Clinical trial NCT02722941
Conditions: Multiple Myeloma
Keywords: autologous hematopoietic cell transplant (HCT) autologous
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2016-06-10; Completion date: 2021-01-18
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to learn more about ways to prevent or delay relapse of multiple myeloma (MM). This study will determine the best dosing schedule of LBH589 maintenance therapy as well as the safety (side effects) and tolerability of LBH589 maintenance therapy after autologous hematopoietic cell transplant (HCT).

Detailed description:

Arms: arm 1: Panobinostat (LBH589): 20 mg by mouth three (3) times per week, every other week, of a 28-day schedule. arm 2: Panobinostat (LBH589): 10 mg by mouth daily for seven (7) days, every other week, of a 28-day schedule.
Interventions: intervention 1: Panobinostat
Intervention descriptions: intervention 1: Maintenance therapy dosing as outlined in Cohorts A and B.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Evaluation of Panobinostat (LBH589) as Maintenance Therapy in Multiple 
Myeloma Following Autologous Hematopoietic Cell Transplantation 
NCT02722941 
 
 
Version 3 
April 13, 2017 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
1 
 
 
Panobinostat 
Clinical Trial Protocol Number CLBH589DUS97T 
“Evaluation of panobinostat (LBH589) as maintenance therapy in multiple 
myeloma following autologous hematopoietic cell transplantation” 
 
Author(s): 
 
 
Principal Investigator: 
Taiga Nishihori, MD 
 
 
Sub-Investigators:  
Frederick Locke, MD 
Jinming Song, MD, PhD 
 
 
 
 
 
 
 
 
 
 
 
Kenneth Shain, MD, PhD 
 
 
 
 
 
Rachid Baz, MD 
 
 
 
 
 
Lia Perez, MD 
 
 
 
 
 
Jose L Ochoa-Bayona, MD 
 
 
 
 
 
Mohamed Kharfan-Dabaja, MD 
 
 
 
 
 
Ernesto Ayala, MD 
 
 
 
 
 
 
 
 
 
 
Hugo Fernandez, 
MD 
 
 
 
 
 
Joseph Pidala, MD, PhD 
 
 
 
 
 
Farhad Khimani, MD 
 
 
 
 
 
Brian Betts, MD 
 
 
 
 
 
Asmita Mishra, MD 
 
 
 
 
 
Claudio Anasetti, MD 
 
 
 
 
 
Melissa Alsina, MD 
 
      
 
Biostatistician: 
 
Jongphil Kim, PhD 
 
 
 
 
H. Lee Moffitt Cancer Center and Research Institute 
Department of Blood and Marrow Transplantation 
12902 Magnolia Drive 
Tampa, FL 33612Confidential 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
2 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of abbreviations ............................................................................................................ 4 
1 
Introduction ......................................................................................................................... 8 
1.1 
Overview of Maintenance Therapy in Multiple Myeloma ...................................... 8 
1.1.1 
Myeloma maintenance therapy after transplant ...................................... 8 
2 
Overview of Panobinostat ................................................................................................. 10 
2.1.1 
Anticancer activity of DAC inhibitors .................................................. 10 
2.1.2 
Panobinostat (LBH589) ........................................................................ 11 
2.1.3 
Overview of clinical experience ............................................................ 12 
2.1.4 
Human pharmacokinetics ...................................................................... 14 
2.1.5 
Cardiac Safety ....................................................................................... 16 
2.2 
HDAC inhibition in Multiple Myeloma ................................................................ 18 
2.2.1 
Role of histone deacetylase inhibition in preclinical myeloma 
models ................................................................................................... 18 
2.2.2 
Role of histone deacetylase inhibition in multiple myeloma 
treatment ................................................................................................ 19 
2.2.3 
Targeting myeloma precursors with histone deacetylase inhibitor ....... 20 
2.2.4 
Potential immunologic anti-myeloma mechanisms of deacetylase 
inhibitor ................................................................................................. 21 
2.2.5 
High-throughput sequencing technology to assess myeloma clones .... 21 
3 
Study rationale/purpose ..................................................................................................... 22 
4 
Study objectives ................................................................................................................. 23 
4.1 
Primary .................................................................................................................. 23 
4.2 
Secondary .............................................................................................................. 23 
5 
Overall study design .......................................................................................................... 23 
6 
Study population ................................................................................................................ 24 
6.1.1 
Patient population .................................................................................. 24 
6.1.2 
Inclusion/exclusion criteria (research sample collection: screening 
consent) ................................................................................................. 24 
6.1.3 
Inclusion and exclusion criteria (for panobinostat maintenance) ......... 25 
7 
Treatments ......................................................................................................................... 27 
7.1 
Investigational therapy........................................................................................... 27 
7.1.1 
Cardiac precautions ............................................................................... 29 
7.2 
Treatment assignment ............................................................................................ 29 
7.3 
Treatment cycle and duration ................................................................................ 29 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
3 
 
7.4 
Interruption or discontinuation of treatment .......................................................... 29 
7.4.1 
Dose reduction for panobinostat ........................................................... 30 
7.4.2 
Dose modifications for study drug-related toxicity (see section 
7.4.3 for dose modifications for prolonged QTc): ................................ 30 
7.4.3 
Dose modifications for prolonged QTc ................................................. 33 
7.4.4 
Study drug discontinuation ................................................................... 34 
7.4.5 
Follow-up for toxicities ......................................................................... 34 
7.5 
Other concomitant medications ............................................................................. 34 
7.5.1 
Anti-coagulant therapy .......................................................................... 35 
7.5.2 
CYP2D6 Substrates ............................................................................... 35 
7.5.3 
Drugs that can inhibit/induce CYP3A4/5 ............................................. 36 
7.5.4 
Heptavalent pneumococcal conjugate vaccine administration ............. 36 
7.6 
Treatment compliance ........................................................................................... 36 
8 
Visit schedule and assessments ......................................................................................... 37 
8.1 
Visit schedule......................................................................................................... 37 
8.2 
Efficacy assessments ............................................................................................. 39 
8.3 
Safety assessments ................................................................................................. 39 
8.3.1 
Adverse events ...................................................................................... 39 
8.3.2 
Vital signs.............................................................................................. 40 
8.3.3 
Physical examination ............................................................................ 40 
8.3.4 
Laboratory evaluations .......................................................................... 40 
8.3.5 
Serum pregnancy test ............................................................................ 41 
8.3.6 
ECG ....................................................................................................... 41 
8.4 
Drug levels and pharmacokinetic assessments ...................................................... 42 
9 
Correlative studies ............................................................................................................. 42 
9.1 
Assessment of minimal residual disease and B cell precursors ............................. 42 
9.2 
Assessment of immune response ........................................................................... 43 
9.3 
High-throughput sequencing of CDR3 from IgH, IgK and IgL somatic 
rearrangements ....................................................................................................... 45 
10 Safety monitoring .............................................................................................................. 46 
10.1.1 
Definitions ............................................................................................. 46 
10.1.2 
Reporting ............................................................................................... 47 
10.2 
Pregnancies ............................................................................................................ 47 
10.3 
Data Safety and Monitoring Plan .......................................................................... 48 
10.4 
Initial and Ongoing Monitoring and Review ......................................................... 49 
10.4.1 
Principal Investigator (PI) ..................................................................... 49 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
4 
 
10.4.2 
The Scientific Review Committee (SRC) ............................................. 49 
10.4.3 
The Protocol Review and Monitoring Committee (PRMC) ................. 49 
10.4.4 
The Research Compliance Division of the Cancer Center’s 
Compliance Office (RCD) .................................................................... 50 
11 Protocol amendments, or changes in study conduct .......................................................... 50 
12 Data review and management ........................................................................................... 51 
12.1 
Data collection and monitoring ............................................................................. 51 
13 Statistical methods ............................................................................................................. 51 
13.1 
Statistical methods and data analysis ..................................................................... 51 
13.1.1 
Populations for analysis ........................................................................ 52 
13.1.2 
Patient demographics/other baseline characteristics ............................. 52 
13.1.3 
Primary objective and hypothesis ......................................................... 52 
13.1.4 
Secondary objective and hypothesis ..................................................... 53 
13.1.5 
Early stopping rule ................................................................................ 53 
14 Procedures and instructions ............................................................................................... 53 
14.1 
Publication of results ............................................................................................. 53 
14.2 
Disclosure and confidentiality ............................................................................... 53 
14.3 
Discontinuation of study ........................................................................................ 54 
15 Ethics and Good Clinical Practice ..................................................................................... 54 
15.1 
Institutional Review Board/Independent Ethics Committee ................................. 54 
15.2 
Informed consent ................................................................................................... 54 
16 References ......................................................................................................................... 55 
16.1 
Appendix A: Medications requiring caution for potential drug-drug 
interactions ............................................................................................................. 63 
16.1.1 
Medications which have a risk of causing Torsades de pointes 
ventricular arrhythmia should be avoided ............................................. 63 
16.1.2 
Medications which are known strong CYP3A4/5 inhibitors to be 
used with caution................................................................................... 65 
16.1.3 
Medications which are known CYP2D6 substrates to be used with 
caution ................................................................................................... 66 
16.2 
Appendix B: Criteria for Symptomatic Multiple Myeloma .................................. 69 
16.3 
Appendix C: Uniform Response Reporting Criteria for Multiple Myeloma by 
the International Myeloma Working Group (IMWG) ........................................... 70 
16.4 
Appendix D: ECOG Performance Status Score .................................................... 71 
16.5 
Appendix E: Karfnosky Performance Score .......................................................... 72 
List of abbreviations 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
5 
 
ADME 
absorption, distribution, metabolism and excretion
AE 
adverse event 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT
AML 
acute myeloid leukemia
ANC 
absolute neutrophil count
APL 
acute promyelocytic leukemia
AST 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATRA 
all trans-retinoic acid
AUC 
area under the curve
BCR-ABL 
a fusion gene of the BCR and ABL genes
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network
bpm 
beat per minute 
BUN 
blood urea nitrogen
CALGB 
Cancer and Leukemia Group B
CBR 
clinical benefit rate 
CD 
cluster of differentiation
CHF 
congestive heart failure
CI 
confidence interval 
Cmax 
maximum concentration of drug
CML 
chronic myelogenous leukemia
CNS 
central nervous system
CP 
clinical pharmacology
CR 
complete response/remission
CS&E 
clinical safety and epidemiology
CTCAE 
NCI common terminology criteria for adverse events (version 4.03 
CTCL 
cutaneous T-cell lymphoma
CV 
coefficient of variation
CYP 
cytochrome P450 
DAC 
deacetylase 
DACi 
deacetylase inhibitor
DLT 
dose-limiting toxicity
DNA 
deoxyribose nucleic acid
DSMP 
Data Safety and Monitoring Plan
ECG 
12 lead electrocardiogram
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group
EFS 
event-free survival 
eRT 
eResearchTechnology
ETO 
eight-twenty-one 
FACT 
functional assessment of cancer therapy
FDA 
Food and Drug Administration
FLC 
free light chain  
G-CSF 
granulocyte colony-stimulating factor (e.g. filgrastim)
GI 
gastrointestinal 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
6 
 
GM-CSF 
granulocyte-macrophage colony-stimulating factor (e.g. sargramostim) 
GMMG 
German Multicenter Myeloma Group
H3, H4 
histones H3, H4 
HR 
hazard ratio 
HAT 
histone acetyltransferase
HCT 
hematopoietic cell transplantation
HDAC 
histone deacetylase
HDACi 
histone deacetylase inhibitor
hERG 
human ether-a-go-go related gene
HIF 
Hypoxia inducible factor
HIV 
human immunodeficiency virus
HOVON 
Dutch-Belgian Hemato-Oncology Cooperative Group
HR 
hazard ratio 
HR 
heart rate 
HSP 
heat shock protein 
i.v. 
intravenous(ly) 
ICH 
international conference on harmonization
IEC 
independent ethics committee
IFM 
Intergroupe Francophone du Myélome
IHC 
immunohistochemistry
IMWG 
International Myeloma Working Group
IRB 
institutional review board
KDR 
kinase insert domain receptor
LCR 
light chain restricted
LLN 
lower limit of normal
LMWH 
low molecular weight heparin
LVEF 
left ventricular ejection fraction
MHC 
major histocompatibility complex
mg/m2 
milligrams per square meter
MTD 
maximum tolerated dose
MR 
minimal response 
MRD 
minimal residual disease
MRC 
Medical Research Council
MUGA 
multiple uptake gated acquisition scan
MWF 
Monday, Wednesday, Friday
N/A 
not applicable 
NCI 
National Cancer Institute
NCIC-CTG  
National Cancer Institute of Canada Clinical Trials Group
nCR 
near complete response
NHL 
non-Hodgkin’s lymphoma
NIH 
National Institutes of Health
ORR 
overall response rate
OS 
overall survival 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
7 
 
PANORAMA 
Pan-deacetylase Inhibitor Panobinostat in Combination with Bortezoimb and 
Dexamethasone in Relapsed and Bortezomib-refractory Multiple Myeloma 
PBMC 
peripheral blood mononuclear cell
PCR 
polymerase chain reaction
PD 
Pharmacodynamics
PD 
progressive disease
PETHEMA/GEM 
Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de 
Mieloma 
PFS 
progression-free survival
P-gp 
p-glycoprotein 
PI 
princial investigator
PK 
pharmacokinetic 
PLT 
platelet 
PLZF 
promyelocytic leukemia zinc finger
PML 
promyelocytic leukemia
PO 
by mouth 
PR 
partial response 
PRMC 
Protocol Review and Monitoring Commitee
QOW 
every other week 
QW 
every week 
RAR 
retinoic acid receptor
RCD 
Research Compliance Dvision
REB 
research ethics board
RNA 
ribonucleic acid 
SAE 
serious adverse event
SAHA 
suberoylanilide hydroxamic acid
sCR 
stringent complete response
SD 
stable disease 
SD 
standard deviation 
SOP 
standard operating procedure
SRC 
Scientific Review Committee
T4 
Thyroxine 
TAA 
Tumor associated antigens
Th 
helper T cell 
TIW 
three times per week
TSH 
thyroid stimulating hormone
TTP 
time to progression
ULN 
upper limit of normal
VEGF 
vascular endothelial growth factor
VGPR 
very good partial response
WBC 
white blood cell 
WNL 
within normal limits
WOCBP 
women of childbearing potential
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
8 
 
1 
Introduction 
1.1 
Overview of Maintenance Therapy in Multiple Myeloma 
1.1.1 
Myeloma maintenance therapy after transplant 
Multiple myeloma is an incurable plasma cell malignancy despite recent advances in therapy 
with novel agents including lenalidomide and bortezomib.1,2  High-dose melphalan followed 
by autologous hematopoietic cell transplantation (HCT) offers progression-free survival (PFS) 
and overall survival (OS) benefits when compared to conventional chemotherapy.3-5  Recent 
phase 3 trials of lenalidomide maintenance post-autologous HCT demonstrated significant 
increase in PFS.6,7  In the Cancer and Leukemia Group B (CALGB) 100104 study (Table 1-
1), 462 multiple myeloma patients were randomized to lenalidomide 10 mg daily or placebo 
after single autologous HCT.6  The median time to progression (TTP) was 46 months for the 
lenalidomide arm and 27 months for the placebo arm (P < .001). At a median follow-up of 34 
months, the 3-year OS rates were 88% for the lenalidomide arm and 80% for the placebo arm 
(P =.028).6   A total of 23 out of 231 patients (10%) on lenalidomide arm discontinued 
maintenance due to adverse events.  Hematologic adverse events were more common in 
lenalidoimde group as well as grade 3 non-hematologic adverse events compared to the 
placebo group.  In the Intergroupe Francophone du Myélome (IFM) 05-02 study (Table 1-1), 
605 myeloma patients were randomized to lenalidomide 10 mg daily versus placebo until 
disease progression after single or tandem autologous HCT.7  The median PFS was 41 months 
for the lenalidomide arm and 23 months for the placebo arm (P < .001).  The OS was 74% for 
the lenalidomide arm and 76% for the placebo arm (P = .7) at a median follow-up of 45 
months.7  A total of 83 patients (27%) discontinued lenalidomide due to adverse events.  Any 
Seventy-four percent of patients in the lenalidomide group experienced any grade 3-4 adverse 
events and hematologic was the most common adverse events.  Approximately one third of 
patients experienced grade 3-4 non-hematologic adverse events. 
Table 1-1. Lenalidomide maintenance therapy after autologous HCT 
Study 
N 
Outcomes 
Maintenance 
No Maintenance 
CALGB 100104 
(McCarthy et al.)6 
460 
 Median TTP 46 months 
 3-yr PFS 66% 
 Median EFS 43 months 
 3-yr OS 88% 
 Median TTP 27 months (P < .001) 
 3-yr PFS 39% (P < .001) 
 Median EFS 27 months (P < .001) 
 3-yr OS 80% 
IFM 05-02 (Attal et 
al.)7 
614 
 Median PFS 41 months 
 4-yr PFS 43% 
 Median EFS 40 months 
 4-yr OS 73% 
 Median PFS 23 months (P < .001) 
 4-yr PFS 22% (P < .001) 
 Median EFS 23 months (P < .001) 
 4-yr OS 75% 
Abbreviations: EFS, event-free survival 
There have been extensive studies evaluating other maintenance options including 
thalidomide and bortezomib (Tables 1-2 and 1-3).8-18  Maintenance therapy can be associated 
with significant side effects such as constipation, fatigue, drug rash, cytopenias, peripheral 
neuropathy and thromboembolic events. Due to the complexity of potential side effects, these 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
9 
 
choices may pose significant challenges to clinicians. As for lenalidomide, an increased 
incidence of second primary malignancies has been associated with its use.6,7,19  Despite PFS 
and OS benefits shown in some studies, no single therapeutic agent has been established as 
the widely agreed-upon standard for maintenance therapy after autologous HCT in multiple 
myeloma. As was described by the International Myeloma Working Group (IMWG) 
consensus statement on maintenance therapy, maintenance treatment decisions for individual 
patients must balance potential benefits and risks carefully.20 
 
Table 1-2. Thalidomide maintenance therapy after autologous HCT 
Study 
N 
Outcomes 
Maintenance 
No Maintenance 
IFM 99 (Attal et 
al.)9 
597 
 3-yr EFS 52% 
 4-yr OS 87% 
 3-yr EFS 37% (P < .009) 
 4-yr OS 75% (P < .04) 
Total Therapy 2 
(Barlogie et al.)10 
668 
 5-yr EFS 64% 
 8-yr OS 57% 
 5-yr EFS 43% (P < .001) 
 8-yr OS 44% (P = .09) 
HOVON-50 
(Lokhorst, et al.)11 
556 
 Median EFS 43 months 
 Median OS 73 months 
 Median EFS 22 months (P < .001) 
 Median OS 60 months (P = .77) 
Spencer et al.13a 
243 
 3-yr PFS 42% 
 3-yr OS 86% 
 3-yr PFS 23% (P <.001) 
 3-yr OS 75% (P = .004) 
MRC IX (Morgan 
et al.)12b 
820 
 Median PFS 30 months 
 3-yr OS 75% 
 Median PFS 23 months (P = .003) 
 3-yr OS 80% (P = .26) 
BMT CTN 0102 
(Krishnan et al.)14c 
436 
 3-yr PFS 49% 
 3-yr OS 80% 
 3-yr PFS43% (P = .08) 
 3-yr OS 81% (P = .817) 
NCIC-CTG MY.10 
(Stewart et al.)16d 
332 
 4-yr PFS 32% 
 4-yr OS 68% 
 4-yr PFS 14% (P < .0001) 
 4-yr OS 60% (P = .18) 
Abbreviations: BMT CTN, the Blood and Marrow Transplant Clinical Trials Network; HOVON, the Dutch-Belgian 
Hemato-Oncology Cooperative Group; MRC, the Medical Research Council; NCIC-CTG MY.10, the National Cancer 
Institute of Canada Clinical Trials Group, the Myeloma. 10 
aIn the Australian trial by Spencer et al., the study design was thalidomide plus prednisone vs. prednisone. 
bThe MRC IX study included 1970 patients who were treated with intensive therapy including autologous HCT vs. 
nonintensive therapy. The cohort for intensive therapy was randomized to thalidomide vs. observation. 
cThe BMT CTN 0102 study included 710 patients who were treated with autologous-allogeneic transplant vs. tandem 
autologous transplants. The cohort for tandem autologous transplants was randomized to thalidomide plus dexamethasone vs. 
observation. 
dThe NCIC-CTG MY.10 study randomized patients to thalidomide plus prednisone vs. prednisone. 
Table 1-3. Bortezomib maintenance therapy after autologous HCT 
Study 
N 
Outcomes 
Maintenance 
No Maintenance 
HOVON-
65/GMMG-HD4 
(Sonneveld et al.)17 
827 
 Median PFS 35 months 
 5-yr OS 61% 
 Median PFS 28 months (P = .002) 
 5-yr OS 55% (P = .07) 
PETHEMA/GEM 
(Rosiñol)18 
386 
 2-yr PFS 78% (bortezomib 
plus thalidomide) 
 2-yr PFS 63% (thalidomide) vs. 
49% (IFN-: P = .01) 
Abbreviations: GMMG, the German Multicenter Myeloma Group; IFN, interferon; PETHEMA/GEM, Programa para el 
Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
10 
 
Although maintenance therapy is an attractive strategy to achieve longer disease control, 
relapse or progression of myeloma after autologous HCT remains inevitable.  Myeloma 
progression after autologous HCT is likely secondary to the existence of minimal residual 
disease as high-dose melphalan fails to eliminate myeloma reservoirs including putative 
myeloma stem cells or B cell progenitors, and to reset the bone marrow stromal and 
immunologic niche which supports myeloma cell survival. There is an unmet need to improve 
treatment outcomes for myeloma patients and research strategy on maintenance therapy 
continues to evolve.  
2 
Overview of Panobinostat 
2.1.1 
Anticancer activity of DAC inhibitors 
Alterations in chromosome structure play critical roles in the control of gene transcription.  
These epigenetic alterations include modification of histones and others proteins by 
acetylation and/or phosphorylation.  Normally, these modifications are balanced finely and 
are highly reversible in normal tissues, but they may be imbalanced and heritable in tumor 
cells.  Deacetylase (DAC) inhibitors increase histone acetylation, thereby modulating the 
expression of a subset of genes in a coordinated fashion.  Several tumors suppressor genes 
associated with the malignant phenotype are repressed by epigenetic mechanisms in sporadic 
cancers.  Thus therapy with DAC inhibitors may alter tumor phenotype and inhibit growth in 
such tumors. 
Multiple hallmarks of cancer are regulated by acetylation/deacetylation: 
 
DAC inhibition targets both histone and nonhistone proteins.  Targeting the acetylation 
status of nonhistone, tumor-associated proteins that mediate proliferation may be the 
underlying antitumor mechanism of DAC inhibitors.21  
 
Nonhistone proteins regulated by acetylation include α-tubulin, p53, HIF-1, and HSP90.  
These proteins are substrates of DACs.22 
 
The ability of a single agent to target multiple molecular features of tumor cells may result 
in good efficacy against a range of different tumor types. 
 
HSP90 is involved in protein stability and degradation; the inhibition of HSP90 affects 
protein turnover in diseases such as multiple myeloma and B-cell malignancies.23 
 
Acetylated HIF-1 is degraded and can no longer act as a tumor growth factor.  Class II 
DAC inhibitors target histone deacetylase (HDAC or DAC) 6, resulting in increased 
acetylation of HIF-1 and decreased vascular endothelial growth factor (VEGF), thereby 
inhibiting angiogenesis.24 
 
Both acetylation and ubiquitylation often occur on the same lysine residue, but these 
processes cannot occur simultaneously.  Acetylation allows for increased stability, and 
ubiquitylation leads to protein degradation.  Therefore, DACs decrease the half-life of a 
protein by exposing the lysine residue for ubiquitylation.25 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
11 
 
2.1.2 
Panobinostat (LBH589) 
Panobinostat (LBH589) is a deacetylase inhibitor (DACi) belonging to a structurally novel 
cinnamic hydroxamic acid class of compounds.  It is a potent class I/II pan-DAC inhibitor 
(pan-DACi) that has shown anti-tumor activity in pre-clinical models and cancer patients.  
Deacetylases (DAC) target lysine groups on chromatin and transcription factors and various 
non-histone proteins such as p53, tubulin, HSP90 and Rb.  Panobinostat is formulated as an 
oral capsule and a solution for intravenous (i.v.) injection.  Both the oral and i.v. formulations 
are currently being investigated in ongoing Phase I and Phase II studies in advanced solid 
tumors and hematological malignancies.   
Inhibition of DAC provides a novel approach for cancer treatment.  Histones are part of the 
core proteins of nucleosomes, and acetylation and deacetylation of these proteins play a role 
in the regulation of gene expression.  Highly charged deacetylated histones bind tightly to the 
phosphate backbone of DNA, inhibiting transcription, presumably, by limiting access of 
transcription factors and RNA polymerases to DNA.  Acetylation neutralizes the charge of 
histones and generates a more open DNA conformation.  This conformation allows 
transcription factors and associated transcription apparatus access to the DNA, promoting 
expression of the corresponding genes.  The opposing activities of two groups of enzymes, 
histone acetyltransferase (HAT) and DAC control the amount of acetylation.  In normal cells 
a balance exists between HAT and DAC activity that leads to cell specific patterns of gene 
expression.  Perturbation of the balance produces changes in gene expression. 
Several lines of evidence suggest that aberrant recruitment of DAC and the resulting 
modification of chromatin structure may play a role in changing the gene expression seen in 
transformed cells.  For example, silencing of tumor suppressor genes at the level of chromatin 
is common in human tumors,26-33 and DAC complexes have been shown to be crucial to the 
activity of the AML-specific fusion proteins PLZF-RAR-α, PML-RAR-α, and AML1/ETO.34-
37  DAC inhibitors (DACi) have been shown to induce differentiation, cell cycle arrest or 
apoptosis in cultured tumor cells, and to inhibit the growth of tumors in animal models.38-44  In 
addition, DACi have been shown to induce expression of p21, a key mediator of cell cycle 
arrest in G1 phase and cellular differentiation.45-48 
Tumor growth inhibition and apoptosis in response to DACi treatment may also be mediated 
through changes in acetylation of non-histone proteins (e.g., HSP90, p53, HIF-1α, α-tubulin).  
For example, the chaperone protein HSP90 has been shown to be acetylated in cells treated 
with DACi.49-51  Acetylation of HSP90 inhibits its ability to bind newly synthesized client 
proteins, thus preventing proper client protein folding and function.  In the absence of HSP90 
function, misfolded proteins are targeted for degradation in the proteasome.  Many proteins 
that require HSP90 association are critical to cancer cell growth, including ErbB1, ErbB2, 
AKT, Raf, KDR, and BCR-ABL.  Acetylation of HSP90 in cells treated with DACi inhibits 
the chaperone function of HSP90, leading to degradation of the client proteins and eventual 
cell death. 
The potential clinical utility of the use of DACi in cancer therapy was first suggested by the 
activity of the DACi, sodium phenylbutyrate, against acute promyelocytic leukemia (APL).  
An adolescent female patient with relapsed APL, who no longer responded to all trans-


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
12 
 
retinoic acid (ATRA) alone, achieved a complete clinical remission after treatment with a 
combination of ATRA and the DACi sodium phenylbutyrate.52 
2.1.3 
Overview of clinical experience 
Currently, the clinical development of panobinostat focuses on the oral formulation.  As of 
31st December 2013, 36 clinical studies, including clinical pharmacology (CP), phase I and 
phase II trials, as well as 2 randomized phase III studies, have either been completed or are 
ongoing. A total of 2428 patients were enrolled (235 for i.v. and 2193 for oral), received at 
least one dose of panobinostat either as a single agent or in combination with other agents, 
and for whom safety data are available. These patients constitute the safety population. 
The most common AEs, regardless of their study drug relationship, concern the 
gastrointestinal tract (nausea, diarrhea and vomiting mostly of grade 1/2). For the 
hematopoietic system, the most frequent findings continue to be thrombocytopenia, anemia 
and neutropenia, mostly of grade 3/4, while febrile neutropenia, as expected, has been noted 
much more frequently in patients being treated for hematologic malignancies involving the 
bone marrow. Additional common toxicities include fatigue Grade 3/4 reported with a 
frequency of 9.2% in an every week (QW) dosing schedule vs. 15.7% in an every other week 
(QOW) dosing schedule.  
The most common ECG findings adjudicated by central review included post-baseline 
increase in frequency of sinus tachycardia, T-waves changes (flat, biphasic, inverted), as well 
as depressed ST segment findings. 
The most frequently encountered laboratory abnormalities in both QW and QOW schedules 
and regardless of disease, refer to hematological parameters, including decreased WBC, 
platelet and neutrophil count and hemoglobin. Worsening of these hematologic parameters 
was more evident for the QW schedule and appears to be dose-dependent. Liver function tests 
alterations were mostly of grade 1/2 with either schedule, with grade 3 reported at the highest 
dose of 60 mg TIW QW. Decreasing electrolytes and elevated glucose was mostly grade 1/2 
worsening from baseline, but again increased severity (up to grade 3) was seen at the highest 
dose of 60 mg with the QW schedule. 
Thyroid function, as monitored by the measurement of TSH and free T4, did not reveal overt 
hyper- or hypo- thyroidism, with fluctuations in TSH values being within normal limits. 
As the number of patients is quite different across doses, the following rules have been 
applied to report these events in the tables below: in doses where the number (n) of patients is 
≥25 patients, AEs reported in ≥10% of patients are listed; in doses where n is <25 patients, 
AEs reported in ≥50% of patients are listed.  If an AE frequency matches the criteria in one 
dose category, the frequency of that event is shown for all doses. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
13 
 
 
Table 2-1 
All grade adverse events regardless of causality in patients receiving oral 
panobinostat three-times-a-week every-other-week (TIW QOW) 
Primary System Organ Class 
Preferred term 
30 mga 
N = 28 
n    (%) 
45 mga 
N = 18 
n    (%) 
60 mga 
N = 24 
n    (%) 
 Any primary system organ class 
28 (100.0) 
18 (100.0) 
24 (100.0) 
 
 
 
 
 Blood and lymphatic system disorders 
16 (57.1) 
14 (77.8) 
21 (87.5) 
 Anemia 
5 (17.9) 
6 (33.3) 
11 (45.8) 
 Neutropenia 
3 (10.7) 
5 (27.8) 
10 (41.7) 
 Thrombocytopenia 
10 (35.7) 
10 (55.6) 
14 (58.3) 
 
 
 
 
 Gastrointestinal Disorders 
25 (89.3) 
17 (94.4) 
24 (100.0) 
 Constipation 
6 (21.4) 
3 (16.7) 
10 (41.7) 
 Diarrhea 
15 (53.6) 
11 (61.1) 
16 (66.7) 
 Nausea 
17 (60.7) 
9 (50.0) 
19 (79.2) 
 Vomiting 
12 (42.9) 
6 (33.3) 
12 (50.0) 
  
 
 
 
 General Disorders and Site Conditions 
27 (96.4) 
17 (94.4) 
23 ( 95.8) 
Asthenia 
5 (17.9) 
5 (27.8) 
4 (16.7) 
 Fatigue 
18 (64.3) 
12 (66.7) 
15 (62.5) 
 Edema peripheral 
6 (21.4) 
5 (27.8) 
4 (16.7) 
 Pyrexia 
11 (39.3) 
9 (50.0) 
10 (41.7) 
  
 
 
 
 Investigations 
14 (50.0) 
8 (44.4) 
11 (45.8) 
 Weight decreased 
10 (35.7) 
5 (27.8) 
3 (12.5) 
  
 
 
 
 Metabolism and nutrition disorders 
22 (78.6) 
9 (50.0) 
18 (75.0) 
 Anorexia 
17 (60.7) 
6 (33.3) 
10 (41.7) 
 Hypokalemia 
4 (14.3) 
3 (16.7) 
6 (25.0) 
 
 
 
 
 Musculoskeletal and connective tissue disorders 
16 (57.1) 
7 (38.9) 
13 (54.2) 
 Arthralgia 
3 (10.7) 
0 (0.0) 
6 (25.0) 
 Back Pain  
3 (10.7) 
4 (22.2) 
3 (12.5) 
 Pain in extremity 
3 (10.7) 
2 (11.1) 
3 (12.5) 
 
 
 
 
 Nervous system disorders 
17 (60.7) 
6 (33.3) 
14 (58.3) 
 Headache 
7 (25.0) 
3 (16.7) 
6 (25.0) 
 
 
 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
14 
 
Primary System Organ Class 
Preferred term 
30 mga 
N = 28 
n    (%) 
45 mga 
N = 18 
n    (%) 
60 mga 
N = 24 
n    (%) 
 Respiratory, thoracic and mediastinal disorders 
15 (53.6) 
8 (44.4) 
17 (70.8) 
 Cough 
5 (17.9) 
4 (22.2) 
7 (29.2) 
 Dyspnea 
9 (32.1) 
6 (33.3) 
6 (25.0) 
 
 
 
 
 Skin and subcutaneous tissue disorders 
12 (42.9) 
5 (27.8) 
9 (37.5) 
 Pruritus 
5 (17.9) 
1 (5.6) 
3 (12.5) 
 Rash 
3 (10.7) 
1 (5.6) 
4 (16.7) 
 
 
 
 
a. 
Includes patients from [B1101], [B2101], [B2102] (Group X and Y), [B2201], [B2202], [B2203], 
[B2211], [B2212], [E2214]; events occurring in ≥10% of patients 
A patient with multiple occurrences of an AE in one SOC is counted only once in the AE category 
 
As shown on the above Table 2-1, AEs have been reported for 70 patients (100% of the safety 
population) for the QOW schedule. The most commonly reported AEs across doses were 
fatigue and nausea in 45 patients each (64.3% each), diarrhea in 42 patients (60%), 
thrombocytopenia in 34 patients (48.6%) and anorexia in 33 patients (47.1%). 
Of note, the safety profile appears to be qualitatively similar between the two schedules.  At 
present, a quantitative comparison is limited by the significantly different number of patients 
available in both safety populations. 
2.1.4 
Human pharmacokinetics 
After oral administration, panobinostat is rapidly absorbed with no observed lag phase. 
Maximum plasma concentrations were generally reached within 1 hour after oral dosing. The 
absolute bioavailability was 30% (data on file) and the mean (SD) half-life of panobinostat 
was comparable following i.v. and oral dosing ~15.0 (5) hours. Moderate drug accumulation 
was observed with oral three-times-a-week schedule but not with the weekly i.v. schedule 
(1.4-fold drug accumulation with oral three-times-a-week dosing), consistent with the 
terminal half-life of 15 hours and dosing interval. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
15 
 
Figure 2-1 
Mean panobinostat plasma concentration versus time profiles 
following single oral or intravenous administration 
 
Table 2-2  
Pharmacokinetic parameters of panobinostat in three ongoing Phase I 
studies [CLBH589A2101], [CLBH589B2101], and [CLBH589B2102] 
Route of administration 
& Dose (No. of patients 
following single dose) 
Mean (CV%) 
Single dose 
Cmax(ng/mL) 
Mean (CV%) 
Single dose 
AUC0-inf (ng*hr/mL) 
Mean (CV%) 
Multiple dose 
AUC0-48 (ng*hr/mL) 
i.v. 20 mg/m2 (n=31) 
784 (45) 
1041 (38) 
n/a 
p.o. 20 mg (n=45) 
22.8 (58) 
194 (58) 
258 (65) 
p.o. 30 mg (n=49) 
36.2 (62) 
267 (54) 
279 (54) 
p.o. 40 mg (n=24) 
58.0 (59) 
329 (77) 
270 (59) 
p.o. 60 mg (n=57) 
66.1 (68) 
362 (62) 
306 (50) 
p.o. 80 mg (n=18) 
63.5 (58) 
397 (49) 
369 (52) 
n/a: not applicable 
with weekly i.v. 
administration 
 
In vitro experiments suggested that the hepatic oxidative metabolism of panobinostat is 
mediated primarily by cytochrome P450 (CYP) 3A4, and to a lesser extent by CYP2D6 and 
CYP2C19. In addition to monooxygenation, hydrolysis of the hydroxamic sid chain (M43.5) 
were also found to be mediated (at least in-part) by the CYPs. These same metabolic 
pathways, were also observed in the recent human ADME and mass balance study 
[CLBH589B218]. 
Dose proportionality 
A positive and linear dose-exposure relationship was found following single i.v. 
administration (1.2 to 20 mg/m2, Rs = 0.83; p<0.0001).  After oral dosing with 15 mg to 80 
0.0
0.1
1.0
10.0
100.0
1000.0
0
5
10
15
20
25
30
35
40
45
50
Time (hr)
20 mg PO
20 mg/m2 IV


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
16 
 
mg of panobinostat, dose-proportionality analysis indicated that systemic exposure increased 
nearly dose-proportionally at doses below 60 mg and there is less than proportional increase 
in AUC after 60 mg and 80 mg doses of panobinostat.  It appears that absorption may become 
limiting at doses ≥ 60 mg of panobinostat.   
Food Effect 
Influence of food on panobinostat PK was evaluated in patients with advanced cancer who 
received 20 mg panobinostat twice a week and were randomized to receive panobinostat 
under fasting, high fat, and normal breakfast conditions [CLBH589B2111]. The overall 
exposure and inter-patient variability (CV 59%) in 34 patients remained unchanged with or 
without food, whereas Cmax was transiently reduced by <45% and Tmax prolonged by food 
(i.e., both normal and high fat breakfast).  Since food did not alter the overall extent of 
absorption, food is unlikely to significantly impact panobinostat’s systemic exposure in cancer 
patients. The findings from this formal food effect are consistent with the results from an 
earlier pilot food effect [CLBH589B2101] arm 1. Therefore, panobinostat can be 
administered without regard to food in future studies.   
2.1.5 
Cardiac Safety 
As of 31 December 2013, cardiac safety data for 666 patients treated with oral panobinostat 
TIW QW are presented in Table 2-3. All patients underwent intensive pre- and post-dose 
ECG monitoring intended to measure the occurrence of QTcF (Fridericia Correction Formula) 
and to capture other ECG abnormalities as well. The most common finding continues to be a 
post-baseline QTcF increase of >30 and ≤60 msec with both dosing schedules (approximately 
22%). No cases of torsades de pointes have been observed with either oral dosing schedule. 
QTcF abnormalities are shown in Table 2-3, for the QW schedule. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
17 
 
Table 2-3 
QTcF changes in patients receiving oral panobinostat three-times-a-
week every-week (TIW QW) 
QTcF variable 
20 mg 
(N=309 
Total  n  % 
30 mg 
(N=81) 
Total  n  % 
40 mg 
(N=163) 
Total  n  % 
60 mg 
(N=113) 
Total  n  % 
TOTAL 
(N=666) 
Total  n  % 
QTcF increase from baseline 
> 30 and <= 60 ms 
309  47 
(15.2) 
81  12 
(14.8) 
163  46 
(28.2) 
113  38 
(33.6) 
666 143 
(21.5) 
QTcF increase from baseline 
> 60 ms 
309   7 
( 2.3) 
81   1 
( 1.2) 
163   6 
( 3.7) 
113  13 
(11.5) 
666  27 
( 4.1) 
Absolute QTcF > 450 and <= 
480 ms 
305  38 
(12.5) 
81  10 
(12.3) 
162  13 
( 8.0) 
110  27 
(24.5) 
658  88 
(13.4) 
Absolute QTcF > 480 ms and 
<= 500 ms 
309   5 
( 1.6) 
81   1 
( 1.2) 
163   4 
( 2.5) 
113   7 
( 6.2) 
666  17 
( 2.6) 
Absolute QTcF > 500 ms 
309   1 
( 0.3) 
81   0 
( 0.0) 
163   0 
( 0.0) 
113   5 
( 4.4) 
666   6 
( 0.9) 
N= Number of patients in the group. 
n= Number of patients at risk for a designated change with both non-missing baseline and post-
baseline values. 
Patients are counted only for the worst grade observed post-baseline. 
As shown in Table 2-3 above, post-baseline increase of >30 and ≤60 msec (Grade 1) was 
frequently reported (143 patients, 21.5%). A post-baseline increase of >60 msec was less 
frequent (27 patients, 4.1%). QTcF prolongation translating into an absolute value of 450 to 
480 msec and of > 480 - 500 msec was measured in 88 patients (13.4%) and in 17 patients 
(2.6%), respectively. Absolute QTcF prolongation > 500 msec was uncommon (6 patients, 
0.9%), mostly referred to 5 patients treated at 60 mg weekly dose level. 
For the QOW schedule post-baseline increased values of >30 and ≤60 msec were observed in 
16 (16.7%) patients. Post-baseline increase of >60 msec was less frequent (4 patients, 4.2%). 
Absolute QTcF prolongation values of 450 msec to 480 and of >480 to 500 msec were 
reported in 9 patients (9.6%) and in 1 patient (1.0%), respectively. Absolute QTcF 
prolongation above 500 msec was not observed. 
2.1.5.1 
Relationship between panobinostat plasma concentrations and 
QTcF 
As presented in Figure 2-2 (po) below, the maximum change of QTcF from baseline does not 
coincide with the peak plasma concentration-time course of panobinostat suggesting a 
possible delayed effect.   
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
18 
 
Figure 2-2 
QTcF change from baseline over time vs. panobinostat conc-time 
course following the first oral panobinostat doses of a MWF schedule 
 
2.2 
HDAC inhibition in Multiple Myeloma 
2.2.1 
Role of histone deacetylase inhibition in preclinical myeloma models  
There are several HDAC inhibitors in development that induce protein acetylation and anti-
myeloma activity. The first preclinical evidence of anti-myeloma activity of HDAC inhibitor 
comes from the study evaluating suberoylanilide hydraxamic acid (SAHA), the prototypic 
hydroxamic acid-based HDAC inhibitor, or vorinostat in cell lines and patient-derived 
samples.53 Subsequent studies showed that molecular profile of myeloma cells exposed to 
SAHA contained an array of antiproliferative and/or proapoptotic molecular events.54  SAHA 
also suppresses proteasomal activity and enhances myeloma cell sensitivity to proteasome 
inhibition.  Combinations of a proteasome inhibitor and an HDAC inhibitor produced 
synergistic anti-myeloma activities.55-57 HDAC inhibitors targeting HDAC6 prevent 
aggresome formation in myeloma cells that were treated with proteasome inhibitors.58,59  
Blockade of both the aggresomal and proteasomal protein degradation pathways produces 
misfolded protein accumulation and leads to apoptosis.58,60,61 Agents that have been shown to 
enhance anti-myeloma activity in various preclinical models in combination with an HDAC 
inhibition include lenalidomide, pomalidomide, and melphalan.54,55  HDAC inhibitors as 
single agents including panobinostat have also been shown to induce myeloma cell death in 
the U226 cell line primarily through the inhibition of class I HDACs (HDAC 1, 2, 3, and 8).62  
Bone marrow angiogenesis, mediated by VEGF ligand-receptor signaling, is also considered 
to be important in the pathogenesis of multiple myeloma.63,64  HDAC inhibition has been 
shown to suppress the expression of VEGF and VEGF-induced angiogenesis via HIF1- 
downregulation.65-67  Other preclinical studies have suggested that HDAC inhibition may 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
19 
 
target chaperone proteins such as heat shock proteins (including HSP27 and HSP90).  
Inhibition of HDACs and HSP90 downregulate proteins involved in cell proliferation and 
survival.68,69  Combination of an HSP90 inhibitor and HDAC inhibitors can result in 
synergistic downregulation of HSP90 chaperone activity and is associated with myeloma cell 
death.70  Single agent activity of both panobinostat and vorinostat has been demonstrated in 
the Vk*MYC transgenic mouse model of multiple myeloma.71  Based on promising 
preclinical activity of HDAC inhibition, panobinostat has been evaluated for the treatment of 
multiple myeloma. 
2.2.2 
Role of histone deacetylase inhibition in multiple myeloma treatment  
A phase 1a/2 , two-arm, open-label dose-escalation study of panobinostat administered in 2 
oral dosing schedules in patients with hematologic malignancies including multiple myeloma 
has been conducted.72  In patients with multiple myeloma, 40 mg was the recommended dose 
for phase 2 evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was 
the MTD for biweekly panobinostat.  In early phase clinical trials, HDAC inhibitors were 
examined in heavily pretreated multiple myeloma patients.  In the single-agent setting, 
panobinostat, vorinostat and romidepsin have all been demonstrated to have modest clinical 
activity.73-76  In a phase 2 trial, 38 patients with relapsed/refractory multiple myeloma were 
treated with panobinostat (Table 2-4).74  There was one patient with durable partial response 
(PR) and another patient had minimal response (MR).  There were 9 other patients who 
achieved stable disease (SD) at best response. HDAC inhibitors such as panobinostat, 
romidepsin, vorinostat, and belinostat have also been evaluated in combination with multiple 
agents.77-82  In a phase 1b study (Table 2-4), the combination of panobinostat and bortezomib 
was studied in relapse and refractory multiple myeloma.78  The maximum tolerated dose 
(MTD) was established at panobinostat 20 mg plus bortezomib 1.3 mg/m2.  Grade 3/4 AEs 
included thrombocyotopenia (85.1%), neutropenia (63.8%), and asthenia (29.8%) in the dose 
escalation phase, and thrombocytopenia (66.7%), neutropenia (46.7%), and fatigue (20%) in 
the expansion phase.  Among bortezomib-refractory patients, the overall response rate (ORR) 
was 26.3%, and 42.1% of patients had at least MR.78   Panobinostat has also been examined in 
a phase 2 trial, PANORAMA 2 (Pan-deacetylase Inhibitor Panobinostat in Combination with 
Bortezomib and Dexamethasone in Relapsed and Bortezomib-refractory Multiple Myeloma) 
trial (Table 2-3).79  In this heavily pretreated (median of 4 prior regimens), bortezomib-
refractory (a median of 2 prior bortezomib-containing regimens) myeloma patient population 
(N = 55), an ORR of 34.5% and a CBR of 52.7% were observed.  The safety profile was 
similar to the phase 1b dose-escalation study, with thrombocytopenia being the most 
commonly observed grade 3/4 AE (63.3%).  Grade 3/4 diarrhea occurred in 20% of patients.  
In a phase 3 double-blinded study, PANORAMA 1, a total of 768 relapsed or refractory 
multiple myeloma patients were randomized to either panobinostat or placebo in combination 
with bortezomib and dexamethasone.83  The primary endpoint was met with median PFS of 
12 months versus 8.1 months (P < .0001; hazard ratio (HR) 0.63, 95% confidence interval 
(CI) 0.52 – 0.76) for the group treated with panobinostat versus placebo, respectively.  OS 
data were not mature.  AEs led to the discontinuation in 36% in the panobinostat group 
compared to 20% in the control group.  The trial demonstrated significant PFS improvement 
with panobinostat in combination with bortezomib plus dexamethasone in patients with 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
20 
 
relapsed/refractory multiple myeloma.83  These promising results corroborate with preclinical 
studies underscoring the scientific rationale for the drug development.  Other clinical trials 
evaluating the efficacy of panobinostat in multiple myeloma are in active development.  
Table 2-4. Summary of selected clinical trials of panobinostat in multiple myeloma 
Agent(s)/Study 
Phase 
N 
Panobinostat Dose 
Clinical Efficacy 
Safety 
Panobinostat 
single agent 
(Wolf et al.)74 
2 
38 
20 mg PO TIW 
weekly every 21 
days 
PR n=1; MR n=1; SD 
n=9 
Grade 3/4 neutropenia 
31.6%; grade 3/4 
thrombocytopenia 26.3%; 
grade 3/4 GI 10.5%  
Panobinostat + 
bortezomib + 
dexamethasone 
(San-Miguel et 
al.)78 
1b 
62 
20 mg PO TIW 
every weekly every 
21 days 
CBR* 61.3%; ORR 
51.6%; PR 35.5%; 
VGPR 9.7%; MR 
9.7% 
Grade 3/4 
thrombocytopenia 80.6%; 
grade 3/4 neutropenia 
59.7%; grade 3/4 asthenia 
25.8%; grade 3/4 anemia 
17.7% 
PANORAMA 2 
(panobinostat + 
bortezomib + 
dexamethasone: 
Richardson et 
al.)79 
2 
55 
20 mg PO TIW on a 
2-weeks-on/1-week-
off schedule, every 
21 days 
CBR 52.7%; ORR 
34.5%; SD 36.4%; PR 
32.7%; MR 18.2% 
Grade 3/4 
thrombocytopenia 63.6%; 
grade 3/4 diarrhea 20%; 
grade 3/4 neutropenia 
14.6% 
PANORAMA 1 
(panobinostat + 
bortezomib + 
dexamethasone 
vs. placebo: 
Richardson et 
al.)83 
3 
768 
20 mg PO TIW on a 
2-weeks-on/1-week-
off schedule, every 
21 days 
Median PFS 12 
months vs. 8.1 
months; ORR 61% vs. 
55%; nCR/CR 28% 
vs. 16% 
Grade 3/4 
thrombocytopenia 67% 
vs. 31%; grade 3/4 
neutropenia 35% vs. 11%; 
grade 3/4 diarrhea 26% 
vs. 8% 
Panobinostat + 
melphalan 
(Berenson et al.)77 
1/2 
40 
15 – 20 mg PO TIW 
1 week or 2 weeks, 
every 4 weeks 
At least PR n=3; SD 
n=23, PD n=14 
Grade 3/4 neutropenia 
30.8%; grade 3/4 
thrombocytopenia 23.1% 
Panobinostat + 
melphalan + 
thalidomide + 
prednisone 
(Offidani et al.)80 
1/2 
31 
10 – 20 mg PO TIW 
on a 3-weeks-on/1-
week off schedule, 
every 4 weeks 
CR n=2; VGPR n=2; 
SD n=11 
Grade 3/4 neutropenia 
71%; grade 3/4 
thrombocytopenia 35% 
Abbreviations: CBR, clinical benefit rate; CR, complete response; GI, gastrointestinal; nCR, near complete response; PD, 
progressive disease; VGPR, very good partial response 
*CBR is defined as the percentage of patients with a confirmed response of MR or better. 
2.2.3 
Targeting myeloma precursors with histone deacetylase inhibitor 
Recent breakthroughs in the understanding of tumor biology shed light to the existence of 
cancer stem cells.84-86  Previous work demonstrated that putative cancer stem cells in multiple 
myeloma may resemble the memory B cell fraction and express myeloma-type 
immunoglobulin genes without plasma cell characteristics.  These so-called “clonotypic” B 
cells are characterized functionally and phenotypically as chemoresistant and are postulated to 
be partly responsible for disease recurrence.87-89  There is an unmet need for targeted therapy 
to eliminate the resistant B cells progenitor clone.  Boucher and colleagues at Moffitt Cancer 
Center evaluated clonotypic B cells (CD19+) in primary human myeloma samples which 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
21 
 
showed light chain restriction (termed light chain restricted, LCR) and showed panobinostat 
(an oral histone deacetylase inhibitor) induced apoptosis of LCR B cells with the same 
efficacy as malignant CD138+ cells.90  Therefore, we hypothesize that administration of 
panobinostat in a state of minimal residual disease after autologous HCT could potentially 
eradicate myeloma B cell progenitors implicated as a reservoir of minimal residual disease. 
2.2.4 
Potential immunologic anti-myeloma mechanisms of deacetylase 
inhibitor 
Numerous immunotherapeutic strategies including immune modulation to reduce myeloma 
burden has been attempted.91  Locke and colleagues at Moffitt Cancer Center have 
demonstrated persistence of T effectors against myeloma tumor associated antigens after 
autologous HCT. It has been shown that such cells have the ability to exert cytotoxic effects 
upon autologous myeloma cells, however, this response is blunted in vivo as they are unable 
to eradicate the tumor spontaneously.92,93   
Several preclinical studies performed at Moffitt strongly suggest that panobinostat may 
increase immune responses against tumor. Both in vitro and in vivo studies by Woods and 
Villagra et al. showed that panobinostat increases the immunogenicity of tumors and 
promotes major histocompatibility complex (MHC) and costimulatory molecules upon tumors 
and increases antigen specific T cells.94  Wang and colleagues showed elevated Th1 cytokines 
and increased immune activation when panobinostat was administered after in allogeneic 
HCT in a murine model.95  Skewing of T cells toward the Th1 cytokine profile may enhance 
cytotoxic T-cell mediated anti-tumor activity.   
Vaccination with heptavalent pneumococcal conjugate vaccine (PCV13, PrevnarTM: 
pneumococcal protein + adjuvant CRM protein), is performed as standard of care typical 
around day +90 after autologous HCT for myeloma. We have demonstrated that this vaccine 
leads to measurable humoral immunity against pneumococcal serotypes, and T-cell mediate 
immunity against the CRM protein. Administration of panobinostat after autologous HCT 
may augment the T-cell immune responses against known myeloma tumor associated 
antigens; produce skewing of the cytokine profile to Th1 subtype; and augment responses 
against a standard of care pneumococcal vaccine.96,97 
2.2.5 
High-throughput sequencing technology to assess myeloma clones 
 
Depth of myeloma response has been considered one of the prognostic indicators following 
HCT and it may be critical to achieve deeper responses for long-term disease control.98 Multi-
parameter flow cytometry is a viable method for minimal residual disease monitoring in 
majority of myeloma patients by differentiating normal and neoplastic plasma cells based on 
the surface marker expression.99 However, a sensitivity of flow cytometry is limited to 
0.01%,100,101 and there is an increasing need for more sensitive minimal residual disease 
monitoring techniques with more broader applicability. 
 
Emerging technology such as high-throughput sequencing of lymphoid receptors (including B 
cells and T cells) can provide comprehensive disease monitoring after high-dose melphalan 
followed by autologous HCT. The Illumina HiSeq platform for multiplex PCR is useful for 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
22 
 
sequencing clonal either B-cell or T-cell receptor complementarity-determining region 3 
(CDR3).102 The high-throughput sequencing was more sensitive than flow cytometry in 
patients with acute T-lymphoblastic leukemia.102 Similar technology was used on 
determination of germline IgH repertoires.103 The high-throughput sequencing to track IgH 
and IgL sequences in malignant plasma cells would be an ideal method for minimal residual 
disease monitoring following high-dose therapy and autologous HCT and could potentially be 
correlated with better long-term disease control. 
 
Previous study evaluated the high-throughput sequencing of PCA-amplified IgH (VDJ and 
DJ) and kappa/lambda (VJ) rearrangements from bone marrow aspirates of patients with 
multiple myeloma (n=9) and other plasma cell disorders (n=3). In many of the sample (9/12), 
an aliquot was enriched for CD138+ cells by immunomagnetic separation. In 11/12 samples, a 
clearly dominant IgH and/or kappa/lambda rearrangement (> 2.7% of sequences, range 2.7 – 
99.9%) was identified with clear separation from background frequency (at least 2.7-fold 
higher frequency than next most common clone). In 9/9 cases with paired CD138-enriched 
samples, the dominant sequences in the enriched and un-enriched samples were identical, 
indicating successful identification of the malignant clonal Ig rearrangements in the un-
enriched sample.  
 
In our preliminary study (unpublished) with limited sample size, we compared two different 
bone marrow samples (CD138 selected DNA extract vs. formalin-fixed paraffin embedded 
(FFPE) bone marrow clot section) from same patients (from Moffitt Cancer Center) and 
demonstrated that high-throughput sequencing technology by Adaptive Biotechnologies can 
identify the index myeloma clones (data not shown). We hypothesize that high-throughput 
sequencing technology using PCR on CDR3 sequences will identify minimal residual disease 
in myeloma patients after autologous HCT followed by panobinostat maintenance and bone 
marrow samples will be obtained prospectively to analyze this technology. 
3 
Study rationale/purpose 
Optimal maintenance therapy after autologous HCT in multiple myeloma has not been 
defined.  Based on preclinical and clinical data demonstrating anti-myeloma activity of 
panobinostat, we propose an open-label, trial to determine the safety and tolerability of 2 
dosing schedules of panobinostat maintenance therapy in patients with multiple myeloma who 
underwent autologous HCT.  As noted in prior maintenance therapy in myeloma, the dose of 
maintenance single agent is usually started at a lower dose (such as 10 mg starting dose for 
lenalidomide maintenance compared to 25 mg full dose in relapsed/refractory disease 
treatment) due primarily to (1) lower disease burden after autologous HCT and (2) limited 
tolerability and susceptibility to cytopenias immediately after autologous HCT.  Panobinostat 
maintenance therapy will be initiated between 90 days and 180 days after autologous HCT at 
a starting dose of (a) 20 mg PO three times a week, every other week, every 4 weeks (Cohort 
A), or (b) 10 mg po daily x 7 days, every other week, every 4 weeks (Cohort B).  Maintenance 
therapy will be prescribed for a maximum for 12 cycles (4 weeks x 12 cycles = 48 weeks) for 
both cohorts.  The dose delivered to each cohort would be 60 mg per week for Cohort A and 
70 mg per week for Cohort B.  Long-term tolerability of each dose schedule of panobinostat 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
23 
 
maintenance therapy after autologous HCT is unknown and the study intends to evaluate the 
safety and tolerability in multiple myeloma patients.  
4 
Study objectives 
4.1 
Primary 
To determine tolerability and safety profile of 2 different dosing schedule of single agent 
panobinostat maintenance therapy for a maximum of 12 intended cycles after autologous HCT 
in patients with multiple myeloma. We will calculate relative dose intensity (RDI) for each 
cohort. 
4.2 
Secondary 
 To evaluate the complete response rate to panobinostat maintenance therapy after 
autologous HCT. 
 To determine the 2-year PFS and OS of autologous HCT followed by panobinostat 
maintenance therapy in patients with multiple myeloma. 
 Exploratory secondary objectives: 
o To evaluate histone acetylation (H3 and/or H4) of peripheral blood 
mononuclear cells 
o To isolate and identify clonotypic B cell progenitors in multiple myeloma 
patients from the bone marrow, peripheral blood and stem cell grafts. 
o To evaluate T-cell immune response against known myeloma tumor 
associated antigens while on panobinostat maintenance. 
o To evaluate humoral immunity against pneumococcal serotypes included in 
the standard of care heptavalent pneumococcal conjugate vaccine, and to 
assess cellular immune responses against CRM adjuvant found in the 
heptavalent pneumococcal conjugate vaccine.  
o To evaluate minimal residual disease (MRD) after autologous HCT followed 
by panobinostat maintenance therapy using flow cytometry 
o To evaluate MRD after autologous HCT followed by panobinostat 
maintenance therapy using multiplex PCR for CDR3 seqeunces 
 
5 
Overall study design 
This is an open-label trial to determine the safety and tolerability of 2 different dosing 
schedules of single agent panobinostat maintenance therapy in patients with multiple 
myeloma who underwent high-dose melphalan followed by autologous HCT in patients with 
multiple myeloma.  It is unknown whether the toxicity profile of panobinostat will be 
accentuated in patients after autologous HCT in the setting of maintenance therapy, hence the 
dose chosen for maintenance therapy is lower than MTD dosing or other phase 2 studies.   
There are 2 dosing schedules evaluated in this protocol in order to assess optimal tolerable 
schedule for panobinostat maintenance therapy after autologous HCT.  As secondary 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
24 
 
objectives, we will evaluate response after completion of treatment, and 2-year PFS and OS.  
As correlative studies, we plan to evaluate MRD, and to assess clonotypic B cells following 
an autologous HCT.  We also plan to evaluate T effector immune response after autologous 
HCT while on panobinostat maintenance therapy. 
The trial includes the option for patients to provide peripheral blood, stem cell graft and bone 
marrow samples prior to receiving high-dose melphalan and autologous HCT for additional 
research on multiple myeloma.  The screening consent for research samples will be offered to 
potential subjects while they undergo pre-transplant workup prior to autologous HCT and 
prior to enrollment on this maintenance study.  
6 
Study population 
6.1.1 
Patient population 
Adult patients with multiple myeloma who received high-dose melphalan (from 140 mg/m2 to 
200 mg/m2) followed by autologous HCT are eligible.  A total of 30 patients (15 for each 
maintenance cohort) will be enrolled to the study.  
Potentially eligible patients will be approached prior to autologous HCT for an optional 
research sample collection (where peripheral blood, bone marrow including archived 
formalin-fixed paraffin embedded bone marrow clot, and stem cell graft will be obtained) 
using a screening consent. Enrollment to the panobinostat maintenance therapy will occur 
after autologous HCT. 
6.1.2 
Inclusion/exclusion criteria (research sample collection: screening 
consent) 
Patients will be contacted while undergoing pre-HCT workup for research sample collection. 
Patients will be approached for the research sample collection of peripheral blood, bone 
marrow, and stem cell graft. Peripheral blood sample and bone marrow sample will be 
obtained after they agree to participate in the research sample collection study while 
undergoing pre-HCT vital organ testing. Stem cell graft (apheresis) sample will be obtained 
after autologous stem cell collection. Please refer to the correlative study section for the 
details of sample analysis. 
 
Inclusion criteria (for research sample collection) 
1.  Adult patients age ≥ 18 years old with histologically confirmed diagnosis of multiple 
myeloma 
2.  Considered for high-dose melphalan followed by autologous hematopoietic cell 
transplantation and undergoing pre-HCT workup. 
 
 
 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
25 
 
Exclusion criterion (for research sample collection) 
 
1.  Myeloma patients who are not candidates for high-dose melphalan followed by 
autologous HCT based on institutional standards. 
 
6.1.3 
Inclusion and exclusion criteria (for panobinostat maintenance) 
Patients will be enrolled to the panobinostat maintenance therapy study after receiving 
autologous HCT. Patients must have baseline evaluations performed prior to the first dose of 
study drug and must meet all inclusion and exclusion criteria. Results of all baseline 
evaluations confirming eligibility must be reviewed by the Principal Investigator (or co-
investigator) prior to enrollment of that patient.  In addition, the patient must be thoroughly 
informed about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent. The written informed 
consent must be obtained from the patient prior to enrollment. The following criteria apply to 
all patients enrolled onto the study unless otherwise specified. 
Inclusion criteria (for panobinostat maintenance) 
1. Adult patients, age ≥ 18 years old 
2. Ability to provide written informed consent obtained prior to participation in the study and 
any related procedures being performed 
3. Histologically confirmed diagnosis of multiple myeloma 
4. Meeting the criteria for symptomatic multiple myeloma (“CRAB” criteria – See 
Appendix B) before the initiation of systemic chemotherapy 
5. Received high-dose melphalan (≥ 140 mg/m2) followed by autologous HCT based on the 
institutional guidelines and within +45 and +180 after autologous HCT at the time of 
panobinostat maintenance initiation. 
6. Patients must have achieved at least PR prior to autologous HCT and must not have 
progressive disease (PD) prior to the initiation of maintenance therapy (See Appendix C 
for response criteria) 
7. Patients must meet the following laboratory criteria (prior to the initiation of panobinostat 
maintenance): 
 ANC ≥ 1 x 109/L  
 Hemoglobin ≥ 8 g/dl  
 Platelets ≥ 50 x 109/L (without transfusion support) 
 Creatinine clearance ≥ 40 ml/min or serum creatinine ≤ 2.5 x ULN 
 AST and ALT ≤ 2.5 x ULN  
 Serum bilirubin  1.5 x ULN 
 Albumin > 3.0 g/dl 
 Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone 
supplements to treat underlying hypothyroidism. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
26 
 
8. Baseline (pre-HCT) MUGA or ECHO must demonstrate LVEF ≥ the LLN of the 
institutional normal.  
9. ECOG Performance Status of ≤ 2 or Karnofsky performance status 70% (See Appendix 
D and Appendix E) 
10. Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer is 
allowed. 
 
Exclusion criteria (panobinostat maintenance) 
1. Patients who have purely non-secretory multiple myeloma (i.e., the absence of a 
measurable protein in serum by electrophoresis and immunofixation and the absence of 
Bence-Jones protein in the urine defined by use of electrophoresis and immunofixation) 
2. Prior allogeneic HCT 
3. Prior solid organ transplant requiring immunosuppressive therapy 
4. Patients who will need valproic acid for any medical condition during the study or within 
5 days prior to first panobinostat treatment 
5. Impaired cardiac function or clinically significant cardiac diseases, including any one of 
the following: 
 History or presence of sustained ventricular tachyarrhythmia. (Patients with a history 
of atrial arrhythmia are eligible but should be discussed with Novartis prior to 
enrollment) 
 Any history of ventricular fibrillation or torsade de pointes 
 Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥ 
50 bpm. 
 Screening ECG with a QTc > 470 msec  
 Right bundle branch block + left anterior hemiblock (bifascicular block) 
 Patients with myocardial infarction or unstable angina  ≤ 12 months prior to starting 
study drug 
 Other clinically significant heart disease (e.g., CHF NY Heart Association class III or 
IV, uncontrolled hypertension, history of labile hypertension, or history of poor 
compliance with an antihypertensive regimen) 
4. Patients with diarrhea > CTCAE grade 2 
5. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled 
diabetes or active or uncontrolled infection) including abnormal laboratory values, that 
could cause unacceptable safety risks or compromise compliance with the protocol 
6. Patients using medications that have a relative risk of prolonging the QT interval or 
inducing torsade de pointes (see Table 17-1) if treatment cannot be discontinued or 
switched to a different medication  prior to starting study drug    
7. Patients who have received targeted agents within 2 weeks or within 5 half-lives of the 
agent and active metabolites (whichever is longer) and who have not recovered from side 
effects of those therapies. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
27 
 
8. Patients who have received either immunotherapy within < 8 weeks; chemotherapy within 
< 4 weeks; or radiation therapy to > 30% of marrow-bearing bone within < 2 weeks prior 
to starting study treatment; or who have not yet recovered from side effects of such 
therapies.  
9. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who 
have not recovered from side effects of such therapy 
10. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) 
not using an effective method of birth control. WOCBP are defined as sexually mature 
women who have not undergone a hysterectomy or who have not been naturally 
postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in 
the preceding 12 consecutive months). Women of childbearing potential must have a 
negative serum pregnancy test within 24hrs of receiving the first dose of study medication.   
11. Male patients whose sexual partners are WOCBP not using effective birth control 
12. Patients with a prior malignancy with in the last 5 years (except for basal or squamous cell 
carcinoma, or in situ cancer of the cervix) 
13. Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; 
baseline testing for HIV and hepatitis C is not required 
14. Patients with any significant history of non-compliance to medical regimens or unwilling 
or unable to comply with the instructions given to him/her by the study staff. 
 
7 
Treatments 
7.1 
Investigational therapy 
Screening consents will be signed prior to autologous HCT to access pre-HCT stem cell graft, 
bone marrow and peripheral blood samples for the correlative studies.  Patients will be 
enrolled after autologous HCT. Patients will be initiated on panobinostat maintenance therapy 
between day +90 and +180 after autologous HCT. Patients who develop disease progression 
before day +90 after autologous HCT will be ineligible for the study. 
Panobinostat (also known as LBH589) will be provided by Novartis. Oral panobinostat will 
be supplied as 5-mg, 10-mg, 15-mg or 20-mg pink/opaque-colored, hard gelatin capsules. 
Medication labels will comply with US legal requirements and be printed in English. They 
will supply no information about the patient. The storage conditions for study drug will be 
described on the medication label. 
During the study, panobinostat will be administered orally as either (1) once daily dose of 20 
mg (1 x 20-mg capsule) three times per week, every other week, of a 28-day schedule (Cohort 
A), or (2) once daily dose of 10 mg (1 x 10-mg capsule) daily x 7 days, every other week, of a 
28-day schedule (Cohort B).  Both cohorts will receive a maximum of 12 cycles of 
maintenance therapy (Figure 7-1). 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
28 
 
Figure 7-1. Panobinostat maintenance schedule 
 
Patients should be instructed to take their once-a-day oral dose of panobinostat at the same 
time each morning. Each dose of panobinostat should be taken with an 8 oz / 240 ml glass of 
water.  Patients should be instructed to swallow the capsules whole and not chew them. 
Patients must avoid grapefruit or grapefruit juice and seville (sour) oranges during the entire 
study. 
If a subject experiences toxicity, the dose of panobinostat will be reduced to one level lower 
(Table 7-1) and maintained at this level for all subsequent cycles unless further toxicities 
occur.  Panobinostat dose modifications will be made according to the toxicity grading. Once 
a subject’s dose of panobinostat is reduced, then that dose will be the maximal dose 
administered. 
On the days of ECG monitoring, drug administration should be supervised by study center 
personnel and administration time should be recorded.   
If the patient forgets to take his/her dose during the morning on scheduled treatment day (i.e., 
day 1 of each cycle), then he/she should take panobinostat (LBH589) on that same day within 
12 hours after the missed dose if possible.  After more than 12 hours, that day’s dose should 
be withheld, and the patient should wait to take panobinostat (LBH589) until the next 
scheduled treatment day (i.e., patients should be instructed not to try to make-up the missed 
dose after 12 hours).  The patient should then continue treatment with the original dosing 
schedule 
The investigator should instruct the patient to take the study drug exactly as prescribed 
(promote compliance).  All dosages prescribed and dispensed to the patient and all dose 
changes during the study should be recorded. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
29 
 
7.1.1 
Cardiac precautions 
All patients must have an assessment of serum potassium, magnesium, and calcium (total 
corrected for albumin, or ionized calcium) ≤ 72 hours prior to the administration of oral 
panobinostat on day 1 of cycle 1 and the results must all be ≥ LLN before the first dose of 
panobinostat is administered.  Throughout the study serum biochemistry values including 
serum potassium, calcium, phosphorous and magnesium will be monitored closely.  On any 
day and time in which serum potassium, calcium, phosphorous and magnesium are assessed, 
if the value is < LLN, then the patient’s potassium, calcium, phosphorous or magnesium 
should be immediately supplemented following the availability of that laboratory result, in 
order to minimize the time patients have low values.  Patients must then undergo a repeat 
chemistry tests for repleted electrolytes (potassium, calciu, phosphorous or magnesium) to 
demonstrate values ≥ LLN.  These values must be ≥ LLN before the patient is re-dosed with 
oral panobinostat. 
Patients must be instructed to not take panobinostat if their most recent biochemistry values 
demonstrates potassium, calcium, phosphorous or magnesium < LLN.  At a minimum, 
potassium, magnesium, phosphorous and calcium will be checked according to the protocol.  
More frequent testing should be done if clinically indicated, e.g. patient has had prior low 
values, patient is taking medications (e.g., diuretics) that can result in lowering of their 
potassium, magnesium, phosphorous or calcium levels.   
7.2 
Treatment assignment  
This is an open label, oral panobinostat maintenance therapy trial evaluating 2 different 
dosing schedules (cohorts A and B).  Patients will be sequentially enrolled to alternating 
cohorts.  There will be no randomization procedure involved in this study.  
7.3 
Treatment cycle and duration  
One treatment cycle consists of oral panobinostat either (1) 20 mg PO three times per week, 
every other week, of a 28-day schedule, or (2) 10 mg PO daily x 7 days, every other week, of 
a 28-day schedule.  Patients may continue treatment with oral panobinostat until they 
experience unacceptable toxicity that precludes further treatment, disease progression, and/or 
at the discretion of the investigator.  The planned treatment is for a total of 12 cycles (48 
weeks).  
7.4 
Interruption or discontinuation of treatment 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the patient on study drug. If administration of 
panobinostat must be interrupted because of unacceptable toxicity, drug dosing will be 
interrupted or modified according to rules described in Tables 7-1, 7-2, and 7-2. Toxicity will 
be assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 
4.0 
(CTCAEv4.03,( 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf ). All interruption or changes to study drug administration must 
be recoded.  


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
30 
 
7.4.1 
Dose reduction for panobinostat 
This is an open-label trial to determine the safety and tolerability of single agent panobinostat 
(2 dosing schedules) as maintenance therapy after autologous HCT in patients with multiple 
myeloma.  Patients will receive either 20 mg PO TIW, every other week, every 28-days 
(Cohort A) or 10 mg po daily x 7 days, every other week, every 4 weeks (Cohort B).  If no 
grade 3 or 4 toxicities occur after completing a 28-day cycle of panobinostat maintenance 
therapy, and all non-hematologic toxicities improved to grade 1 or better, then the next cycle 
of panobinostat will be initiated as long as the minimal hematologic parameters are met (ANC 
≥ 1 x 109/L; hemoglobin ≥ 8 g/dl; platelets 50 x 109/L) prior to each cycle.  If a subject 
experiences toxicity, the dose of panobinostat will be reduced to one level lower (Table 7-1) 
and maintained at this level for all subsequent cycles unless further toxicities occur. 
Panobinostat dose modifications will be made according to the toxicity grading.  Once a 
subject’s dose of panobinostat is reduced, then that dose will be the maximal dose 
administered.  The provisional dose levels of panobinostat (LBH589) to be investigated in this 
study are described in Table 7-1. 
Table 7-1 
Provisional dose reduction for panobinostat (LBH589) 
 
Panobinostat oral dose  
Dose level# 
Cohort A 
 (TIW, every other week, every 4 
weeks) 
Cohort B 
 (Daily x 7 days, every other week, 
every 4 weeks) 
1 (starting dose level) 
20 mg 
10 mg 
-1  
15 mg 
10 mg on days 1, 3, 5, and 7 
 
7.4.2 
Dose modifications for study drug-related toxicity (see section 7.4.3 
for dose modifications for prolonged QTc):  
The criteria for dose modifications for study drug-related toxicity are detailed in Table 7-2. 
Table 7-2 
Criteria for dosing delays, dose-reductions, and re-initiation of 
treatment due to study drug-related toxicity (excluding QT 
prolongation) 
 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
HEMATOLOGICAL TOXICITIES 
Thrombocytopenia 
Grade 3 (<50 and ≥ 25 x 109/L) 
with bleeding and Grade 4 (< 
25 x 109/L) 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 2, or 
baseline, then, restart panobinostat at 
reduced level as per Table 7-1 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
31 
 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
Neutropenia (ANC) 
Grade 4 (ANC < 0.5 x 109/L) 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 3, or 
baseline, then: 
 If resolved within 7 days after 
suspending panobinostat, then 
restart panobinostat at an 
unchanged dose level 
 If resolved in more than 7 days after 
suspending panobinostat, then 
restart panobinostat reduced by one 
dose level 
Febrile neutropenia 
(ANC < 1.0 x 109/L, fever ≥ 
38.5°C) 
Temporarily discontinue panobinostat 
dosing until fever resolved and ANC ≤ 
grade 2, then restart panobinostat 
reduced by one dose level 
NON-HEMATOLOGICAL TOXICITIES 
CARDIAC 
Cardiac - Prolonged QT interval** 
Please refer to Section 7.4.3. 
GASTROINTESTINAL 
Diarrhea 
Grade 2 (4-6 stools/day over 
baseline, etc) despite the use 
of optimal antidiarrheal 
medications 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 1, or 
baseline, then restart at unchanged 
dose level 
Grade 3 (≥ 7 stools/day over 
baseline, etc) despite the use 
of optimal antidiarrheal 
medications 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 1, or 
baseline, then restart panobinostat 
reduced by one dose level 
Grade 4 (life-threatening 
consequences, hemodynamic 
collapse, etc) despite the use 
of optimal antidiarrheal 
medications 
Discontinue panobinostat dosing 
Vomiting/Nausea*** 
Grade 1 & 2 not requiring 
treatment or controlled using 
standard anti-emetics 
Maintain dose level 
Grade 3 or 4 vomiting or Grade 
3 nausea that cannot be 
controlled despite the use of 
standard anti-emetics 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 1, or 
baseline, then restart panobinostat 
reduced by one dose level 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
32 
 
Fatigue 
Fatigue 
Grade 3 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 2, or 
baseline, then: 
 If resolved within 7 days after 
suspending panobinostat, then 
restart panobinostat at an 
unchanged dose level 
 If resolved in more than 7 days after 
suspending panobinostat, then 
restart panobinostat reduced by one 
dose level 
Grade 4 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 2, or 
baseline, then: 
 restart panobinostat reduced by one 
dose level 
HEPATIC 
Total Bilirubin 
Grade 3 or 4 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 2, or 
baseline, then restart panobinostat 
reduced by one dose level 
Note: If Grade 3 or Grade 4 hyperbilirubinemia is due to the indirect component only, and hemolysis 
as the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood 
smear and haptoglobin determination), then reduction of one dose level and continuation of treatment 
is at the discretion of the Investigator. 
AST/SGOT, ALT/SGPT 
> 5-10 x ULN 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 1 (or ≤ 
grade 2 if liver infiltration with tumor is 
present), or baseline, then: 
 If resolved within 7 days, then: 
 restart panobinostat at 
unchanged dose level 
 
If resolved in more than 7 days, 
then reduce panobinostat by one 
dose level 
> 10 x ULN 
Temporarily discontinue panobinostat 
dosing until resolved to ≤ grade 1, or 
baseline, then: 
 restart panobinostat reduced by 
one dose level 
All dose modifications should be based on the worst preceding toxicity. 
* Common Terminology Criteria for Adverse Events (CTCAE Version 4.03) 
 ** It is critical that electrolyte abnormalities be followed closely and corrected prior to dosing 
*** See also concomitant medication Section 7.5 
 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
33 
 
7.4.3 
Dose modifications for prolonged QTc 
All cardiac events should be treated as per the local standard of care and referred to a 
cardiologist if clinically indicated. The localized readings of ECGs will use the Fridericia 
correction for QTc interval assessment: QTcF. Any final decisions concerning dose 
modifications or permanently discontinuing the patient from study drug due to QTcF 
prolongation will be based on the Investigator’s clinical assessment. Any plan to deviate from 
these guidelines must be previously discussed and agreed upon with Novartis. 
Patients must have QTcF < 470 msec to be eligible for the trial. If QTcF is ≥ 470 msec or 
above 60 msec from baseline on a screening or pre-dose ECG, correct any electrolyte 
abnormalities (hypokalemia, hypomagnesemia, hypocalcemia), and conduct triplicate ECGs 
(5 minutes apart) and calculate average QTcF. If the average QTcF from the triplicate ECGs 
remains > 470 ms, patient must not be dosed. Pre-dose ECG monitoring is mandatory on days 
1 and 5 of cycle 1, and day 1 of cycles 2 through 4. Post dose ECG (3 hours (± 15 minutes) 
post dosing) is mandatory only on days 1and 5 of cycle 1.  
If a screening, pre-dose, or post-dose ECG shows a QTcF > 500 ms, patient is not eligible for 
further treatment. If any of these mandatory ECGs show QTcF ≥ 470 msec or 60 msec above 
baseline, dosing should be held and the above specified measures including follow-up 
triplicate ECGs and correction of electrolyte abnormalities should be performed.  If QTcF 
abnormality resolves, patients should resume treatment and have QTcF checked pre-dose on 
day 1 of each cycle for at least the next 3 subsequent cycles. Additional QTcF monitoring 
should be performed if clinically indicated. If a patient cannot be dosed due to prolonged 
QTcF for more than 7 days since last dose, patient must be discontinued from study treatment. 
Table 7-3 
Dose Reductions for QTc Prolongation 
 
Time Point 
Average QTcF* 
Action 
Screening and pre-
dose cycle 1 day 1 
≥ 470 msec 
Delay treatment 
Correct any electrolyte abnormal values 
** and repeat ECG, if the average QTcF 
≥ 470 msec, do not dose 
Above 500 msec 
Patient is not eligible 
Pre-dose cycle 1 day 
5 
Pre-dose day 1 of 
subsequent cycles 
≥ 470 msec or above 60 msec 
from baseline for any pre-dose 
ECG after the patient has 
commenced treatment*** 
Omit dose 
If unresolved within 7 days, discontinue 
treatment 
If resolved within 7 days, resume 
treatment at prior dose for initial 
occurrence or at reduced dose if recurrent 
Above 500 msec 
Permanently discontinue treatment 
*QTcF: Heart rate corrected QT interval using the Fredericia formula: QTc=QT/RR0.33 
**: serum potassium, magnesium, calcium,  
***If a single pre-dose QTcF is ≥ 470 msec or 60 msec from baseline, subsequent ECGs should be 
performed in triplicate 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
34 
 
7.4.4 
Study drug discontinuation 
It will be documented whether or not each patient completed the clinical study. If for any 
patient either study treatment or observations were discontinued, the reason will be recorded.  
Reasons that a patient may discontinue treatment are considered to constitute one of the 
following: 
1. Disease progression 
2. Adverse event(s) related to the study drug 
3. Abnormal laboratory value(s) related to the study drug 
4. Abnormal test procedure result(s) related to the study drug 
5. Protocol violation  
6. Subject withdrew consent  
7. Lost to follow-up 
8. Administrative problems 
9. New cancer therapy 
10. Death  
7.4.5 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first.  
If a patient requires a dose delay of > 28 days from the intended day of the next scheduled 
dose, then the patient must be discontinued from the study.  If however the patient was clearly 
benefiting from panobinostat therapy, the patient may be able to continue treatment with a 
dose reduction at the Investigator discretion, after resolution of the adverse event.  All patients 
will be followed for adverse events and serious adverse events for at least 4 weeks following 
the last dose of oral panobinostat.  
7.5 
Other concomitant medications 
Patients must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator.  All medications 
taken within 30 days of enrollment should be recorded.  If concomitant therapy must be added 
or changed within 30 days of enrollment, the reason and name of the drug/therapy should be 
recorded. Other concomitant medications are collected once at enrollment (within 30 days of 
screening). 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient are allowed, including drugs given prophylactically (e.g. antiemetics) with the 
following exceptions: 
 Any medications listed in Appendix 17.1.1 which may cause QTc prolongation or 
inducing torsades de pointes should not be used.  


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
35 
 
 Any medications that have the potential to alter serum electrolytes (e.g., diuretics) should 
be monitored very closely for electrolyte abnormalities as these can contribute to the risk 
of QT prolongation and ventricular arrhythmias.  
 No other investigational therapy should be given to patients 
 No anticancer agents other than the study medications administered as part of this study 
protocol should be given to patients.  If such agents are required for a patient then the 
patient must first be withdrawn from the study. 
 Leukocyte growth factors (e.g.G-CSF and GM-CSF) are not to be administered 
systematically but may be prescribed by the investigator for severe neutropenia if this is 
thought to be appropriate.  
 Medications known to be substrates of the isoenzyme CYP2D6 should be used with 
caution with panobinostat as panobinostat can inhibit isoenzyme CYP2D6 at low 
micromolar ranges.  Please refer to Appendices 17.1.2 and 17.1.3 for the lists of  CYP2D6 
substrates.  . 
 Concomitant use of CYP3A4 inhibitors with panobinostat should be used with caution due 
to a potential increase in panobinostat exposure during concomitant treatment with these 
drugs.   
 Oral contraceptives are generally metabolized by CYP3A4.  Since the induction potential 
of panobinostat to induce CYP3A4 is unknown, patients who are using oral contraceptives 
as a method of contraception, and are sexually active, should use another effective 
contraceptive method. 
7.5.1 
Anti-coagulant therapy 
Panobinostat therapy is commonly associated with mild to moderate degree of 
thrombocytopenia.  This may lead to an increase in the risk of bleeding with concomitant 
sodium warfarin (Coumadin®).  It is recommended that patients who require anticoagulation 
therapy while on panobinostat therapy use low molecular weight heparin (LMWH).  
However, if the use of LMWH is not feasible, patients on sodium warfarin may continue such 
therapy while on panobinostat but for such patients, a close and frequent monitoring of the 
coagulation parameters, including PT/INR should be followed and they should be maintained 
within a therapeutic range.  The dose of sodium warfarin may be adjusted as needed while on 
panobinostat.  For patients requiring anti-platelet therapy while on panobinostat, aspirin ≤ 325 
mg or clopidogrel ≤ 75mg daily are allowed while on study.  It is recommended that anti-
platelet therapy be held if platelet counts fall below 50 x 109/L. 
7.5.2 
CYP2D6 Substrates 
In in vitro assays, panobinostat was shown to inhibit the cytochrome P450 isoenzyme  
CYP2D6 at low micromolar ranges, thereby suggesting a potential risk of drug-drug 
interactions with concomitant medications that are also metabolized by CYP2D6.  A clinical 
drug-drug interaction study with dextromethorphan (a CYP2D6 probe drug) and panobinostat 
is currently ongoing in cancer patients.  In the meantime, medications that are known to be 
CYP2D6 substrates should be used with caution when given concomitantly with panobinostat.  
Patients must be carefully monitored for signs of toxicity as a result of concomitant 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
36 
 
medication which may require dose titration or reduction of the CYP2D6 substrate as 
medically necessary.  Please see Appendices 17.1.2 and 17.1.3, and refer to the following 
website: http://medicine.iupui.edu/flockhart/table.htm for a list of substrates of CYP2D6. 
7.5.3 
Drugs that can inhibit/induce CYP3A4/5 
7.5.3.1 
Drugs that can inhibit CYP3A4/5 
Panobinostat is metabolized in vitro by CYP3A4/5. A clinical drug-drug interaction study 
with ketoconazole and panobinostat has recently been completed.  The less than 2-fold 
increase in panobinostat AUC upon co-administration with ketoconazole suggests that 
CYP3A contribution to the total clearance of panobinostat is low.   The observed interaction is 
not considered clinically relevant, as panobinostat doses at least 2-fold greater than 20 mg (40 
and 60 mg) have been safely administered in patients.   CYP3A4 inhibitors should have no 
major impact on the exposure of panobinostat and may be co-administered when medically 
necessary. 
7.5.3.2 
Drugs that are potent CYP3A4/5 inducers 
As it is with other medications that are metabolized by CYP3A4, clinical judgment is to be 
exercised when potent CYP3A4 inducers are concomitantly taken with panobinostat. 
7.5.4 
Pneumococcal-13 conjugate vaccine administration (standard of care) 
As a standard of care, pneumococcal-13 conjugate vaccine (Prevnar-13TM) will be 
administered to many of autologous HCT recipients at around day +90 (prior to the initiation 
of maintenance therapy).  
7.6 
Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to 
return all unused study medication. 
 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
37 
 
8 
Visit schedule and assessments 
8.1 
Visit schedule 
Table 8-1  Evaluation and visit schedule 
 
Pre-HCT 
(Screeni
ng, not 
required
) 
Prior to 
maintenanc
e 
(Enrollment: 
+45 to 
+180)
$ 
Cycle 
#1 
(start 
betwe
en +90 
and 
+180) 
Cycle 
#2**** 
Cycle 
#3**** 
Cycle 
#4**** 
Cycle 
#5**** 
Cycle 
#6**** 
Cycle 
#7**** 
Cycle 
#8**** 
Cycle 
#9**** 
Cycle 
#10***
* 
Cycle 
#11***
* 
Cycle 
#12***
* 
End of 
study visit 
(4 weeks (± 
14 days) 
follow up 
after the 
first dose 
of cycle 
#12) 
Consent 
X
+ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
H&P (SOC) 
 
X 
X
$$$ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity 
(adverse event 
(AE)) 
assessment
$$ 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital 
signs 
(SOC) 
 
X
++ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
 
X 
X* 
X** 
X** 
X** 
 
 
 
 
 
 
 
 
 
CBC and CMP 
(SOC) 
 
X 
X*** 
X*** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/INR/PTT 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
LDH, 
cholesterol 
panel, 
GGT, 
uric acid 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
TSH, free T4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum 
pregnancy 
test
+++ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SPEP, 
UPEP 
and serum free 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version3  (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
38 
 
light 
chains 
(SOC) 
Pneumococcal-
13 
conjugate 
vaccine 
(at 
around day +90 
– SOC) 
 
X
# 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral 
blood research 
samples 
X 
X 
X
++++ 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
Bone 
marrow 
research 
samples 
X
@ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Stem cell graft 
research 
samples 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Single 12 lead EKG will be performed for pre-dose and 3 hours (± 15 minutes) post-dose on days 1 and 5 of cycle 1. A total of 4 EKGs during cycle 1 will be performed.  
**Single 12 leak EKG will be performed for pre-dose on day 1 of cycle 2 and beyond at each cycle (at least through cycle 4). If no significant QTcF prolongation is noted 
during the first cycle, then QTc monitoring is no longer required beyond cycle 4 (and may be performed at the investigator’s discretion). One EKG per cycle from cycle 2 
to 4 (minimum). 
***CBC to be performed weekly during cycle #1 and #2. CBC/CMP will also be performed on day 5 of cycle 1. 
****Window to start cycles #2 to #12 would be ±7 days from the planned first day of each cycle. 
+Screening consent for research samples (bone marrow, peripheral blood and stem cell graft) 
++Height will be measured at screening visit prior to starting panobinostat maintenance therapy 
+++Only for women of child bearing potential 
++++Peripheral blood research samples will be also collected on day 5 of cycle 1. 
#It is advised that the standard of care heptavalent pneumococcal conjugate vaccine be administered at around day +90 prior to the initiation of maintenance therapy. 
@Archived (formalin-fixed paraffin embedded) bone marrow clot will be accessed to identify myeloma index clones for high-throughput sequencing.  
$Patients can be enrolled after autologous HCT without having the pre-HCT screening visit (which is not require). 
$$Only grade ≥ 3 adverse event (AE) will be collected. 
$$$Patients will be evaluated (history and physical) on day 5 of cycle 1. 
Abbreviations: SOC, standard of care 


Novartis Protocol No. CLBH589DUS97T 
Version 3 (04/13/2017) 
 
8.2 
Efficacy assessments 
All subjects will be evaluated every 3 months with multiple myeloma restaging (standard of 
care) including serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP) 
and serum free light chains.  Response assessment will be performed approximately at cycle 
3, 6, 9, and 12 of maintenance panobinostat therapy.  Responses will be classified by 
according to the IMWG response criteria (Appendix C). 
8.3 
Safety assessments 
Safety assessments will consist of monitoring and recording unexpected grades ≥ 3 adverse 
events and serious adverse events, the regular monitoring of hematology, blood chemistry and 
urine values, vital signs, ECOG performance status, and the regular physical examinations and 
ECG assessments.  All patients will be seen on day 1 of each cycle throughout the 
maintenance therapy until disease progression or unacceptable toxicities occur (Table 8-1). 
Additional evaluations may be performed if clinically indicated. 
Adverse events will be assessed according to the Common Toxicity Criteria for Adverse 
Events (CTCAE) version 4.03.  CTCAE v4.0 can be accessed on the NIH/NCI website at  
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf)  
8.3.1 
Adverse events 
Information about unexpected grades ≥ 3  adverse events, whether volunteered by the subject, 
discovered by investigator questioning, or detected through physical examination, laboratory 
test or other means, will be collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered to 
be related to study drug.  Medical conditions/diseases present before starting study drug are 
only considered adverse events if they worsen after starting study drug.  Abnormal laboratory 
values or test results constitute adverse events only if they induce clinical signs or symptoms, 
are considered clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study.  Adverse events also may be detected when they are volunteered 
by the patient during 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 (moderate, severe) or (grade 3-4) – only grades adverse events will be 
reported its relationship to the study drug(s) (suspected/not suspected) 
2. its duration (start and end dates or if continuing at final exam) 
3. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
4. whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately.  Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
40 
 
any other medically required intervention.  Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the [Investigators’ Brochure] or will be communicated between IB updates 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. 
8.3.2 
Vital signs 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight. Blood pressure, pulse and respiration rate should be measured on 
patients after at least 3 minutes in the sitting position 
8.3.3 
Physical examination 
Physical examination will be performed which comprises examination of skin, lungs, heart, 
abdomen, lymph nodes, and extremities at minimum. 
Significant findings made after the start of study drug which meet the definition of an grades 
≥ 3 Adverse Event must be recorded. 
8.3.4 
Laboratory evaluations 
Laboratory evaluation should be done at baseline (within ≤ 72 hours prior to dosing prior to 
the first administration of oral LBH589), during the course of the study and at the time of the 
study treatment completion visit. Results must be reviewed prior to administering LBH589. 
More frequent examinations may be performed if medically indicated; results should be 
recorded.  
Hematology 
Hematology must include hemoglobin, hematocrit, platelets, total white blood cell count 
(WBC) and differential. The coagulation profile includes a prothrombin time or International 
Normalized Ratio (INR), activated partial thromboplastin time and fibrinogen. 
Blood chemistry 
Biochemistry includes the following parameters: BUN, creatinine, sodium, potassium, 
chloride, CO2 (HCO3), glucose, calcium, albumin, total protein, total bilirubin, alkaline 
phosphatase, LDH, AST/SGOT, ALT/SGPT, phosphorous, magnesium.  If total bilirubin is 
greater than the upper limit of normal, direct and indirect bilirubin may be performed. 
Biochemistry tests should be obtained after patient has fasted, if possible. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
41 
 
Urinalysis 
Standard urinalysis dipstick assessment (pH, protein, glucose, blood, ketones, and leukocytes) 
should be performed. This must be supplemented with laboratory quantification of any 
potentially relevant abnormalities. 
Thyroid function test 
Thyroid Stimulating Hormone (TSH) and free T4 (thyroxine) will be measured at baseline and  
at study treatment completion. 
8.3.5 
Serum pregnancy test 
All females of childbearing potential should complete a serum pregnancy test within 7 days 
prior to the administration of LBH589 on day 1 of cycle 1. The pregnancy test should be 
repeated in week 1 of every cycle (except for cycle 1). Postmenopausal women must have 
been amenorrheic for ≥ 12 months in order to be considered “of non-childbearing potential”. 
8.3.6 
ECG 
A screening 12-lead ECG will be performed to assess study eligibility. Additional 12-lead 
ECGs will be performed at a minimum at scheduled time points as indicated in Table 8-2. Pre-
dose ECG monitoring is required for the first four cycles of treatment. Post-dose ECGs will be 
required during cycle one, on days 1 and 5. Additional ECG monitoring should be done at the 
discretion of the Investigator, as clinically indicated. All ECGs will be read locally. 
Table 8-2 
Cardiac assessment monitoring schedule 
Cycle 
Day of cycle 
ECG monitoring a 
 
Screening b 
Single ECG to assess eligibility 
Cycle 1 
1, 5 
Pre-dose: 
Single 12 lead ECG 
 
1, 5 
3 hours (± 15 minutes) post dose: 
Single 12 lead ECG 
Cycle 2 and beyond 
1 
Pre-dose: 
Single 12 lead ECG 
a Refer to Table 7-3 for the recommended dose modifications due to QTc interval prolongation 
b The screening ECGs will be analyzed locally to assess eligibility of the patient. (Note: the mean QTc 
interval at baseline must be ≤ 470 msec for the patient to be eligible for participation in the trial) 
Note: If no significant QTcF prolongation is noted during the first 4 cycles, the QTc monitoring is no 
longer required and may be performed at the Investigator’s discretion, if medically indicated. 
All cardiac events should be treated as per the local standard of care and referred to a 
specialist if clinically indicated. The localized readings of ECGs will use the Fridericia 
correction with MUSE system: QTcF. Any final decisions concerning dose modifications or 
permanently discontinuing the patient from study drug due to QTcF prolongation will be 
based on the assessment performed by the Investigators using QTcF correction derived from 
MUSE system. Any plan to deviate from these guidelines should be previously discussed and 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
42 
 
agreed upon with Novartis. If a patient cannot be dosed due to prolonged QTcF for more than 
7 days since last dose, patient should be discontinued from study. 
8.3.6.1 
Performance status 
Performance status will be assessed using Karnofsky performance score at baseline, at day 1 
of each cycle and at the end of stud visit. 
8.4 
Drug levels and pharmacokinetic assessments 
 Drug levels and pharmacokinetic assessments will not be performed as part of this study.  
9 
Correlative studies 
9.1 
Assessment of minimal residual disease and B cell precursors 
Aliquots of 50uL bone marrow aspirate in sodium heparin will be incubated in the dark for 15 
minutes at room temperature with combination of fluorescent-labeled antiobodies, followed 
by red blood cell lysis with FACS lysing solution (BD biosciences).  Cytoplasmic staining 
will be performed by permeabilizing cells with Fix & Perm reactives (Caltag), followed by 
incubation in the dark with fluorescent-labeled antibodies for 5 minutes at 4ºC.  Standarized 
10-color antibody  combinations will be used (Pac Blue/Krome Orange/FITC/PE/ECD/PerCP-
Cy5.5/CD7-PE-Cy7/APC/APC-Alexa-Fluor-700/APC-Alexa-Fluor 750), including an isotype 
control tube plus 4 tubes: 
 cytoplasmic-κ/cytoplasmic-λ/CD56/CD138/isotype/CD20/CD19/CD117/CD38/CD45 
 CD49d/CD52/CD13/Cd138/CD33/CD40/isotype/CD44/CD38/CD45 
 CD28/CD81/CD27/CD138/isotype/CD200/isotype/CD117/CD38/CD45 
 isotype/CD319/CD56/CD138/isotype/CD269/CD19/CD117/CD38/CD45 
Stained cells will be resuspended in phosphate buffered saline containing 2% 
paraformaldehyde.  At least 500,000 events were acquired on a Gallios 10-color flow 
cytometer (Beckman Coulter).  Flow cytometry data will be analyzed on ad-hoc templates 
created on Kaluza version 1.2 (Beckman Coulter) using standardized gating strategies to 
identify and characterize neoplastic clonal plasma cells, residual benign plasma cell 
populations, maturing B-cell precursors and mature B-cells.  In particular, B-cells will be 
analyzed to identify putative clonal stem cell populations.     
Peripheral blood and peripheral blood stem cell graft samples will also be collected, and 
multi-parameter flow cytometry will be performed for phenotype characterization of B cell 
precursors as described above. 
Pharmacodynamic effects on various cell subtypes and evaluation of protein acetylation 
with panobinostat maintenance therapy 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
43 
 
In order to determine whether 2 different panobinostat maintenance dosing schedules have 
any correlation with HDACs enzymatic activity, we will evaluate HDAC enzymatic activity 
in peripheral blood from patients. Peripheral blood samples will be obtained at baseline 
(before starting panobinostat), on day 5 of cycle 1, at cycle #6 and after the completion of 
maintenance.  To this end we will use a HDAC fluorimetric cellular activity assay (Biomol, 
Catalog # AK503). A fluorogenic-cell permeable substrate, Fluor de Lys, is added to 
peripheral blood mononuclear cells (PBMC) grown in patient’s serum and enter the cells 
where if there is remaining HDAC activity, the fluor de lys gets deacetylated producing a 
fluorescent signal. A detergent is used to allow contact between the non-cell permeable 
developer and both intra and extracellular deacetylated substrate. In addition, the HDACi 
trichostatin A is added along with the detergent to insure that no deacetylation occurs after 
cell lysis. To run this test approximately 1 x 105 PBMC are required/sample.  
In order to determine the level of protein acetylation and more specifically of hyper-acetylated 
histones (H3 and/or H4), we will use a multiparameter flow cytometry assay for peripheral 
blood mononuclear cells.  If acetyl-group removal from HDAC substrates is blocked we 
speculate that will lead to an overall increase in the number of acetylated proteins being the 
vast majority of these proteins the histones in cells population in peripheral blood.  The blood 
leukocyte count will be obtained using a Coulter Ac-T Hematology analyzer.  Multiparameter 
staining protocol will be adjusted from Chun and/or Ronzoni et al. In summary, whole blood 
will be collected at baseline, on day 5 of cycle 1, at cycle #6 and after the completion of 
panobinostat maintenance therapy.  PBMCs (5-10x106) will be obtained by gradient 
separation on Ficoll-Paque.  Aliquots of PBMs will be briefly incubated with Zombie Yellow 
(Biolegend) to stain and gate-out non-viable cells. Cells will then be washed and incubated 
with antibodies conjugated to methanol-resistant fluorophore (BD Horizon V450/Brilliant 
Violet-711-/FITC/Alexa Fluor 647) on a 2-tube/4-color panel for surface antigens: 
CD3/CD4/CD8/CD19 and CD3/CD7/CD45/CD14.  Stained cells will be fixed in 2% 
formaldehyde for 30 min at 4ºC and then permeabilized in 100% ice-cold methanol for 10 
minutes at 4ºC. After fixation and permeabilization, cells will be stained with anti-acetyl 
histone H3 and anti-acetyl tubulin, conjugated to PE and PerCP-Cy5.5, respectively.  Events 
will be acquired on a FACSDiva flow-cytometer (BD) and analyzed on Kaluza v1.2 
(Beckman Coutler) with appropriate controls.  Gating strategies will be devised using surface 
markers to assess the level of acetyl histone H3 and acetyl tubulin on CD4 T-cells, CD8 T-
cells, NK cells, B-cells, monocytes and neutrophils. 
9.2 
Assessment of immune response 
Bone marrow research samples obtained (only for those who consent for screening research 
sample consents) will be analyzed to determine the presence of common multiple myeloma 
tumor associated antigens (TAAs) including survivin, WT-1, NY-ESO, and MAGE using 
immunohistochemistry (IHC) or polymerase chain reaction (PCR). Prior biopsy specimens 
may be requested if available, in order to perform IHC for the described TAAs. Research 
blood samples will be obtained prior to transplant, at baseline (prior to the initiation of 
maintenance), after 3 cycles of maintenance therapy, and after panobinostat maintenance 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
44 
 
(after completing of therapy) to evaluate for the presence of T-cell precursors against 
individual patient’s identified TAA using peptide pools.   
As a standard of care, all autologous HCT recipients will receive heptavalent pneumococcal 
conjugate vaccine (PCV13, PrevnarTM) at around 3 months from the time of transplant.  We 
hypothesize that patients immunized with heptavalent pneumococcal conjugate vaccine, who 
then receive panobinostat maintenance therapy, may have augmented immune responses.   
(stan Each vaccine specific serotype IgG level will serve as a marker for immune response.  
We propose to measure following anti-pneumococcal IgG antibody serotype panel at baseline, 
at cycle #6 and after completion of maintenance (completion of 12 cycles) to assess immune 
reconstitution with panobinostat maintenance therapy. The antibody panel contains serotypes 
1, 4, 5, 7F, 8, 9V, 9N, 12F and 18C. A positive response of IgG antibody is considered to be 
greater than or equal to 1 microgram/mL. Patients may also receive standard of care 
pneumococcal conjugate vaccine (usually at 6 months and 12 months after autologous HCT).   
T cell response in the setting of panobinostat maintenance therapy will be evaluated at 
baseline, after cycle #3 and cycle #6, and after completion of maintenance therapy 
(completion of 12 cycles). Specifically we will measure the % of T1 cells and cytotoxic T 
cells specific for intracellular IFN-gamma production after co-culture of patients with T cells 
with the inactivated diphtheria conjugate (CRM197) which is a component of the 
pneumococcal conjugate vaccine. 
In addition, we will evaluate the phenotype of T cells at baseline, after cycle #3 and #6, and 
after completion of maintenance therapy (completion of 12 cycles). We will employ flow 
cytometry panels. In brief, whole PBMCs will be stained with flow cytometry antibodies for 
CD3, CD4, CD8, CD62L, CD45RO, and CD95 in order to evaluate for naïve, effector 
memory, or central memory phenotype. We will also test for CD4, CD8, PD-1, PD-L1, 
CLTA-4, CD25, CD127, and FOXP3 to evaluate for costimulatory molecules and regulatory 
T cells. 
 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
45 
 
 
9.3 
High-throughput sequencing of CDR3 from IgH, IgK and IgL 
somatic rearrangements 
Adaptive Biotechnologies have developed 
assays that use multiplex PCR to amplify 
rearranged CDR3 sequences from the 
adaptive immune receptor loci (T-cell 
receptors in T-cells, Immunoglobulins in B-
cells) that exploit the capacity of high-
throughput sequencing technology to 
sequence thousands to millions of CDR3 
chains simultaneously in a sample. At all IG 
loci, forward primers were selected for each 
V segment, upstream of the recombination 
signal sequence (RSS), and reverse primers 
were selected for each J segment, 
downstream of the RSS. In the IGH assay 
forward primers are also selected upstream of 
the D segments, allowing for amplification of 
immature DJ rearrangements (Fig 1C). In the 
IGK assay a forward primer is also selected 
for iRSS, and a reverse primer for KDE, 
allowing for amplification of iRSS/KDE and 
V/KDE junctions (Fig 1H), as well as VJ 
CDR3 segments. The forward and reverse 
primers for each locus are separated by many 
thousands of base pairs in the germline, but 
each somatic rearrangement event brings one 
pair within 300 bp. The multiplex PCR 
reaction amplifies only these rearranged 
sequences, and incorporates external adaptor 
sequences allowing the amplified library to 
be directly sequenced.  
Any multiplex PCR system is susceptible to amplification bias for specific templates, so they 
designed a panel of synthetic templates representing all possible V/J pairings at each locus.104 
Amplification and sequencing from an equimolar mixture of these synthetic templates allows 
them to directly measure amplification bias. In both assays, primer amplification effects are 
independent for forward and reverse primers, so primer concentrations are titered to minimize 
amplification differentials within the assay, yielding a final primer mix that amplifies all 
synthetic templates with between 0.5X and 2X cumulative yield after 35 cycles of PCR, 
relative to the median yield. The residual differential in amplification efficiency is highly 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
46 
 
reproducible within each assay, so the frequency of each sequence after amplification can be 
computationally adjusted for the specific forward and reverse primer that amplified that clone, 
yielding a direct estimate of the frequency of each clonal CDR3 rearrangement in the starting 
template material. If the high-throughput sequencing is performed on a sample containing one 
million nucleated cells, then its sensitivity in that circumstance is estimated to be 1 in a 
million.  
Sequencing CDR3 regions:  
IGH CDR3 regions can be amplified and sequenced from DNA samples. Amplification and 
sequencing of IGH CDR3 regions will be carried out on the ClonoSEQ platform (Adaptive 
Biotechnologies, Seattle, WA). The sequences for IGH CDR3 regions are delineated 
according 
to 
the 
definition 
established 
by 
the 
International 
ImMunoGeneTics 
collaboration.105,106 A standard algorithm is used to identify which V, D, and J segments 
contributed to each IGH CDR3 sequence and which V and J segments contributed to each 
CDR3 sequence.105,106 Rearranged CDR3 sequences are classified as non-productive if 
insertions or deletions were identified that resulted in frame-shifts or premature stop-codons. 
Bone marrow samples (with CD138 selected DNA) will be obtained prior to autologous HCT, 
prior to the initiation of HCT, at cycle #6 of maintenance and after completion of planned 
panobinostat maintenance therapy to evaluate myeloma clones. To identify index myeloma 
clones, archived FFPE bone marrow clot sections (prior to start of systemic chemotherapy) 
will be obtained at Moffitt Cancer Center.  
Table 9-1 
Research Sample Acquisition Schedule 
 
Pre-HCT 
Pre-
maintenance 
Cycle #1 
(days 1, 5) 
Cycle 
#2 
Cycle #3 
Cycle #6 
Cycle #9 
End of study 
Peripheral 
blood  
1 tiger 
top/6 
green 
top 
1 tiger top/6 
green top 
1 tiger top/6 
green top ( 
day 1); 2 
green top 
(day 5) 
1 tiger 
top/6 
green 
top 
1 tiger 
top/6 
green 
top 
1 tiger 
top/6 
green top 
1 tiger 
top/6 
green top 
1 tiger top/6 
green top 
Bone 
marrow  
1 tiger 
top/4 
green 
top 
1 tiger top/4 
green top 
- 
 
- 
- 
- 
- 
1 tiger top/4 
green top 
Stem cell 
graft 
(Apheresis) 
3mL in a 
50mL 
falcon 
tube 
- 
- 
- 
- 
- 
- 
- 
 
 
 
 
 
 
 
 
10 
Safety monitoring 
10.1.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
 Is fatal or life-threatening 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
47 
 
 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 
10.1.2 
Reporting 
All SAEs will be reportedas assessed by the investigator. SAEs will be followed until 
resolution or until clinically relevant improvement or stabilization.  
To ensure patient safety, every SAE with 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 SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE 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. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form as outlined per contractual agreement; 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 send the completed, signed 
form by fax within 24 hours to the oncology Novartis Drug Safety and Epidemiology (DS&E) 
department. 
The telephone and telefax number of the contact persons in the local department of Drug 
Safety and Epidemiology (DS&E) are included in the contractual agreement. The original 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
48 
 
copy of the SAE Report Form and the fax confirmation sheet should be kept with the case 
report form documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original 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, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) 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. 
10.2 
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 the panobinostat 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. 
10.3 
Data Safety and Monitoring Plan 
The Data Safety & Monitoring Plan (DSMP) will ensure that this trial is well designed, 
responsibly managed, appropriately reported, and that it protects the rights and welfare of 
patients. The following internal and external review and monitoring processes provide 
oversight and active monitoring of this trial: 
The Principal Investigators (PI) 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
49 
 
The Scientific Review Committee (SRC) 
The Protocol Review and Monitoring Committee (PRMC); 
The Research Compliance Division (RCD) of the Cancer Center's Compliance Office; 
 Institutional Review Board (IRB). 
The protocol includes a section that specifies the following with respect to Adverse Event 
reporting: what constitutes an adverse event (versus what is a serious adverse event), the 
entities to which adverse events should be reported, the timing of this reporting, and the 
person or persons responsible for reporting. This includes prompt (within one day of 
knowledge of the event) reporting to the IRB for unanticipated risks to subjects and reporting 
in writing within five working days to the IRB and the supporting company (Novartis). 
10.4 
Initial and Ongoing Monitoring and Review 
10.4.1 
Principal Investigator (PI) 
The PI of the study has primary responsibility for ensuring that the protocol is conducted as 
approved by the SRC and the IRB. The PI will ensure that the monitoring plan is followed, 
that all data required for oversight of monitoring are accurately reported to the Scientific 
Review Committee (SRC), Protocol Review and Monitoring Committee (PRMC) and IRB as 
required, and that all adverse events are appropriately reported. 
10.4.2 
The Scientific Review Committee (SRC) 
The Cancer Center's internal Scientific Review Committee (SRC) provides for a formal 
internal peer review of all protocols and general scientific oversight of interventional clinical 
research. The Committee has a defined membership representing all of the major research 
divisions of the Cancer Center, including biostatisticians. All new protocol submissions must 
contain the required elements of the protocol, and must include a DSMP prior to approval by 
the Committee. The plan has to be appropriate for the phase and risk of the proposed study. 
10.4.3 
The Protocol Review and Monitoring Committee (PRMC) 
The Protocol Review and Monitoring Committee (PRMC) will monitor this trial for safety, 
progress, protocol compliance, accrual, adverse event reporting, and data integrity. The 
membership of the PRMC includes physician representation from each program area and a 
biostatistician. In addition to the existing stopping rules, the PRMC is authorized to suspend a 
trial for non-compliance with a DSMP or as a result of audit findings deemed unacceptable. 
The PRMC will report significant findings to the IRB, the supporting company (Novartis), 
and the applicable regulatory body. Interim meetings are scheduled to address specific issues 
that require immediate attention to ensure safety of research participants. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
50 
 
10.4.4 
The Research Compliance Division of the Cancer Center’s Compliance 
Office (RCD) 
The Research Compliance Division (RCD) Office conducts internal audits of all clinical trials 
conducted at the Cancer Center and its affiliates. The purpose of the internal audit program is 
to: 
1. Assure patient safety by monitoring compliance 
2. Assure regulatory compliance by reviewing consent and adverse event reporting 
3. Assure scientific value by monitoring accuracy and completeness of data collection 
4. Monitor and coordinate research compliance activities associated with institutional 
and individual conflict of interest 
5. Make recommendations for modification of research practices as necessary and 
provide education on issues that are critical to good research practices 
Audits are conducted by the RCD in accordance with applicable regulatory standards. 
Investigator initiated trials, such as the one proposed here, receive the highest priority for 
audit. The RCD will conduct and report the findings of audits to the PMC in accordance with 
a protocol's annual review. The PRMC will determine the findings to be acceptable with 
minor deviations, acceptable with corrective action, or unacceptable with suspension or 
closure. The PRMC Chairperson will notify the IRB of the audit findings. The RCD will 
follow-up to ascertain whether corrective actions, which have been agreed to, are achieving 
the desired results. The PRMC will be informed of all significant open follow-up items. For 
those observations where no action has been taken, the Research Compliance Office will 
inform the PRMC and may conduct a focused audit. 
11 
Protocol amendments, or changes in study conduct 
Any change or addition to this protocol requires a written protocol amendment that must be 
reviewed by Novartis and the investigator before implementation. Amendments significantly 
affecting the safety of subjects, the scope of the investigation or the scientific quality of the 
study require additional approval by the IRB.  A copy of the written approval of the IRB must 
be provided to Novartis.  


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
51 
 
12 
Data Review and Management 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Novartis in the interests of preserving the safety of all patients 
included in the trial.  If an immediate change to the protocol is felt to be necessary by the 
investigator and is implemented for safety reasons Novartis must be notified and the IRB must 
be informed immediately.   Data review and management 
Internal Monitoring Plan Data will be captured in Oncore, Moffitt’s Clinical Trials Database. 
Regulatory documents and case report forms will be reviewed routinely by the MCC Clinical 
Research Monitoring Core for accuracy, completeness and source verification of data entry, 
validation of appropriate informed consent process, adherence to study procedures, and 
reporting of SAEs and protocol deviations according to MCC Monitoring Policies.  
 
12.1 
Data collection and monitoring 
Investigators must enter the information required by the protocol onto Case Report Forms 
(CRFs) for unexpected grades ≥ 3 adverse events and serious adverse events. Additional data 
to be captured may be identified at the time of study activation or review by ongoing 
monitoring committees. 
 
13 
Statistical methods 
13.1 
Statistical methods and data analysis 
This is an open label study of 2 different panobinostat maintenance dosing schedules after 
autologous HCT in patients with multiple myeloma.  There are 2 cohorts and patients will be 
enrolled sequentially to cohort A, then to cohort B.  The sample size is 30 patients for this trial 
(15 for each cohort).  We expect that at least 2/3 of each cohort will complete 12 cycles of 
maintenance panobinostat (regardless of dose modification) and will be evaluable for the 
primary endpoint.  The widths of 95% confidence interval (CI) are 0.356, 0.438, 0.487, 0.514, 
and 0.522 when the proportions of patients tolerating 12 cycles of maintenance are 0.9, 0.8, 
0.7, 0.6, and 0.5, respectively.  
A patient who withdraws from the study due to reasons other than death, disease progression 
or toxicity will be replaced and is considered as non-evaluable for primary endpoint.  The 
proportion of patients tolerating the therapy will be reported with 95% CI.  All 30 patients are 
eligible for secondary endpoints.  We will compute the overall response rates before the 
transplant, after autologous HCT, and after the completion of maintenance therapy, and at best 
response.  The OS and PFS will be estimated using the Kaplan-Meier method.  We will also 
report the incidences of all grades and grade ≥ 3 toxicities.   The two-sided 95% CIs for 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
52 
 
proportion, and OS and PFS will be computed using the Clopper-Pearson method and the 
Greenwood formula, respectively.  In addition, the frequency of B cell precursor as well as 
other cell subsets, and their 95% CI will be evaluated using t-distribution.  If data do not meet 
normality assumption, the power transformation (e.g., log-transformation) will be conducted.  
Those patients who are not in CR before the transplant would be most suitable for T-effector 
activity analysis.  This will be examined by the paired t-test or the Wilcoxon signed-rank test, 
depending on the data distribution. 
Relative dose intensity (RDI) represents the ratio of the amount of a drug actually delivered 
[actual dose intensity (DI)] to the amount planned (planned DI). The purpose of calculating 
RDI is to evaluate whether the planned DI of a chemotherapy treatment was actually achieved 
which may suggest the feasibility of planned treatment regimen. There are multitude of 
reports demonstrating a correlation between RDI and survival in cancer treatment.  
 
RDI = (total dose received by the patient = mg)/(planned full dose of drug = mg) 
Optimal RDI for maintenance therapy in multiple myeloma has not been fully defined though 
it would be a surrogate measure for treatment feasibility. We intend to calculate RDI on two 
cohorts both together and separately. Missed doses, dose reduction and dose delay will be 
reportedly per cohort. The investigator will review the tolerability as a whole for 2 different 
cohorts and report feasibility of each cohort. 
13.1.1 
Populations for analysis 
This is an open-label, panobinostat maintenance therapy trial evaluating 2 different dosing 
schedules after autologous HCT in patients with multiple myeloma.  Eligible patients have 
histologically confirmed multiple myeloma and have chemosensitive disease prior to starting 
the maintenance therapy.  Fifteen patients per cohort will be enrolled and a total of 30 patients 
will be on this study.  
13.1.2 
Patient demographics/other baseline characteristics 
Standard patient demographics and baseline disease characteristics will be collected: age, 
gender, immunophenotype, Durie-Salmon staging system, International Staging System, 
albumin, beta-2 microglobulin, myeloma risk stratification (high versus standard), prior 
systemic therapy, number of prior therapy, chemotherapy conditioning regimen and dose, and 
stem cell dose.  Results will be tabulated.  
13.1.3 
Primary objective and hypothesis 
The primary objective of this study is to determine the tolerability and safety profile of 2 
different dosing schedules of single agent panobinostat maintenance therapy for a maximum 
of 12 cycles after autologous HCT in patients with chemosensitive multiple myeloma.  We 
hypothesize that at least two-thirds of patients will be able to complete 12 cycles of intended 
maintenance therapy.  The completion rate of 12 cycles of maintenance therapy in 15 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
53 
 
evaluable patients will be reported along with 95% confidence intervals using the exact 
binomial distribution.  We plan to calculate RDI for each cohort. 
13.1.4 
Secondary objective and hypothesis 
The secondary objectives of the study are to evaluate following parameters in patients who 
receive panobinostat maintenance therapy after autologous HCT: overall response rate, best 
response rate, 2-year PFS and 2-year OS.  The exploratory secondary objectives include 
evaluation of minimal residual disease, frequency of B cell precursors and immune subsets, 
protein acetylation, and immune response against pneumococcal vaccines and CRM. The 
association of minimal residual disease, B cell precursors, and immune response with 
response, PFS and OS will be evaluated using the Cox proportional hazards regression model. 
13.1.5 
Early stopping rule 
No early stopping rule is considered in this study but the safety and efficacy data will be 
continuously monitored by PI and the supporting company (Novartis).  Patient accrual will be 
temporarily suspended if the completion rate of maintenance therapy at the end of 12 cycles is 
equal to or less than 60% or if the non-hematologic grade 3 or 4 toxicity rate is 40% or higher.  
The PI and the supporting company (Novartis) will review safety data, and the study may be 
early terminated based on the review results. 
14 
Procedures and instructions 
14.1 
Publication of results 
Any formal presentation or publication of data from this trial may be published after review 
and comment by Novartis and prior to any outside submission.  Novartis must receive copies 
of any intended communication in advance of publication (at least fifteen working days for 
presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis’ responsibility to provide peer input regarding the 
scientific content and conclusions of such publications or presentations.  Principal 
Investigation/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the 
interests of Novartis and, in accord with the trial contract and shall not permit disclosure of 
Novartis confidential or proprietary information. 
14.2 
Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and 
to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by Novartis (investigators' brochures and other material) will be stored appropriately 
to ensure their confidentiality. The information provided by Novartis to the investigator may 
not be disclosed to others without direct written authorization from Novartis, except to the 
extent necessary to obtain informed consent from patients who wish to participate in the trial. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
54 
 
14.3 
Discontinuation of study 
Novartis reserves the right to discontinue any study under the conditions specified in the 
clinical trial agreement. 
15 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in Novartis standard operating procedures and: 
1. 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
2. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
3. 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects). 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
15.1 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Novartis before study initiation. Any amendments to the 
protocol, other than administrative ones, must be reviewed by Novartis approved by this 
committee. 
15.2 
Informed consent 
The investigators and/or designee (including clinical trial coordinators or advanced practice 
professionals)  must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any 
time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document. If the subject cannot read or 
sign the documents, oral presentation may be made or signature given by the subject’s legally 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
55 
 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by 
the investigator with it for IRB/IEC/REB approval. 
 
16 
References 
1. 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. 
CA Cancer J Clin. 2011;61(2):69-90. 
2. 
Kumar S, Rajkumar S, Dispenzieri A, et al. Improved survival in multiple myeloma 
and the impact of novel therapies. Blood. 2008;111(5):2516-2520. 
3. 
Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of 
autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe 
Francais du Myelome. N Engl J Med. 1996;335(2):91-97. 
4. 
Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic 
stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348(19):1875-1883. 
5. 
Kyle R, Rajkumar S. Multiple myeloma. Blood. 2008;111(6):2962-2972. 
6. 
McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell 
transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770-1781. 
7. 
Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell 
transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782-1791. 
8. 
Barlogie B, Attal M, Crowley J, et al. Long-term follow-up of autotransplantation 
trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du 
myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin 
Oncol. 2010;28(7):1209-1214. 
9. 
Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide 
improves survival in patients with multiple myeloma. Blood. 2006;108(10):3289-3294. 
10. 
Barlogie B, Pineda-Roman M, van Rhee F, et al. Thalidomide arm of Total Therapy 2 
improves complete remission duration and survival in myeloma patients with metaphase 
cytogenetic abnormalities. Blood. 2008;112(8):3115-3121. 
11. 
Lokhorst HM, van der Holt B, Zweegman S, et al. A randomized phase 3 study on the 
effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, 
followed by thalidomide maintenance in patients with multiple myeloma. Blood. 
2010;115(6):1113-1120. 
12. 
Morgan GJ, Gregory WM, Davies FE, et al. The role of maintenance thalidomide 
therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 
2012;119(1):7-15. 
13. 
Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose 
thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
56 
 
a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27(11):1788-
1793. 
14. 
Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell 
transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in 
patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. The 
lancet oncology. 2011;12(13):1195-1203. 
15. 
Maiolino A, Hungria VT, Garnica M, et al. Thalidomide plus dexamethasone as a 
maintenance therapy after autologous hematopoietic stem cell transplantation improves 
progression-free survival in multiple myeloma. Am J Hematol. 2012;87(10):948-952. 
16. 
Stewart AK, Trudel S, Bahlis NJ, et al. A randomized phase 3 trial of thalidomide and 
prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life 
assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. 
Blood. 2013;121(9):1517-1523. 
17. 
Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and 
maintenance treatment in patients with newly diagnosed multiple myeloma: results of the 
randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946-2955. 
18. 
Rosiñol L, Oriol A, Teruel AI, et al. Superiority of bortezomib, thalidomide, and 
dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a 
randomized phase 3 PETHEMA/GEM study. Blood. 2012;120(8):1589-1596. 
19. 
Palumbo A, Bringhen S, Kumar SK, et al. Second primary malignancies with 
lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient 
data. Lancet Oncol. 2014;15(3):333-342. 
20. 
Ludwig H, Durie BG, McCarthy P, et al. IMWG consensus on maintenance therapy in 
multiple myeloma. Blood. 2012;119(13):3003-3015. 
21. 
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone 
deacetylases and cancer: causes and therapies. Nat Rev Cancer. 2001;1(3):194-202. 
22. 
Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-
histone proteins. Gene. 2005;363:15-23. 
23. 
Aoyagi S, Archer TK. Modulating molecular chaperone Hsp90 functions through 
reversible acetylation. Trends Cell Biol. 2005;15(11):565-567. 
24. 
Diaz-Gonzalez JA, Russell J, Rouzaut A, Gil-Bazo I, Montuenga L. Targeting hypoxia 
and angiogenesis through HIF-1alpha inhibition. Cancer Biol Ther. 2005;4(10):1055-1062. 
25. 
Walsh CT, Garneau-Tsodikova S, Gatto GJ. Protein posttranslational modifications: 
the chemistry of proteome diversifications. Angew Chem Int Ed Engl. 2005;44(45):7342-
7372. 
26. 
Herman JG, Latif F, Weng Y, et al. Silencing of the VHL tumor-suppressor gene by 
DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994;91(21):9700-9704. 
27. 
Pratt WB, Ruddon RW, Endminger WD, Maybaum J. The anti-cancer drugs: Oxford 
University Press; 1994. 
28. 
Szyf M. DNA methylation properties: consequences for pharmacology. Trends 
Pharmacol Sci. 1994;15(7):233-238. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
57 
 
29. 
Herman JG, Merlo A, Mao L, et al. Inactivation of the CDKN2/p16/MTS1 gene is 
frequently associated with aberrant DNA methylation in all common human cancers. Cancer 
Res. 1995;55(20):4525-4530. 
30. 
Merlo A, Herman JG, Mao L, et al. 5' CpG island methylation is associated with 
transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat 
Med. 1995;1(7):686-692. 
31. 
Herman JG, Jen J, Merlo A, Baylin SB. Hypermethylation-associated inactivation 
indicates a tumor suppressor role for p15INK4B. Cancer Res. 1996;56(4):722-727. 
32. 
Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of 
hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A. 
1998;95(12):6870-6875. 
33. 
Cameron EE, Bachman KE, Myöhänen S, Herman JG, Baylin SB. Synergy of 
demethylation and histone deacetylase inhibition in the re-expression of genes silenced in 
cancer. Nat Genet. 1999;21(1):103-107. 
34. 
Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA. Aberrant 
recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute 
myeloid leukemia fusion partner ETO. Mol Cell Biol. 1998;18(12):7185-7191. 
35. 
Grignani F, De Matteis S, Nervi C, et al. Fusion proteins of the retinoic acid receptor-
alpha recruit histone deacetylase in promyelocytic leukaemia. Nature. 1998;391(6669):815-
818. 
36. 
Lin RJ, Nagy L, Inoue S, Shao W, Miller WH, Evans RM. Role of the histone 
deacetylase complex in acute promyelocytic leukaemia. Nature. 1998;391(6669):811-814. 
37. 
Redner RL, Wang J, Liu JM. Chromatin remodeling and leukemia: new therapeutic 
paradigms. Blood. 1999;94(2):417-428. 
38. 
Yoshida M, Nomura S, Beppu T. Effects of trichostatins on differentiation of murine 
erythroleukemia cells. Cancer Res. 1987;47(14):3688-3691. 
39. 
Yoshida M, Beppu T. Reversible arrest of proliferation of rat 3Y1 fibroblasts in both 
the G1 and G2 phases by trichostatin A. Exp Cell Res. 1988;177(1):122-131. 
40. 
Yoshida M, Hoshikawa Y, Koseki K, Mori K, Beppu T. Structural specificity for 
biological activity of trichostatin A, a specific inhibitor of mammalian cell cycle with potent 
differentiation-inducing activity in Friend leukemia cells. J Antibiot (Tokyo). 
1990;43(9):1101-1106. 
41. 
Yoshida H, Sugita K. A novel tetracyclic peptide, trapoxin, induces phenotypic change 
from transformed to normal in sis-oncogene-transformed NIH3T3 cells. Jpn J Cancer Res. 
1992;83(4):324-328. 
42. 
Itazaki H, Nagashima K, Sugita K, et al. Isolation and structural elucidation of new 
cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents. 
J Antibiot (Tokyo). 1990;43(12):1524-1532. 
43. 
Sugita K, Koizumi K, Yoshida H. Morphological reversion of sis-transformed 
NIH3T3 cells by trichostatin A. Cancer Res. 1992;52(1):168-172. 
44. 
Medina V, Edmonds B, Young GP, James R, Appleton S, Zalewski PD. Induction of 
caspase-3 protease activity and apoptosis by butyrate and trichostatin A (inhibitors of histone 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
58 
 
deacetylase): dependence on protein synthesis and synergy with a mitochondrial/cytochrome 
c-dependent pathway. Cancer Res. 1997;57(17):3697-3707. 
45. 
Biggs JR, Kudlow JE, Kraft AS. The role of the transcription factor Sp1 in regulating 
the expression of the WAF1/CIP1 gene in U937 leukemic cells. J Biol Chem. 
1996;271(2):901-906. 
46. 
Nakano K, Mizuno T, Sowa Y, et al. Butyrate activates the WAF1/Cip1 gene promoter 
through Sp1 sites in a p53-negative human colon cancer cell line. J Biol Chem. 
1997;272(35):22199-22206. 
47. 
Sowa Y, Orita T, Minamikawa S, et al. Histone deacetylase inhibitor activates the 
WAF1/Cip1 gene promoter through the Sp1 sites. Biochem Biophys Res Commun. 
1997;241(1):142-150. 
48. 
Sambucetti LC, Fischer DD, Zabludoff S, et al. Histone deacetylase inhibition 
selectively alters the activity and expression of cell cycle proteins leading to specific 
chromatin acetylation and antiproliferative effects. J Biol Chem. 1999;274(49):34940-34947. 
49. 
Yu X, Guo ZS, Marcu MG, et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 
expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst. 
2002;94(7):504-513. 
50. 
Fuino L, Bali P, Wittmann S, et al. Histone deacetylase inhibitor LAQ824 down-
regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, 
gemcitabine, and epothilone B. Mol Cancer Ther. 2003;2(10):971-984. 
51. 
Nimmanapalli R, Fuino L, Bali P, et al. Histone deacetylase inhibitor LAQ824 both 
lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of 
imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. 
Cancer Res. 2003;63(16):5126-5135. 
52. 
Warrell RP, He LZ, Richon V, Calleja E, Pandolfi PP. Therapeutic targeting of 
transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J 
Natl Cancer Inst. 1998;90(21):1621-1625. 
53. 
Mitsiades N, Mitsiades CS, Richardson PG, et al. Molecular sequelae of histone 
deacetylase inhibition in human malignant B cells. Blood. 2003;101(10):4055-4062. 
54. 
Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone 
deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl 
Acad Sci U S A. 2004;101(2):540-545. 
55. 
Campbell RA, Sanchez E, Steinberg J, et al. Vorinostat enhances the antimyeloma 
effects of melphalan and bortezomib. Eur J Haematol. 2010;84(3):201-211. 
56. 
Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in 
human multiple myeloma cells by the proteasome inhibitor bortezomib and histone 
deacetylase inhibitors. Clin Cancer Res. 2004;10(11):3839-3852. 
57. 
Kikuchi J, Wada T, Shimizu R, et al. Histone deacetylases are critical targets of 
bortezomib-induced cytotoxicity in multiple myeloma. Blood. 2010;116(3):406-417. 
58. 
Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and 
aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl 
Acad Sci U S A. 2005;102(24):8567-8572. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
59 
 
59. 
Hideshima T, Bradner JE, Chauhan D, Anderson KC. Intracellular protein degradation 
and its therapeutic implications. Clin Cancer Res. 2005;11(24 Pt 1):8530-8533. 
60. 
Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor 
bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor 
LBH589 are synergistic in myeloma cells. Blood. 2006;108(10):3441-3449. 
61. 
Nawrocki ST, Carew JS, Maclean KH, et al. Myc regulates aggresome formation, the 
induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA. 
Blood. 2008;112(7):2917-2926. 
62. 
Mithraprabhu S, Khong T, Jones SS, Spencer A. Histone deacetylase (HDAC) 
inhibitors as single agents induce multiple myeloma cell death principally through the 
inhibition of class I HDAC. Br J Haematol. 2013;162(4):559-562. 
63. 
Alexandrakis MG, Passam FH, Boula A, et al. Relationship between circulating serum 
soluble interleukin-6 receptor and the angiogenic cytokines basic fibroblast growth factor and 
vascular endothelial growth factor in multiple myeloma. Ann Hematol. 2003;82(1):19-23. 
64. 
Medinger M, Fischer N, Tzankov A. Vascular endothelial growth factor-related 
pathways in hemato-lymphoid malignancies. J Oncol. 2010;2010:729725. 
65. 
Mie Lee Y, Kim SH, Kim HS, et al. Inhibition of hypoxia-induced angiogenesis by 
FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity. 
Biochem Biophys Res Commun. 2003;300(1):241-246. 
66. 
Sasakawa Y, Naoe Y, Inoue T, et al. Effects of FK228, a novel histone deacetylase 
inhibitor, on tumor growth and expression of p21 and c-myc genes in vivo. Cancer Lett. 
2003;195(2):161-168. 
67. 
Deroanne CF, Bonjean K, Servotte S, et al. Histone deacetylases inhibitors as anti-
angiogenic agents altering vascular endothelial growth factor signaling. Oncogene. 
2002;21(3):427-436. 
68. 
Bali P, Pranpat M, Bradner J, et al. Inhibition of histone deacetylase 6 acetylates and 
disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia 
activity of histone deacetylase inhibitors. J Biol Chem. 2005;280(29):26729-26734. 
69. 
Mahalingam D, Swords R, Carew JS, Nawrocki ST, Bhalla K, Giles FJ. Targeting 
HSP90 for cancer therapy. Br J Cancer. 2009;100(10):1523-1529. 
70. 
Kaiser M, Lamottke B, Mieth M, et al. Synergistic action of the novel HSP90 inhibitor 
NVP-AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple 
myeloma. Eur J Haematol. 2010;84(4):337-344. 
71. 
Chesi M, Matthews GM, Garbitt VM, et al. Drug response in a genetically engineered 
mouse model of multiple myeloma is predictive of clinical efficacy. Blood. 2012;120(2):376-
385. 
72. 
DeAngelo DJ, Spencer A, Bhalla KN, et al. Phase Ia/II, two-arm, open-label, dose-
escalation study of oral panobinostat administered via two dosing schedules in patients with 
advanced hematologic malignancies. Leukemia. 2013;27(8):1628-1636. 
73. 
Schmitt S, Ho AD, Goldschmidt H. The oral histone deacetylase inhibitor LBH589 is 
a potential and promising therapeutic agent in multiple myeloma after at least two lines of 
chemotherapy including bortezomib or lenalidomide. Onkologie. 2010;33(4):183-186. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
60 
 
74. 
Wolf JL, Siegel D, Goldschmidt H, et al. Phase II trial of the pan-deacetylase inhibitor 
panobinostat as a single agent in advanced relapsed/refractory multiple myeloma. Leuk 
Lymphoma. 2012;53(9):1820-1823. 
75. 
Niesvizky R, Ely S, Mark T, et al. Phase 2 trial of the histone deacetylase inhibitor 
romidepsin for the treatment of refractory multiple myeloma. Cancer. 2011;117(2):336-342. 
76. 
Richardson P, Mitsiades C, Colson K, et al. Phase I trial of oral vorinostat 
(suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leuk 
Lymphoma. 2008;49(3):502-507. 
77. 
Berenson JR, Hilger JD, Yellin O, et al. A phase 1/2 study of oral panobinostat 
combined with melphalan for patients with relapsed or refractory multiple myeloma. Ann 
Hematol. 2014;93(1):89-98. 
78. 
San-Miguel JF, Richardson PG, Günther A, et al. Phase Ib study of panobinostat and 
bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol. 
2013;31(29):3696-3703. 
79. 
Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA 2: panobinostat in 
combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-
refractory myeloma. Blood. 2013;122(14):2331-2337. 
80. 
Offidani M, Polloni C, Cavallo F, et al. Phase II study of melphalan, thalidomide and 
prednisone combined with oral panobinostat in patients with relapsed/refractory multiple 
myeloma. Leuk Lymphoma. 2012;53(9):1722-1727. 
81. 
Harrison SJ, Quach H, Link E, et al. A high rate of durable responses with romidepsin, 
bortezomib, and dexamethasone in relapsed or refractory multiple myeloma. Blood. 
2011;118(24):6274-6283. 
82. 
Dimopoulos M, Siegel DS, Lonial S, et al. Vorinostat or placebo in combination with 
bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, 
double-blind study. Lancet Oncol. 2013;14(11):1129-1140. 
83. 
Richardson PG, Hungria VTM, Yoon S-S, et al. Panorama 1: A randomized, double-
blind, phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in 
relapsed or relapsed and refractory multiple myeloma. ASCO Meeting Abstracts. 
2014;32(15_suppl):8510. 
84. 
Basak G, Carrier E. The search for multiple myeloma stem cells: the long and winding 
road. Biol Blood Marrow Transplant. 2010;16(5):587-594. 
85. 
Park CH, Bergsagel DE, McCulloch EA. Mouse myeloma tumor stem cells: a primary 
cell culture assay. J Natl Cancer Inst. 1971;46(2):411-422. 
86. 
Hamburger A, Salmon SE. Primary bioassay of human myeloma stem cells. J Clin 
Invest. 1977;60(4):846-854. 
87. 
Szczepek AJ, Seeberger K, Wizniak J, Mant MJ, Belch AR, Pilarski LM. A high 
frequency of circulating B cells share clonotypic Ig heavy-chain VDJ rearrangements with 
autologous bone marrow plasma cells in multiple myeloma, as measured by single-cell and in 
situ reverse transcriptase-polymerase chain reaction. Blood. 1998;92(8):2844-2855. 
88. 
Matsui W, Huff CA, Wang Q, et al. Characterization of clonogenic multiple myeloma 
cells. Blood. 2004;103(6):2332-2336. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
61 
 
89. 
Bergsagel PL, Smith AM, Szczepek A, Mant MJ, Belch AR, Pilarski LM. In multiple 
myeloma, clonotypic B lymphocytes are detectable among CD19+ peripheral blood cells 
expressing CD38, CD56, and monotypic Ig light chain. Blood. 1995;85(2):436-447. 
90. 
Boucher K, Parquet N, Shain KH, et al. Characterization of Clonotypic B Cell 
Progenitors in Bone Marrow of Multiple Myeloma Patients. ASH Annual Meeting Abstracts. 
2011;118(21):4002-. 
91. 
Dhodapkar MV, Osman K, Teruya-Feldstein J, et al. Expression of cancer/testis (CT) 
antigens MAGE-A1, MAGE-A3, MAGE-A4, CT-7, and NY-ESO-1 in malignant 
gammopathies is heterogeneous and correlates with site, stage and risk status of disease. 
Cancer Immun. 2003;3:9. 
92. 
Dhodapkar M, Krasovsky J, Olson K. T cells from the tumor microenvironment of 
patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to 
autologous, tumor-loaded dendritic cells. Proc Natl Acad Sci U S A. 2002;99(20):13009-
13013. 
93. 
Wen YJ, Barlogie B, Yi Q. Idiotype-specific cytotoxic T lymphocytes in multiple 
myeloma: evidence for their capacity to lyse autologous primary tumor cells. Blood. 
2001;97(6):1750-1755. 
94. 
Woods DM, Woan K, Cheng F, et al. The antimelanoma activity of the histone 
deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and 
increased tumor immunogenicity. Melanoma Res. 2013. 
95. 
Wang D, Iclozan C, Liu C, Xia C, Anasetti C, Yu XZ. LBH589 enhances T cell 
activation in vivo and accelerates graft-versus-host disease in mice. Biol Blood Marrow 
Transplant. 2012;18(8):1182-1190.e1181. 
96. 
Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity 
in patients after clonal repopulation with antitumor lymphocytes. Science. 
2002;298(5594):850-854. 
97. 
Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H. The 
central role of CD4(+) T cells in the antitumor immune response. J Exp Med. 
1998;188(12):2357-2368. 
98. 
Harousseau J, Attal M, Avet-Loiseau H. The role of complete response in multiple 
myeloma. Blood. 2009;114(15):3139-3146. 
99. 
Sarasquete ME, García-Sanz R, González D, et al. Minimal residual disease 
monitoring in multiple myeloma: a comparison between allelic-specific oligonucleotide real-
time quantitative polymerase chain reaction and flow cytometry. Haematologica. 
2005;90(10):1365-1372. 
100. 
de Tute RM, Jack AS, Child JA, Morgan GJ, Owen RG, Rawstron AC. A single-tube 
six-colour flow cytometry screening assay for the detection of minimal residual disease in 
myeloma. Leukemia. 2007;21(9):2046-2049. 
101. 
Rawstron AC, Davies FE, DasGupta R, et al. Flow cytometric disease monitoring in 
multiple myeloma: the relationship between normal and neoplastic plasma cells predicts 
outcome after transplantation. Blood. 2002;100(9):3095-3100. 
102. 
Wu D, Sherwood A, Fromm JR, et al. High-throughput sequencing detects minimal 
residual disease in acute T lymphoblastic leukemia. Sci Transl Med. 2012;4(134):134ra163. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
62 
 
103. 
Larimore K, McCormick MW, Robins HS, Greenberg PD. Shaping of human germline 
IgH repertoires revealed by deep sequencing. J Immunol. 2012;189(6):3221-3230. 
104. 
Carlson CS, Emerson RO, Sherwood AM, et al. Using synthetic templates to design an 
unbiased multiplex PCR assay. Nat Commun. 2013;4:2680. 
105. 
Lefranc MP, Giudicelli V, Ginestoux C, et al. IMGT-ONTOLOGY for 
immunogenetics and immunoinformatics. In Silico Biol. 2004;4(1):17-29. 
106. 
Yousfi Monod M, Giudicelli V, Chaume D, Lefranc MP. IMGT/JunctionAnalysis: the 
first tool for the analysis of the immunoglobulin and T cell receptor complex V-J and V-D-J 
JUNCTIONs. Bioinformatics. 2004;20 Suppl 1:i379-385. 
 
 
 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
63 
 
Appendices 
16.1 
Appendix A: Medications requiring caution for potential drug-
drug interactions 
16.1.1 
Medications which have a risk of causing Torsades de pointes 
ventricular arrhythmia should be avoided 
Patients who are currently receiving treatment of the medications in Table 17-1 and cannot 
either discontinue from this treatment or switch to an alternative medication prior to 
enrollment in a panobinostat clinical study, will be excluded from the study.  Patients may not 
begin panobinostat treatment with any of the medications listed in Table 17-1 unless this is 
discussed with the supporting company (Novartis) and an approval is granted by the 
supporting company (Novartis). The supporting company (Novartis) may agree to temporarily 
discontinue panobinostat treatment (e.g., for 72 hours) during administration with these drugs 
or withheld medications in Table17-1 for at least 72 hours when panobinostat is to be 
administered.   
 
NOTE: It is of great importance to avoid combining drugs listed below in Table 17-1 and 
Table 17-2 (CYP3A inhibitors) especially in the presence of electrolyte abnormalities, notably 
decreased potassium or magnesium levels commonly associated with diuretic usage. 
In general, medications listed in Table 17-1 should be avoided while medications listed in 
Tables 17-2 and 17-3 are to be used with caution when co-administered with panobinostat.   
Please select the most stringent recommendation for concomitant medications (i.e., to be 
avoided) which are common among the tables (e.g., erythromycin, clarithromycin) 
Table 17-1 
Medications which have a risk of causing 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 
bretylium 
disopryramide 
dofetilide 
ibutilide 
any other class III antiarrhythmic drug 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
64 
 
Antibiotics 
Macrolide antibiotics* 
 erythromycin 
 clarithromycin 
 telithromycin 
Quinolone antibiotics* 
sparfloxacin 
Antipsychotics 
thioridazine 
mesoridazine 
chlorpromazine 
pimozide 
Antimalarials 
 halofantrine 
 chloroquine 
Miscellaneous drugs 
 arsenic trioxide 
 astemizole 
 bepridil 
 domperidone 
 levomethadyl 
 methadone 
 pentamidine 
 droperidol 
 
*Note: azithromycin, ciprofloxacin, levofloxacin, pefloxacin, ofloxacin, 
tosufloxacin, difloxacin, temafloxacin, fleroxacin, acrosoxacin, nalidixic 
acid and enoxacin are allowed. 
 
This is not a comprehensive list of medications which may prolong the QT interval or have a 
risk of causing 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 point lack 
substantial evidence for causing Torsades de pointes: 
http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm#. 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
65 
 
Medications listed on the website which do not appear in Table 17-1 above may be used with 
caution at the discretion of the investigators.  
The serotonin (5HT3) antagonists, often used as antiemetics, such as ondansetron, dolasetron, 
(also are known CYP2D6 substrates, see Table 17-3), or granisetron have been associated 
with Torsades de points and QT prolongation but have not been shown to cause Torsades de 
pointes. Therefore, 5HT3 antagonists are not per se prohibited but close monitoring for signs 
and symptoms of QT prolongation is recommended.  Caution is to be exercised when using 
these or other agents that may prolong QT intervals in combination with panobinostat.  
   
16.1.2 
Medications which are known strong CYP3A4/5 inhibitors to be used 
with caution 
Panobinostat is a substrate of CYP3A4 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 cancer 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 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)1 are recommended 
not to receive panobinostat concomitantly with strong CYP3A inhibitors because potential 
interaction has not been established in this population. 
Table 17-2   
Medications which are known strong CYP3A4/5 inhibitors to be used 
with caution 
Macrolide antibiotics* 
 clarithromycin 
 telithromycin 
 troleandomycin  
 erythromycin 
Antifungals (azoles)* 
 ketoconazole 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
66 
 
 itraconazole  
 fluconazole  
Antidepressants 
 nefazodone 
Calcium channel blockers* 
 diltiazem 
 verapamil 
HIV protease inhibitors: 
 indinavir 
 nelfinavir 
 ritonavir 
 saquinavir  
 Miscellaneous drugs or products 
 aprepitant 
 grapefruit product or juice 
* azithromycin, voriconazole, regular orange juice and dihydropyridine 
calcium channel blockers (e.g. amlodipine, felodipine, nicardipine, 
nifedipine) are allowed. 
This is not a comprehensive list of medications which may inhibit CYP3A4/5.  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: http://medicine.iupui.edu/clinpharm/DDIs 
 
16.1.3 
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 generally safe to be co-administered with panobinostat.  
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 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
67 
 
narrow therapeutic window (e.g., the ratio of toxicity exposure is ≤ 2-fold higher than the 
efficacious or therapeutic exposure).  
Table 17-3   
Medications which are known CYP2D6 substrates to be used with 
caution 
Beta blockers (listed below): 
Antipsychotics (listed below): 
carvedilol 
aripiprazole 
metoprolol 
haloperidol 
propafenone 
perphenazine 
timolol 
risperidone 
Antidepressants (listed below): 
thioridazine 
amitriptyline 
zuclopenthixol 
chlormipramine 
amphetamine  
desipramine 
alprenolol 
imipramine 
bufuralol 
fluoxetine 
chloropheniramine 
paroxetine 
Antiarrhythmics (listed below): 
venlafaxine 
quinidine 
bupropion 
lidocaine 
duloxetine  
mexiletine
Antiemetics (listed below): 
propafenone
dolasetron 
Others:
ondansetron 
oxycodone
metoclopramide 
codeine
 
hydrocodone
 
terbinafine
 
promethazine
 
tamoxifen
 
tramadol
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: 
http://medicine.iupui.edu/clinpharm/DDIs  
 
Reference:  
1. Synold TW, Takimoto CH, Doroshow JH, Gandara D, Mani S, Remick SC, Mulkerin DL, 
Hamilton A, Sharma S, Ramanathan RK, Lenz HJ, Graham M, Longmate J, Kaufman 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
68 
 
BM, Ivy SP. Dose-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  
 
 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
69 
 
16.2 
Appendix B: Criteria for Symptomatic Multiple Myeloma 
 
All three required: 
1. Monoclonal plasma cells in the bone marrow ≥ 10% and/or presence of a biopsy-
proven plasmacytoma 
2. Monoclonal protein present in the serum and/or urinea 
3. Myeloma-related organ dysfunction (1 or more)b 
(C) Calcium elevation in the blood (serum calcium > 10.5 mg/L or upper limit 
of normal) 
(R) Renal insufficiency (serum creatinine > 2 mg/dL) 
(A) Anemia (hemoglobin < 10 g/dL) 
(B) Lytic bone lesions or osteoporosisc 
 
*Note: These criteria identify Stage IB and Stages II and III A/B myeloma by Durie-Salmon 
stage. Stage IA becomes smoldering or indolent myeloma. 
 
aIf no monoclonal protein is detected (nonsecretory disease), then ≥30% monoclonal bone 
marrow plasma cells and/or a biopsy-proven plasmacytoma required. 
bA variety of other types of end organ dysfunctions can occasionally occur and lead to a need 
for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be 
myeloma-related. 
cIf a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the 
sole defining criteria, then ≥30% plasma cells are required in the bone marrow. 
 
 
Reference: 
*Myeloma management guidelines: a consensus report from the Scientific Advisors of the 
International Myeloma Foundation. The Hematology Journal 2003;4:379-398 
 
 
 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
70 
 
16.3 
Appendix C: Uniform Response Reporting Criteria for Multiple 
Myeloma by the International Myeloma Working Group (IMWG) 
 
Response 
subcategory 
Response Criteria 
sCR1 
 
CR as defined below plus normal FLC ratio and absence of clonal cells in bone 
marrow by immunohistochemistry or 2- to 4-color flow cytometry 
CR2 
 
Negative immunofixation of serum and urine, disappearance of any soft tissue 
plasmacytomas, and < 5% plasma cells in bone marrow 
VGPR2 
 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis 
or ≥ 90% reduction in serum M-component plus urine M-component  < 100 mg per 
24 hours 
PR 
 
≥ 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by 
≥ 90% or to < 200 mg per 24 hours  
 
If the serum and urine M-protein are not measurable, a decrease  ≥ 50% in the 
difference between involved and uninvolved FLC levels is required in place of the 
M-protein criteria.  
 
If serum and urine M-protein and serum FLC are not measurable, and serum free 
light assay is also not measurable,  ≥ 50% reduction in bone marrow plasma cells is 
required in place of M-protein, provided baseline bone marrow plasma cell 
percentage was ≥ 30%  
 
In addition to the above listed criteria, if present at baseline, ≥ 50% reduction in the 
size of soft tissue plasmacytomas is also required 
SD 
 
Not meeting criteria for CR, VGPR, PR, or PD   
PD1 
 
Increase of 25% from lowest response value in any of the following:  
- Serum M-component (absolute increase must be ≥ 0.5 g/dL) 
- Urine M-component (absolute increase must be ≥ 200 mg/24 h)  
- Only in patients without measurable serum and urine M-protein levels: the 
difference between involved and uninvolved FLC levels (absolute increase must 
be > 10 mg/dL)  
- Only in patients without measurable serum and urine M protein levels and without 
measurable disease by FLC levels, bone marrow plasma cell percentage (absolute 
percentage must be ≥ 10% ) 
- Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue plasmacytomas  
- Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that can be 
attributed solely to the plasma cell proliferative disorder 
 
Footnotes:  
1: Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in patients 
without measurable disease by M protein and by FLC levels; “25% increase” refers to M protein, FLC, and 
bone marrow results, and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the 
“lowest response value” does not need to be a confirmed value. 
2: Clarifications to IMGW criteria for coding CR and VGPR in patients in whom the only measurable disease is 
by serum FLC levels: CR in such patients indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR 
criteria listed above. VGPR in such patients requires a > 90% decrease in the difference between involved and 
uninvolved FLC levels. 
 
Reference: 


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
71 
 
Rajkumar SV et al. Consensus recommendations for the uniform reporting of clinical trials: 
report of the International Myeloma Workshop Consensus Panel 1. Blood 2011; 117:4691-
4694  
16.4 
Appendix D: ECOG Performance Status Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCORE  
DESCRIPTION  
0  
Fully active, able to carry on all pre-disease performance without 
restriction.  
1  
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, 
office work.  
2  
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours.  
3  
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.  
4  
Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair.  
5  
Dead.  


 
 
Novartis Protocol No. CLBH589DUS97T 
 
 
Version 3 (04/13/2017)  
 
 
 
Confidential 
MCC 18430 / IRB Pro00015697 
 
72 
 
16.5 
Appendix E: Karfnosky Performance Score 
 
Percentage  
100  
Normal, no complaints, no evidence of disease  
90  
Able to carry on normal activity; minor signs or symptoms of disease  
80  
Normal activity with effort; some signs or symptoms of disease  
70  
Cares for self; unable to carry on normal activity or do active work  
60  
Requires occasional assistance, but is able to care for most of his/her needs  
50  
Requires considerable assistance and frequent medical care  
40  
Disabled; requires special care and assistance  
30  
Severely disabled, hospitalization indicated. Death not imminent  
20  
Very sick, hospitalization necessary, active supportive treatment necessary  
10  
Moribund, fatal processes, progressing rapidly  
0  
Dead  
 
Reference: 
Karnofsky DA: Meaningful clinical classification of therapeutic responses to anti-cancer 
drugs. Editorial: Clin Pharmacol Ther 2:709-712, 1961.