous study, site/center and subject number, and relevant medical history will be 
collected.
7.1.3
Treatment period
The starting dose of panobinostat should be the same as the dose that was given in the parent 
panobinostat study. A quarterly (every 12 +/- 2 weeks) supply of panobinostat will be 
dispensed to the patient/or as per local practice.
Patients must return to the study center on a quarterly (every 12 +/- 2 weeks) basis for 
resupply of study medication at which time limited drug dispensing information will be 
collected. At every quarterly visit, the investigator is required to confirm that the patient 
continues to have clinical benefit and may continue receiving study treatment. At this time the 
dose of panobinostat is based on the investigator’s judgment. The patients may return to the 
clinic more frequently at the physician’s discretion as clinically indicated or as per standard of 
care. These unscheduled visits will only be captured in the source documents at the study 
center and not in the eCRF. All adverse eventsand serious adverse events will be collected and 
documented in the eCRF. 
The study is expected to remain open for 5 years or until such time that enrolled patients no 
longer need treatment with panobinostat and all follow-up is completed, whichever comes 
earlier.
7.1.4
Pregnancy and assessment of fertility
Since highly effective contraception is required during the study, female patients of child 
bearing potential are required to test negative for a pregnancy (either with serum testing if 
routinely/locally available or urine pregnancy test) before enrolling into the study. 


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Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception during the study 
and for 3 months after the final dose of panobinostat.
Highly effective contraception is defined as either:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment.

Male sterilization (at least 6 months prior to enrolling). For female patients on the study 
the vasectomized male partner should be the sole partner for that patient.

Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. Women using hormonal 
contraceptives should additionally use a barrier method of contraception. 
If patient has tested negative at the end of study on the parent study, no pregnancy testing is 
required if enrollment into this study is carried out on the same day or within few days 
(maximum 5 days) from each other.
Female patients of child bearing potential are required to perform monthly home urine 
pregnancy tests and complete a simple diary with the dates and the outcome of the home
urinary test while on study treatment and during safety follow-up (30 days after the final dose 
of study medication).
A pregnancy test (either with serum testing if routinely/locally available or urine pregnancy 
test) on female patients of child bearing potential is required at the final study visit.
Any positive results will be recorded in the database and followed up as per Section 8.4.
7.1.5
Discontinuation of study treatment
Patients will continue to be treated until they are no longer benefiting from panobinostat 
treatment, develop unacceptable toxicities, withdraw consent, are non-compliant to the 
protocol, lost to follow-up or other administrative problem, the investigator feels it is no 
longer in the patient’s best interest to continue panobinostat therapy (e.g., pregnancy, disease 
progression, adverse events) or the patient dies, whichever comes first.
At the time the patient discontinues study treatment, a visit should be scheduled as soon as 
possible, at which time the assessments listed for the End of Treatment (EOT) visit will be 
performed. EOT information will be completed in the eCRF giving the date and reason for 
stopping the study treatment (see Section 7.1.5.1).
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for a safety evaluation approximately 30 days 


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following the last dose of study treatment. The completion of the Study Evaluation 
Completion eCRF page is required any time a patient discontinues from the study and must be 
completed 30 days after the end of treatment.
Patients who discontinue study treatment should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments.
If a study withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s withdrawal from the study and record this 
information on the appropriate eCRF page.
A patient will reach the end of study when panobinostat treatment is permanently 
discontinued and there will be no further follow-up study visits.
7.1.5.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator at any time.
Patients may be withdrawn from the study if any of the following occur:
1. Adverse event(s).
2. Subject withdrew consent.
3. Lost to follow-up.
4. Administrative problems.
5. Death.
6. Disease progression.
7. Protocol deviation.
8. Pregnancy.
9. Study terminated by sponsor
7.1.5.2
Replacement policy
Not applicable. 
7.1.6
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone,
e-mail, letter) to understand the primary reason for this decision and record this information.
Study treatment must be discontinued and no further assessments conducted.


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Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
7.1.7
Follow up for safety evaluations
All patients must be followed up for safety evaluations for 30 days after the last dose of study 
treatment. At the end of this period, the investigator should contact the patient to inquire about 
any adverse events or serious adverse events observed during this period. This could be done 
via a phone contact. Following this, there are no further follow-up study visits.
Patients lost to follow up should be recorded as such on the appropriate eCRF. For patients 
who are lost to follow-up, the investigator should show "due diligence" by documenting in the 
source documents steps taken to contact the patient, e.g., dates of telephone calls, registered 
letters, etc.
Data collected should be added to the Adverse Events eCRF.
7.1.8
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
At every quarterly visit, the investigator is required to confirm that the patient continues to 
have clinical benefit and may continue receiving study treatment. 
7.2.2
Other assessments
No additional tests will be performed on patients entered into this study.
7.2.3
Safety and tolerability assessments
Safety will be monitored by collecting of the adverse events at every visit. For details on AE 
collection and reporting, refer to Section 8.
7.2.4
Pharmacokinetics
Not applicable. 
7.2.4.1
Analytical method
Not applicable.


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7.2.5
Resource utilization
Not applicable.
7.2.6
Patient reported outcomes
Not applicable.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Any ongoing adverse events from the parent study will be captured as medical history in the 
roll-over database. Any AE that begins (or worsens) after signing of the informed consent for 
the roll-over and during the 30-day (or 28-day) safety follow-up period defined in the parent 
protocol should be reported in both clinical databases.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed according to the current version of Common Terminology 
Criteria for Adverse Events (CTCAE).
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected through the EOT 
eCRF page.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (start and end dates)


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3. Its relationship to the study treatment (reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
If the event worsens the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF noting the start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines 
for hematological malignancies), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia 
instead of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse 
Events should be followed until they have returned to normal or an adequate explanation of 
the abnormality is found. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the laboratory abnormality would still, by definition, be 
an adverse event and must be reported as such.


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8.1.3
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may 
be appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data and including acute pancreatitis, interstitial lung disease, ischaemic colitis, hepatic 
dysfunction, pneumonia, sepsis, renal dysfuction, cardiac failure, ischaemic heart disease, 
pericardial effusion, tachyarrhythmias, and venous thromboembolism. AESIs are discussed in 
detail in the Investigator Brochure.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAE that begins or worsens after signing of the informed consent for the roll-over and 
during the 30-day (or 28-day) safety follow up period defined in the parent protocol should be 
reported as an adverse event in both clinical databases; however, only one SAE will be sent to 
Novartis.


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
Any SAE that begins or worsens during the 30-day (or 28-day) safety follow-up period 
specified in the parent study should have an SAE report submitted to Novartis with the 
parent protocol study number. 

Any SAE that begins or worsens after the 30-day (or 28-day) safety follow-up period 
specified in the parent study should have an SAE report submitted to Novartis with the 
roll-over protocol study number. 
Any additional information for the SAE including complications, progression of the initial 
SAE, and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one 
should be reported separately as a new event.
It is important to use the right SAE form with the correct protocol number for these two 
scenarios, to avoid confusion in SAE processing. For a patient already on the roll-over 
protocol but follow up information is reported for the previous SAEs in the parent protocol, it 
must be clearly labeled that this is for the parent protocol number.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated and whether the patient 
continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) or 
Package Insert and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable. This is an open-label study.


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8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to panobinostat of any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. The collection of this information could last for up to 12 
months following the birth of the child. The Study Doctor and Novartis may decide what 
pertinent information is collected as necessary or indicated based on the study.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between [Investigator Brochure] updates 
will be communicated in the form of Investigator Notifications. This information will be 
included in the patient informed consent and should be discussed with the patient during the 
study as needed.
8.6
Data Monitoring Committee
Not applicable. 
8.7
Steering Committee 
Not applicable. 
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

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In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the 
CRFs are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRFs is 
complete, accurate, and that entry and updates are performed in a timely manner.


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9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the 
nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated 
investigator site staff are required to respond promptly to queries and to make any necessary 
changes to the data.
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and made available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint 
written agreement between the Global Head of Biostatistics and Data Management and the 
Global Head of Clinical Development.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
10.1
Analysis sets
The following analysis sets will be used for statistical analysis and data reporting.
10.1.1
Full Analysis Set
Not applicable.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication after 
enrolling into the roll-over protocol.
10.1.3
Dose-determining analysis set
Not applicable.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data characteristics will be summarized descriptively for the 
Safety Set.
10.3
Treatments (study treatment, compliance)
Dose administration data will be summarized using the Safety Set.
10.4
Primary objective
The primary objective is to evaluate long term safety as assessed by the occurrence of 
AEs/SAEs.


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10.4.1
Variable
See Section 10.5.3.
10.4.2
Statistical hypothesis, model, and method of analysis
No hypothesis will be tested. 
10.4.3
Handling of missing values/censoring/discontinuations
Not applicable.
10.4.4
Supportive analyses
No supportive analysis will be performed.
10.5
Secondary objectives
10.5.1
Key secondary objective(s)
Not applicable.
10.5.2
Other secondary efficacy objectives
The secondary objective of the study was to evaluate clinical benefit as assessed by the 
investigator. Proportion of patients with clinical benefit as assessed by the investigator will 
be summarized at scheduled visits.
10.5.3
Safety objectives
The assessment of safety will be based mainly on the frequency of AEs and SAEs.
10.5.3.1 Analysis set and grouping for the analyses
The overall observation period will be divided into two mutually exclusive segments:
1. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
2. post-treatment period: starting at day 30+1 after last dose of study medication.
10.5.3.2 Adverse events (AEs)
Summary tables of adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the post-treatment periods) will be listed and those collected during the 
post treatment period are to be flagged. 
The incidence of treatment emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and/or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event. 


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10.5.3.3 Other safety data
Not applicable.
10.5.3.4 Tolerability
Not applicable.
10.6
Interim analysis
Not applicable.
10.7
Sample size calculation
Not applicable.
10.8
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the patient source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their CRFs.


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Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Additional consent form 
Not applicable. 
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.


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Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported 
on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF 
should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic CRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site, prior to study start.


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12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the study 
site should be informed according to local regulations (e.g. UK requires the notification of 
urgent safety measures within 3 days) but not later than 10 working days.


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13
References (available upon request)
Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): successes 
and challenges. Cancer Lett;280:233-241.
Atadja P (2011) HDAC inhibitors and cancer therapy. In: SM Gasser and Li E(Eds), 
Epigenetics and Disease, Progress in Drug Research 67 DOI 10.1007/978-3-7643-8989-5_9.
Boumber Y, Issa JP (2011) Epigenetics in Cancer: What’s the Future? Oncology;25:1-13.
Duvic M, Vu J (2007) Vorinostat: a new oral histone deacetylase inhibitor approved for 
cutaneous T-cell lymphoma. Expert Opin Investig Drugs;16:1111-1120.
Duvic M. Dummer R. Becker JC, et al (2012) Panobinostat activity in both bexarotene-
exposed and naïve patients with refractory cutaneous T-cell lymphoma: Results of a phase II 
trial. European Journal of Cancer available at sciencedirect.com.
Grant C, Rahman F, Piekarz R, et al (2010) A new therapy for cutaneous T-cell lymphoma 
and a potential therapy for solid tumors. Expert Rev Anticancer Ther;10:997-1008.
Hamberg P, Woo MM, Chen LC, et al ( 2011) Effect of ketoconazole-mediated CYP3A5 
inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone 
deacetylase inhibitor. Cancer Chemoth Pharmacol;68:805-813.
Hidaka M, Fujita K, Ogikubo T, et al (2004) Potent inhibition by star fruit of human 
cytochrome P450 3A (CYP3A) activity, Drug Metab Dispos 2004; 32: 581.
Issa JP, Kantarijan HM, Kirkpatrick P(2005) Azacitidine. Nat Rev Drug Discov;4:275-6.
Issa JP (2007) DNA methylation as a therapeutic target in cancer. Clin Cancer Res;13:1634-
1637.
Kantarijan H, Issa JP, Rosenfeld CS, et al (2006) Decitabine improves patient outcomes in 
myelodysplastic syndromes:results of a phase III randomized study. Cancer; 106:1794-1803.
Prince MH, Bishton MJ, Johnstone RW (2009). Panobinostat (LBH589): a potent pan-
deacetylase inhibitor with promising activity against hematologic and solid tumors. Future 
Oncol;5(5):601-612.
Shapiro GI, Frank R, Dandamudi UB, et al (2012) The effect of food on the bioavailability of 
panobinostat. An orally active pan-histonee deacetylase inhibitor, in patients with advanced 
cancer. Cancer Chemother Pharmacol;69:555-562.
Shou M, Hayashi M, Pan Y, et al (2008) Modeling, prediction, and in vitro in vivo correlation 
of CYP3A4 induction. Drug Metab Dispos;36:2355–2370.
Synold TW, Takimoto CH, Doroshow JH, et al (2007) Escalating and Pharmacological Study 
of Oxaliplatin in Adult Cancer Patients with Impaired Hepatic Function: A National Cancer 
Institute Organ Dysfunction Working Group Study, Clin Cancer Res. 2007 13; 3660.
Younes A, Sureda A, Ben-Yehuda D, et al (2012) Panobinostat in patients with 
relapsed/refractory Hodgkin’s Lymphoma after autologous stem-cell transplantation:Results 
of a phase II study. J Clin Oncol published ahead on April 30, 2012 as 
10.1200/JCO.2011.38.1350.


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14
Appendices
14.1
Concomitant medication
In general, medications listed in Table 14-1 should be avoided and medications listed in
Table 14-2 and Table 14-3 are to be used with caution when co-administered with
panobinostat. The use of any of the drugs in Table 14-1, Table 14-2 and Table 14-3 in
combination with panobinostat must be discussed with the Sponsor.
14.1.1
Medications which are known to prolong the QT interval and/or induce
Torsades de pointes ventricular arrhythmia should be avoided
It is of great importance to avoid such drugs listed below in Table 14-1 in combination with
panobinostat, especially in the presence of electrolyte abnormalities, notably decreased
potassium or magnesium levels commonly associated with diuretic usage.
This is not a comprehensive list of medications which may prolong the QT interval
and/or induce Torsades de pointes. This list of medications was developed in collaboration
with an external cardiology consultant and represents those medications which are deemed to
have an unacceptable risk of co-administration with panobinostat.
The following website may be referenced as a supplemental guide for drugs which have been 
associated with Torsades de pointes or prolonging the QT interval but at this time lack 
substantial evidence for causing Torsades de pointes: azcert.org/medical-pros/drug-lists/drug-
lists.cfm.(version 3/25/2008).
Medications listed on the website which do not appear in Table 14-1 above may be used with 
caution at the discretion of the investigator.
Ondansetron (a known CYP2D6 substrate, see Table 14-3) has prolongation but has not been
shown to cause Torsades de pointes. Therefore, ondansetron is not per se prohibited when
combined with panobinostat but caution is to be exercised and close monitoring for signs and
symptoms of QT prolongation is recommended.
Table 14-1
Medications which are known to prolong the QT interval and/or induce 
Torsades de Pointes to be avoided
All Class IA antiarrhythmics
Quinidine
Procainamide
Disopyramide
any other class IA antiarrhythmic drug
All Class III antiarrhythmics
Amiodarone
Sotalol
Dofetilide
Ibutilide
any other class III antiarrhythmic drug
Macrolide antibiotics*
Erythromycin
clarithromycin
Quinolone antibiotics*
Sparfloxacin
Antifungals
pentamidine


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Antimalarials
Halofantrine
chloroquine
Antihistamines
Astemizole
terfenadine
Anti-emetics
Chlorpromazine
Domperidone
Droperidol
dolasetron (intravenous and oral)^
Antipsychotics
Thioridazine
Mesoridazine
Chlorpromazine
pimozide
Miscellaneous drugs
arsenic trioxide
bepridil
domperidone
cisapride
levomethadyl
methadone
*
Note: azithromycin, ciprofloxacin, levofloxacin, pefloxacin, ofloxacin, tosufloxacin, difloxacin,
temafloxacin, fleroxacin, acrosoxacin, nalidixic acid and enoxacin are allowed.
^
Intravenous dolasetron is contraindicated for preventing nausea and vomiting associated with
chemotherapy based on FDA drug safety communication dated December 17, 2010. Based on this
finding, both intravenous and oral dolasetron are prohibited to be taken with panobinostat.
14.1.2
Medications which are known strong CYP3A4/5 inhibitors to be 
avoided 
Panobinostat is a substrate of CYP3A4/5 with minor involvement of CYP2D6, and CYP2C19
in in vitro evaluation of its metabolism. Thus, a clinical drug-drug interaction study was 
conducted using ketoconazole, a strong CYP3A inhibitor, in combination with panobinostat 
in study CLBH589B2110.
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of panobinostat by 1.6-and 
1.8-fold, respectively, but with no change in Tmax or half-lives in 14 cancers patients. The less 
than 2-fold increase in panobinostat AUC upon co-administration of a strong CYP3A 
inhibitor
is
considered
a
weak
drug
inhibition
and
not
clinically
relevant,
as
panobinostat doses at least 2-fold greater than the evaluated 20 mg dose (i.e., 40 mg and 60
mg have been safely administered in patients. Thus, co-administration of panobinostat with
a moderate or weak CYP3A inhibitor is allowed. However, clinical monitoring of signs
and symptoms of panobinostat treatment related to adverse events is recommended when
long-term (≥1 week) concomitant administration of any strong CYP3A inhibitors and
panobinostat is medically indicated or investigated in a clinical study.
Patients with impaired liver function (as defined by NCI CTEP criteria) (Synold et al 2007) 
are
recommended
not
to
receive
panobinostat
concomitantly
with
strong
CYP3A
inhibitors because potential interaction has not been established in this population.


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Table 14-2
Medications which are known strong CYP3A4/5 inhibitors to be used 
with caution
Macrolide antibiotics*
Telithromycin
troleandomycin
Antifungals (azoles)
Ketoconazole
Itraconazole
Posaconazole
voriconazole
Antidepressants
nefazodone
HIV protease inhibitors:
Indinavir
Nelfinavir
Ritonavir
Saquinavir
lopinavir
Miscellaneous drugs or products
1Star fruit and pomegranate product and juice
convaptan
* azithromycin and regular orange juice are allowed.
1 Hidaka et al (2004).
Although clarithromycin is a known strong CYP3A inhibitor, it is also known to prolong QT intervals
which is listed in Table 14-1 and is prohibited to be taken with panobinostat. This drug is thus not listed
again in Table 14-3.
This is not a comprehensive list of medications which may inhibit CYP3A4/5. The above list 
was compiled by using information listed under “draft guidance for industry, drug interaction 
studies, CDER 2006”, Indiana University School of Medicine drug interaction tables at 
medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp and “drug interaction database” from
University of Washington.
Additional updated versions with moderate and weak CYP3A inhibitors, which are meant
to
be
used
as
a
guide,
may
be
found
at
the
following
website: 
medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp.
14.1.3
Medications which are known CYP2D6 substrates to be used with
caution
Panobinostat was also shown to be a CYP2D6 inhibitor (Ki 0.17 µM) in vitro. Thus, clinical 
drug-drug interaction study with panobinostat as CYP2D6 inhibitor and dextromethorpan
as CYP2D6 substrate was recently conducted in study [CLBH589B2109].
Multiple panobinostat doses increased Cmax and AUC of dextromethorphan by a mean of 1.8-
and 1.6-fold respectively, but with no change in Tmax in 17 cancer patients. An approximately 
2-fold increase in dextromethorphan AUC upon co-administration with panobinostat
indicated that in vivo CYP2D6 inhibition of panobinostat is weak.
As the study was conducted using a sensitive CYP2D6 substrate which resulted in a
weak inhibition,
drugs
with
a
large therapeutic index
such
as
anti-emetics,
anti-
hypertensives, and anti-depressants are generallysafe to be co-administered with panobinostat.


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Patients should be carefully monitored for potential signs and symptoms of toxicity and may 
require dose titration or dose reduction of a sensitive CYP2D6 substrate which also have
a narrow therapeutic window (e.g., the ratio of toxicity exposure is ≤2-fold higher than
the efficacious or therapeutic exposure).
Table 14-3
Medications which are known CYP2D6 substrates to be used with 
caution
Beta blockers
S-metoprolol
Propafenone
timolol
Antipsychotics
Aripiprazole
Haloperidol
Risperidone
thioridazine
Antidepressants
Amitriptyline
Clomipramine
Desipramine
Imipramine
Fluoxetine
Paroxetine
Venlafaxine
duloxetine
Antiarrhythmics
Mexilletine
flecainide
Others
Codeine
Dextromethorphan
Tamoxifen
tramadol
Anti-emetics
ondansetron^
^
Intravenous dolasetron is a CYP2D6 substrate and contraindicated for preventing nausea and 
vomiting associated with chemotherapy based on FDA drug safety communication dated December
17, 2010. Please see Table 14-1.
This is not a comprehensive list of CYP2D6 substrates. Additional updated versions of
this list, which are meant to be used as a guide, may be found at the following website: 
medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp.

SAP_001.pdf: 
Clinical Development
LBH589 (Panobinostat)
CLBH589B2402B / NCT01802879
An open-label multi-center single agent panobinostat roll-over 
protocol for patients who have completed a previous Novartis-
sponsored panobinostat study and are judged by the investigator 
to benefit from continued single agent panobinostat treatment
RAP Module 3 – Detailed Statistical Methodology 
Amendment 1
Author:
, Trial Statistician; 
, Trial Statistician
Document type:
RAP Documentation
Document status:
Draft Version 1.0
Release date:
14-June-2016
Number of pages:
14
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
Version 1.0
24-Mar-2014
Original
Version 1.1
14-June-2016
The following changes have been made under RAP amendment 1:
Section 2 (Statistical methods planned in the protocol and 
determination of sample size)
The objectives of the study were updated accordingly based on protocol 
amendment 1 
Section 5.5 (Efficacy evaluation)
Investigator benefit assessment was added
Section 5.6 (Safety evaluation)
AEs summary was added


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................3
List of figures ......................................................................................................................3
1
Introduction .........................................................................................................................4
1.1
Document content....................................................................................................4
1.2
References................................................................................................................4
2
Objectives and endpoints.....................................................................................................5
3
Study design ........................................................................................................................5
3.1
Description of study design .....................................................................................5
3.2
Timing of interim analyses and design adaptations.................................................6
3.3
Definition of end of the study..................................................................................6
3.4
Early study termination............................................................................................6
4
Population............................................................................................................................6
4.1
Patient population....................................................................................................6
5
CSR Section 9.7 – Statistical methods planned in the protocol and determination of 
sample size...........................................................................................................................7
5.1
CSR Section 9.7.1 – Statistical and analytical plans ...............................................7
5.2
Data included in the analysis ...................................................................................7
5.3
Analysis populations................................................................................................7
5.4
Patients and treatments ............................................................................................7
5.4.1
Patient disposition...................................................................................7
5.4.2
Background and demographic characteristics.........................................8
5.4.3
Extent of study drug exposure.................................................................8
5.4.4
Prior and concomitant therapy ................................................................8
5.5
Efficacy evaluation ..................................................................................................8
5.6
Safety evaluation .....................................................................................................8
5.7
Other analysis ..........................................................................................................9
5.7.1
Interim analysis .......................................................................................9
5.8
CSR Section 9.7.2 – Sample size and power considerations...................................9
List of tables
Table 2-1
Objectives and related endpoints ............................................................5
List of figures
Figure 3-1
Basic Study Design .................................................................................6


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Abbreviation
Abbreviation
Detail
AE
Adverse event
BSA
Body surface area
CRF
Case Report/ Record Form
CSR
Clinical study report
DAR
Dose administration record
ECG
12 lead electrocardiogram
PT
Preferred term
RAP
Report and analysis plan
SAE
Serious adverse event
s.a.
Single Agent
VAP
Validation and planning
1
Introduction
1.1
Document content
This Report Analysis Plan (RAP) module describes the planned statistical analyses. A clinical 
study report (CSR) will be produced at the completion of the trial. 
This module is structured as

A draft of Section 9.7 of the CSR [Statistical methods planned in the protocol and 
determination of sample size]

A draft of Appendix 16.1.9 (Documentation of statistical methods). 
Appendix 16.1.9 text will contain details of statistical methods and issues that are too long to 
include in the CSR text. 
It is written in future tense. It will be reviewed and updated (including conversion to past 
tense) for entry into the clinical study report after the statistical analysis has taken place.
1.2
References
Please refer to the following documents:

CSR template (Full or Abbreviated Clinical Study Report)

Master Analysis Plan for LBH589

Guidelines for content of Statistical Appendices of the Clinical Study Report

Clinical Study Protocol for study CLBH589B2402B

Case Report Forms for study CLBH589B2402B


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2
Objectives and endpoints
Objectives and related endpoints are described in Table 2-1 below altogether with the planned 
analysis of collected data.
Table 2-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To evaluate long term safety data 
(SAEs and AEs)
Frequency and severity of AEs/SAEs
AEs/SAEs from safety database will be 
reviewed and reported as part of the 
regular pharmacovigilance activities.
Key secondary
To evaluate clinical benefit as assessed 
by the investigator
Proportion of patients with clinical 
benefit as assessed by the investigator 
at scheduled visits
Proportion of patients with clinical 
benefit as assessed by the investigator 
will be summarized at scheduled visits.
3
Study design
3.1
Description of study design
This is a multi-center, open-label study to better characterize the long term safety of s.a. oral 
panobinostat in patients being treated in a current Novartis-sponsored, Oncology OGD&GMA 
study and who are benefiting from the treatment with s.a. oral panobinostat as determined by 
the guidelines of the parent protocol (for which the study objectives have been met) and based 
on the investigator’s clinical judgment.
This roll-over study will not include screening period as patients will transfer directly from 
the parent study and commence with panobinostat as soon as they are consented and meet 
inclusion criteria of the roll-over protocol. All patients must report to the study site for their 
first visit and commence study participation. At that time, a quarterly (12 +/- 2 weeks) supply 
of oral panobinostat will be dispensed to the patient or as per local practice.
Patients must return to the study center on a quarterly (every 12 +/- 2 weeks) basis for 
resupply of study medication at which time limited drug dispensing information will be 
collected. Changes in dosing which might occur any time during the study treatment will be 
documented on the dose administration page.
Patients may return to the study center more frequently at the physicians’ discretion as 
clinically indicated or as per standard of care, however, data from these visits will not be 
captured in the eCRF, but rather only in the source documents at the study center.
Reported AEs/SAEs, defined as per standard Novartis guidelines, will be collected 
continuously throughout the study in the safety database.
Patients entering the roll-over protocol should be followed at the investigator’s discretion for 
known and/or clinically notable AEs that occur on panobinostat treatment as described in the 
current version of the [Investigator Brochure].
Patients will continue to be treated in the roll-over protocol until they are no longer benefiting 
from the s.a. oral panobinostat treatment, develop unacceptable toxicities, withdraw consent, 


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are non-compliant to the protocol, the investigator feels it is no longer in the patient’s best 
interest to continue s.a. oral panobinostat therapy, pregnancy occurs or the patient dies, 
whichever comes first.
A patient will reach the end of the study treatment when s.a. oral panobinostat treatment is 
permanently discontinued. A 30-day safety follow-up after last dose of study drug should be 
conducted.
The study is expected to remain open for 5 years or until such time that enrolled patients no 
longer need treatment with panobinostat, whichever occurs earlier.
Figure 3-1
Basic Study Design
*Note: The starting dose and schedule of s.a. panobinostat will be the same as the last assigned dose and 
schedule received in the parent study.
3.2
Timing of interim analyses and design adaptations
No interim analyses are planned.
3.3
Definition of end of the study
End of study is defined as either a 5 year duration or when all patients in this study have 
permanently discontinued panobinostat treatment and the end of treatment visit plus the 30-
day safety follow up have been performed for each patient (and no further follow-up is 
needed), whichever comes earlier.
3.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in [Section 7.1.3 of the study protocol]. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the patient’s interests. The investigator will be responsible for informing 
IRBs and/or ECs of the early termination of the trial.
4
Population
4.1
Patient population
The study population is constituted of patients with various malignancies who participated in 
a Novartis-sponsored, Oncology OGD&GMA clinical trial for their specific indication and 
qualify to transfer to this roll-over protocol.


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The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5
CSR Section 9.7 – Statistical methods planned in the protocol and 
determination of sample size
5.1
CSR Section 9.7.1 – Statistical and analytical plans
The statistical analysis of this study will be performed by Novartis personnel. SAS ® version 
9.3 or later version will be used in all analyses.
This study follows an open-label, multi-center design. It is planned that the data from all 
centers that participate in this protocol will be pooled and utilized.
5.2
Data included in the analysis
Patients will continue to be treated in the roll-over protocol until they are no longer benefiting 
from the s.a. oral panobinostat treatment, develop unacceptable toxicities, withdraw consent, 
are non-compliant to the protocol, the investigator feels it is no longer in the patient’s best 
interest to continue s.a. oral panobinostat therapy, pregnancy occurs or the patient dies, 
whichever comes first.
A patient will reach the end of the study treatment when s.a. oral panobinostat treatment is 
permanently discontinued. A 30-day safety follow-up after last dose of study drug should be 
conducted.
The study is expected to remain open for 5 years or until such time that enrolled patients no 
longer need treatment with panobinostat, whichever occurs earlier.
All data reported in the database will be included in the analyses.
5.3
Analysis populations
The following populations will be considered in the data analysis:
Full Analysis Set (FAS): consists of all patients who received at least one dose of 
panobinostat after enrolling into the roll-over protocol.
Safety set: consists of all patients who received at least one dose of panobinostat after 
enrolling into the roll-over protocol.
FAS and safety set are defined the same.
5.4
Patients and treatments
5.4.1
Patient disposition
Patient disposition will be summarized for the FAS by the number of patients who discontinue
along with the reason for discontinuation according to the data recorded on the end of 
treatment CRF panel.


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5.4.2
Background and demographic characteristics
Age and gender will be summarized. Patients’ parent studies will also be summarized so 
patients in this study can be linked to their parent studies for more information.  
5.4.3
Extent of study drug exposure
5.4.3.1
Drug exposure
All study medication data will be summarized using the safety set. 
Duration of exposure will be summarized by dose regimen. For the purposes of analysis, the 
following rules will be applied: 
If the last entry in the dose administration CRF page has a reported end date which is non -
missing and before the last known date patient took the study drug from the end of treatment 
CRF page, the gap between those 2 dates will be filled-in by imputing the dose assigned at the 
beginning of the study.  
This rule will be applied before using any of the following definitions.
Date of first dose is defined as the date of first intake of panobinostat in this study. This will 
be considered as treatment day 1. There is no study day 0.
Date of last dose is defined as follows:

For patients who discontinued study treatment, the date of last dose is defined as the date 
of the last non-zero dose of panobinostat reported in the dose administration CRF page. 
5.4.3.2
Dose changes
Dose administrative records for all patients will be listed. For patients with dose change, 
reasons will be displayed. 
5.4.4
Prior and concomitant therapy
No prior and concomitant therapy information is collected for this study. 
5.5
Efficacy evaluation
Proportion of patients with clinical benefit as assessed by the investigator will be listed using 
FAS.
5.6
Safety evaluation
All safety analyses will be performed based on the safety set.
The overall observation period will be divided into two mutually exclusive segments:
On-treatment period: from day of first dose of study medication to 30 days after last 
dose of study medication;
Post-treatment period: starting at day 30+1 after last dose of study medication.


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Adverse events (AEs)
Adverse events (AEs) will be summarized in tables to include only AEs that started or 
worsened during the on-treatment period, the treatment-emergent AEs. However, all safety 
data (including those from the post-treatment periods) will be listed and those collected during 
the post treatment period are to be flagged. The incidence of treatment emergent adverse 
events (new or worsening from baseline) will be summarized by system organ class and/or 
preferred term, severity (based on CTCAE grades), type of adverse event, relation to study 
treatment. Deaths reportable as SAEs and non-fatal serious adverse events will be listed by 
patient and tabulated by type of adverse event, throughout the study and for 30 days after the 
last dose of the study medication. 
Other safety data
No laboratory tests, ECG, and vital signs will be collected.
5.7
Other analysis
5.7.1.1
Interim analysis
There will be no interim analysis for this study. 
5.8
CSR Section 9.7.2 – Sample size and power considerations
There will be no sample size calculation for this study. All consented patients who meet all 
the inclusion criteria and none of the exclusion criteria are eligible to receive panobinostat. 


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Clinical Development
LBH589 (Panobinostat)
CLBH589B2402B
Appendix 16.1.9: Documentation of statistical methods
Document type:
Clinical Study Report - Appendix 16.1.9
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents ...............................................................................................................11
1                Introduction ............................................................................................................12
2
Definitions and general methodology ...............................................................................12
2.1
Study drug..............................................................................................................12
2.1.1
Date of first administration of study drug.............................................12
2.1.2
Date of last administration of study drug..............................................12
2.2
Study day ...............................................................................................................12
2.3
Baseline..................................................................................................................12
2.4
Partial dates and imputation rules..........................................................................13
2.5
Screening failure....................................................................................................13
2.6
Protocol deviations ................................................................................................13
2.7
Patient demographics.............................................................................................13
2.8
Patient disposition..................................................................................................14
2.9
Study drug exposure ..............................................................................................14
2.9.1
Duration of study drug exposure...........................................................14


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1   Introduction
The statistical methodology used (Section 9.7) will be described and discussed in the main 
part of the clinical study report.  In Appendix 16.1.9, details of the statistical methods and 
their justification are provided for the statistical reviewers.
The statistical analysis of this study will be performed by Novartis personnel. SAS® version 
9.3 (SAS Institute Inc., Cary, NC, USA) will be used for all analyses. All data are part of the 
Clinical Database and will be exported to SAS® files for analysis.
2
Definitions and general methodology
2.1
Study drug
Study drug and investigational treatment refer to s.a. oral panobinostat (hereof defined as the 
study treatment).
2.1.1
Date of first administration of study drug
The date of first administration of study drug is derived as the first date when a nonzero do se 
of study drug was administered and recorded on the dose administration record (DAR) eCRF. 
For the sake of simplicity, the date of first administration of study drug will also be referred as 
the start of study drug.
2.1.2
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug was administered and recorded on the end-of-treatment eCRF.
2.2
Study day
Study days will be calculated relative to the first day of panobinostat wh ich is Day 1.  If the 
event date is greater than or equal to the first dose date, then study day will be calculated as:
    Study Day = Event date - Date of first dose + 1.
Time from events prior of panobinostat to the start of panobinostat, e.g., time since diagnosis, 
study days will be calculated as:
    Study Day = Event date - Date of first dose.
Note that, the day of first dose is day 1 and the day before the date of first dose is day – 1, not 
day 0. If duration is calculated in months, the duration in days will be divided by 1 month = 
30.4375 days.
2.3
Baseline 
There will be no baseline defined for this study.


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2.4
Partial dates and imputation rules
Partial dates will be listed as partial dates. For computing time/duration, imputation rules will 
be used to impute the partial dates. All events with a start date on or before the cut-off date 
and with an end date after the cut-off date will be reported as ‘continuing at the cut-off date’. 
The same rule will be applied to events starting on or before the cut-off date and not having a 
documented end date.
Sometimes it may be necessary to impute a date to be able to calculate a specific statistic. If 
the day and month is missing, it will be replaced by July 1; if only the day is missing, it will 
be replaced by the 15th of that month. For dates prior to treatment start, the treatment start date 
– 1 will be used if this imputation makes the date later than the treatment start (for panels 
without standard imputation rules).
2.5
Screening failure
This roll-over study will not include screening period as patients will transfer directly from 
the parent study and commence with panobinostat as soon as they are consented and meet 
inclusion criteria of the roll-over protocol. Hence, screen failure is not applicable for this 
study.
2.6
Protocol deviations
Protocol deviations as specified in the VAP module 3 will also be identified, summarized and 
listed. The table below shows the project specific assignment of protocol deviation severity 
codes to each set used in this trial and identifies the deviation codes corresponding to each 
severity.
Code
Action
Deviation code
5
Exclude from all safety analyses
n/a
8
Exclude from all analysis
E06
49
Report relevant protocol deviation –
include in all analyses
E01, E02, E03, E04, E05, E07, E08, E09, E10, C01, 
C02, O01, O02, O03, S01, S02, S03, S04, W01, 
W02, W03, W04
Analysis set
Severity codes
5
8
49
Safety analysis set
No
No
Yes
Note: 'Yes’ means include in population, ‘No’ means exclude from population
2.7
Patient demographics
Demographic data will be summarized by patient. Categorical data will be presented as 
frequencies and percentages. For continuous data, summary statistics will be presented.


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2.8
Patient disposition
The FAS will be used for the patient disposition summaries. The number and percentage of 
patients included in the following categories will be provided:

Enrolled  (treated)

Treatment ongoing 

End of treatment

Primary reason of end of treatment:

Adverse event (s)

Subject withdrew consent

Lost to follow up

Administrative problems

Death 

Disease progression

Protocol deviation

Pregnancy

Study terminated by sponsor
2.9
Study drug exposure
Duration of study treatment exposure [months] will be summarized by dose regimen of 
panobinostat. In addition, the duration of exposure to study treatment will be categorized into 
time intervals in months; frequency counts and percentages will be presented for the number 
of patients in each interval. The safety set will be used for all summaries and listings. 
2.9.1
Duration of study drug exposure
Duration of study drug exposure as well as duration of study drug will be summarized by dose 
regimen. 
Duration of study drug exposure 
Duration of exposure (days) = [(date of last administration of study drug) – (date of 
first administration of study drug) + 1 day]
The date of last administration of study drug is taken from the “dosage administration record” 
CRF page of the study drug.  The calculation of ‘duration of exposure’ does not consider the 
potential ‘lagging effect’ from the last dose.
The duration includes the periods of temporary interruption (of the study drug for any reason). 
‘Date of first administration of study drug’ and ‘date of last administration of study drug’ is 
defined in Section 2.1.1 and Section 2.1.2 respectively. For patients who did not take any 
study treatment the duration of exposure is defined as zero days. If patients are still on 
treatment at the time of data cut-off, the time for duration of exposure will be calculated until 
the cut-off date.