Conditions: Waldenstrom's Macroglobulinemia
Keywords: LBH589 WM panobinostat relapsed waldenstrom macroglobulinemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
The purpose of this research study is to assess the overall response rate of LBH589 in patients with relapsed or refractory Waldenstrom's Macroglobulinemia. LBH589 is a newly discovered compound that has killed Waldenstrom cells in laboratory studies, however, it is not known if LBH589 will show the same activity in people with Waldenstrom's Macroglobulinemia. This drug has been used in research for the treatment of other types of cancer, such as multiple myeloma.

Detailed description:
This phase II study is designed to assess the toxicity profile and the proportion of overall response in patients with relapsed or refractory WM. This will study the effect of single agent LBH589 on response in these patients. Efficacy measures will include both objective clinical measurements and investigator-reported outcomes. Response and time to event analyses will follow the criteria set forth in the International Waldenstrom consortium recommendations. Prior to the start of the study, investigators will assess disease and perform a CT scan of the chest, abdomen and pelvis.

Response will be assessed after 2 cycles. If patients have stable disease or response, then they will continue on therapy until progression or unacceptable toxicity, being assessed every cycle until the sixth cycle and then every 3 months. Patients who show progression after 2 cycles will come off therapy and undergo event monitoring every 3 months. All responses will be assessed by M-protein quantification and immunofixation from serum and IgM monoclonal protein level. In addition, BM biopsies will be done at baseline, at the end of cycle 6 and at the end of all therapy. The protocol was amended because of concerns of toxicity to allow a starting dose of 25 mg; 12/36 (33%) patients were enrolled on the 25 mg dose.

Arms:
arm 1: 30 mg three days a week (Mondays, Wednesdays and Fridays).

1 cycle was 28 days

Dose modifications for attributable toxicities allowed for reduction to:

* 25 mg, 20 mg three times a week every week
* Or 20 mg three times a week every other week. No dose re-escalation was allowed.

  * The protocol was amended on 6/15/2010 because of concerns of toxicity to allow a starting dose of 25 mg; 12/36 (33%) patients were enrolled on the 25 mg dose.

Interventions: intervention 1: LBH589
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
 
Phase II Trial of LBH589 (panobinostat) in relapsed or relapsed and refractory 
Waldenstrom’s Macroglobulinemia  
 
 
Novartis Protocol: CLBH589BUS57T 
 
Author(s): 
Principal Investigator: Irene M. Ghobrial, MD 
 
Participating Investigators and Institutions 
 
Steven P. Treon M.D., M.A., Ph.D. 
Nikhil Munshi, MD 
Paul Richardson, MD 
Robert Schlossman, MD 
Timothy J. Murphy, MD 
David Siegel, MD 
 
Dana-Farber Cancer Institute, Boston, MA, USA (Coordinating Center) 
Brigham and Women’s Hospital, Boston, MA, USA 
Rocky Mountain Cancer Centers, Denver, CO, USA 
Hackensack University Medical Center, Hackensack, NJ, USA 
 
Protocol Date/Version: 
April 25, 2019/ Version 15 
Statistician 
Lorenzo Trippa, PhD 
Clinical Research 
Coordinator 
Govind Bindra 
Research Nurse 
Erin Frey, RN 


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Table of contents 
Table of contents .............................................................................................................................. 2 
1 
Introduction ...................................................................................................................................... 7 
1.1 
Overview of Waldenstrom Macroglobulinemia .................................................................. 7 
1.2 
Overview of LBH589 .......................................................................................................... 9 
1.2.1 
Anticancer activity of DAC inhibitors .............................................................. 9 
1.2.2 
Panobinostat (LBH589) ..................................................................................... 9 
1.2.3 
Preclinical data of LBH59 in Waldenstrom’s Macroglobulinemia ................. 11 
1.2.4 
Preclinical pharmacology ................................................................................ 13 
1.2.5 
Animal pharmacokinetics and drug metabolism ............................................. 14 
1.2.6 
Animal toxicology ........................................................................................... 15 
1.2.7 
Clinical experience with LBH589 in humans ................................................. 16 
2 
Study rationale/purpose .................................................................................................................. 31 
3 
Study objectives ............................................................................................................................. 31 
3.1 
Primary .............................................................................................................................. 31 
3.2 
Secondary .......................................................................................................................... 31 
4 
Overall study design ....................................................................................................................... 31 
5 
Study population ............................................................................................................................ 33 
5.1 
Patient population .............................................................................................................. 33 
5.2 
Inclusion and exclusion criteria ......................................................................................... 33 
6 
Treatments ...................................................................................................................................... 35 
6.1 
Investigational therapy ...................................................................................................... 35 
6.1.1 
Cardiac precautions ......................................................................................... 36 
6.2 
Treatment cycle and duration: ........................................................................................... 36 
6.3 
Dose modification, interruption or discontinuation of treatment ...................................... 36 
6.3.1 
Dose modifications for non-hematologic adverse events:............................... 37 
6.3.2 
Dose modifications for prolonged QTc ........................................................... 39 
6.3.3 
Dose Reduction levels for LBH589 ................................................................ 44 
6.3.4 
Study drug discontinuation .............................................................................. 45 
6.3.5 
Follow-up ........................................................................................................ 45 
6.4 
Other concomitant medications ......................................................................................... 46 
6.4.1 
Drugs that can inhibit/induce CYP3A4/5 ........................................................ 46 
6.5 
Treatment compliance ....................................................................................................... 47 
7 
Investigational Plan ........................................................................................................................ 48 
7.1 
Visit Schedule ................................................................................................................... 48 
7.2 
Registration Procedures ..................................................................................................... 49 
7.3 
Efficacy assessments ......................................................................................................... 50 


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8 
Safety Assessments and Monitoring .............................................................................................. 52 
8.1 
Adverse events .................................................................................................................. 53 
8.2 
Safety Meetings ................................................................................................................. 55 
8.3 
Monitoring ......................................................................................................................... 56 
8.4 
Novartis instructions for rapid notification of serious adverse events .............................. 56 
8.5 
Pregnancies ....................................................................................................................... 57 
8.6 
Vital signs .......................................................................................................................... 57 
8.7 
Physical examination......................................................................................................... 57 
8.8 
Laboratory evaluations ...................................................................................................... 57 
8.8.1 
Hematology ..................................................................................................... 57 
8.8.2 
Blood chemistry .............................................................................................. 57 
8.8.3 
Serum Pregnancy Test ..................................................................................... 57 
8.9 
ECG ................................................................................................................................... 57 
8.10 
Performance status ............................................................................................................ 58 
8.11 
Special tests ....................................................................................................................... 58 
9 
Pharmacodynamic assessments and correlative studies ................................................................. 58 
10 Regulatory Considerations ............................................................................................................. 59 
10.1 
Protocol Review and Amendments ................................................................................... 59 
11 Data management ........................................................................................................................... 60 
11.1 
Data collection................................................................................................................... 60 
11.2 
Data Submission ................................................................................................................ 60 
12 Statistical methods ......................................................................................................................... 60 
12.1 
Statistical methods............................................................................................................. 60 
13 Procedures and instructions............................................................................................................ 63 
13.1 
Publication of results ......................................................................................................... 63 
13.2 
Disclosure and confidentiality ........................................................................................... 63 
13.3 
Discontinuation of study ................................................................................................... 63 
14 Ethics and Good Clinical Practice .................................................................................................. 63 
14.1 
Informed consent ............................................................................................................... 64 
14.2 
Declaration of Helsinki ..................................................................................................... 64 
References .............................................................................................................................................. 65 
Appendix 1.    LBH589 study prohibited medication list. ..................................................................... 70 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status Scale ...................... 75 
Appendix 3: New York Heart Association Classification of Cardiac Disease ...................................... 76 
Appendix 4: Study Medication Diary .................................................................................................... 77 
Appendix 5: Address and Instructions for Shipping Pharmacodynamic Sample .................................. 80 
Appendix 6A: Information Sheet for ECGs and Labs Completed at Local Physician’s Offices .......... 81 


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Appendix 6B: Information Sheet for ECGs and Labs Completed at Local Physician’s Offices ........... 83 
Appendix 7: Study Summary for Participant Reference ........................................................................ 85 
Appendix 8: LBH589 Order Form ......................................................................................................... 87 
Appendix 9: Novartis Pregnancy Reporting Form ................................................................................ 88 
Appendix 10: DFHCC Multi-Center Data and Safety Monitoring Plan ................................................ 93 
 


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List of abbreviations 
 
AE 
 
adverse event 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
absolute neutrophil count 
APL 
acute promyelocytic leukemia 
ASCO 
American Society of Clinical Oncologists 
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 
BUN 
blood urea nitrogen 
CIS 
carcinoma in-situ 
Cmax 
maximum concentration of drug 
CML 
chronic myelogenous leukemia 
CNS 
central nervous system 
CR 
complete response/remission 
CS&E 
clinical safety and epidemiology 
CTCAE 
NCI common terminology criteria for adverse events (version 3.0) 
CTCL 
cutaneous T-cell lymphoma 
CV 
coefficient of variation 
DLT 
dose-limiting toxicity 
DNA 
deoxyribose nucleic acid 
ECG 
12 lead electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eRT 
eResearchTechnology 
FACT 
functional assessment of cancer therapy 
FDA 
food and drug administration 
G-CSF 
granulocyte colony-stimulating factor (e.g. filgrastim) 
GM-CSF 
granulocyte-macrophage colony-stimulating factor (e.g. sargramostim) 
H3, H4 
histones H3, H4 
HAT 
histone acetyltransferase 
HDAC 
histone deacetylase 
HDACi 
histone deacetylase inhibitor 
hERG 
human ether-a-go-go related gene 
HIV 
human immunodeficiency virus 
i.v. 
intravenous(ly) 
ICH 
international conference on harmonization 


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IEC 
independent ethics committee 
IRB 
institutional review board 
LLN 
lower limit of normal 
LVEF 
left ventricular ejection fraction 
mg/m2 
milligrams per square meter 
MTD 
maximum tolerated dose 
MUGA 
multiple uptake gated acquisition scan 
MWF 
monday, wednesday, friday 
NCI 
national cancer institute 
NHL 
non-hodgkin’s lymphoma 
NIH 
national institutes of health 
PD 
pharmacodynamic 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic 
PLT 
platelet 
PR 
partial response 
REB 
research ethics board 
SAE 
serious adverse event 
SAHA 
suberoylanilide hydroxamic acid 
SD 
stable disease 
SOP 
standard operating procedure 
T4 
thyroxine 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 
WNL 
within normal limits 
WOCBP 
women of childbearing potential 
 


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1 Introduction 
1.1 
Overview of Waldenstrom Macroglobulinemia 
WM is a distinct B-cell lymphoproliferative disorder characterized primarily by BM infiltration with 
lymphoplasmacytic cells, along with demonstration of an IgM monoclonal gammopathy (Dimopoulos, 
Panayiotidis et al. 2000; Owen, Treon et al. 2003; Ghobrial and Witzig 2004; Dimopoulos, Kyle et al. 
2005). This condition is classified as a lymphoplasmacytic lymphoma according to the REAL and WHO 
systems(Owen, Treon et al. 2003; Dimopoulos, Kyle et al. 2005). The overall incidence of WM is about 3 
per million persons per year, with 1,500 new cases diagnosed per year in the US and a median age of 
diagnosis of 60 years(Herrinton 1993; Jemal, Murray et al. 2005). Unlike multiple myeloma (MM), WM 
is more common in Caucasians than in African Americans(Jemal, Murray et al. 2005). The median overall 
survival of patients with WM is 5-6 years; however a recent study in 337 patients with symptomatic WM, 
showed a median disease specific survival of 11.2 years(Ghobrial, Fonseca et al. 2006). Because the 
outcome of patients with WM varies widely, an international prognostic scoring system (IPSS) was 
defined using a series of 587 patients. This IPSS staging system is widely accepted as the prognostic 
staging system for WM. The scoring system based on the 5 risk factors as well as the survival of patients 
at 5 years is shown in table 1 below, showing that patients with low risk disease had a 5-year survival of 
87%, while only 36% of patients with high-risk disease had a 5-year survival. . 
 
    Table 1: IPSS scoring system 
Risk 
Low  
Intermediate  
High  
 
Age > 65 years 
- 
X 
or 
 
 
> 2 factors 
 
Hb ≤ 11.5 g/dL 
 
≤ 1 factor 
 
  2 factors 
 
Platelet ≤ 100 x109/L  
 
B2M > 3 mg/L 
 
IgM > 7 g/dL 
 
N (%) 
158 (27%) 
223 (38%) 
206 (35%) 
 
Survival at 5 years 
87% 
68% 
36% 
P<0.001 
Hb : hemoglobin; B2M : beta2-microglobulin; N : number of patients; % : percentage 
 
Limitations of current therapy in WM: Despite continuing advances in the therapy of WM, the disease 
remains incurable, thereby necessitating the development and evaluation of novel therapeutics(Ghobrial, 
Gertz et al. 2003; Kyle, Treon et al. 2003; Dimopoulos, Kyle et al. 2005). Most treatment options were 
originally derived from other lymphoproliferative diseases including multiple myeloma and chronic 
lymphocytic leukemia (CLL)(Vijay and Gertz 2007). Current therapies used in the upfront or relapsed 
settings include alkylator agents (e.g. chlorambucil), nucleoside analogues (cladribine or fludarabine), and 
the monoclonal antibody rituximab(Dimopoulos, O'Brien et al. 1993; Gertz, Anagnostopoulos et al. 2003; 


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Treon, Emmanouilides et al. 2005; Treon, Morel et al. 2005). The overall response rates (ORR including 
CR, PR and MR) in the upfront setting is in the range of 30-70% with complete response (CR) rates of 
less than 10%, and median durations of response averaging 2-3 years(Weber, Dimopoulos et al. 2003; 
Treon, Morel et al. 2005). In the salvage setting, the ORR is in the range of 30-40%, with a median 
response duration of 1 year or less(Dimopoulos, Weber et al. 1995; Treon, Morel et al. 2005). The use of 
fludarabine or alkylating agents in combination therapy in these patients induces high responses, but leads 
to significant toxicities in these elderly patients(McLaughlin, Estey et al. 2005; Treon, Gertz et al. 2006). 
Rituximab is the most widely used therapeutic agent in WM. It regulates the PI3K, NF-kB as well as the 
ERK signaling pathways(Bonavida 2007). Standard rituximab (4 weekly infusions of 375 mg/m2) or four 
weekly rituximab treatments repeated at 3 months (extended rituximab) triggered response rates of 35-
48%(Dimopoulos, Zervas et al. 2002; Dimopoulos, Zervas et al. 2002; Gertz, Rue et al. 2004; Treon, 
Emmanouilides et al. 2005). However, all these studies included rituximab naïve patients. Most patients 
receive rituximab re-treatment after prior exposure to rituximab either alone or in combination with other 
therapies. In addition, the IgM level may initially increase in response to rituximab, a phenomenon termed 
IgM flare that occurs in about in 54% of patients(Ghobrial 2004; Treon 2004). These levels may persist 
for up to 3-4 months and do not indicate treatment failure.  
 
Novel therapeutic agents that have demonstrated efficacy in WM include thalidomide, bortezomib and 
alemtuzumab(Dimopoulos, Zomas et al. 2001; Hunter 2004; Treon 2005; Treon, Morel et al. 2005). The 
ORR to these agents ranges between 25-80%(Dimopoulos, Zomas et al. 2001; Hunter 2004; Treon 2005; 
Treon, Morel et al. 2005). Unfortunately, some of these agents have a high toxicity profile such as 
Alemtuzumab therapy in WM(Hunter 2006; Chen, Kouroukis et al. 2007; Treon, Hunter et al. 2007). The 
use of bortezomib as a single agent in WM has been tested in two phase II clinical trials in relapsed WM. 
The agent was used in the standard dose of 1.3 mg/m2 twice a week on days 1, 4, 8 and 11. Chen et 
al(Chen, Kouroukis et al. 2007) treated 27 patients with bortezomib in both untreated (44%) and 
previously treated (56%) patients with WM. The overall response rate to bortezomib was 78%, with major 
responses (PR or better) observed in 44% of patients, however, sensory neuropathy occurred in 20/27 
patients, 5 with grade >3, and occurred following 2-4 cycles of therapy. However, there were no complete 
responses observed on these studies. Due to the significantly high risk of peripheral neuropathy in these 
patients, subsequent trials of bortezomib used the treatment schedule of once a week at 1.6 mg/m2. 
 
We recently tested the activity of LBH589 on WM cells and cell lines in vitro. LBH589 induced a 
significant decrease of proliferation and triggered cytotoxicity in all cell lines tested and primary CD19+ 
WM cells (IC50 of 20-40nM), even in the presence of BMSC, IL-6 and IGF-1, which induce resistance to 
conventional therapies. Importantly, LBH589 did not induce cytotoxicity in healthy donor peripheral 
blood mononuclear cells. LBH589 induced both intrinsic and extrinsic apoptotic pathways, with caspase-
9, caspase-8, caspase-3, and PARP cleavage in a dose-dependent manner. We also demonstrated 
significant upregulation of the pro-apoptotic transcription factor p53 and down-regulation of the anti-
apoptotic proteins Bcl-xL, Mcl-1 and c-myc.  We then demonstrated that LBH589 induced apoptosis in 
WM cells in a caspase-independent manner through induction of autophagy, as shown by upregulation of 
LC3B and Rab7 expression. We further determined the mechanism of action of LBH589 in WM, 
investigating the effect of LBH589 on histone acetylation and NF-kB pathways. We found that LBH589 
induced a dose-dependent increase in histone H3-H4 acetylation; and inhibited both canonical and non-


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canonical pathways of NF-kB, as shown by western blot and immunofluorescence. In addition, LBH589 
augmented rituximab, fludarabine, bortezomib and perifosine-induced cytotoxicity in WM cells 
1.2 
Overview of LBH589 
1.2.1 
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.  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 (Marks et al 2001). 
• Nonhistone proteins regulated by acetylation include α-tubulin, p53, HIF-1α, and HSP90.  These 
proteins are substrates of DACs (Glozak et al 2005). 
• 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 (Aoyagi and Archer 2005). 
• Acetylated HIF-1α 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-1α 
and decreased vascular endothelial growth factor (VEGF), thereby inhibiting angiogenesis (Diaz-
Gonzalez et al 2005). 
• 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 (Walsh Garneau-Tsodikova and Gatto 2005). 
1.2.2 
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.   


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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 
(Herman 1994, Pratt 1994, Szyf 1994, Herman 1995, Merlo 1995, Herman 1996, Herman 1998, Cameron 
1999) 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 (Gelmetti 1998, Grignani 1998, Lin 1998, Redner 
1999).  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 (Yoshida 1987, Yoshida 1988, 
Itazaki 1990, Yoshida 1990, Sugita 1992, Yoshida 1992, Medina 1997).  In addition, DACi have been 
shown to induce expression of p21, a key mediator of cell cycle arrest in G1 phase and cellular 
differentiation (Biggs 1996, Nakano 1997, Sowa 1997, Sambucetti 1999). 
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 (Yu 2002, Fuino 
2003, Nimmanapalli 2003).  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-retinoic acid (ATRA) alone, achieved a 
complete clinical remission after treatment with a combination of ATRA and the DACi sodium 
phenylbutyrate (Warrell et al 1998).  Recent evidence suggests that there is activity in a variety of solid 
and hematological tumors with Vorinostat (Zolinza™), an orally administered, structurally-related DACi.  
Vorinostat has been reported to have single-agent activity in cutaneous T-cell lymphoma (CTCL), diffuse 
large cell lymphoma, and head and neck cancer (Heaney 2003, Kelly 2003).  Similar activity has been 
reported in clinical studies with other DACi, including i.v. romidepsin (Kim et al 2007 ASH abstract).  
Vorinostat was approved by the FDA for the treatment of cutaneous manifestations of cutaneous T-cell 
lymphoma for patients who have progressive, persistent or recurrent disease on or following two systemic 
therapies in October 2006 (Mann et al 2007).   


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1.2.3 
Preclinical data of LBH59 in Waldenstrom’s Macroglobulinemia 
 
Epigenetic regulation of gene expression including histone acetylation is commonly deregulated in many 
malignancies leading to aberrant transcription. We sought to examine the role of histone acetylation in 
WM, and determine the activity of histone deacetylase inhibitors in this disease. We showed that WM 
cells aberrantly expressed a high level of HDAC activity compared to control B cells. We then identified 
the activity of the potent HDAC inhibitor LBH589 on the acetylation of H3 and H4 histones in cell lines 
and patient samples and the effect of HDAC inhibition on genes regulated by histone modification in WM 
cells using gene expression profiling, and demonstrated that HDAC inhibition led to upregulation of p53 
and decreased expression of c-myc, Bcl-2 and BCl-xL.  
 
To determine whether the imbalance of HDAC/HAT activity occurs in WM, we first examined the level 
HDAC activity in CD19+ selected WM cells from patients and BCWM.1 cells, compared it to control 
CD19+ cells from healthy subjects. As shown in Figure 1A, the level of HDAC activity was significantly 
higher in all the WM patient samples and BCWM.1 compared to the average of 3 normal controls, 
indicating that indeed in WM cells, HDAC/HAT activity is elevated. We then determined the effect of the 
HDAC inhibitor LBH589 on HDAC activity in BCWM.1. Figure 1B shows that HDAC activity was 
significantly inhibited by LBH589 (40nM) within 2 hours of incubation (p= 0.04). We next investigated 
the effect of LBH589 on specific histone acetylation in WM cells. BCWM.1 cells were incubated with 
LBH589 (20-60nM for 16 hours), and whole-cell extracts were then analyzed by immunoblotting. 
LBH589 induced a dose-dependent increase in histone H3 and H4 acetylation (Figure 1C). In addition, 
LBH589 induced α-tubulin and lysine hyperacetylation in a dose-dependent fashion. We next confirmed 
LBH589-induced hyperacetylation in BCWM.1 cells by immunofluorescence. BCWM.1 cells were 
treated with medium or LBH589 (40nM for 16 hours). LBH589-treated cells showed a hyperacetylated 
segmented α-tubulin, in contrast with untreated cells where a reticulated pattern of acetyl-α-tubulin, 
forming a latticed network was observed (Figure. 1D). Finally, we confirmed that patient CD19+ cells 
expressed low levels of acetylated Histone H4 levels using immunofluorescence staining, while treatment 
of these cells with LBH589 (40nM for 16 hours) led to a significant increase in the expression of 
acetylated Histone H4 in the nuclei of these cells, as confirmed by DAPI blue staining for nuclei (Figure 
1E).  
 
We further showed that HDAC inhibition leads to a significant reduction of both the canonical and non-
canonical NFkB pathways in WM. Based on these studies, we showed that LBH589 induced significant 
cytotoxicity, cell cycle arrest, and apoptosis with an IC50 of 20-40nM, even in the presence of bone 
marrow stromal cells, IL-6 and IGF-1, which induce resistance to conventional therapies. LBH589 
induced both intrinsic and extrinsic apoptotic pathways. In addition, LBH589 induced apoptosis in WM 
cells in a caspase-independent manner through induction of autophagy, as shown by upregulation of 
LC3B and Rab7 expression. Finally, we demonstrated that LBH589 augmented rituximab, fludarabine, 
and bortezomib-induced cyotoxicity in WM cells, providing the scientific rationale for studying this agent 
in clinical trials in WM (data not shown).  


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1.2.4 
Preclinical pharmacology 
1.2.4.1 
In vitro pharmacology 
LBH589 was devised through iterative design and combinatorial approach using in vitro histone 
deacetylase inhibition assays, activation of the p21 promoter and inhibition of the proliferation of tumor 
cell lines in monolayer as selection criteria. LBH589 is active as an inhibitor of histone deacetylase 
activity purified from H1299 lung carcinoma cell lines (IC50 = 0.03 µM)  and, in nanomolar 
concentrations, transcriptionally activates a p21 promoter luciferase construct transiently transfected into 
H1299 cells. 
Consistent with the proposed mechanism of action for LBH589, tumor cells exposed to LBH589 for 2 
hours or more demonstrated increased levels of histone-H3 and -H4 acetylation, and the increased histone 
acetylation levels persisted for up to 24 hours. LBH589 induced cell death in transformed cells while, 
under similar conditions, induced growth arrest in normal cells. Exposure of tumor cells to low nanomolar 
concentrations of LBH589 for 16 hours or longer resulted in significant cell death. Exposure of normal 
dermal human fibroblasts to similar concentrations of LBH589 for similar durations induced growth arrest 
but not cell death. Similarly, treatment of SV40-T antigen and telomerase transformed bronchial epithelial 
cells with LBH589 induced apoptosis as assessed by annexin V staining. However, similar treatment of 
normal bronchial epithelial cells with higher concentrations of LBH589 did not induce apoptosis. 
1.2.4.2 
Effects of panobinostat on solid tumor cell lines in vitro 
LBH589 exhibits potent antiproliferative activity against a broad range of tumor cell lines including 
HCT116 colon carcinoma cells (IC50 = 0.005 µM), H1299 lung carcinoma cells (IC50 = 0.069 µM), 
DU145 prostrate cancer cells (IC50 = 0.016 µM) and PC-3 prostate cancer cells (IC50 = 0.022 µM). 
Antiproliferative activity in the tumor cell lines is accompanied by increased histone acetylation, 
suggesting that LBH589 modulates the intended target. Further, LBH589 demonstrates antiproliferative 
activity against tumor cell lines resistant to paclitaxel due to over-expression of P-gp. 
1.2.4.3 
In vivo pharmacology and in vivo anti-tumor activity 
The activity of LBH589 was assessed in two different in vivo anti-tumor models using two different 
human tumor cell lines; HCT116 (colon adenocarcinoma) and PC3-M2AC6 (prostate adenocarcinoma). 
Since the oral bioavailability of LBH589 is < 5% in nude mice, all efficacy studies in vivo were 
performed with the intravenous formulation. 
Following intravenous administration to tumor bearing mice, LBH589 was rapidly absorbed by tumor 
cells with concentrations in tumor higher than plasma. The LBH589 tumor concentration at 16 hours in 
mice bearing HCT116 xenographs was 0.71 µM, which is 142 times the IC50 and 41 times the LD90 
observed in the HCT116 cell line. 
The levels of histone-H3 and -H4 acetylation were examined in LBH589-treated mice bearing either 
HCT116 subcutaneous tumors or PC-3M2AC6 orthotopic tumors. IV administration of LBH589 to the 
tumor-bearing mice resulted in consistent increases in histone H3 and H4 acetylation in the tumor. In the 
HCT116 model, histone acetylation was seen after doses as low as 1.25 mg/kg, the lowest dose that 
induced significant tumor growth inhibition. Increased levels of histone acetylation persisted post-dose for 
at least 48 hours in the PC-3M2AC6 model and 24 hours in the HCT116 model 


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In the HCT116 subcutaneous human tumor xenograft, i.v administration of LBH589 induced regressions 
at doses of 20 and 40 mg/kg administered once daily 5x/wk for 3 weeks. Intravenous LBH589 treatment 
resulted in tumor stasis in the human orthotopic PC3-M2AC6 bone metastases model. 
The effects of dose scheduling on the efficacy and tolerability of LBH589 were evaluated in the HCT 116 
human tumor xenograft model. The number of i.v doses (1, 3 or 5) per week was varied, while the total 
amount of compound administered per week was kept constant at 40 mg/kg per week and the duration of 
treatment was kept constant at 3 weeks. There was no significant difference in efficacy when LBH589 
was administered for 5 consecutive days (8 mg/kg/day) followed by 2 days without treatment (12% 
tumor/control [T/C]) and when LBH589 was administered for 3 consecutive days (13.3 mg/kg/day) 
followed by 4 days without treatment (20% T/C) as compared to controls. Although a regimen of a total 
weekly dose of 40 mg/kg administered 1 day per week was less efficacious than when the same dose was 
split over 3 or 5 days, this dosing schedule produced statistically significant efficacy (48% T/C) as 
compared to controls.  
1.2.5 
Animal pharmacokinetics and drug metabolism 
The absolute oral bioavailability of panobinostat in rats was found to be ~6%; however, absolute oral 
bioavailability in dogs following a 1.5 mg/kg dose was ~50%.  The oral bioavailability of panobinostat in 
humans was estimated to be ~31% (23-40%), similar to that in dogs. 
After a single intravenous dose of radiolabeled LBH589, the drug is cleared rapidly from blood and 
extensively distributed into the organs and tissues with concentration in many tissues exceeding those in 
blood. In rats at 5 minutes post dose, the highest tissue radioactivity concentrations were measured in the 
kidney. Numerous other tissues and organs (i.e., adrenal cortex, adrenal medulla, brown fat, heart, liver, 
pancreas, salivary gland, spleen, glandular stomach, and thyroid gland) had radioactivity levels that were 
at least five times higher than those in blood. Despite the nearly complete recovery of radiolabeled 
material at 96 hours post dose, relatively low amounts of radioactivity were observed in most tissues and 
organs, with the highest levels observed in the adrenal medulla, skin of pigmented animals, and the uveal 
tract of pigmented animals. The latter observation indicates that LBH589 and/or its metabolites are bound 
to melanin. 
LBH589 was moderately bound to plasma proteins and binding was independent of concentrations over 
the 0.1 to 100 µg/mL test range in the mouse, rat, dog, and human. At 37°C, the average bound fraction in 
dogs, mice, rats, and humans measured 78.7%, 82.8%, 88.9%, and 89.6% respectively. Elimination of 
panobinostat in the rat and dog was primarily by metabolism as recovery of panobinostat in the excreta 
after oral or i.v. administration was 8.6 and 6.1- 9.8 % of the dose in rat, and ~2% and ~3% of the dose in 
the dog, respectively.  Excretion of [14C] panobinostat and drug-related material occurred primarily via 
the fecal route, with urinary excretion accounting for 12.5% (rat) and ~33% (dog) and fecal excretion 
accounting for 81% (rat) and 49% (dog) of the administered intravenous dose.  Data from the rat bile 
study indicated that excretion of drug related material was primarily by the biliary route.  The metabolism 
of [14C]- panobinostat following i.v. or oral administration in the rat and dog was extensive and involved 
many types of biotransformation reactions including reduction, oxidation, hydrolysis, and glucuronidation 
(rat only).  Metabolites M34.4 (glucuronide) and M36.9 (carboxylic acid metabolite) were major 
components following an oral dose in the rat and M36.9 was the predominant metabolite in the dog, 
accounting for about half of the total exposure to panobinostat and its metabolites.   


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Incubation of human liver microsomes with selective probe substrates of the cytochrome P450 isoforms 
showed that panobinostat is a potent inhibitor of CYP2D6 but not CYP1A2, CYP2C8, CYP2C9, 
CYP2E1, CYP2C19, and CYP3A4.  Therefore, if therapeutic concentrations of panobinostat are 
sufficiently high, drug-drug interactions may result from concomitant administration of panobinostat with 
drugs eliminated primarily by CYP2D6-dependent metabolism.  Panobinostat was found to be 
metabolized in human liver, in part, by human cytochrome P450s CYP3A4, CYP2D6, and CYP2C19.  
CYP3A4 appears to be the main enzyme involved in the oxidative metabolism of panobinostat (70-98%) 
in human liver microsomes.  It is possible that inhibitors of CYP3A would affect the clearance of 
panobinostat in vivo, however, the magnitude of interaction is dependent upon the actual fraction of the 
dose eliminated by this pathway.  This information is pending the radiolabeled human ADME study.  
Panobinostat was determined not to be an in vitro inducer of CYP1A1/2, CYP2B6, CYP2C8/9/19, or 
CYP3A mRNA or activity in primary human hepatocytes.  In addition, panobinostat was not an inducer 
of UGT1A1, ABCB1 (Pgp) or ABCC2 (MRP2) mRNAs.  It is unlikely that panobinostat would act as an 
inducer of drug metabolizing enzymes and transporters in vivo. 
1.2.6 
Animal toxicology 
Following oral administration of panobinostat using a 3-day/week (Monday, Wednesday, Friday) dosing 
schedule to rats and dogs in studies up to 26 (rats) or 39-weeks (dogs) in duration, the primary target 
organs were identified as the erythropoietic and myelopoietic systems, and lymphatic system.  Reductions 
in peripheral red cell parameters, lymphocyte, eosinophil and basophil counts and lymphoid depletion in 
thymus and lymph nodes were present in rats and dogs.  Platelet counts were decreased in rats but 
elevated in dogs.  Bone marrow atrophy was characterized by maturation arrest of the granulocytic 
lineage, consisting of a decrease in the proportion of later stage granulocytic precursors and mature cells, 
and accompanied by decreases in the number of cells from the erythroid series and an increase in the 
proportion of cells from the eosinophilic series.  Evidence of reversibility was observed for all white 
blood cell and red blood cell parameters, indicating that the bone marrow had not lost its regenerative 
capability.   
Other target organs were the gastrointestinal (GI) tract, reproductive system, thyroid and bone.  Diarrhea 
was observed at higher doses, as used in the oral rising-dose toxicity study in dogs.  Gastrointestinal 
changes ranged from mild inflammatory changes to necrosis and ulceration and was associated with 
diarrhea in dogs at doses exceeding the maximal tolerated dose (MTD).  Reproductive target organs 
included the prostate, testis and changes in estrus cycling was also noted.  Thyroid changes, including 
thyroid follicular hypertrophy (rat and dog) and follicular adenoma (1 high dose (75 mg) recovery rat in 
26-week study) were noted in both species.  Histone deacetylases have been reported to be involved in the 
negative feedback regulation of thyroid hormone (T3) and in the secretion of thyroid stimulating hormone 
(TSH) (Sasaki et al 1999), and thyroid changes may have resulted from an over stimulation of the thyroid 
epithelium by excess circulating thyroid hormone.  Hyperostosis was observed in rats at high doses of 100 
mg/kg only at 13 weeks.  This finding was not observed in longer term studies in rat and dog.  All effects 
in repeated-dose toxicity studies are considered related to the pharmacology of panobinostat.  While 
effects on the hematopoietic system showed clear signs of reversibility, histopathological changes in the 
thyroid and male reproductive organs were still present at the end of the 4-week recovery period.   
Oral administration of panobinostat during gestation to rats and rabbits is associated with embryo-fetal 
toxicity including embryo-lethality, and an increase in skeletal variations/anomalies (i.e. ossification 


 Study Protocol                                 Confidential 
16 
 
 
 
 
changes, supernumerary vertebrae, sternabrae and ribs) at doses which also produced maternal toxicity in 
rats (doses ≥ 30 mg/kg/day) and rabbit (doses ≥ 40 mg/kg/day).  No major malformations were observed.  
Fertility and early embryonic studies indicate an increase in early resorptions indicating embryo-lethality 
at doses which also produced maternal toxicity (doses ≥ 30 mg/kg/day).  The No Observable Adverse 
Effect level (NOAEL) for both fertility study in rats and embryo-fetal toxicity studies in rats and rabbits is 
10 mg/kg/day.   
Panobinostat has a clear genotoxic potential in bacterial and eukaryotic systems (mutagenic and 
endoreduplication inducing effects).  Safety pharmacology studies indicate that the compound has a low 
likelihood to interfere with vital functions of the respiratory and CNS systems.  In vitro electrophysiology 
data from the hERG channel assay revealed an IC50 of 3.9 µM and the compound showed a prolongation 
of the action potential duration in the isolated rabbit heart at a concentration of 2 µM.  There was no 
evidence of cardiovascular toxicity in the in vivo dog studies including telemetry study in animal.  
Based upon the results of preclinical studies, hematology parameters, thyroid function, and cardiac 
function monitoring assessments are included in this trial.  Panobinostat has a potential for genotoxicity 
and patients should be advised of the risk for developing secondary tumors.  Furthermore, panobinostat 
poses a reproductive risk to men and women of child bearing potential, therefore use of adequate birth 
control methods is required in the study. 
1.2.7 
Clinical experience with LBH589 in humans  
Overview of clinical experience 
In clinical studies, both oral and i.v. formulations of panobinostat are being explored for further 
development.  As of 31st December 2007, fifteen phase I and/or phase II studies have either been 
completed or are ongoing.  Preliminary safety data have been reviewed for 462 patients who received 
panobinostat in these studies.   
Most adverse events have been grade 1 or grade 2.  The most common adverse events seen in the human 
studies concern the gastrointestinal tract (nausea, diarrhea) and the hematopoietic system 
(thrombocytopenia and neutropenia).  The incidence of diarrhea is slightly more frequent in patients who 
received the oral formulation of panobinostat.  The more commonly encountered grade 3 and grade 4 
events, as anticipated from the preclinical studies, have included thrombocytopenia, neutropenia and 
fatigue.  The occurrence of thrombocytopenia appears to be related to the underlying disease (incidence is 
higher in patients with malignancies that involved the bone marrow e.g., acute myeloid leukemia, chronic 
myeloid leukemia, multiple myeloma, myelodysplastic syndrome, etc.) 
Since the dosing in this study will follow the three-times-per-week schedule, Table 1-1 below, provides a 
summary of adverse events that occurred in >15% of the patients at any dose using this schedule and the 
footnote to the table describes the grade 3 and grade 4 events that occurs in > 10% of the patients with 
solid tumors or lymphoma.   


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Table 1-1 
All grade adverse events (>15% incidence) regardless of causality, in patients receiving 
panobinostat three-times-per-week 
Preferred Term 
Dose in mg/dose given three-times-per-week (N) 
Total 
N = 129  
15 (7) 
20 (102) 
30 (13 
40 (3) 
60 (4) 
n 
n 
n 
n 
n 
N (%) 
Diarrhea 
4 
53 
10 
2 
0 
69 (53.5) 
Nausea 
4 
50 
5 
2 
1 
62 (48.1) 
Fatigue 
2 
41 
7 
2 
2 
54 (41.9) 
Thrombocytopen
ia 
2 
39 
8 
1 
3 
52 (40.3) 
Anorexia 
2 
35 
6 
1 
0 
44 (34.1) 
Vomiting 
3 
22 
4 
0 
0 
29 (22.5) 
Dizziness 
2 
20 
3 
0 
1 
26 (20.2) 
Weight 
decreased 
2 
20 
3 
0 
0 
25 (19.4) 
Dysgeusia 
0 
20 
2 
1 
0 
25 (19.4) 
Peripheral 
edema 
0 
20 
4 
0 
0 
24 (18.6) 
Anemia 
1 
14 
6 
0 
0 
21 (16.3) 
Headache 
0 
17 
4 
0 
0 
21 (16.3) 
Pyrexia 
0 
16 
3 
0 
1 
20 (15.5) 
Grade 3 and Grade 4 events: Thrombocytopenia = 18.9%; neutropenia  = 9%; diarrhea = 
5%; anemia = 4 %; dyspnea = 4%; ECG QTc prolongation = 4% 
In the first human study, panobinostat was administered intravenously on consecutive days and a 
prolongation of QTc interval on ECG was noted in a few patients.  One patient also suffered with Torsade 
de pointes.  Although comorbidities and concomitant medications could have contributed to these events, 
it was decided to discontinue the daily dosing schedule.  The most common ECG findings reported have 
included clinically non-signifcant changes in T-waves (inverted, flat, or biphasic).  Sporadic APCs and 
VPCs have also been reported. 
The most frequently encountered laboratory abnormalities include thrombocytopenia, neutropenia, some 
degree of anemia, and fluctuations in electrolytes that may not be clinically significant.  Thyroid function, 
as monitored by the measurement of TSH and free T4 have revealed fluctuations in the values of TSH, 
mostly within normal limits, and not clinically overt hyper-or hypo-thyroidism has been reported. 


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Phase I clinical experience with oral panobinostat 
Phase I study of panobinostat in patients with advanced solid tumors and NHL 
[CLBH589B2101] is a first-in-human, multi-arm, multi-center, dose-escalation study of oral panobinostat 
in adult patients with advanced solid tumors or non-Hodgkin’s lymphoma including cutaneous T-cell 
lymphoma.  In this study, panobinostat is administered orally on three dose schedules.  Arms 1, 3 and 5 
explore different dosing schedules; either Monday-Wednesday-Friday (MWF) every week (Arm 1) or 
MWF every other week (Arm 3), or Monday-Thursday (MTh) every week (Arm 5).  Arm 2 has not been 
opened.  The MTD determined in Arm 1, 20 mg/day on MWF every week, was expanded into 2 separate 
cohorts of patients with melanoma or CTCL without prior systemic therapy (Arm 4 and 6, respectively).  
Arm 1, 20 mg/day on MWF every week, was also expanded to include a pilot food effect study in 14 
patients.  This study is primarily designed to determine the maximal tolerated dose (MTD) based upon the 
dose limiting toxicity (DLT) of panobinostat as a single agent, and to characterize the safety, tolerability, 
biologic activity, preliminary efficacy and pharmacokinetic profile of panobinostat.  As of Feb 2008, a 
total of 94 patients have been enrolled, 89 patients have discontinued and 5 patients are on-going as 
follows: 1 patient in Arm 1, 1 patient in Arm 3, and 3 patients in Arm 5.  In Arm 4 (patients with 
melanoma), 2 patients were treated with 20 mg/day on the MWF every week schedule.   
In Arm 1, 3 patients were treated at 15 mg/day on MWF, 10 patients were treated at 30 mg/day on MWF 
and 19 patients have been treated at 20 mg/day on MWF [most common tumor types: CTCL (10 pts), 
melanoma (6 pts), renal (6 pts), prostate (4 pts), rhabdomyosarcoma (1 pt), mesothelioma (1 pt), colon (1 
pt), hepatic (1 pt), parotid gland (1 pt) and bladder (1 pt)].  DLT was observed in 2 patients at the 30 mg 
dose level: one grade 3 diarrhea (1pt) and one grade 4 thrombocytopenia (1 pt).  The third case of DLT in 
Arm 1 occurred at the 20 mg dose level with grade 3 fatigue.  Based upon these clinical findings, 30 mg 
was determined to be the DLT dose level and 20 mg was determined to be the MTD dose level for the 
MWF every week schedule.   
In Arm 3, 21 patients were treated at 30 mg, 2 patients were treated at 45 mg on the MWF every other 
week schedule [most common tumor types: CTCL (9 pts), colon (2 pts), lung (2 pts), NHL (2 pts), 
melanoma (1 pt), vulva (1 pt), breast (1 pt), mesothelioma (1 pt), prostate (1 pt), ovarian (1 pt), and 
hepatocellular carcinoma (2 pts)].  DLT was observed in 2 patients at the 45 mg dose level (grade 4 
thrombocytopenia) and 1 patient at the 30 mg dose level (grade 4 thrombocytopenia).  Based upon these 
clinical findings, 45 mg was determined to be the DLT dose level and 30 mg was determined the MTD 
dose level for the MWF every other week schedule.  
In Arm 5, 3 patients were treated at 30 mg, 4 patients at 60 mg, and 15 patients at 45 mg on the MTh 
every week schedule.  No DLTs were observed at 30 mg and one DLT was observed at the 60 mg dose 
level as grade 4 thrombocytopenia, and 3 DLTs were observed at 45mg as follows: grade 3 fatigue, grade 
3 QTc prolongation, and grade 4 thrombocytopenia.  The patient who experienced grade 3 fatigue at 
45mg only received 3 doses of panobinostat.  
Preliminary pharmacodynamic analysis in study [CLBH589B2101] of histones from normal PBMCs 
reveal increased acetylation at doses of 20 mg and above, and duration of effect for at least 72 hours in 
50% of patients post last dose at doses of 20 mg and 30 mg in both arms 1 and 3. 


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Although efficacy is not the primary endpoint of study [CLBH589B2101], 32 patients were enrolled in 
Arm 1 on the MWF schedule; including 10 patients with CTCL.  Of the CTCL patients, 2 patients have 
achieved a complete response (CR), 4 patients have achieved a partial response (PR), 2 patients have met 
the criteria for stable disease (SD), and 2 patients have progressive disease (PD).  In non-CTCL tumor 
types, the best response has been SD, with 6 of 22 patients having met the SD criteria (RCC [2 pts], 
prostate cancer [1 pt], melanoma [1 pt], mesothelioma [1 pt], and parotid gland cancer [1 pt]).  This 
information pertains to Arm 1 (MWF every week) only and also excludes the food effect cohort of Arm 1. 
Phase I/II study of panobinostat in patients with hematological malignancies 
The safety and tolerability of panobinostat is being explored in a multi-arm, multi-center, Phase I/II study 
[CLBH589B2102] in patients with hematological malignancies, including Hodgkin’s Lymphoma (HL).  
This study is evaluating 2 schedules of panobinostat administration: 
Arm 1 - MWF every week 
Arm 2 - MWF every other week 
Within each schedule (arm) patients are assigned to one of two subgroups based upon the type of 
hematologic malignancy that they have.  Patients with leukemia, MDS and other hematologic 
malignancies characterized by severe thrombocytopenia are included in one subgroup (X), while patients 
with lymphoma or myeloma are included in another subgroup (Y).  The subgroups differ with respect to 
the definition of hematological dose limiting toxicity (DLT); in general, neutropenia and 
thrombocytopenia are considered a DLT only in the Y subgroup. 
As of October 2008, a total of 146 patients (Arm 1 - 90 total, 64 X subgroup, 26 Y subgroup; Arm 2 - 56 
total, 33 X subgroup, 23 Y subgroup) have been enrolled in the study. 
Clinical safety in study [CLBH589B2102]   
In Arm 1 subgroup X, doses of 20 or 30 mg (n=16), 40 (n=10), 60 mg (n=16), and 80 mg (n=11) have 
been evaluated with DLTs of grade 3 fatigue noted at the 40 mg dose level (two patients) and 60 mg dose 
level (1 patient).  At the 80 mg dose level, DLTs comprised of grade 3 QTcF prolongation (2 patients), 
grade 3 fatigue (2 patients), and grade 3 cardiac insufficiency (1 patient). In Arm 1 subgroup Y, doses of 
20 or 30 mg (n=5), 40 (n=16), and 60 mg (n=5) have been evaluated, and DLT of grade 4 
thrombocytopenia has been observed in four patients each at the 40 and 60 mg dose levels.   
In Arm 2 subgroup X, doses of 30, 45, and 60  mg (n=24) have been evaluated with no cycle 1 DLTs 
noted.  At the 80 mg dose level (n=9), DLTs noted include grade 3 QTcF prolongation, atrial fibrillation, 
fatigue, and increase in bilirubin in one patient each. In Arm 2 subgroup Y, at doses of 30 and 45 mg 
(n=8)no DLT has been reported.  At the 60 mg dose level (n=5) 1 patient each had a grade 3 increase in 
troponin and grade 3 thrombocytopenia; additionally, 1 patient had grade 4 thrombocytopenia, grade 3 
fatigue, and grade 3 congestive heart failure.  
Across both arms, the most common adverse events, regardless of grade or causality, have included 
nausea, diarrhea, fatigue, anorexia, vomiting, and thrombocytopenia.   
As of October 2008, central review of a total of 4,834 post-dose ECGs from the 146 patients has been 
performed.  A dose-dependent increase in mean change from baseline QTcF has not been observed.  Five 


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patients (3%) experienced QTcF >500 msec.  However, all five patients were among the 76 patients (7%) 
treated at dose levels > 60 mg. 
Clinical activity in patients with Hodgkin’s Lymphoma in study [CLBH589B2102] 
Encouraging preliminary efficacy has been seen in the 28 patients enrolled to study [CLBH589B2102] 
with a primary diagnosis of HL. As shown in Table 1-2 below, more than 80% of the patients had been 
treated with stem cell transplant.  These patients were heavily pre-treated with antineoplastic therapies 
consisting of chemotherapeutic agents and radiotherapy. 
Table 1-2 
Demography and disease characteristics for HL patients enrolled in study 
[CLBH589B2102] 
Parameter 
Arm 1 
Panobinostat dosed three 
times per week every week 
Arm 2 
Panobinostat dosed three 
times per week every 
other week 
Number of patients treateda 
18 
10 
 
Female/male 
6 (33%) / 12 (67%) 
2 (20%) / 8 (80%) 
 
Median age, years [range] 
34 [16-52] 
31 [19-45] 
Prior antineoplastic medication regimens [range] 
5 [0-15] 
5 [0-14] 
Prior antineoplastic radiation regimens [range] 
2 [0-7] 
3 [0-12] 
Number of patients with prior stem cell 
transplantation 
15 (83%) 
8 (80%) 
a Data cut-off: October 17, 2008 
More specifically, most patients received doxorobucin, bleomycin, vinblastine, dacarbazine (ABVD) at 
their first treatment. 
Due to its significance in defining the entry criteria for this Phase II study, the use of gemcitabine-, or 
vinorelbine-, or vinblastine-containing regimens as part of prior treatments has been further assessed with 
regards to the timing of their use and for patients who achieved a response with panobinostat treatment. 
Twenty-two of the 28 patients received a vinka-alkaloid in the first-line setting; seven patients received 
one of these agents in the second-line setting and 15 patients received these drugs after second relapse 
(third-line setting) or beyond. Only 4 patients received any of these drugs as a single agent at any time. 
Responses, as assessed by CT scan and PET scan are shown in Table 1-3. 


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Table 1-3 
CT and PET responses by dose and use of prior therapy with gemcitabine or vinorelbine 
or vinblastine at any time in patients with HL enrolled in study [CLBH589B2102] 
Arm 
Dose Level (mg) 
Prior therapy with 
G/V/V 
N (%) 
Number of 
Responders by CT   
N (%) 
Number of 
Responders by 
PET               
N (%) 
Arm 1 
 
30 mg 
(n = 2) 
1 (50.0)a 
1 (50.0) 
2 (100.0) 
40 mg  
(n = 11) 
8 (73.0)b 
5 (45.0) 
8 (73.0) 
60 mg  
(n = 5) 
5 (100.0) 
1 (20.0) 
1 (20.0) 
Total-Arm 1 
n = 18 
14 (77.8) 
7 (38.9) 
11 (61.1) 
Arm 2 
 
45 mg 
(n = 3) 
2 (67.0)c 
1 (33.0) 
1 (33.0)e 
60 mg 
(n = 7) 
4 (57.0)d 
0 (0.0) 
3 (43.0)e 
Total-Arm 2 
n = 10 
6 (60.0) 
1 (10.0) 
4 (40.0) 
TOTAL 
PATIENTS 
N = 28 
20 (71.4) 
8 (28.6) 
15 (53.6) 
 
Abbreviations: CT = computerized tomography; G = gemcitabine, PET = positron emission tomography;       V = vinblastine or 
vinorelbine 
a None of the 2 patients at the 30 mg dose level in Arm 1 received G/V/V after the 1st line treatment and 1 patient had a CT 
response 
b Two patients at the 40 mg dose level in Arm 1 did not received G/V/V after the 1st line treatment and 1 of these 2 patients had a 
CT response 
c Two patients at the 45 mg dose level in Arm 2 did not received G/V/V after the 1st line treatment and 1 of these 2 patients had a 
CT response 
d Two patients at the 60 mg dose level in Arm 1 did not received G/V/V after the 1st line treatment and 2 of these patients had a 
CT response 
In Arm 1 (MWF every week) at dose levels of 30 mg, 40 mg, or 60 mg, 11 of 18 patients (2 patients at 30 
mg, 8 patients at 40 mg, and 1 patient at 60 mg) achieved a metabolic partial response (PR) as measured 
by positron emission tomography (PET) scan, and 7 of these 18 patients also achieved a PR as assessed 
by CT scan (1 patient at 30 mg, 5 patients at 40 mg and 1 patient at 60 mg).  These 18 patients have 
completed a median of 4 cycles of treatment (range 1-18, 28 days/cycle), and 5 of 18 patients remain on 
study.   
In Arm 2 (MWF every other week) 10 patients with relapsed/refractory HL have been enrolled to dose 
levels of 45 mg and 60 mg, and 4 have achieved a metabolic PR or CR (1 patient had a PR at 45 mg and 3 
patients had a PR at 60 mg ).  One patient at the 45 mg dose had a PR by CT evaluation.  In Arm 2, 
patients with Hodgkin’s lymphoma have completed a median of 5.5 cycles of treatment (range 2-18) with 
5 of 10 patients remaining on study (Ottmann, et al 2008).   
As shown in Table 1-3, the use of gemcitabine, vinorelbine, or vinblastine-containing regimens as prior 
treatment did not seem to make a difference in the patients who achieved a response. Three of the 8 
responders did not receive prior treatment with these specific drugs beyond 1st line treatment for HL.  The 
number of prior chemotherapy regimens did not seem to make a difference for achieving response.   


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Phase I study of panobinostat in patients with hormone refractory prostate cancer 
Study [CLBH589B2105] is a two-arm dose-escalating phase IA/IB study of oral panobinostat with and 
without docetaxel in patients with hormone refractory prostate cancer.  In Arm I, single agent 
panobinostat was administered at 20 mg/day on days 1, 3, and 5 every week for two weeks followed by 
one week off.  Eight patients were enrolled on this Arm.  One AE was reported that met criteria for DLT 
(grade 3 dyspnea).  In Arm 2, panobinostat dosing started at 15 mg/day on days 1, 3, and 5 every week for 
two weeks on/one week off in combination with docetaxel 75 mg/m2 i.v. once every 21 days and 
prednisone 5 mg p.o. twice daily.  Of the 8 patients treated on this Arm, 7 were considered eligible for 
MTD evaluation per protocol.  One patient experienced a DLT (grade 3 neutropenia lasting > 7 days).  
One patient was discontinued from study treatment for febrile neutropenia, 1 patient had disease 
progression, 3 patients had stable disease, and 3 patients achieved partial response with 2 remaining on 
treatment as of March 2008.  This study is now closed to enrollment in order to focus on development of 
the i.v. formulation of panobinostat in prostate cancer.  
Phase I clinical experience with IV panobinostat 
Two phase I, dose-escalation, single agent studies of panobinostat, administered as a 30-minute i.v. 
infusion examining various dose schedules of administration, were initiated. 
[CLBH589A2101] is a first-in-human, multi-arm, dose-escalation phase I study in patients with advanced 
solid tumors or NHL.  As of December 2007, 77 patients with a wide spectrum of solid tumors received 
i.v. panobinostat on three schedules of administration.  Twenty-three patients were treated on Arm 1 
[dosing on days 1-3, days 8-10 q21 days] at the following dose levels (mg/m2/day): 1.2 (2 pts), 2.4 (3 pts), 
4.8 (3 pts), 7.2 (7 pts), and 9 (8 pts).  Seven patients were treated on Arm 2 [dosing on days 1-3, days 15-
17 q28 days] at the following dose levels (mg/m2/day): 2.4 (1 pt), 4.8 (1 pt), 9.6 (1 pt), 15 (3 pts), and 20 
(1 pt).  Forty-seven patients are treated on Arm 3 [dosing on days 1, 8, and 15 q28 days] at dose levels: 10 
(8 pts), 15 (8 pts), and 20 (31 pts).   
In [CLBH589A2101] Arm 1, DLT was observed in 1 patient at the 7.2 mg/m2/day dose level (grade 2 
thrombocytopenia).  Four of 8 patients at the 9 mg/m2/day dose level experienced DLT, grade 3/4 
thrombocytopenia (3 pts) and grade 4 neutropenia (1 pt).  The myelosuppression observed was transient 
and reversible.  Due to myelosuppression, 9 mg/m2/day was determined to be the DLT dose level, and 7.2 
mg/m2/day was determined the MTD dose level for Arm 1.  
For [CLBH589A2101] Arm 2, no significant toxicity was observed at dose levels ≤ 9.6 mg/m2/day.  A 
patient treated at the 20 mg/m2/day dose level had a prolonged QT interval, grade 3 sinus bradycardia, 
grade 4 neutropenia, grade 3 thrombocytopenia, grade 2 anemia, and grade 3 transaminitis.  In addition, 
this patient had a temporary pacemaker placement and a 13 beat episode of Torsades de Pointes which 
was transient and did not cause hemodynamic compromise.  When this episode occurred, 36 hours after 
the second dose of panobinostat, the patient had significant co-morbidities including prolonged QTc at 
baseline, hypokalaemia, bradycardia, and co-administration of medications that have been shown to be 
associated with prolonged QTc (i.e. granisetron, citalopram, and prochlorperazine).  It was the judgment 
of the treating physicians that hematologic toxicity and transaminitis were related to panobinostat 
administration and a contribution of panobinostat to the cardiac events could not be ruled out.  Enrollment 
was completed at a decreased dose of 15 mg/m2/day for 3 patients and no toxicity was observed at this 


 Study Protocol                                 Confidential 
23 
 
 
 
 
dose level.  For both arms, all other adverse events were not unexpected for a patient population with 
advanced cancers.  No responses (CR or PR) have been reported.   
In [CLBH589A2101] Arm 3 panobinostat was given once a week for 3 consecutive weeks and one week 
off.  The dosing frequency was reduced from a 3-day consecutive dose to a weekly dose in effort to: 1) 
determine if the QTc prolongation is due to a drug accumulation effect; 2) reduce adverse events; and 3) 
improve drug tolerability.  All patients in Arm 3 tolerated the lower dose levels.  No DLTs were observed 
in the 10 or 15 mg/m2 dose.  Two patients on 15mg/m2 experienced thrombocytopenia (grade 3) prior to 
receiving the day 15 dose.  Thrombocytopenia was transient and reversible in ≤ 4 days.  In the 20 mg/m2 
dose, six of the 31 enrolled patients have experienced grade 3/4 thrombocytopenia (lasting > 7 days) and 
five (grade 3) anemia.  In addition, patients experienced (grade 3) dyspnea, cardiac failure, atypical 
dermatitis, fatigue, hypotension, and/or leucopenia while on study.  In this study arm, 11 patients with 
prostate cancer were treated; one patient, treated weekly at the 20 mg/m2 dose, had a PR per RECIST and 
a > 50% decrease in PSA (ongoing response after 9 treatment cycles). 
When panobinostat is given IV once weekly the greatest increases in QTcF seems to occur after the first 
weekly dose.  For reasons that are still not understood, QTcF interval prolongation substantially 
diminishes with subsequent weekly doses.  The maximum increase in QTcF occurs approximately 26 
hours after the first infusion has been given, and with the 20 mg/m2 dose the QTcF increases from 
baseline by an average of 18 msec (95% CI = 11-25 msec) at this point in time.  Mean increases in QTcF 
at points before and after are lower, and by 48 hours post-infusion there is no perceptible effect of the 
treatment on the QTcF interval.  Of 1247 ECGs performed on 21 patients treated at the 20mg/m2 dose, 
there were 3 QTc outliers; one ≥ 500msec and two > 60msec from baseline.  This data suggests that there 
is not a strong QTc signal when panobinostat is administered on a day 1, 8, 15 of a 28-day schedule.  
Study [CLBH589A2102] is a two-arm, dose-escalation phase IA/II study in patients with advanced 
hematologic malignancies examining two dose schedules of administration.  In Arm 1 (dosing on days 1-
7 q21 days), 15 patients were treated at the following dose levels (mg/m2/day): 4.8 (3 pts), 7.2 (3 pts), 9.0 
(1 pt), 11.5 (3 pts), 14.0 (5 pts).  Four DLTs (grade 3 QTcF prolongation) have been observed, in 3 
patients at 14.0 mg/m2 and in 1 patient at 11.5 mg/mg2.  All patients with QTcF prolongation were 
asymptomatic and recovered upon discontinuation of panobinostat.  One patient treated at 14.0 mg/m2 
died of pulmonary hemorrhage resulting from sepsis while on study.  Treatment with panobinostat as well 
as the patient’s underlying disease (MDS) were considered contributing factors to the sepsis.  A white cell 
differentiation syndrome (which was successfully treated with high-dose steroids) was observed in 1 
patient with refractory AML treated at 14.0 mg/m2.  Arm 2 was not opened to enrollment. 
Human pharmacokinetics 
Following a single oral dose administration, the PK profile of panobinostat was best described by a rapid 
absorption phase with a large volume of distribution followed by a biphasic distribution and elimination.  
Maximum plasma concentration (Cmax) was reached within 1 hr (range 0.5-3 hrs) and a large volume of 
distribution was consistent with an extensive tissue distribution as seen in the animals (Figure 1-2). 
Panobinostat systemic exposure and Cmax increased linearly with doses (10-80 mg) but with moderate 
inter-patient variability (CV% in AUC = 60%) (Table 1-3).  Both Cmax and AUC increased slightly after 
every MWF administrations of panobinostat with an AUC ratio (R value ~1.4) which was consistent with 
the terminal half-life and dosing interval.  The mean terminal half-life was estimated to be 15.6 (± 5) 


 Study Protocol                                 Confidential 
24 
 
 
 
 
hours.  Absolute bioavailability was estimated to be 31% (23-40%) with an inter-study comparison 
(CLBH589A2101, CLBH589B2101, and CLBH589B2102). 
Food influence on panobinostat PK was evaluated in patients with advanced cancer who received 20 mg 
panobinostat twice a week and were randomized to receive 1 of 6 treatment sequences where PK was 
evaluated weekly 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 (<45%) by food (i.e., both normal and high fat breakfast).  Since the 
overall extent of absorption was not altered by food, food is unlikely to significantly impact 
panobinostat’s systemic exposure in cancer patients. It is recommended that panobinostat can be 
administered without regard to food in future studies. 
Figure 1-1 
Mean plasma concentrations of panobinostat following a single i.v or oral panobinostat 
administration 
0
0
1
10
100
1000
0
5
10
15
20
25
30
35
40
45
50
Time (hr)
20 mg PO
20 mg/m2 IV
30 mg PO
45 mg PO
 
Table 1-4  
Mean panobinostat PK parameters following i.v. or oral administration 
Daily dose 
(No. of patients) 
Median Tmax  
(hr) 
Mean [CV%] Cmax 
(ng/mL) 
Mean [CV%] AUC0-∞ 
(ng*hr/mL) 
PO 20 mg (n=42) 
1 
23 [57] 
183 [56] 
PO 30 mg (n=40) 
1 
37 [55] 
288 [51] 
PO 40 mg (n=14) 
0.7 
48 [67] 
235 [65] 
IV 20 mg/m2 (n=26) 
0.48 
836 [48] 
922 [42] 
Abbreviations: IV = intravenous, PO = oral 


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Preliminary pharmacodynamic analysis evaluating acetylated histones status in peripheral blood 
mononuclear cells (PBMCs) revealed that acetylated histones were maintained over 72 hours in majority 
of the patients, supporting a three-times weekly schedule [CLBH589B2101]. 
Panobinostat underwent reduction, oxidative metabolism, hydrolysis, and glucorindation in human livers.  
The oxidative metabolism of panobinostat was found to be mediated by CYP3A4/5 and CYP2D6 in 
human liver microsomes, of which CYP3A contribution is major.  Using results from clinical drug-drug 
interaction study [CLBH589B2110], it is predicted that panobinostat fraction metabolized by CYP3A is 
37.5% (Ohno, et al 2008). 
A clinical drug-drug interaction study between ketoconazole, a potent CYP3A inhibitor, and panobinostat 
was evaluated in 14 cancer patients in study [CLBH589B2110]. Single-dose panobinostat at 20 mg did 
not change ketoconazole concentrations.  Multiple ketoconazole doses at 400 mg increased Cmax and AUC 
of panobinostat by 1.6- and 1.7-fold, respectively, but with no change in Tmax.  The < 2-fold increase in 
panobinostat AUC upon co-administration suggests that CYP3A contribution to the total panobinostat 
clearance is low.  The observed interaction is not considered clinically relevant, as panobinostat doses at 
least 2-fold greater than 20 mg (40 mg 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. 
Electrocardiographic experience with panobinostat  
Panobinostat i.v. 
A total of 3,272 pre- and post-dose ECGs have been collected from 47 patients who received intravenous 
panobinostat at various doses in 2 Phase I studies as shown in the table below. 
Table 1-5  
Studies and the number of patients evaluated for QTcF monitoring in the intravenous 
panobinostat studies 
Study Number 
Dose  
(mg/m2) 
Number of 
Patients 
Number of ECGs 
CLBH589A2101 
(Dosing on Days 
1, 8, and 15 every 
28 days) 
10.0 
8 
579 
15.0 
8 
656 
20.0 
31 
2037 
CLBH589A2102 
(Dosing on Days 
1-7 every 21 days - 
a schedule that will 
not be further 
explored) 
4.8 
3 
40 
7.2 
3 
25 
9.0 
1 
12 
11.5 
3 
30 
14.0 
5 
42 
The maximum mean change of QTcF from baseline was noted to be 17.95 msec (range of QTcF change 
from baseline values = -64.66 msec: 126.83 msec).  A delayed effect for maximal QTcF increase was 
noted at approximately 24 hours after dosing.  However, at the highest dose (20 mg/m2), similar 
elevations of approximately 10 msec – 18 msec were observed spanning from 4 hours post-1st dose to day 
2.   


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26 
 
 
 
 
• Four patients had at least 1 ECG that was > 60 msec increase from baseline or absolute QTcF > 500 
msec  
• Two of these patients had the ECG finding sometime in the first two days, but at least 4 hours 
post-dose.  
• The third patient experienced the >60 msec increase during cycle 3 
• The fourth patient had a QTcF value of 512 msec on day 2.  This patient was the only one on the 
weekly IV schedule to experience QTcF > 500 msec.  
All four patients experiencing either > 60 msec increase or QTcF > 500 msec were at the highest dose.  In 
addition, in Arm 2 of [CLBH589A2101] there was one event of Torsades de Pointe in a patient treated at 
the 20 mg/m2/day dose, 36 hours after 2 consecutive iv dosings, who entered the study with 
hypokalaemia, and at time of event was using drugs that are known to prolong QT (i.e. citalopram, 
prochlorperazine and granisetron) and presenting with bradycardia (see Section 1.2.6).  
Additionally, 2,249 post-dose ECGs obtained from 55 patients enrolled to the [CLBH589A2101] and 
[CLBH589A2102] i.v. studies (where a daily x 3 schedule was used) were analyzed for changes in QTc 
interval duration.  These schedules are no longer in use.  For Arms 1 & 2, central tendency analysis (mean 
change from baseline) demonstrated no measurable change in QTc in the 24 hours after day 1 dosing.  
However, a dose related increase in QTc of < 20 msec was detected after day 3 of dosing.  An analysis of 
outlier ECGs (ECGs with > 60 msec change from baseline and/or absolute QTcF > 500 msec) 
demonstrated that 10 of the 12 patients with at least 1 outlier ECG, had their initial outlier ECG on day 3 
of dosing or later.   
Together these data suggests that panobinostat has a delayed effect on QTc, and that the effect may 
require administration of consecutive doses.  In Arm 3 of study [CLBH589A2101] where a weekly 
schedule was used, only two out of 47 patients experienced a QTcF change from baseline > 60 msec and 
one patient experienced a new absolute QTcF ≥ 500 msec.  This data suggests that accumulation of 
panobinostat from the daily x 3 dosing may have contributed to the delayed effect on QTc while the QTc 
change is less apparent from the weekly dosing schedule.  
Panobinostat oral 
As of November 2007 a total of 5549 ECGs have been collected from 132 patients who received oral 
panobinostat at a dose of 20 mg three times every week in a 28 day cycles.  Of the 132 patients, 44 
patients were treated in the two phase I studies (CLBH589B2101 and CLBH589B2102) and 108 have 
been treated in four disease specific phase II studies enrolling patients with CTCL, multiple myeloma, 
chronic myelogenous leukemia (CML) or CML with blast crisis.  Patients had received panobinostat for a 
mean number of 66 days (range 1-815 days; SD = 87 days).   
Preliminary analysis of the data suggests that panobinostat is generally well tolerated with minimal effects 
on QTc interval following oral dosing.   
The mean change of QTcF from baseline was less than 5 msec for time points at which data were 
available for more than 6 patients.  The maximum change from baseline was seen in Cycle 1, Day 5, Hour 
3 = 4.20 msec [range of QTcF change from baseline values = 26.83 : 70.83] and a slight delayed effect 
was noted.   


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A total of 8 patients have been considered as outliers (ECG findings of QTcF > 480 msec or change of > 
60 msec from baseline): 
• Number of patients with QTcF > 500 msec = 2 
• Number of patients with QTcF > 480 msec but < 500 msec  and a QTcF change from baseline > 60 
msec = 2 
• Number of patients with QTcF > 480 msec but < 500 msec and a QTcF change from baseline < 60 
msec = 1 
• Number of patients with only QTcF change from baseline > 60 msec = 3 
In all patients with prolonged QTcF or with >60 msec change from baseline, confounding factors were 
present (e.g., hypokalaemia, severe bradycardia, pulmonary embolism, myocardial infiltration in context 
of hypereosinophilia, complete left bundle branch block, atrial fibrillation) and could have contributed to 
the prolongation.  Additionally, continuation of dosing despite the finding of QTcF prolongation (after a 
break) did not worsen the observation and in most cases, the ECG reverted to baseline or normal.   
The timing of the QTcF prolongation or observation of > 60 msec change from baseline in these studies 
have been: 
• Day 1 of Cycle 1 - 1 patient 
• Day 5 of Cycle 1 and on Day 113 - 1 patient 
• Day 5 of Cycle 1 and Day 15 - 1 patient 
• Day 5 of Cycle 1 - 3 patients 
• Day 17 of Cycle 1 - 1 patient 
• Day 26 of Cycle 1 - 1 patient 
No patient dosed at the 20 mg/dose on MWF experienced prolongation of QTc in Cycle 2 or beyond 
except for the 1 patient (on Day 113 as stated above).   
A review of the serious adverse events received by Novartis as recommended in the guideline ICH E14 
(i.e. sudden death, ventricular arrhythmia, ventricular tachycardia, syncope, seizures) found 3 additional 
cases of QTc prolongation.  These were reported as syncope.  In these 3 cases confounding factors of 
vasovagal signs and hypotension were present. 
In study [CLBH589B2102], 2,584 post-dose ECGs have been reviewed centrally on 77 patients who all 
received dose levels higher than 20 mg (i.e. 30 mg, 40 mg, 60 mg, and 80 mg) on various dosing 
schedules. Among those, 1384 post-dose ECGs have been centrally reviewed in 43 patients who all 
received doses on the MWF weekly schedule specifically. The following results were found: 
• 30 mg dose: 391 ECGs in 12 patients - no event of QTcF > 500 msec or QTcF > 60 msec increase 
from baseline  
• 40 mg dose: 540 ECGs in 16 patients - no event of QTcF > 500 msec or QTcF > 60 msec increase 
from baseline  
• 60 mg dose: 370 ECGS in 12 patients, 1 patient with QTcF to >500 msec, and 2 patients with QTcF > 
60 msec increase from baseline  


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28 
 
 
 
 
• 80 mg dose: 83 ECGs in 3 patients, 1 patient with QTcF to >500 msec, and 2 patients with QTcF > 60 
msec increase from baseline  
In the phase I studies, cardiac troponin, creatinine phosphokinase (CK) and MB isoenzyme of CK (CK-
MB) were tested at baseline and Day 8 of cycle 1, CK and CK-MB were slightly elevated in 2 patients but 
not clinically significant.  Based upon the available data, panobinostat oral has demonstrated minimal 
clinically meaningful ECG changes to date. 
Relationship between panobinostat plasma concentrations and QTcF 
As presented in Figure 1-3 (i.v.) and Figure 1-4 (po) below, the maximum change of QTcF from baseline 
does not coincide with the peak plasma concentration-time course of panobinostat for either route of 
administrations suggesting a possible delayed effect.   
It is noteworthy (as shown in Table 1-3) that the mean maximum concentration (Cmax) and overall 
exposure (AUC) for the oral formulation is at least 30-fold and 5-fold, respectively lower than that has 
been seen with intravenous panobinostat.  It does not appear that QTcF change is directly related to 
panobinostat plasma concentrations. 
Figure 1-2 
QTcF change from baseline over time vs. panobinostat conc-time course following the first 
intravenous panobinostat weekly doses   
All data points with n>3, all dose levels
QTcF change
PK conc
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Time from dose (hr)
0
10
20
30
40
50
60
0
100
200
300
400
500
600
700
 


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Figure 1-3 
QTcF change from baseline over time vs. panobinostat conc-time course following the first 
oral panobinostat doses of a MWF schedule 
All data points with n>3, all dose levels
QTcF change
PK conc
-10
0
10
20
Time from dose (hr)
0
10
20
30
40
50
0
10
20
30
40
 
Biomarker analysis 
Chemokine production, including TARC (CCL17) and MDC1 (CCL22), are the major mechanism by 
which RS cells drive the intratumoral accumulation of reactive cells (Hasenclever and Diehl 1998). 
Crucially, TARC and MDC1 levels are elevated in the blood of HL patients and levels fall in response to 
therapy. Eotaxin is an eosinophil specific chemotactic agent secreted by tumour associated fibroblasts, 
and serum levels correlate directly with the degree of eosinophilic infiltration in HL, which has 
historically been correlated with a poorer survival. Pre and post-Panobinostat levels of TARC, eotaxin 
and MDC1 will be monitored and correlated to PET responses. 
The intense inflammatory infiltrate induced by the HL cells is driven by cytokine and chemokine 
secretion.  IL-10 is an anti-inflammatory cytokine secreted by RS cells, which down-regulates the Th1 
immune response (normally associated with increased IFN-gamma and IL-2 and decreased IL-4, IL-10, 
and TGF-beta) in HL and is associated with an inferior overall response to chemotherapy (Barath, et al 
2006).  Activated TGF beta is also secreted by RS cells and eosinophils, stimulating fibroblast 
proliferation and collagen synthesis, and high serum levels are consistently associated with nodular 
sclerosing HL. Pre and post-panobinostat levels of IL-2, IL-4, IL-10, IFN-gamma and TGF-beta will be 
measured and correlated with PET responses. 
In order to assess biomarkers such as Akt in archival tissue and to correlate with response to panobinostat, 
collection of the archival tumor sample is required when available.   


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Exploratory analysis to assess changes in adaptive immunity as a surrogate marker of the reactive cellular 
infiltrate may be performed by optional patient consent. Changes in the protein acetylation status of 
circulating T-cells may also be assessed as a surrogate marker of the reactive cellular infiltrate.  


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2 Study rationale/purpose 
Our in vitro preclinical data indicate that LBH589 shows high activity on WM cells from patients and 
WM cell lines. HDAC activity in WM cells is elevated, indicating that targeting HDAC will lead to 
cytotoxicity of the cells. LBH589 has significant clinical activity in other lymphomas and other 
hematological malignancies. Based on this data, we believe that LBH589 will demonstrate a high 
response rate in patients with relapsed or refractory WM. 
3 Study objectives 
3.1 
Primary 
The primary objective of the phase II study is to assess the overall response rate 
(CR+nCR+VGPR+PR+MR) in patients with relapsed or relapsed/refractory WM. 
3.2 Secondary 
1. To evaluate the safety of LBH589 in patients with relapsed or relapsed/refractory WM. 
2. To assess duration of response, time to progression, and progression free survival in these patients. 
 
3. To determine the pharmacodynamic effects of LBH589 on histone acetylation, induction of 
apoptosis and activity on the NFkB and Akt pathways in samples obtained pre and post-treatment 
with LBH589.  
4 Overall study design 
This phase II study is designed to assess the toxicity profile and the proportion of overall confirmed 
responses (CR+nCR+VGPR+PR+MR) in patients with relapsed or refractory WM. This will study the 
effect of single agent LBH589 on response in these patients.  
 
A cycle will be 28 days (+/- 5 days). Response will be assessed after 2 cycles. If patients have stable 
disease or response, then they will continue on therapy until progression or unacceptable toxicity. Patients 
who show progression after 2 cycles will come off therapy.  
 
 
 
 
 
 
 
 


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Protocol Schedule: 25 mg/day PO on Mondays, Wednesdays and Fridays for every cycle.  
 
A cycle is 28 days (+/- 5 days). 
 
Patients will be assessed for toxicity and response after 2 cycles and then after every cycle for the first 6 
cycles at the participating center. After 6 cycles, patients will be assessed every 3 months for response at 
the participating center.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LBH589 25 mg/day PO on Mondays, 
Wednesdays and Fridays for 28 days, +/- 5 
days (one cycle). 
 
Continue for 2 cycles 
Progression, 
unacceptable toxicity, 
refusal, or alternative 
therapy at any time 
Stable disease or 
Response 
Continue until progression, 
unacceptable toxicity, refusal or 
alternative therapy at any time 
Stop therapy 
Event Monitoring 
 Event Monitoring 
Registration 


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33 
 
 
 
 
5 Study population 
5.1 
Patient population 
A minimum of 14 and a maximum of 37 patients will be enrolled on this phase II study. 
5.2 
Inclusion and exclusion criteria 
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, which assure that all inclusion and 
exclusion criteria have been satisfied, must be reviewed by a participating 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  
1. Male or female patients aged ≥ 18 years old. 
2. Ability to provide written informed consent prior to participation in the study and any related 
procedures being performed. 
3. Patients must have received prior therapy for their WM, any number of prior therapies is allowed. 
4. Patients must have relapsed or refractory WM. Patients with relapsed WM must be symptomatic 
and/or have a ≥ 25% increase in their serum monoclonal IgM protein from their last treatment. 
Patients with refractory WM must have no response to prior therapy for at least 3 months. 
5. Monoclonal IgM protein in the blood of ≥ 0.5 g/dL and ≥ 10% lymphoplasmacytic cells in the bone 
marrow during any previous bone marrow. 
6. Patients must meet the following laboratory criteria: 
• ANC ≥ 1.0 x 109/L 
• Hemoglobin ≥ 8 g/dl   
• Platelets ≥ 75 x 109/L  
• AST and ALT ≤ 3 x ULN  
• Serum bilirubin ≤ 1.5 x ULN 
• Serum potassium ≥ LLN 
• Calculated serum creatinine clearance ≥ 50 mL/min  
• Serum magnesium ≥ LLN 
• Serum phosphorus ≥ LLN 
7. Clinically euthyroid 
Note: Patients are permitted to receive thyroid hormone supplements to treat underlying 
hypothyroidism. 


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34 
 
 
 
 
8. ECOG Performance Status of ≤ 2 
 
Exclusion criteria 
1. Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer. 
2. Patients who will need valproic acid for any medical condition during the study or within 5 days prior 
to first LBH589 treatment. 
3. Peripheral neuropathy ≥ CTCAE grade 2. 
4. Impaired cardiac function or clinically significant cardiac diseases, including any one of the 
following: 
• Patients with congenital long QT syndrome 
• History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of atrial 
arrhythmia are eligible but should be discussed with the Principal Investigator 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 > 450 msec  
• Right bundle branch block + left anterior hemiblock (bifascicular block) 
• Patients with myocardial infarction or unstable angina  ≤ 6 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) 
5. Impairment of GI function or GI disease that may significantly alter the absorption of  LBH589.  
6. Patients with diarrhea > CTCAE grade 1.  
7. 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. 
8. Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade 
de pointes if treatment cannot be discontinued or switched to a different medication  prior to starting 
study drug.    
9. Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and 
active metabolites (which ever is longer) and who have not recovered from side effects of those 
therapies. 
10. Patients who have received chemotherapy or rituximab within < 3 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.  
11. Patients who have received corticosteroids ≤ 2 weeks prior to registration. Patients may be receiving 
chronic corticosteroids if they are being given for disorders other than Waldenstrom’s 
Macroglobulinemia (e.g. hemolytic anemia). 


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12. Patients with an active bleeding tendency or receiving any treatment with therapeutic doses of sodium 
warfarin (Coumadin®) or coumadin derivatives. Low doses of Coumadin® (e.g. ≤ 2 mg/day) to 
maintain line patency (if applicable) is allowed. 
13. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not 
recovered from side effects of such therapy. 
14. 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 women ≥ 55 years of age 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 7-days 
of registration.   
15. Male patients whose sexual partners are WOCBP not using effective birth control. 
16. Patients with a prior malignancy within the last 5 years (except for basal or squamous cell carcinoma, 
or in situ cancer of the cervix). 
17. Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline 
testing for HIV and hepatitis C is not required. 
18. 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. 
6 Treatments 
6.1 
Investigational therapy 
LBH589 will be provided by Novartis. Oral LBH589 will be supplied as 5 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, LBH589 will be administered orally as 25 mg/day orally on Mondays, Wednesdays and 
Fridays. 
Patients should be instructed to take their oral dose of LBH589 at the same time each morning during 
cycle 1. Patients may choose to take their LBH589 in the morning or evening after the completion of 
cycle 1. Each dose of LBH589 should be taken with an 8 oz / 240 ml glass of water, with or without food. 
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 the patient forgets to take his/her dose at the scheduled time on treatment day, then he/she should take 
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 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. 


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36 
 
 
 
 
If the patient vomits after taking LBH589, that dose should be skipped. The patient is not to take another 
LBH589 capsule.  
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. 
6.1.1 Cardiac precautions 
All patients must have an assessment of serum potassium, calcium, phosphorous and magnesium ≤ 72 
hours prior to the administration of oral LBH589 on day 1 of cycle 1 and the results must all be ≥ LLN 
before the first dose of LBH589 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 biochemistry test to demonstrate values ≥ LLN. 
These values must be ≥ LLN before the patient is re-dosed with oral LBH589. 
Patients must be instructed to not take LBH589 if their most recent biochemistry values demonstrates 
potassium, calcium, phosphorous or magnesium < LLN. At a minimum, potassium, calcium, phosphorous 
and magnesium 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, calcium, phosphorous or magnesium levels.   
6.2 
Treatment cycle and duration:  
A treatment cycle is 28 days (+/- 5 days). Patients will be assessed every 28 days (+/- 5 days). After 6 
cycles of monthly evaluations, patients will be assessed every 3 months (+/- 7 days). 
Patients may continue treatment with oral LBH589 until they experience unacceptable toxicity that 
precludes further treatment, disease progression, and/or at the discretion of the investigator. Please see 
Section 6.3.4 for further details.  
6.3 
Dose modification, 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 LBH589 must be interrupted 
because of unacceptable toxicity, drug dosing will be interrupted or modified according to rules described 
in Tables 6-1 and 6-2 and Figure 6-1. Toxicity will be assessed using the NIH-NCI Common 
Terminology 
Criteria 
for 
Adverse 
Events, 
version 
3.0 
(CTCAEv3.0, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). All interruption or 
changes to study drug administration must be recorded.  
 


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6.3.1 
Dose modifications for non-hematologic adverse events (see section 6.3.2 for dose 
modifications for prolonged QTc):  
Table 6.1 
Criteria for dosing delays, dose-reductions, and re-initiation of treatment due to study drug-
related toxicity (excluding QTc prolongation) 
Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 
3.0 (CTCAEv3.0, http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). 
Treatment modifications are based on adverse events. Each adverse event should be assessed for 
relationship to LBH589 so that modifications can be made accordingly. Further clarification can be 
obtained in consultation with the PI. If multiple toxicities are noted, the dose adjustments should be made 
according to the most severe toxicity guidelines. Dose modification recommendations listed below are 
general guidelines, and appropriate dose adjustments for patient safety should be done if needed after 
approval by the PI or her representative. 
 
Dose modifications may be made at any time during a cycle of therapy. Toxicities will be collected and 
monitored throughout each cycle. 
 
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 LBH589 
therapy, the patient may be able to continue treatment with a 10 mg dose reduction at the Investigator 
discretion, after resolution of the adverse event. 
 
Worst Toxicity 
CTCAE Grade* unless otherwise 
specified (Value) 
Dose Modification Guidelines at any time during a cycle of therapy (including 
intended day of dosing) 
HEMATOLOGIC TOXICITIES 
 
 
Thrombocytopenia 
Grade 4 (< 25 x 109/L) 
Temporarily discontinue LBH589 dosing until 
resolved to < grade 2, or baseline, then: 
- 
restart LBH589 reduced by one dose level 
 
Neutropenia (ANC) 
Grade 4 (ANC < 0.5 x 109/L) 
Temporarily discontinue LBH589dosing until 
resolved to < grade 3, or baseline, then: 
- 
if resolved within 7 days after suspending 
LBH589, then restart LBH589at an 
unchanged dose level 
- 
If resolved in more than 7 days after 
suspending LBH589, then restart 
LBH589reduced by one dose level 
 
Febrile neutropenia  
(ANC < 1.0 x 109/L, fever  
> 38.5 oC) 
 
Temporarily discontinue LBH589 dosing until 
fever resolved and ANC < grade 2, then restart 
LBH589 reduced by one dose level 
 
NON-HEMATOLGOICAL TOXICITIES 
CARDIAC 
Cardiac – Prolonged QT interval ** 
Please refer to Section 6.3.2 


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Worst Toxicity 
CTCAE Grade* unless otherwise 
specified (Value) 
Dose Modification Guidelines at any time during a cycle of therapy (including 
intended day of dosing) 
GASTROINTESTINAL 
Diarrhea 
Grade 2 (4-6 stools/day over baseline, 
etc) despite the use of optimal 
antidiarrheal medications 
Temporarily discontinue LBH589 
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 LBH589 
dosing until resolved to < grade 1, or 
baseline, then restart LBH589 reduced 
by one dose level.  
 
Grade 4 (life-threatening 
consequences, hemodynamic collapse, 
etc.) despite the use of optimal 
antidiarrheal medications 
Discontinue LBH589 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 LBH589 
dosing until resolved to < grade 1, or 
baseline then restart LBH589 reduced 
by one dose level 
 
   FATIGUE 
Fatigue 
Grade 3 
Temporarily discontinue LBH589 
dosing until resolved to < grade 2, or 
baseline, then: 
- 
if resolved within 7 days after 
suspending LBH589, then restart 
LBH589 at an unchanged dose 
level 
- 
If resolved in more than 7 days 
after suspending LBH589, then 
restart LBH589 reduced by one 
dose level 
 
Fatigue 
Grade 4 
Temporarily discontinue LBH589 
dosing until resolved to < grade 2, or 
baseline, then  
- 
restart LBH589 reduced by one 
dose level 
 


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Worst Toxicity 
CTCAE Grade* unless otherwise 
specified (Value) 
Dose Modification Guidelines at any time during a cycle of therapy (including 
intended day of dosing) 
HEPATIC 
Total Bilirubin 
Grade 3 or 4 
Temporarily discontinue LBH589 dosing until 
resolved to < grade 2, or baseline then restart 
LBH589 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 LBH589 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 LBH589 at unchanged dose level 
- 
If resolved in more than 7 days, then reduce 
LBH589 by one dose level 
 
> 10 x ULN 
Temporarily discontinue LBH589 dosing until 
resolved to < grade 1, or baseline then: 
- 
restart LBH589 reduced by one dose level 
 
Glomerular filtration rate 
Calculated 
GFR > 30 mL.min 
No change in dosing 
 
Calculated  
GFR 30 – 20 mL/min 
Omit LBH589 until resolved < grade 1. Restart 
LBH589 with one dose-reduction 
 
Calculated  
GFR < 20 mL/min OR 
Chronic dialysis OR 
Renal transplantation 
Omit LBH589 and discontinue participant from 
study. 
All dose modifications should be based on the worst preceding toxicity. 
* Common Terminology Criteria for Adverse Events (CTCAE Version 3.0) 
** It is critical that electrolyte abnormalities be followed closely and corrected prior to dosing 
***See also concomitant medication Section 6.4 
 
6.3.2 Dose modifications for prolonged QTc 
QTc monitoring schedule 
Patients on this study will have extensive QTc monitoring on specified days. If a prolonged QTc interval 
is noted, additional days of extensive QTc monitoring may be required (see details below). Treatment 
decisions will be based on QTc as determined by the automated machine reading at Dana-Farber Cancer 
Institute (DFCI) or participating centers (or as measured and calculated by trained personnel at DFCI or 
participating centers).   


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All ECG tracings will be submitted to eRT for central review and results will be faxed back to DFCI or 
participating center within 3 working days (72hr turn-around time). The ECG interpretations from eRT 
will be the formal data entered into the clinical trial database. 
ECG requirements:  
Screening: 
•  Single ECG to assess eligibility.   
Baseline/Cycle 1: 
• 
 Pre dose ECGs on cycle 1 day 1: 3 ECGs will be performed 5-10 minutes apart before the first dose. 
On day 1 post the first dose, 3 ECGs will be performed 5-10 minutes apart 3 hrs post dose. On day 5 
(+ 2 days), 3 ECGs pre-dose, and 3 ECGs 3-hours post dose will be performed (these ECGs may be 
completed at the participant’s local doctor’s office and faxed to the participating center, see note 
below). These ECGs will be performed only for the first cycle.  
Cycle 2 through Cycle 8: 
• Three pre-dose ECGs will be performed 5-10 minutes apart on Day 1.   
 
Note: If participants choose to have Cycle 1 Day 5 ECGs performed at their local physician’s office, they 
will be given the information sheet provided in Appendix 6. This information sheet must accompany them 
to their doctor’s office at the time of the ECGs. Participants are only to proceed with LBH589 dosing after 
the ECGs have been sent, and reviewed by a study doctor at DFCI or participating center.  
 
Note: If participants experience QTc > 480 msec in Cycle 1 or in any subsequent cycle, then repeat Cycle 
1 monitoring schedule until they have a Cycle with no QTc prolongation. 
 
Note: If no significant QTc prolongation is noted during first 8 Cycles, the QTc monitoring is no longer 
required and may be performed at the Investigator’s discretion, if medically indicated.    
 
At end of treatment 
• A single ECG will be performed at the end of study treatment 
  
Table 6.2 outlines the criteria for interruption and re-initiation of LBH589 treatment due to QTc changes. 
Table 7-2 outlines the schedule for ECG monitoring. 
General monitoring principles 
1. On treatment days when ECGs are to be obtained, the patients will take their medication in the clinic.  
For the multiple pre-dose ECGs, the average of the QTc intervals must be ≤ 450 msec before the 
patient is dosed. 


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41 
 
 
 
 
2. If the patient does not meet the QTc criteria for dosing at any time, the Principal Investigator must be 
notified immediately. In addition, the patient’s serum potassium, magnesium, calcium and phosphorus 
must be measured immediately, and the patient must receive supplements to correct any low values. 
3. At any time, if any ECGs (pre- or post-dose) demonstrate a QTc value ≥ 480 msec the Principal 
Investigator must be notified and transmit ECGs to DFCI immediately.  In addition, the patient’s 
serum potassium, magnesium, calcium and phosphorus must be measured immediately, and the 
patient must receive supplements to correct any low values.   
Any final decisions concerning any dose modification or patients discontinuing study drug 
permanently will be based on assessments of the ECG by the Principal Investigator at the Dana-
Farber Cancer Institute and evaluated via a discussion with the Principal Investigator. 
4. In general, dose reductions will occur in the following circumstances: 
• Repeat dosing delays due to prolonged QTc intervals 
• Multiple QTc ≥ 480 msec but < 500 msec 
• Any QTc ≥ 500 msec but < 515 msec 
For patient’s requiring a dose reduction, extensive ECG monitoring will be done on the first day of 
the new reduced-dose as well as 5 and 26 days following the first day of the lowered dose. 
5. Any QTc ≥ 515 msec will lead to the patient being permanently discontinued from study treatment. 
All other cardiac events should be treated as per the local standard of care or referred to a Cardiologist by 
the investigator (if clinically indicated) 


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42 
 
 
 
 
Table 6.2   Criteria for dosing delays, dose-reductions, and re-initiation of treatment due to study 
drug-related QTcF abnormalities  
 
ECGs to be performed at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy (including 
intended day of dosing) 
Dose modifications are based on local readings of the average QTcF of triplicate ECGs. 
Cycle 1 dose modification criteria: 
Pre-dose on cycle 1, 
days 1 and 5: 
3 ECGs separated by 5-
10 minutes, obtained 
prior to panobinostat 
dosing 
 
 
 
 
 
 
 
 
Day 1: 
Average QTcF > 450 
msec 
 
 
 
 
 
 
Day 5: 
Average QTcF: 
≥ 480 msec to < 500 
msec 
OR 
> 60 msec increase from 
baseline average 
Check and correct the patient’s serum potassium, 
magnesium, calcium and phosphorus immediately, 
as well as evaluate con-meds. 
Notify Sponsor and transmit to eRT immediately 
for prompt review. 
 
If abnormality noted on Day 1 of Cycle 1: 
Repeat 3 pre-dose ECGs. 
If the 3 pre-dose ECGs: 
Do not meet criteria again, discontinue patient 
from study. 
Do meet criteria for dosing; administer study drug 
treatment.  
 
If abnormality noted on Day 5 of Cycle 1: 
Delay dose at least 3 days and repeat 3 pre-dose 
ECGs. 
If the repeat 3 pre-dose ECGs: 
Do not meet pre-dose ECG criteria again, 
discontinue patient from study. 
Do meet pre-dose ECG criteria for dosing and QT 
prolongation determined to be related to study 
drug, resume study drug treatment with a dose 
reduction of 5 mg. If however, it was determined 
that the QT prolongation was secondary to 
electrolyte abnormalities or con-meds, continue at 
the same dose level. Repeat ECGs - pre-dose (x3), 
3-hours post-dose (x3), on the next scheduled 
dosing day.  


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ECGs to be performed at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy (including 
intended day of dosing) 
Dose modifications are based on local readings of the average QTcF of triplicate ECGs. 
 
Average QTcF ≥ 500 
msec 
Check and correct the patient’s serum potassium, 
magnesium, calcium and phosphorus immediately. 
Notify Sponsor and transmit to eRT immediately 
for prompt review. 
Discontinue patient from study therapy. 
If however, it was determined that the QT 
prolongation was secondary to electrolyte 
abnormalities or con-meds: 
Omit dose. On the next scheduled dosing day 
continue at the same dose level. Repeat ECGs - 
pre-dose (x3), 3-hours post-dose (x3), on the next 
scheduled dosing day. 
Post-dose on cycle 1, 
days 1 and 5: 
3 ECGs separated by 5-
10 minutes, obtained 3 
hours +/- 0.5 hours after 
panobinostat dosing: 
 
Average QTcF ≥ 480 
msec to < 500 msec 
OR 
> 60 msec increase from 
baseline 
Check and correct the patient’s serum potassium, 
magnesium, calcium and phosphorus immediately, 
as well as evaluate con-meds. 
Monitor ECG hourly or by telemetry until at least 
2 consecutive hourly ECGs performed at least 6 
hours post dose are <480. 
Notify Sponsor and transmit to eRT immediately 
for prompt review. 
Next scheduled dosing day: repeat 3 pre-dose 
ECGs. 
If these 3 pre-dose ECGs: 
Do not meet pre-dose ECG criteria for dosing 
(average QTcF ≤ 480 msec), discontinue patient 
from study. 
Do meet pre-dose ECG criteria for dosing (average 
QTcF ≤ 480 msec) and QT prolongation 
determined to be related to study drug, resume 
study drug treatment with a dose reduction of 5 mg. 
If however, it was determined that the QT 
prolongation was secondary to electrolyte 
abnormalities or con-meds, continue at the same 
dose level. Repeat ECGs - pre-dose (x3), 3-hours 
post-dose (x3) on the next scheduled dosing day. 


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ECGs to be performed at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy (including 
intended day of dosing) 
Dose modifications are based on local readings of the average QTcF of triplicate ECGs. 
Average QTcF ≥ 500 
msec 
Check and correct the patient’s serum potassium, 
magnesium, calcium and phosphorus immediately. 
Notify Sponsor and transmit to eRT immediately 
for prompt review. 
 
Discontinue patient from study therapy 
If however, it was determined that the QT 
prolongation was secondary to electrolyte 
abnormalities or con-meds: omit dose. On the next 
scheduled dosing day continue at the same dose 
level. Repeat ECGs - pre-dose (x3), 3-hours post-
dose (x3), on the next scheduled dosing day. 
 
6.3.3 Dose Reduction levels for LBH589 
Dose reduction levels for LBH589 
 
Dose Level 
LBH589 Dose 
Starting Dose 
25 mg (M, W, F) 
-1 
20 mg (M, W, F) 
-2 
20 mg (M, W, F every other week)* 
-3 
15 mg (M, W, F every other week)* 
 
Once a dose has been reduced, it cannot be re-escalated. 
*Note: If a patient is dose reduced to dose level -2, patients will be instructed to take 20 mg of LBH589 
on M, W, F every other week. Cycles will remain 28 (+/- 5 days) long. 


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45 
 
6.3.4 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. Subject’s condition no longer requires study treatment (e.g. satisfactory therapeutic response) 
2. Disease progression 
Note: If biochemical progression is confirmed by m-spike, but the participant is clinically benefitting 
from therapy, or had been holding therapy, participants may remain on study at the discretion of the 
overall Principal Investigator. If the treating physician and overall Principal Investigator are in 
agreement that the participant may benefit from continued LBH589, the participant may continue on 
treatment for one additional cycle to assess response again and re-discuss benefit of therapy. 
3. Adverse event(s) 
4. Abnormal laboratory value(s) 
5. Abnormal test procedure result(s) 
6. Protocol violation  
7. Subject withdrew consent  
8. Lost to follow-up 
9. Administrative problems 
10. New cancer therapy 
11. Death  
6.3.5 Follow-up  
After progression, or removal from the study for other reasons (as outlined in 6.3.4), patients will be 
observed for Event Monitoring every 3 months (as outlined in the Test Schedule, Section 7.1, page 50). 
This will include the notation of death, any second malignancies, and other therapy for Waldenstrom’s 
Macroglobulinemia. This information may be obtained by mail or phone contact. 
If a patient refuses treatment after they have been registered (and is classified as a cancel), it is not 
necessary to provide follow-up information. On-study material is to be submitted. 
If a participant experiences one of the following, the participant will be removed from event monitoring: 
•   Decision of the patient to withdraw from the study 
•   Patient death 
•   Administration of alternative therapy for Waldenstrom’s Macroglobulinemia 
•   Lost to follow-up 
6.3.5.1 
Toxicity Follow-up 
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 LBH589 
therapy, the patient may be able to continue treatment with a 10 mg dose reduction at the Investigator 


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46 
 
 
 
 
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 LBH589.  
6.4 
Other concomitant medications 
Patients should receive full supportive care while on this study.  This includes blood product support 
(platelets and G-CSF), antibiotic treatment and treatment of other newly diagnosed or concurrent medical 
conditions.  All blood products and concomitant medications such as antidiarrheals, analgesics, anti-
emetics received from the first administration of study drugs until 28 days after the final dose are to be 
recorded in the medical record. 
Each patient should be instructed to have loperamide readily available and to begin treatment for diarrhea 
at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more 
frequent than normally expected for the patient.  Loperamide 4 mg should be taken at the first loose stool 
or more frequent than usual bowel movements, followed by 2 mg as needed, no more frequently than 
every 4 hours not to exceed a total of 16 mg in 24 hours.  Patients with diarrhea ≥ grade 2 despite this 
loperamide regimen should interrupt treatment with LBH589 as described in Table 6.1.  If the above 
regimen is inadequate then additional evaluation and treatment should be pursued as medically indicated. 
 
Some concomitant medications are discouraged, or prohibited, as described: 
• Any medications listed in Appendix 1.1 which may cause QTc prolongation or inducing torsades de 
pointes should not be used.  
• 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 
LBH589 as LBH589 can inhibit isoenzyme CYP2D6 at low micromolar ranges. Please refer to 
Appendix 1.3 for the list of  CYP2D6 substrates.   
6.4.1 
Drugs that can inhibit/induce CYP3A4/5 
• Oral contraceptives are generally metabolized by CYP3A4.  Since the induction potential of LBH589 
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 in addition 
to the oral contraceptive.  


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6.4.1.1 
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. Drugs which are listed in Appendix 1.2 may be 
co-administered when medically necessary." Drugs which are listed in Appendix 1.2 may be co-
administered when medically necessary. 
6.4.1.2 
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 LBH589. 
 
6.5 
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. 
 
 
 
 


 
7 Investigational Plan 
7.1 
Visit Schedule 
Table 7.1 Test and Visit Schedule 
 
Pre-Registration 
Treatment Phase 
Follow-Up 
Tests and Procedures 
≤ 28 Days 
Prior to 
Registration 
≤ 14 Days 
Prior to 
Registration 
Weekly 
During 
Cycle 1 
Day 1 of 
Cycles 1-6 
(q 28 days)1 
Day 1 of 
Cycle 4 
At the End of 
Cycle 6, 
and/or End of 
Therapy 
Maintenance 
Therapy, 
Every 3 
Cycles 
Every 3 
months 
History, Exam2, Vital Signs 2A 
X 
  
  
X 
X 
X 
X 
  
ECOG 
X 
  
  
X 
X 
X 
X 
 
Toxicity Assessment 
X 
  
  
X 
X 
X 
X 
  
Hematology Labs3 
  
X 
X 
X 
X 
X 
X 
X 
Biochemistry4 
  
X 
 
X 
X 
X 
X 
X 
Serum Protein Electrophoresis5 
 X 
 
  
X 
X  
X 
X 
X 
Viscosity 
 X 
 
  
X 
X 
X 
X 
  
beta-2 Microglobulin 
 X 
 
  
  
X 
X 
X 
  
Serum Pregnancy Test6 
  
X 
  
  
  
  
  
  
ECG7 
X7 
  
X7 
X7 
X7 
X7 
X7 
  
CT (chest, abdomen, pelvis) 
X 
  
  
  
  
X 
  
  
Unilateral Bone Marrow Aspirate & 
Biopsy; Cytogenetics 
X 
  
  
  
X8 
 X 
  
  
Research Bone Marrow & AspirateR 
X 
  
  
  
X 
X 
  
  
1 A cycle is 28 days, +/- 5 days to accommodate scheduling conflicts. Day 1 procedures may be completed +/- 5 days before the start of LBH589 (Day 1 of the Cycle) 
2 - Physical exams include: a total body examination (general appearance, skin, neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and basic 
nervous system) 
2A - Vital Signs include: height (first visit only), pulse, blood pressure, respiration rate, temperature and weight 
3 - Hematology Includes: CBC with differential, platelet count, hemoglobin, absolute neutrophil count 
4 - Biochemistry Includes: Blood urea nitrogen (BUN), creatinine (for calculated creatinine clearance), sodium, potassium, chloride, CO2, glucose, calcium, albumin, total protein, 
total bilirubin (if elevated, draw direct and indirect bilirubin), alkaline phosphatase, LDH, AST, ALT, phosphorous, magnesium 
5 - Serum Protein Electrophoresis Includes: quantitative M-spike, quantitative IgM level and serum free light chain 
6 - For women of childbearing potential; must be done ≤ 7 days prior to registration 
7 - Please see Table 7.2 for detailed ECG schedule 
 
 
 
 
 
 
8 - Bone marrow and aspirate will be required at this time point only to confirm a CR. 
R – These are OPTIONAL procedures (research funded) 


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Table 7.2 
Cardiac assessment monitoring schedule 
Cycle 
Day of cycle 
ECG monitoring a  
Cycle 1 
 
Screeningb 
Single ECG to assess eligibility 
1 
Pre-dose: 3 sequential ECGs separated by 5-10 minutes 
Post-dose: 3 sequential ECGs separated by 5-10 minutes, 
3 hours (+ ½ hour) after dosing 
 
5 (+ 2 days) 
Pre-dose: 3 sequential ECGs separated by 5-10 minutes 
Post-dose: 3 sequential ECGs separated by 5-10 minutes, 
3 hours (+ ½ hour) after dosing 
Cycle 2 -8c 
 
1 
 
Pre-dose: 3 sequential ECGs separated by 5-10 minutes 
  
End of treatment 
Last 
Single ECG 
a Refer to Table 6.2 for the recommended dose modifications due to QTc interval prolongation 
b The mean QTc interval at baseline must be ≤ 450msec for the patient to be eligible for participation in the trial. 
c Note: If participants experience QTc > 480 msec in Cycle 1 or in any subsequent cycle, then repeat Cycle 1 
monitoring schedule until they have a Cycle with no QTc prolongation. 
If no significant QTc prolongation is noted during first 8 Cycles, the QTc monitoring is no longer 
required and may be performed at the Investigator’s discretion, if medically indicated.    
7.2 
Registration Procedures 
The below procedures outline the process of registering DFCI patients. To register a patient from 
a participating center, please follow registration procedures as outlined in DF/HCC multi-center 
DSMP (Appendix 9, Section 5.7). 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin treatment during 
off-hours or holidays, call the QACT registration line at 617-632-3761 and follow the 
instructions for registering participants after hours.   
The registration procedures are as follows: 
1. 
Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments. 
2. 
Complete the protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical/research record. To be eligible for registration 
to the study, the participant must meet each inclusion and exclusion criteria listed 
on the eligibility checklist.  
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for the 
treatment study. Registration to both treatment and ancillary studies will not be 
completed if eligibility requirements are not met for all studies.  


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3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617-
632-2295.  
4. 
The QACT Registrar will (a) validate eligibility, (b) register the participant on the 
study, and (c) randomize the participant when applicable.  
5. 
The QACT Registrar will send an email confirmation of the registration and/or 
randomization to the person initiating the registration immediately following the 
registration and/or randomization.  
7.3 
Efficacy assessments 
Efficacy measures will include both objective clinical measurements and investigator-reported outcomes.  
Response and time to event analyses will follow the criteria set forth in the International Waldenstrom 
consortium recommendations. Prior to the start of the study, investigators will assess disease and perform 
a CT scan of the chest, abdomen and pelvis. Response to treatment will be determined after cycle 2 is 
complete and then after every cycle until the end of the sixth cycle. After 6 cycles, response will be 
assessed every 3 months. All responses will be assessed by M-protein quantification and immunofixation 
from serum and IgM monoclonal protein level.  In addition, BM biopsies will be done at baseline, at the 
end of cycle 6 and at the end of all therapy.  An optional BM assessment will occur at the beginning of 
cycle 4. Assessment of BM malignant cells, lymphadenopathy or hepatosplenomegaly will be conducted 
to confirm responses on all patients who complete therapy.   
 
Definition of Efficacy Measures  
 
Time to progression is defined as the elapsed time from the date of study enrollment to the date of 
objectively determined PD.  Analysis of TTP will be as follows:    
 
• For patients who die without documented objective PD (including death from study disease), TTP will 
be censored at the date of the last objective progression-free disease assessment.    
• For patients not known to have died as of the data cut-off date and who do not have objective PD, 
TTP will be censored at the date of the last objective progression-free disease assessment.    
• For patients who receive subsequent systemic anticancer therapy (after discontinuation from study 
treatment) prior to objectively determined disease progression, TTP will be censored at the date of the 
last objective progression-free disease assessment prior to post discontinuation therapy.    
• The duration of response is defined as the elapsed time from the date when the measurement criteria 
are first met for a complete or partial response (whichever status is recorded first) until the date of first 
observation of objective disease progression. Analysis of duration of response will be as follows:    
• For responding patients who die without objective PD (including death from study disease), duration 
of response will be censored at the date of the last objective progression-free disease assessment.    
• For responding patients not known to have died as of the data cut-off date and who do not have 
objective PD, duration of response will be censored at the date of the last objective progression-free 
disease assessment.    
• For responding patients who receive subsequent systemic anticancer therapy (after discontinuation 
from the study chemotherapy) prior to objectively determined disease progression, duration of 
response will be censored at the date of the last objective progression-free disease assessment prior to 
postdiscontinuation therapy.  


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Hematologic Response Considerations 
 
Terms and definitions 
 
M-protein: synonyms include M-spike, serum monoclonal IgM concentration, monoclonal protein, 
monoclonal paraprotein, M-component. 
 
Response terms: The following response terms will be used: complete response (CR), near complete 
response (nCR), very good partial response (VGPR), partial response (PR), minimal response (MR), 
stable disease or no response (NR), and progression or relapse (PD).  
 
Measurable disease: Patients who have a measurable serum M-protein and IgM protein level are eligible 
for this protocol. Other measurable disease includes the lymph nodes and organomegaly as assessed by 
CT scan. 
The serum free light chain (FLC) assay will also be used in monitoring response to therapy, but is not 
considered part of the official response measurements. When using this assay, it is important to note that 
the FLC levels vary considerably with changes in renal function and do not solely represent monoclonal 
elevations. Thus both the level of the involved and the uninvolved FLC isotype (i.e., the kappa/lambda 
ratio) should be considered in assessing response.  
Patients will be formally evaluated for response using the following criteria (taken from the Second 
International Workshop on Waldenstrom's Macroglobulinemia): 
 
NOTE: If a participant’s serum m-protein is not quantifiable for any reason (e.g., atypical m-spike, 
migration to beta region, etc), the immunoglobulin M (serum IgM) may be used to assess response.


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Table 7.3: response criteria for WM:  
 
Complete Response 
(CR) 
Disappearance of monoclonal protein by immunofixation; no 
histologic evidence of bone marrow involvement, resolution of 
any adenopathy/organomegaly (confirmed by CT scan), or 
signs or symptoms attributable to WM.  Reconfirmation of the 
CR status is required with a second immunofixation. 
Near complete 
response (nCR) 
As above except that immunofixation is still positive. 
Very good partial 
response (VGPR)  
At least 90% reduction of serum monoclonal IgM 
concentration on protein electrophoresis. 
Partial Response (PR) 
At least 50% reduction of serum monoclonal 
IgM 
concentration on protein electrophoresis and at least 50% 
decrease in adenopathy/organomegaly on physical examination 
or on CT scan.  No new symptoms or signs of active disease. 
Minor Response (MR) At least 25% but less than 50% reduction of serum monoclonal 
IgM by protein electrophoresis.  No new symptoms or signs of 
active disease. 
Stable Disease (SD) 
Less than 25% reduction and less than 25% increase of serum 
monoclonal IgM by electrophoresis without progression of 
adenopathy/organomegaly, cytopenias, or clinically significant 
symptoms due to disease and/or signs of WM. 
Progressive Disease 
(PD) 
At least 25% increase in serum monoclonal IgM protein 
electrophoresis confirmed by a second measurement , or 
progression of clinically significant findings due to disease 
(i.e., anemia, thrombocytopenia, leucopenia, bulky 
adenopathy/organomegaly) or symptoms (unexplained 
recurrent fever of at least 38.4oC, drenching night sweats, at 
least 10% body weight less, or hyperviscosity, neuropathy, 
symptomatic cryoglobulinemia, or amyloidosis) attributable to 
WM. 
8 Safety Assessments and Monitoring 
Safety assessments will consist of monitoring and recording all 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.  
Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) 
version 
3.0. 
 
CTCAE 
v3.0 
can 
be 
accessed 
on 
the 
NIH/NCI 
website 
at   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. 


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8.1 
Adverse events 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a patient administered a pharmaceutical 
product, which does not necessarily have a causal relationship with the treatment.  An adverse event can 
be any unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the drug, whether or not it is considered to be drug related.  
This includes any newly occurring event or previous condition that has increased in severity or frequency 
since the administration of drug.  
Serious Adverse Event Definition 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality 
that: 
• Results in death. 
• Is life-threatening.  Life-threatening means that the patient was at immediate risk of death from 
the reaction as it occurred, i.e., it does not include a reaction which hypothetically might have 
caused death had it occurred in a more severe form. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period, but planned 
prior to study entry are not considered AEs if the illness or disease existed before the patient was 
enrolled in the trial, provided that it did not deteriorate in an unexpected manner during the trial 
(e.g., surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity.  Disability is defined as a substantial 
disruption of a persons’ ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  An important medical event is an event that may not result in 
death, be life-threatening, or require hospitalization but may be considered an SAE when, based 
upon appropriate medical judgment, it may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in the definitions for SAEs.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.   
 
Clarification should be made between the terms “serious” and “severe” since they ARE NOT 
synonymous.  The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as a severe headache).  This is NOT the same as “serious,” which is based on 
patient/event outcome or action criteria described above and are usually associated with events that pose a 
threat to a patient’s life or functioning.  A severe adverse event does not necessarily need to be considered 
serious.  For example, persistent nausea of several hours duration may be considered severe nausea but 
not an SAE.  On the other hand, a stroke resulting in only a minor degree of disability may be considered 
mild, but would be defined as an SAE based on the above noted criteria.  Seriousness (not severity) serves 
as a guide for defining regulatory reporting obligations. 
 


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Additionally, the following events must be reported: 
 
• Grade 2 (moderate) or Grade 3 (serious) events that are unexpected and at least possibly 
related/associated with the intervention. 
• All Grade 4 (life-threatening) events that are unexpected and not specifically listed in the protocol 
as not requiring reporting. 
• Note: Grade 4 expected hematological toxicities (thrombocytopenia, anemia, and low 
white blood cell counts) do not require reporting. 
• All Grade 5 (fatal) events while the subject is enrolled and actively participating in the trial OR 
when the event occurs within 30 days of the last study intervention. 
Procedures for AE and SAE Reporting 
The investigator must report all serious adverse events (SAE) regardless of relationship with any study 
drug or expectedness to the principal investigator at Dana Farber as soon as possible, but no later than 5 
calendar days of the investigator-sponsor’s observation or awareness of the event. Any serious adverse 
event occurring after the patient has provided informed consent and until 4 weeks after the patient has 
stopped study participation must be reported. Any deaths occurring on treatment or within 30 days of 
ending treatment must be reported within 5 days of awareness.  Dana Farber’s principal investigator will 
submit all SAEs to Novartis (please refer to Section 8.4). All sub-investigators must report all SAEs to the 
investigator so that the investigator can meet his/her foregoing reporting obligations to Dana-Farber 
Safety Monitoring Board, FDA and supporting organizations (Novartis). The FDA MedWatch 3500A 
form should be used to report this event to the investigator-sponsor. 
 
These reports should be sent by FAX or E-MAIL to:  
Irene M Ghobrial, MD 
Dana Farber Cancer Institute 
44 Binney Street 
Boston, MA 02115 
Phone: 617-632-4198 
Fax: 617-582-7153 
Email: irene_ghobrial@dfci.harvard.edu 
 
For both serious and non-serious adverse events, the investigator or sub-investigator must determine both 
the intensity of the event and the relationship of the event to drug administration. 
 
Relationship to drug administration will be determined by the investigator or sub-investigator responding 
yes or no to the question: Is there a reasonable possibility that the adverse event is associated with the 
drug? 
Intensity for each adverse event, including any lab abnormality, will be determined by using the NCI 
CTCAE, version 3.0, as a guideline, wherever possible.  The criteria are available online at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf 
 
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 


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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 grade (using the CTCAE as a guideline) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. 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) 
5. 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 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. 
Monitoring of Adverse Events and Period of Observation 
Adverse events, both serious and non-serious, and deaths that occur during the patient’s study 
participation will be recorded in the source documents.  All SAEs should be monitored until they are 
resolved or are clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es). All SAEs will be submitted to the Safety and monitoring Board of each institution and to 
Novartis. 
 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must 
inform her treating physician immediately and permanently discontinue drug therapy. must also be 
contacted immediately by faxing a completed Pregnancy Form.  The pregnancy must be followed through 
outcome (i.e. delivery, still birth, miscarriage). 
Information about common side effects already known about the investigational drug can be found in the 
Investigators’ Brochure (IB) 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. 
8.2 
Safety Meetings 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this trial. The committee is composed of clinical specialists with experience in oncology 
and who have no direct relationship with the study. Information that raises any questions about participant 
safety will be addressed with the Principal Investigator and study team. 
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data.  
Information to be provided to the committee may include:  up-to-date participant accrual; current dose 
level information; DLT information; all grade 2 or higher unexpected adverse events that have been 
reported; summary of all deaths occurring within 30 days for Phase I or II protocols; for gene transfer 


Study Protocol                                 Confidential 
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protocols, summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request. 
8.3 
Monitoring 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the Principal Investigator 
(or Protocol Chair) or DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and data were recorded, 
analyzed, and accurately reported in accordance with the protocol, institutional policy, Good Clinical 
Practice (GCP), and any applicable regulatory requirements.  
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue during 
protocol performance and completion.  
8.4 
Novartis instructions for rapid notification of serious adverse events 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, and 
Novartis Pharmaceuticals Clinical Safety and Epidemiology Department (CS&E). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form).  
All events must be reported, by FAX (888-299-4565), to Novartis Pharmaceuticals CS&E Department 
within 24 hours of learning of its occurrence. This includes serious, related, labeled (expected) and 
serious, related, unlabeled (unexpected) adverse experiences. All deaths during treatment or within 30 
days following completion of active protocol therapy must be reported within 5 working days. 
Any serious adverse event occurring after the patient has provided informed consent and until 4 weeks 
after the patient has stopped study participation must be reported. This includes the period in which the 
study protocol interferes with the standard medical treatment given to a patient (e.g. treatment withdrawal 
during washout period, change in treatment to a fixed dose of concomitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be reported if a 
relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse experiences 
will be forwarded to the product manufacturer by the investigator. 


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8.5 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient safety each 
pregnancy must also 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 
birth, and the presence or absence of any birth defects, congenital abnormalities or maternal and newborn 
complications 
8.6 
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 
8.7 
Physical examination 
Physical examinations will be performed which must comprise a total body examination (general 
appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities and basic nervous system). 
Significant findings made after the start of study drug which meet the definition of an Adverse Event must 
be recorded. 
8.8 
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.  
8.8.1 Hematology 
Hematology must include hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and 
differential.  
8.8.2 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, and uric acid.  If total bilirubin is greater than the upper limit of 
normal, direct and indirect bilirubin should be performed. 
8.8.3 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. Postmenopausal women must have been amenorrheic for 
≥ 12 months in order to be considered “of non-childbearing potential”. 
8.9 
ECG 
See Section 6.1.1 (Cardiac precaution) Section 6.3.2 (Dose modification for prolonged QTc) for 
guidelines on the required close monitoring of patients’ serum biochemistry values (in particular, 


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potassium, magnesium, calcium and phosphorous) and the requirement for rapid correction of low 
values). 
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 7.2. For all patients, a minimum 
of 3 sequential 12-lead ECGs, separated by 15-30 minutes, must be performed on cycle 1 day 1 prior to 
the first administration of oral LBH589 or within 24 hours prior to that day. This is necessary to get an 
accurate baseline QTc calculation. 
All ECGs will be sent to eRT for central review. The ECG interpretations from eRT will be the formal 
data entered into the database. Please contact Karen Kubacke at eRT (215-282-5573, or 
KKubacke@ert.com) to request information and supplies regarding this process. 
8.10 Performance status 
ECOG Performance status will be assessed. Please see Appendix 2. 
8.11 Special tests 
A CT of the chest, abdomen and pelvis will be completed at screening (within 28 days of registration), at 
the end of cycle 6 and at end of therapy. 
9 Pharmacodynamic assessments and correlative studies 
No pharmacokinetics or drug levels will be performed; however pharmacodynamic (PD) assessments will 
be done on research bone marrow and aspirates.  
 
The purpose of these studies is to identify the role of epigenetic alterations in WM and their role in 
resistance to therapy.  
 
1. We will first determine the level of HDAC and HAT in samples obtained pre-therapy 
2. We will then determine mechanisms of activation or overexpression of HDACs in WM, through 
mutation, SNP and epigenetic regulation such as miRNA and methylation studies 
3. We will also determine the effect of LBH589 on signaling pathways and miRNA expression in post-
treatment samples. 
 
Sample collection and prioritization of studies: At the time of collection, 10-15 ml BM aspirate will be 
collected in heparinized tubes and submitted to the Ghobrial lab (please see Appendix 5). Samples may be 
shipped Monday – Friday (we can accept Saturday deliveries if given 1 week notice). Prior to shipment, 
please notify the Ghobrial lab that a sample is being shipped by calling 617-582-8665. 
 
Mononuclear cells (MNC) will be separated from the samples by density gradient centrifugation as 
described in the preliminary data. Malignant cells will then be separated using magnetic bead technology 
with negative selection. We typically isolate 10-30x106 CD19+ cells from the bone marrow using this 
technique.   
 
Timing of BM samples: Pre-therapy, day 1 of cycle 4, and at the end of therapy.  
 
 


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Table 9.1: Studies proposed using samples of patients’ pre and post-therapy  
 
LBH589 
 
                             Response  
 
               No-response 
Pre-therapy 
samples 
1. Is there constitutive activation of HDACs? 
a. If Yes to #1, then identify mechanism of activation of this pathway: mutation, SNP of key 
regulators 
b. If Yes to #1, identify if miRNAs or methylations status are key regulators of activation of 
HDACs 
Post-
therapy 
samples 
1. Did we hit the target? 
a. Determine the level of downstream proteins of LBH589 and correlate with clinical activity 
and pre-sample results  
b. miRNA profile of miRs inhibited by these agents. 
 
 
Table 9.2 : Experimental approach, timing, source, and priority of studies proposed  
Studies proposed  
Experimental approach 
Timing 
Identify whether HDACs are 
constitutively activated  
HDAC/HAT activity using 
Colorimetric HDAC Activity 
Assay Kit, and immunofluorescence 
on BM clots 
Pre-therapy 
Identify mechanism of activation of 
HDACs 
 
 
mutation, SNP of regulators of he 
pathway. 
Pre-therapy 
Identify if miRNA are key regulators 
of resistance 
miRNA by Luminex 
Methylation status of key regulators 
by ChIP on chip 
Pre-and post-
therapy 
Identify the level of main signaling 
proteins downstream of LBH589: did 
we hit the target? 
Luminex phosphoprotein detection 
and immunofluorescence on BM 
clots 
Pre and post-
therapy 
 
10 Regulatory Considerations 
10.1 Protocol Review and Amendments 
A signed and dated statement that the protocol and informed consent have been approved by the IRB must 
be given to Novartis before study initiation.  
Any change or addition (excluding administrative) to this protocol requires a written protocol amendment 
that must be reviewed by Novartis and the investigator before being submitted to the IRB. Any changes to 
the protocol, informed consent and all forms of participant information related to the study (e.g., 
advertisement used to recruit patients) and any other necessary documents must be submitted, reviewed 
and approved by the IRB prior to implementation.  


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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 at the center must be informed immediately.    
11 Data management 
11.1 Data collection 
The QACT will collect, manage, and monitor data for this study. 
11.2 Data Submission 
The schedule for completion and submission of case report forms to the QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
12 Statistical methods 
12.1 Statistical methods 
Overview: 
The primary endpoint of the phase II study is the overall response rate (defined as MR or better) of single 
agent LBH589 in patients with relapsed or relapsed/refractory WM. 
 
 
 


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Design: 
An overall response rate (defined as CR + nCR+ VGPR +PR+MR) of 40% is considering promising in 
this population, whereas a overall response rate of 20% is considering non promising . This study will use 
a two-stage design to allow for early termination of the study if the drug is unlikely to be promising. The 
following two-stage Simon design will be used: a minimum of 14 eligible patients and a maximum of 37 
eligible patients will be entered in the study. The study is designed to have at least 93% probability of 
concluding the treatment is effective if the response rate is at least 40% and a 10% or less chance of 
concluding that the treatment is not effective with true response rate of 20% or less.   
 
Decision rule: 
In this design 14 eligible patients will enter the first stage.  If 2 or fewer response (MR or better) is 
observed, the treatment consideration will be given to early termination of the study. If 3 or more 
responses are observed, accrual will continue to the second stage with an additional 23 eligible patients 
entered onto the study. If 10 or fewer responses are observed after 37 eligible  patients, this treatment  will 
be considered non-promising. If 11 or more responses are observed among the 37 eligible patients, the 
single agent LBH589 will be considered promising for further study.   
 
Design properties: 
Assuming that the number of response is binomially distributed, the probability that the single agent 
LBH589 will considered promising for future study  is at least 0.90 if the true response rate is ≥40% and 
<0.1 if the response rate is ≤20%.  The probability of declaring that the drug is promising and the 
probability of stopping accrual after the first stage  is provided in the table below under various true 
response rates . 
 
True response rate 
0.20 
0.25 
0.30 
0.35 
0.40 
probability of observing 11 or 
more responses among 37 
evaluable patients  
0.1 
0.30 
0.57 
0.77 
0.93 
probability of 
early stopping at stage 1  
(0, 1 or 2 responses among 14 
evaluable patients in first 
stage)  
0.44 
0.28 
0.16 
0.08 
0.04 
  
 
With 37 eligible patients entered on study, the 90% confidence interval of the estimated response rate will 
be no wider than 29% (CI 90%:34-63). The 90% confidence interval width is 25% (CI 90%: 44-18), if 11 
responses are observed among 37.   
 
Stopping rule for toxicity:  
The study will be monitored continuously for all toxicities. If grade 3 or 4 unexpected non-hematologic 
toxicities are observed in 1 or more patients the study will be suspended for toxicity evaluation.  The 
probability of suspending the trial (observing 1 or more toxicity) with 10, 20, or 30 patients treated under 
various true underlying true toxicity percentages are given below. The probability of observing at least 1 
patient among the 37 patients with unexpected grade 3 or 4 non-hematologic toxicity is 0.04, 0.17, 0.31, 
0.53 and 0.85 for true toxicity percentages of 0.1, 0.5, 1,2 and 5%, respectively.  


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True toxicity percentage  
0.1 
0.5 
1 
2 
5 
Pr (observing at least one 
toxicity with 10 patients) 
0.01 
0.05 
0.10 
0.18 
0.40 
Pr (observing at least one 
toxicity with 20 patients) 
0.02 
0.10 
0.18 
0.33 
0.64 
Pr (observing at least one 
toxicity with 30 patients) 
0.03 
0.14 
0.26 
0.46 
0.79 
 
 
In addition, if ECG QTC prolongation is observed in 2 or more patients, the study will be suspended for 
toxicity evaluation. The probability of suspending the trial with 10, 20, or 30 patients treated for various 
true underlying true toxicity percentages are given below. The probability of observing at least 2 patients 
among the 37 patients with ECG QTC prolongation is 0.015, 0.05, 0.17, 0.44 and 0.81 for true toxicity 
percentages of 0.1, 1, 2, 4 and 8%, respectively. 
 
 
True toxicity percentage  
0.1 
1 
2 
4 
8 
Pr (observing at least one 
toxicity with 10 patients) 
0.001 
0.004 
0.016 
0.058 
0.19 
Pr (observing at least one 
toxicity with 20 patients) 
0.004 
0.017 
0.06 
0.19 
0.48 
Pr (observing at least one 
toxicity with 30 patients) 
0.010 
0.036 
0.12 
0.34 
0.70 
 
 
Accrual time and study duration: 
The anticipated accrual rate based on 06077 (perifosine relapsed/refractory WM protocol) for this group 
of patients is approximately 2-3 patients per month.  It will take approximately 6 months to complete the 
first stage of accrual and approximately 10 months to complete the second stage of accrual.  
 
Secondary objectives: 
Secondary objectives include further assessing toxicity, and to assess duration of response (DR), time to 
progression (TTP) and progression-free survival (PFS).  
 
Duration of remission (DR), Time to progression (TTP) and progression free survival (PFS) will be 
estimated using the method of Kaplan and Meier. DR is defined as the time from the date of first response 
after treatment to the date of disease progression or death for any cause. Patients who have died or 
progressed are censored at the date the patient is last know to be progression-free. TTP is defined as the 
time from start of treatment  to progression., Patients who have not progressed are  censored  at the date 
the patient is last known to be progression free.. PFS is defined as the time from start of treatment to 
disease progression or death from any cause. Patients who have not progressed and are alive are censored 
at the date the patient is known to be progression-free.   
 


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The proportion of patients who have reported any toxicity and specific toxicities will be provided along 
with the 90% confidence interval. The 90% confidence interval width will be no wider than 29%.  The 
table below gives the probability of detecting rare events based assuming true toxicity incidence between 
0.1%-5%.  
 
True Incidence rate 
0.1% 
0.5% 
1% 
5% 
Pr (observe at least 
one toxicity) 
0.04 
0.17 
0.31 
0.85 
13  Procedures and instructions 
13.1 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. 
13.2 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. 
13.3 Discontinuation of study 
Novartis reserves the right to discontinue any study under the conditions specified in the clinical trial 
agreement. 
14  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). 


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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. 
14.1 Informed consent 
The investigator 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 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 approval. 
14.2 Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of Helsinki. 
Copies of the Declaration of Helsinki and amendments will be provided upon request or can be accessed 
via the website of the World Medical Association at http://www.wma.net/e/policy/17- 


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Appendix 1.    LBH589 study prohibited medication list.  
1.     Drugs that prolong the QT interval and/or induce Torsades de Pointes ventricular 
arrhythmia 
Patients who are currently receiving treatment with any of the medications in Table 1-1, and cannot either 
discontinue this treatment or switch to a different medication prior to study enrollment, will be excluded 
from the study.  Patients may not begin treatment with any of the medications listed in Table 1-1 while on 
treatment with LBH589. If a patient must receive these drugs, this patient should be discontinued from the 
study.  The patient should be off-treatment with LBH589 for at least 72 hours prior to taking the first dose 
of a medication listed in Table 1-1.  
Table 1-1 
Medications which may prolong the QT interval ALL Class IA  
ALL Class IA antiarrhythmics  
• quinidine 
• procainamide 
• disopyramide 
• any other class IA antiarrhythmic drug 
ALL Class III antiarrhythmics  
• amiodarone 
• sotalol 
• bretylium 
• dofetilide 
• ibutilide 
• any other class III antiarrhythmic drug 
Antibiotics 
• Macrolide antibiotics* 
• erythromycin 
• clarithromycin 
• telithromycin 
Quinolone antibiotics* 
• gatifloxacin 
• moxifloxacin 
• sparfloxacin 
Antipsychotics 
• thioridazine 
• mesoridazine 
• chlorpromazine 
• pimozide 


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• risperidone 
• ziprasidone 
Antidepressants 
• amitriptyline 
• imipramine 
• desipramine 
• doxepin 
• maprotiline 
• venlafaxine 
Antifungals (azoles)* 
• ketoconazole 
• itraconazole 
Antimalarials 
• halofantrine 
• chloroquine 
Anti-emetics* 
• dolasetron 
• ondansetron 
• tropisetron 
Miscellaneous drugs 
• arsenic trioxide 
• bepridil 
• domperidone 
• methadone 
• pentamidine 
• droperidol 
• cisapride 
• tacrolimus 
* Note: azithromycin, ciprofloxacin, levofloxacin,  granisetron are allowed. 
This is not a comprehensive list of medications which may prolong the QT interval.  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 LBH589. 
The following website may be referenced as a supplemental guide for drugs which may prolong the QT 
interval: http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm#.  Medications listed on the 
website which do not appear in Table 1-1 above may be used at the discretion of the investigator.    


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2.    Drugs that can inhibit CYP3A4/5 
Since LBH589 is metabolized in vitro by CYP3A4 clinical judgment is to be exercised when potent 
CYP3A4 inducers are concomitantly taken with LBH589.  Below is a list of CYP3A4/5 drugs.   
Table 2-1 
List of drugs known to inhibit CYP3A4/5 
Macrolide antibiotics* 
• erythromycin 
• clarithromycin 
• telithromycin 
• troleandomycin 
Antifungals (azoles) 
• fluconazole (5 days) 
• ketoconazole 
• itraconazole (12 days) 
• voriconazole 
Antidepressants 
• fluvoxamine 
• nefazodone 
Calcium channel blockers* 
• diltiazem 
• verapamil 
HIV protease inhibitors: 
• indinavir 
• nelfinavir 
• ritonavir 
• any other HIV protease inhibitors 
Miscellaneous drugs or products 
• cimetidine 
• aprepitant 
• grapefruit product or juice 
• Seville (sour) orange or juice* 
* azithromycin, 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 of this list, which are meant to be used as a guide, may be found at the following website: 
http://medicine.iupui.edu/flockhart/clinlist.htm 


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3.  Drugs that are CYP2D6 substrates 
If CYP2D6 substrates listed in Table 3-1 are used concomitantly with LBH589, patients must be carefully 
monitored for potentiation of toxicity due to any individual concomitant medications and may require 
dose titration or reduction of the CYP2D6 substrate. 
Table 3-1 
CYP2D6 substrates 
CYP2D6 substrates 
Beta blockers (listed below): 
carvedilol 
metoprolol 
bufuralol 
alprenolol 
nebivolol 
propranolol 
timolol 
Antidepressants (listed below): 
amitriptyline 
clomipramine 
desipramine 
imipramine 
nortriptyline 
paroxetine 
venlafaxine 
Antipsychotics (listed below): 
aripiprazole 
haloperidol 
perphenazine 
risperidone 
thioridazine 
chlorpromazine 
duloxetine 
fluoxetine 
fluvoxamine 
venlafaxine 
Antiarrhythmics (listed below): 
encainide 
flecainide 


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lidocaine 
mexiletine 
propafenone 
Antiemetics (listed below): 
dolasetron 
ondansetron 
metoclopramide 
Others: 
amphetamine 
atomoxetine 
dextromethorphan 
promethazine 
tamoxifen 
tramadol 
This is not a comprehensive list of medications that are 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/ 
 
 
 


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Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale 
 
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. 
 
 
 


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Appendix 3: New York Heart Association Classification of Cardiac Disease 
 
The following table presents the NYHA classification of cardiac disease: 
Class 
Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective 
evidence of 
cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective 
evidence of 
minimal 
cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective 
evidence of 
moderately 
severe 
cardiovascular 
disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective 
evidence of 
severe 
cardiovascular 
disease. 
 
  


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Appendix 4: Study Medication Diary 


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Medication Diary for LBH589 
 
Protocol No 
Participant ID 
Participant 
Initials 
Cycle 
Dose 
LBH589 
DFCI 09-071 
 
 
 
________ mg 
 
 
Please complete this diary on the days that you take your study medication. Please enter the date and 
time you take the study medication in the appropriate box. 
 
You will receive 5 weeks worth of study medication at the beginning of each cycle (each cycle is 28 days, 
+/- 5 days). Please remember to bring the medication bottle and any remaining pills with you every time 
you have a doctor’s appointment. 
 
You are to take LBH589 by mouth on Mondays, Wednesdays and Fridays, with a glass of water (8 oz), 
with or without food. During the first cycle, please take LBH589 in the morning. After cycle 1 you may 
choose to take LBH589 in the evening. However, please discuss this with your study doctor before 
making any changes to your dosing schedule. 
 
If you vomit while taking LBH589, then you should not take another dose until your next scheduled dose 
of LBH589. If you forget to take your medication in the morning, you can take it up to 12 hours after the 
usual time you take it. After 12 hours, do not take LBH589 that day; instead, wait until your next 
scheduled dose. Do not make up missed doses. 
 
 
Week 1 
 
Monday 
Wednesday 
Friday 
Date: 
 
 
 
Time: 
 
 
 
 
Week 2 
 
Monday 
Wednesday 
Friday 
Date: 
 
 
 
Time: 
 
 
 
 
Week 3 
 
Monday 
Wednesday 
Friday 
Date: 
 
 
 
Time: 
 
 
 
 


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Week 4 
 
Monday 
Wednesday 
Friday 
Date: 
 
 
 
Time: 
 
 
 
 
 
Week 5 
 
Monday 
Wednesday 
Friday 
Date: 
 
 
 
Time: 
 
 
 
 
 
 
 
Participant Signature: ________________________________________ 
 
Date: _____________________ 
 
 
 
 
 
 
 
 
For Site Use Only  
 
RN Initials: _________________ 
 
Date: ______________ 
Pill Count Comments: 
 
# Pills remaining: _______ 
 
# Pills returned to pharmacy: _______ 
 
# Pills given to participant: ________ 
 


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Appendix 5: Address and Instructions for Shipping Pharmacodynamic Sample 
 
Please ship the research bone marrow aspirate to: 
 
Dr. Irene Ghobrial 
Dana-Farber Cancer Institute 
44 Binney St, Dana 802  
Boston, MA 02115 
 
Instructions for shipping the research bone marrow aspirate (taken at ≤28 days prior to registration, at the 
end of cycle 3, and at the end of cycle 6 or at the end of therapy): 
 
Package aspirate green top tube at room temperature and wrap in a liberal amount of paper towel around 
the tube to ensure adequate insulation of the specimen(s) and absorption in the event of a breakage.  Place 
wrapped specimen in a biohazard labeled Ziploc bag and zip close.  Wrap bubble wrap around the bag 
and place in a plastic container.  Place the plastic container in a cardboard box.  If space remains in the 
box, stuff with extra paper towel to reduce shifting of samples.  Complete the shipping label using the 
above address.  Prepare the package for shipping, applying packing tape as needed.  Ship the package 
using FedEx and UPS next day or overnight delivery the same day the sample was collected. Please only 
ship Monday – Friday, the lab is only able to accept Saturday shipments with 1 week advance notice.  
Notify Dr. Ghobrial or study staff at 617-632-4198 or 617-582-8664 that the package has been shipped. 
Please provide the sample type(s), number of tubes, and the tracking number.   


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Appendix 6A: Information Sheet for ECGs and Labs Completed at Local Physician’s 
Offices 
Dana-Farber Cancer Institute Letter: 
 
Participant name: _____________________________________________ Date: ______________ 
 
Cycle: ___________ Day: ___________ 
Dose: __________ 
 
Please take this information sheet with you to your local doctor’s office on the day(s) that you will have 
ECGs and/or labs done.  
 
Triplicate ECGs are to be done on Cycle 1 Day 5: 
3 ECGs before your LBH589 dose 
3 ECGs three hours following your LBH589 dose 
 
Hematology labs are to be completed weekly during the first cycle:  
CBC with differential 
Platelets 
Hemoglobin 
Absolute Neutrophil Count 
 
All ECGs and labs are to be faxed to: 
Dr Irene Ghobrial 
617-582-7153 
 
If you, or your local doctor, have any questions about the ECG or lab schedule, please call: 
Tiffany Poon 
617-632-3742 
 
You should not take your LBH589 dose until the ECG and laboratory results have been received and 
reviewed by a clinician at Dana-Farber. A member of the research team will call you or your local doctor 
to review and discuss the ECG and lab results. If your ECG is normal and your lab results meet dosing 
requirements, you will be instructed to take your LBH589 dose as planned. If your ECG or lab results are 
abnormal, your local doctor and your study doctor will discuss the findings and determine the next step. It 
is possible that you will need blood tests and/or additional ECGs completed.  
 
It is important to remember not to take your LBH589 dose until after your ECG and lab results are 
reviewed, and a member of the research team has instructed you to take your LBH589 dose.  
 
Any invoices or bills you receive for the ECGs should be given to the research team at Dana-Farber. 
ECGs completed for the above timepoints will be paid for by the research study. Any additional ECGs 


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completed for clinical purposes will not be reimbursed by the research study. All labs completed while on 
study will be charged to your insurance. 
  


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Appendix 6B: Information Sheet for ECGs and Labs Completed at Local Physician’s 
Offices 
Participating Centers Letter: 
 
Participant name: _____________________________________________ Date: ______________ 
 
Cycle: ___________ Day: ___________ 
Dose: __________ 
 
Please take this information sheet with you to your local doctor’s office on the day(s) that you will have 
ECGs and/or labs done.  
 
Triplicate ECGs are to be done on Cycle 1 Day 5: 
3 ECGs before your LBH589 dose 
3 ECGs three hours following your LBH589 dose 
 
Hematology labs are to be completed weekly during the first cycle:  
CBC with differential 
Platelets  
Hemoglobin  
Absolute Neutrophil Count  
 
All ECGs and labs are to be faxed to: 
 
______________________________ 
 
At: ___________________________ 
 
If you, or your local doctor, have any questions about the ECG or lab schedule, please call: 
 
_____________________________ 
 
At: __________________________ 
 
You should not take your LBH589 dose until the ECG and laboratory results have been received and 
reviewed by a clinician. A member of the research team will call you or your local doctor to review and 
discuss the ECG and lab results. If your ECG is normal and your lab results meet dosing requirements, 
you will be instructed to take your LBH589 dose as planned. If your ECG or lab results are abnormal, 
your local doctor and your study doctor will discuss the findings and determine the next step. It is possible 
that you will need blood tests and/or additional ECGs completed.  
 
It is important to remember not to take your LBH589 dose until after your ECG is reviewed, and a 
member of the research team has instructed you to take your LBH589 dose.  


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Any invoices or bills you receive for the ECGs should be mailed to the address listed below. ECGs 
completed for the above timepoints will be paid for by the research study. Any additional ECGs 
completed for clinical purposes will not be reimbursed by the research study. All labs completed while on 
study will be charged to your insurance.  
 
 
Please send any invoices to: 
Irene M Ghobrial 
44 Binney St 
LG-LC 
Boston, MA 02115 
 
 


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Appendix 7: Study Summary for Participant Reference 
 
Phase II 
LBH589 (Panobinostat) in relapsed/relapsed refractory 
Waldenstrom’s Macroglobulinemia 
Novartis 
 
Primary objective is to assess the overall response rate in patients with relapsed or relapsed/refractory 
WM. 
 
Cycle=28 days (+/- 5 days) 
Response assessed after 2 cycles 
 
Schedule: 
25 mg/day, orally on Mondays, Wednesdays and Fridays  
 
LBH589 will be provided by Novartis and will be supplied as 5 mg or 20 mg pink/opaque-colored, hard 
gelatin capsules. 
 
Patients should take LBH589 by mouth on Mondays, Wednesdays and Fridays, with a glass of water (8 
oz), with or without food. During the first cycle, please take LBH589 in the morning. After cycle 1 
patients may choose to take LBH589 in the evening. However, please discuss this with the study doctor 
before making any changes to the dosing schedule.  The capsules should be swallowed whole and not 
chewed.  Avoid grapefruit or grapefruit juice and Seville (sour) oranges while on study. 
 
If patient forgets to take his/her dose during the morning on the scheduled treatment day then they should 
take it the same day within 12 hours of the missed dose.  After more than 12 hours, that day’s dose should 
be held and patient should wait to take LBH589 until the next scheduled treatment day. 
 
Patients will be assessed every 28 days (+/- 5 days).  After 6 cycles of monthly evaluations, patients will 
be assessed every 3 months. 
 
Patients may continue to receive treatment with LBH589 until they experience an unacceptable toxicity, 
disease progression and/or discretion of investigator. 
 
ECG Schedule: 
 
Cycle 1 
 
 
Day 1 At Study Doctor’s Office 
Pre-dose:  3 sequential ECGs separated by 5-10 minutes 
Post-dose:  3 sequential ECGs separated by 5-10 minutes, 3 hours (+/- 30 minutes) after 
dosing  
 
 


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Day 5 At Study Doctor’s Office or Locally 
Pre-dose:  3 sequential ECGs separated by 5-10 minutes 
Post-dose:  3 sequential ECGs separated by 5-10 minutes, 3 hours (+/- 30 minutes) after 
dosing  
 
 
Cycle 2 – 8 
 
 
Day 1 At Study Doctor’s Office 
Pre-dose:  3 sequential ECGs separated by 5-10 minutes 
 
**If participants choose to have ECGs performed at their local physician’s office, they will be given an 
information sheet.  The information sheet will accompany them to their doctor’s office at the time of the 
ECGs.  Participants are only to proceed with LBH589 dosing after the ECGs and some lab results have 
been sent and reviewed by a clinician at DFCI. 
 
The research ECGs are not to be charged to patient’s insurance.  Instead, the local office should provide 
patient with an invoice to be hand delivered to the patient’s study team at DFCI or participating center.  
Once we have the invoice, the local office will be reimbursed directly from the DFCI research 
department.  However, please note, any additional ECGs completed for clinical purposes will not be 
reimbursed by the research study. 
 
 
**If an abnormality occurs on an ECG then additional days of extensive ECG monitoring may be 
required.   


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Appendix 8: LBH589 Order Form 
 
Please Fax Request to: 973-781-3478 (Attn: Dorothy Muriuki) 
 
Date: 
      
Study Title: 
 
 
 
Investigator’s Name: 
      
Novartis Protocol Number: 
 
 
 
Requestor’s Name: 
      
Requestor’s Phone#: 
      
 
 
Institution: 
      
Shipping Address: 
      
 
      
 
      
 
 
Shipping Phone#: 
      
 
 
Is this Initial Shipment: 
 
Yes 
          No 
 
 
 
 
 
 
Date by when this shipment is required: 
      
 
*****Please note that oral LBH589 will be provided by Novartis and will be supplied as 5-mg or 20-
mg hard gelatin capsules.  Please note that LBH589 5mg are 45-fill label bottle and 20mg Caps in 
15-fill label bottle. 
 
15 
Drug 
Label Strength 
Number of Bottles 
Requested 
LBH589 
5 mg (45 caps/bottle) 
      
LBH589  
20 mg (15 caps/bottle) 
      
 
Note:  Please allow 10 days for processing of this request and delivery of the shipment. 


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Appendix 9: Novartis Pregnancy Reporting Form 
 


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Trial Drug 
      
Protocol 
      
Tip No. 
      
ID 
 
Centre No. 
Subject No. 
Subject’s Initials 
 
1. 
2. 
fam. 
Randomisation Number 
REPORT TYPE 
 Initial 
 Follow-Up 
 
 
CLINICAL TRIAL PREGNANCY FORM 
Page 1 of 3 
1.  Country: 
      
2.  LOCAL CASE ID: 
      
I. 
MATERNAL INFORMATION 
3. DATE OF BIRTH 
4. 
AGE 
5.  RACE 
6.  HEIGHT 
7.  WEIGHT 
 
day 
month year 
 
yrs./mo. 
  Caucasian 
  Oriental 
 
 
 
   
    
     
 
      
  Black 
  Other 
             cm 
            kg 
8. 
Date of Last Menstrual Period 
 day 
month 
 year 
9. 
Expected Date of Delivery 
day 
month 
year 
 
   
     
     
   
    
     
 
 
 
 
 
 
 
 
 
 
10. 
Method of Contraception 
          
11. Contraception used as instructed 
 
 yes 
 no 
 uncertain 
II. 
HISTORY 
12. 
PATIENT’S PAST MEDICAL HISTORY (include information on familial disorders, known risk factors or conditions that may affect the outcome 
of the pregnancy e.g. alcohol, smoking, other substance consumption, infections, hypertension, diabetes including gestational, environmental 
or occupational exposure that may pose a risk factor). 
13. 
PREVIOUS OBSTETRIC HISTORY – provide details on all previous pregnancies below, including abortion or stillbirth (use page 3 if 
needed) 
 
Gestation week 
Outcome including any abnormalities 
1 
           
                     
2 
           
                     
3 
           
                     
4 
           
                     
14. 
DRUG INFORMATION – please list the Novartis drug(s) first and all other therapies taken prior to or during pregnancy 
Drug Names 
Daily Dose 
Route 
Treatment Dates 
Indication 
(specify week of pregnancy) 
Start 
Stop 
Start 
Stop 
                     
      
      
      
      
                
      
      
                     
      
      
      
      
                
      
      
                     
      
      
      
      
                
      
      
                     
      
      
      
      
                
      
      
                     
      
      
      
      
                
      
      
 
MANUFACTURER INFORMATION (FOR INTERNAL USE ONLY) 
15. DATE MANUFACTURER NOTIFIED 
 
day 
   
month 
    
year 
     
16. DATE OF THIS REPORT 
day 
   
month 
    
year 
     
17. NAME AND ADDRESS OF REPORTING MANUFACTURER 
      
 
PLEASE FILL IN THE CORRECT LOCAL IMS PVO 
ADDRESS
PLEASE SEND FORM TO LOCAL INTEGRATED MEDICAL SAFETY/PVO. 


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Trial Drug 
      
Protocol 
      
Tip No. 
      
ID 
 
Centre No. 
Subject No. 
Subject’s Initials 
 
1. 
2. 
fam. 
Randomisation Number 
REPORT TYPE 
 Initial 
 Follow-Up 
 
 
 
CLINICAL TRIAL PREGNANCY FORM 
Page 2 of 3 
2.  LOCAL CASE ID: 
                
III. 
PREGNANCY INFORMATION 
18. 
PRENATAL 
 
Have any specific tests, e.g. amniocentesis, ultrasound, maternal serum AFP, been performed during the pregnancy so far? 
 
No 
 
Yes 
 
Not known 
If yes, please specify test date and results: 
                               
19. 
PREGNANCY OUTCOME 
 
Delivery 
 
 
Normal 
 
Forceps/Ventouse  
 
Caesarean section 
Maternal complications or problems related to birth:  ________________________________________ 
 
Abortion 
 Therapeutic 
 Planned 
 Spontaneous         Please, specify reason and any abnormalities (if known)  ________________ 
 
____________________________________________________________ 
 
Date of abortion/delivery 
day 
month 
 year 
 
 
at week _______ 
   
    
     
 
 
 
 
20. 
MATERNAL PREGNANCY ASSOCIATED EVENTS:                               
If the mother experiences a serious adverse event (SAE) during a pregnancy, please complete an SAE form and submit as requested 
IV. 
CHILD INFORMATION 
21. 
Neonate 
 
Normal 
 
Abnormal 
 
Stillbirth    please specify any abnormalities with dates:  ______________________________ 
 
Sex 
Height 
Weight 
Apgar Scores 
Head circumference 
 
 
Male 
 
Female 
           cm 
           kg 
 1 min.       
 5 mins.       
10 mins.       
           cm 
 
For additional information, please use page 3 (please provide copies of relevant documentation) 
V. 
ASSESSMENT OF PREGNANCY OUTCOME 
22. 
SERIOUSNESS CRITERIA  
 
 
Non Serious 
 
day 
month year 
day 
month year 
 
 
Mother died 
 
 
 
 
 
 
Stillbirth / Neonate died 
 
 
 
 
 
 
Involved or prolonged inpatient hospitalisation 
 
Life-threatening 
 
 
Results in persistent or significant disability/incapacity 
 
Other Seriousness Criteria: 
 
Congenital anomaly/birth defect 
 
Other significant medical events 
23. 
ASSESSMENT OF CAUSALITY 
Please indicate the relationship between pregnancy outcome and Novartis investigational drug 


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  Not suspected 
  Suspected 
 
 
INFORMATION SOURCE 
24. NAME, ADDRESS AND TELEPHONE NUMBER OF INVESTIGATOR 
      
      
      
 
Signature:       
25. REPORTING DATE BY INVESTIGATOR/PERSON  REPORTING 
EVENT 
 
 
 
day 
month 
year 
 
 
 
   
    
     
PLEASE SEND FORM TO LOCAL INTEGRATED MEDICAL SAFETY/PVO. 


Study Protocol                                 Confidential 
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Trial Drug 
      
Protocol 
      
Tip No. 
      
ID 
 
Centre No. 
Subject No. 
Subject’s Initials 
 
1. 
2. 
fam. 
Randomisation Number 
REPORT TYPE 
 Initial 
 Follow-Up 
 
 
CLINICAL TRIAL PREGNANCY FORM 
Page 3 of 3 
2.  LOCAL CASE ID: 
                
FOR ADDITIONAL INFORMATION: 
      
 
      
      
      
      
      
      
      
      
      
      
      
      
      
      
 
INFORMATION SOURCE 
32. NAME, ADDRESS AND TELEPHONE NUMBER OF INVESTIGATOR 
      
      
      
      
Signature:       
32. REPORTING DATE BY INVESTIGATOR/PERSON  REPORTING 
EVENT 
 
 
 
day 
month 
year 
 
 
 
   
    
     
PLEASE SEND FORM TO LOCAL INTEGRATED MEDICAL SAFETY/PVO. 


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APPENDIX 10 
 
 
 
 
 
DFCI IRB Protocol #: 09-071 
 
 
 
 
 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
1.0  Introduction ………………………………………………………………......... 88 
 
 
1.1  Purpose 
1.2  Data and Safety Monitoring Plan Components 
 
2.0     General Roles and Responsibilities …………………………………………...89 
2.1  Protocol Chair 
 
 
2.2  Coordinating Center 
 
 
2.3  Participating Institution 
 
 
3.0     DF/HCC Quality Assurance Office for Clinical Trials ………………………90 
3.1  Organizational Structure 
 
 
 
4.0 Protocol Development …………………………………………………………..91 
 
  4.1   Activation of a Protocol 
 
 
 
  4.2   Coordinating Center Support Function 
 
5.0   Protocol Management ……………………………………………………………92 
 
5.1 Protocol Distribution 
 
 
5.2 Protocol Revisions and Closures 
5.3 Informed Consent Requirements 
5.4 IRB Documentation 
 
5.5 IRB Re – Approvals 
 
 
5.6 Participant Confidentiality and Authorization 
 
5.7 Participant Registration 
 
 
5.8 DF/HCC Multi-center Protocol Case Number 
 
5.9 DF/HCC Multi-center Protocol Registration Policy 
 
5.10 Schedule of Data Submission 
 
 
5.11 Data Form Review 
 
 
5.12 Missing and Deficient Memorandum 
 
6.0 Requisitioning Investigational Drug ……………………………………………….97 
6.1 CTEP Trial Routine Drug Requisitions 
 
 
6.2 Medical Emergency Drug Ordering 
 
 7.0   Safety Assessments and Toxicity Monitoring …………………………………….97  
7.1 Serious Adverse Events 
 
 
7.2 Guidelines for Reporting Serious Adverse Events 
7.3 Guidelines for Processing IND Safety Reports 
 
 
 
8.0 Protocol Violations and Deviations ………………………………………………….98 
 
8.1 Definitions   
 
 
             8.2 Reporting Procedures 
 
 
9.0 Quality Assurance ……………………………………………………………………..99 
        9.1 Ongoing Monitoring of Protocol Compliance 
 
            9.2 Evaluation of Participating Institution Performance 
 
            9.3 On-Site Auditing 
 
 
            9.4 Substandard Performance 
 
 
 
 
 
 


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1.0 INTRODUCTION 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for a DF/HCC Multi-Center research protocol.  
 
1.1 Purpose 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center (DF/HCC) Multi-
center protocol will comply with Federal regulations (21 CFR Part 11); Good Clinical Practice (GCP) 
Guidelines; and  Health Insurance Portability and Accountability Act (HIPAA) requirements in 
accordance with the CTEP Multi-center Guidelines.        
 
1.2 Multi-Center Data and Safety Monitoring Plan Components 
The Multi-Center Data and Safety Monitoring Plan includes the following components: 
 
DF/HCC Multi-center Protocol:  One or more outside institutions collaborating with Dana-
Farber/Harvard Cancer Center on a research  protocol where DF/HCC is the Lead Institution. 
Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates are not viewed as 
outside sites in this definition. 
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center sites (DFCI, MGH, BIDMC, 
CH, BWH) will be the Lead Institution and will be responsible for the coordination, development, 
submission, and approval of a protocol as well as its subsequent amendments per the DFCI IRB 
and applicable regulatory guidelines (CTEP, FDA, OBA etc.).  
 
DF/HCC Contract Principal Investigator:  Investigator located at the Lead Institution who will 
be charged with the responsibility of the administration of the DF/HCC Project. This most often 
will be the Protocol Chair, but occasionally this may be the overall grant or contract holder, as 
applicable. 
 
Protocol Chair:  The Protocol Chair is the Principal Investigator for the DF/HCC protocol 
submitted as the Lead Institution.  For applicable protocols, the Protocol Chair will be the single 
liaison with any regulatory agencies (i.e. CTEP Protocol and Information Office (PIO), FDA, 
OBA etc.).  
 
Participating Institution:  A participating institution is an institution that desires to collaborate 
with DF/HCC and commits to accruing participants to a DF/HCC protocol.  The participating 
institution acknowledges the Protocol Chair as having the ultimate authority and responsibility for 
the overall conduct of the study.    
 
Coordinating Center: The Lead Institution is the Coordinating Center for the DF/HCC Multi-
center Protocol. The Coordinating Center will provide the administrative support to the Protocol 
Chair in order that he/she may fulfill the responsibilities outlined in the DSMP and as specified in 
applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines).  In addition to the Lead 
Institution, the Quality Assurance Office for Clinical Trials (QACT) provides support services to 
assist the Protocol Chair.  
 
 


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2.0 GENERAL ROLES AND RESPONSIBILITIES 
In accordance with the CTEP Multi-center Guidelines, the Protocol Chair (DF/HCC Principal 
Investigator), Coordinating Center (Lead Institution or designee), and the Participating Institutions 
will all agree to the general responsibilities as follows (specific procedures for these general 
responsibilities are detailed in the DSMP): 
 
2.1 Protocol Chair (DF/HCC Principal Investigator) 
 
The Protocol Chair, Irene Ghobrial, MD will accept responsibility for all aspects of the Multi-
Center Data and Safety Monitoring Plan to: 
• 
Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments.    
• 
Submit the Multi-Center Data and Safety Monitoring Plan as an inclusion to the protocol. 
• 
Assure all participating institutions are using the correct version of the protocol. 
• 
Monitor progress and overall conduct of the study at all participating institutions.  
• 
Ensure all DFCI IRB, DF/HCC and other applicable (i.e. FDA) reporting requirements are 
met.  
• 
Review data and maintain timely submission of data for study analysis.  
• 
Act as the single liaison with FDA. 
 
2.2 Coordinating Center (Lead Institution) 
 
The Coordinating Center is the DF/HCC Lead Institution’s study team or designee (i.e Medical 
Monitor, Clinical Research Organization). The DF/HCC Lead Institution, Dana-Farber Cancer 
Institute, will ensure that all participating sites within the Multi-Center Protocol demonstrate their 
intent and capability of complying with Federal Regulations, GCPs and Health Insurance 
Portability and Accountability Act (HIPAA) requirements.   To assist the Protocol Chair in 
meeting his/her responsibilities as required by the DSMP, the DF/HCC Lead Institution’s study 
team or designee will assume the following general responsibilities: 
• Assist in protocol review. 
• Maintain copies of Institutional Review Board (IRB) approvals from all 
participating institutions. 
• Maintain FDA correspondence. 
• Maintain updated roster of participants.  
• Verify eligibility. 
• Verify response. 
• Collect data on protocol specific CRFs. 
• Prepare all submitted data for review by the Protocol Chair. 
• Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to Protocol Chair for timely review.   
• Distribute external Serious Adverse Event safety reports.  
• Monitor and audit Participating Institutions either by on-site inspection of selected 
participant records and/or with source documents and research records submitted to 
the Lead Institution.  
 


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In addition to the Lead Institution, the DF/HCC Quality Assurance Office for Clinical Trials 
provides the following support services to assist the Protocol Chair: 
• Develop protocol specific case report forms (CRF/eCRFS). 
• QA/QC data of protocol specific CRFs.  
• Provide Central Participant Registration. 
• Confirm eligibility and consent.  
• Provide auditing services (funding and QACT approval required). 
 
2.3 Participating Institution 
 
The Participating Institution(s) will be identified on the title page for each protocol.   In addition, 
each participating institution will provide to the Lead Institution or designee a list of the key 
personnel assigned to the role for oversight of data management at their site. All sites must have 
office space, office equipment, and internet access that meet HIPAA standards. 
The general responsibilities for each participating institution are as follows: 
 
• Commit to accrual to the Lead Institution’s (DF/HCC) protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Update Coordinating Center (Lead Institution or designee) with research staff changes on             
       a timely basis. 
• Register participants through the QACT.  
• Submit source documents, research records, and CRFs per protocol specific                               
       submission guidelines to the Coordinating Center (Lead Institution or designee).  
• Submit Serious Adverse Event reports to local IRB and directly to the Coordinating  
      Center (Lead Institution or designee).  
• Submit deviations and violations to local IRB and the Coordinating Center (Lead  
      Institution or designee). 
• For protocols using investigational agents, the participating institution will order their own        
      investigational agents regardless of the supplier (i.e. NCI, pharmaceutical company). 
 
3.0 DF/HCC QUALITY ASSURANCE OFFICE FOR CLINICAL TRIALS 
 
The DF/HCC QACT is a unit that has been developed to computerize, manage, and monitor data for 
DF/HCC trials.  The DF/HCC QACT is located administratively in the office of the Senior Vice 
President for Clinical Research, at Dana-Farber Cancer Institute.  The QACT uses DF/HCC 
computerized institutional databases for participant registrations and for the management of trial data 
as well as a set of quality assurance programs designed to monitor DF/HCC trials.   
 
3.1 Organizational Structure 
 
The DF/HCC Quality Assurance Office for Clinical Trials administrative structure consists of: 
 
DF/HCC Quality Assurance Officer for Clinical Trials: Oversees the functions of the DF/HCC 
QACT. 
 


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QACT Assistant Director for Data: Provides direct oversight to the QACT Data Analysts 
assigned to CRF design, data collection and computerization for DF/HCC trials.  
 
The DF/HCC QACT Data Analysts will be assigned on a protocol by protocol basis. Each 
protocol’s data analyst is responsible for database management, data entry, data quality assurance, 
and protocol specific correspondence related to the collection and quality assurance of data. 
 
QACT Assistant Director for Monitoring: Provides direct oversight to the QACT Protocol 
Registrars and Clinical Research Auditors. 
 
The DF/HCC Protocol Registrars are responsible for the confirmation of each participant’s 
eligibility and consent prior to protocol registration.  
 
If funded and QACT approved, the DF/HCC Clinical Research Auditors may assist the Lead 
Institution in their auditing responsibilities for multi-center trials. The QACT auditor is 
responsible for systematically evaluating participant safety, protocol compliance, institutional 
SOPs, ICH GCP and Federal regulation compliance, data accuracy and investigational drug 
handling to assure a high standard of quality for DF/HCC trials. 
 
4.0 PROTOCOL DEVELOPMENT 
 
4.1 Activation of a Protocol 
 
The Protocol Chair is responsible for the coordination, development, and approval of the protocol 
as well as its subsequent amendments, and reporting SAEs, violations and deviations per DFCI 
IRB guidelines and FDA Guidelines.  Further, the Protocol Chair will be the single liaison with 
the FDA. 
 
To meet these requirements, the Protocol Chair will be responsible for the following minimum 
standards: 
 
• Inclusion of the DF/HCC Multi-Center Data and Safety Monitoring Plan in the 
protocol as an appendix. 
• Identify participating institutions and obtain accrual commitments. The title page must 
include the names and contact information for all participating institutions that perform 
the function of recruiting, enrolling, and treating participants for the protocol. The 
Coordinating Center (Lead Institution or designee) must be designated on the title 
page.  
• Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the Protocol Chair. 
• Ensure that there is only one version of the Protocol and that all Participating 
Institutions use the correct version.  
• Oversee the development of data collection forms (case report forms) that are of 
common format for use at all the Participating Institutions.  
 
 


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4.2 Coordinating Center Support Function 
 
The DF/HCC Lead Institution’s study staff or designee will provide administrative and clerical 
support to the Protocol Chair for the development and distribution of the protocol.  
 
The tasks to be performed by the DF/HCC Lead Institution’s study staff or designee include: 
 
• Review of the protocol and consent to check for logistics, spelling, and consistency.  
Provide the Protocol Chair a list of queries related to any inconsistencies. 
• Provide necessary administrative sections, including paragraphs related to 
registration logistics, data management schedules, and multi-center guidelines.  
• Maintenance of contact list of all participating institutions in the DF/HCC Multi-
Center Protocol and the distribution of updates to the sites as needed.  
• Derivation of the study calendar, if applicable. 
• Assistance in preparation and maintenance of case report forms. Conduct regular 
communications with all participating sites (conference call, emails, etc). Maintain 
documentation of all communications.  
 
5.0 PROTOCOL MANAGEMENT 
 
The Coordinating Center (Lead Institution of designee) is responsible for assuring that each 
Participating Institution in the DF/HCC Multi-center Protocol has the appropriate assurance on file 
with the Office of Human Research Protection (OHRP).   Additionally, the Lead Institution or 
designee must maintain copies of all IRB approvals, for each participating institution.  
 
5.1 Protocol Distribution 
 
The Coordinating Center (Lead Institution or designee) will distribute the final approved protocol 
and any subsequent amended protocols to all Participating Institutions.    
 
5.2 Protocol Revisions and Closures 
 
The participating institutions will receive phone, fax, mail or e-mail notification of protocol 
revisions from the Lead Institution or designee.  It is the individual participating institution’s 
responsibility to notify its IRB of these revisions. 
 
Non life-threatening revisions: Participating institutions will receive written notification of 
protocol revisions regarding non life-threatening events from the Lead Institution or designee. 
Non-life-threatening protocol revisions should be IRB approved and implemented within 90 days 
from receipt of the notification. 
 
Revisions for life-threatening Causes: Participating institutions will receive telephone 
notification from the Lead Institution or designee concerning protocol revisions required to protect 
lives with follow-up by fax, mail or e-mail.  Life-threatening protocol revisions will be 
implemented immediately followed by IRB request for approval. 
 


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Protocol Closures and Temporary Holds: Participating institutions will receive fax, e-mail, or 
phone notification of protocol closures and temporary holds, with follow-up by mail from the 
Lead Institution or designee. Closures and holds will be effective immediately.  In addition, the 
Lead Institution or designee will update the Participating institutions on an ongoing basis about 
protocol accrual data so that they will be aware of imminent protocol closures. 
 
5.3 Informed Consent Requirements 
 
 
 
The Principal Investigator (PI) at each participating site will identify the physician members of the 
study team who will be obtaining consent and signing the consent form for therapeutic protocols. 
It is DF/HCC policy that Nurses and Fellows cannot obtain consent to greater than minimal risk 
trials.   
 
5.4 IRB Documentation 
 
The following must be on file with the DF/HCC Lead Institution or designee prior to participant 
registration: 
• Approval Letter of the institution's IRB (An Expedited IRB first approval is NOT    
      acceptable) 
• IRB approval for all amendments 
 
It is the individual institution's responsibility to notify its IRB of protocol revisions.  Participating 
institutions will have 90 days from receipt to provide the DF/HCC Lead Institution or designee 
their IRB approval for Major Amendments to a protocol.    
 
DF/HCC defines a Major Amendment as: A substantive change in the study which may 
increase or decrease the risk to study participants.  Major revisions require full IRB approval.  The 
following criteria are examples of revisions to a protocol that are considered to be major 
amendments:  
 
 
 
 
• Change of eligibility (inclusion/exclusion) criteria 
• Change in design of protocol 
• Change in statistical section 
• Change in sample size/accrual (e.g., doubling the sample size) 
• Change in informed consent 
• Change of estimated dropout rate 
• Change of treatment or intervention 
• Change of device 
• Change in primary objective evaluation process 
 
 
5.5 IRB Re-Approval 
 
Annual IRB re-approval from the Participating institution is required in order to register 
participants onto a protocol.  There is no grace period for annual re-approvals. 
 


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Protocol registrations will not be completed if a re-approval letter is not received by the DF/HCC 
Lead Institution or designee from the Participating Institutions on or before the anniversary of the 
previous approval date.   
 
5.6 Participant Confidentiality and Authorization Statement 
The Health Insurance Portability and Accountability Act of 1996 contains,  as one of its six major 
components, the requirement to create privacy standards for health care information that is used or 
disclosed in the course of treatment, payment or health care operations.  The original Privacy Rule, 
as it has come to be known, was published in December 2000.  The Final Rule was published on 
August 14, 2002, which has modified the privacy rule in significant ways vis-à-vis research. 
 
In order for covered entities to use or disclose protected health information during the course of a 
DF/HCC Multi-Center Protocol the study participant must sign an Authorization.  This 
Authorization may or may not be separate from the Informed Consent.  The DF/HCC Multi-
Center Protocol, with the approval from the DFCI IRB and if applicable NCI/CTEP, will provide 
an Informed Consent template, which covered entities (DF/HCC Multi-Center Protocol 
participating institutions) must use.  
 
The DF/HCC Multi-Center Protocol will use all efforts to limit its use of protected health 
information in its trials.  However, because of the nature of these trials, certain protected health 
information must be collected per National Cancer Institute requirements. These are the primary 
reasons why DF/HCC has chosen to use Authorizations, signed by the participant in the trial, 
rather than limited data sets with data use agreements.   
 
5.7 Participant Registration and Randomization  
To register a participant, the following documents should be completed by the DF/HCC Multi-
Center Protocol participating site and faxed to or e-mailed to Meghan Rourke at DFCI 
(Meghan_Rourke@dfci.harvard.edu, fax: 617-632-6752): 
• Copy of all required screening labs and assessments (please refer to Section 7.1 of          
protocol) 
• Signed informed consent form by a physician listed on the 1572 
• HIPAA authorization form (if separate from the informed consent document) 
• Eligibility Checklist signed by the treating physician, physician assistant, nurse practitioner 
and/or registered nurse. 
 
The research DF/HCC Multi-center Protocol participating site will then call or e-mail Meghan 
Rourke to verify eligibility. To complete the registration process, Meghan Rourke will: 
• Register the participant on the study with the DF/HCC Quality Assurance Office              
for Clinical Trials (QACT) 
• Fax or e-mail the participant case number, and if applicable the dose treatment level, to the 
participating site 
• Call the research nurse or data manager at the participating site and verbally confirm 
registration 
 
Randomization can only be done between normal QACT business hours, 8:30am-5:00pm EST. 
 


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5.8 DF/HCC Multi-center Protocol Case Number 
 
Once eligibility has been established and the participant successfully registered, the participant is 
assigned a five digit protocol case number.  This number is unique to the participant on this trial 
and must be used for QACT eCRF completion and written on all data and QACT correspondence 
for the participant. 
 
5.9 DF/HCC Multi-center Protocol Registration Policy 
 
    5.9.1      Initiation of Therapy: Participants must be registered with the DF/HCC QACT before 
receiving treatment.  Treatment may not be initiated until the site receives a faxed or e-
mailed copy of the participant’s Registration Confirmation memo from the DF/HCC 
QACT. Therapy must be initiated per protocol guidelines.  The Protocol Chair and 
DFCI IRB must be notified of any exceptions to this policy.  
 
5.9.2    Eligibility Exceptions: The DF/HCC QACT will make no exceptions to the eligibility 
requirements for a protocol without DFCI IRB approval.   
 
5.9.3    Verification of Registration, Dose Levels, and Arm Designation: A registration 
confirmation memo for participants registered to DF/HCC Multi-Center Protocol will 
be faxed or emailed to the registering institution within one working day of the 
registration. Treatment may not be initiated until the site receives a faxed or e-mailed 
copy of the registration confirmation memo.  
 
5.9.4    Confidentiality: All documents, investigative reports, or information relating to the 
participant are strictly confidential. Any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Lead Institution or 
designee must have the participant’s full name & social security number “blacked out” 
and the assigned DF/HCC QACT case number and protocol number written in (with 
the exception of the signed informed consent document). Participant initials may only 
be included or retained for cross verification of identification. 
  
 
5.10 Schedule of Data Submission 
The DF/HCC QACT develops a set of either paper or electronic case report forms, 
(CRF/eCRFs) for use with the DF/HCC Multi-Center Protocol.  QACT provides a web based 
training for eCRF users.  These forms are designed to collect data for each study. The schedule 
for submission of case report forms to the DF/HCC QACT is specified in Section 11.2.  
 
5.11 Data Form Review 
When data forms arrive at the DF/HCC QACT, they are reviewed for: 
  
Timeliness:  
Did the form arrive on time as specified in the protocol? 
 
 
 
 
Completeness:  
Is all the information provided as required per protocol? 


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Participant Eligibility:  
Does the participant meet the eligibility requirements for the study based on the demographic 
data, lab values and measurements provided? 
 
Stratification:  
Are the stratification parameters consistent with what was given at the time of registration? 
 
Protocol Treatment Compliance:  
Are the body surface area (BSA) and drug dosage calculations correct?  The dose must be within 
10% of the calculated protocol dose. 
  
Adverse Events (Toxicities):  
Did the participant experience adverse events (toxicities or side effects) associated with the 
treatment? Was the treatment delayed due to the adverse event? What was the most severe 
degree of toxicity experienced by the participant? 
 
Notations concerning adverse events will address relationship to protocol treatment for each 
adverse event grade.  All adverse events encountered during the study will be evaluated 
according to the NCI Common Toxicity Criteria assigned to the protocol and all adverse events 
must be noted on the participant's Adverse Event (Toxicity) Forms. 
 
Response:  
Did the participant achieve a response?  What level of response did they achieve?  On what date 
did the participant achieve the response and how was the response determined? 
 
Response criteria are defined in the protocol.  A tumor assessment must be performed prior to 
the start of treatment and while the participant is on treatment as specified by the protocol.   
 
Objective responses must have documentation such as physical measurements, x-rays, scans, or 
laboratory tests.   
 
A subjective response is one that is perceived by the participant, such as reduction in pain, or 
improved appetite. 
 
5.12 Missing and Deficient Memorandum 
 
Data submissions are monitored for timeliness and completeness of submission. Participating 
institutions are notified of their data submission delinquencies in accordance with the following 
policies and procedures: 
 
Incomplete or Questionable Data 
 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written query from the DF/HCC QACT Data Analyst.  Responses to the query should 
be completed and returned within 14 days.  Responses may be returned on the written query or 


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on an amended case report form. In both instances the query must be attached to the specific 
data being re-submitted in response.   
 
Missing Forms 
 
If study forms are not submitted on schedule, the participating institution will receive a Missing 
Form Report from the DF/HCC QACT noting the missing forms.  These reports are compiled by 
the DF/HCC QACT and distributed a minimum of three times a year.  
 
6.0 REQUISITIONING INVESTIGATIONAL DRUG 
 
The ordering of investigational agent is specified in Appendix 8 (LBH589 Order Form).  
 
Participating sites should order their own agent regardless of the supplier (i.e., NCI or a 
pharmaceutical company.)  
 
If the agent is commercially available, check with the local Director of Pharmacy and/or the 
Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the 
agent can be ordered once the protocol is approved by the local IRB. If the agent is investigational, 
ensure that the pharmacy will be able to receive and store the agent. The local IRB should be kept 
informed of who will supply the agent (i.e., NCI or a pharmaceutical company) so that any 
regulatory responsibilities can be met in a timely fashion.  
 
7.0 SAFETY ASSESSMENTS AND TOXICITY MONITORING 
 
All participants receiving investigational agents will be evaluated for safety.   The safety 
parameters include all laboratory tests and hematological abnormalities, physical examination 
findings, and spontaneous reports of adverse events reported to the investigator by participants.  
All toxicities encountered during the study will be evaluated according to the NIH-NCI Common 
Terminology Criteria for Adverse Events, version 3.0 (CTCAEv3.0, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf) and 
recorded prior to each course of therapy.  Life-threatening toxicities should be reported 
immediately to the Protocol Chair and Institutional Review Board (IRB).  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
7.1 Serious Adverse Events 
 
A serious adverse event (SAE) is any adverse drug experience at any dose that results  in any of 
the following outcomes: death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.  Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.  


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Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions in a participant who has never 
had seizure activity in the past that do not result in inpatient hospitalization, or the development 
of drug dependency or abuse. 
 
The NIH-NCI Common Terminology Criteria for Adverse Events, version 3.0 (CTCAEv3.0, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf) will be 
utilized for AE reporting.  
 
7.2 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Serious Adverse Events (SAEs) will be followed as is delineated in the 
protocol Section 8. 
 
 
 
 
 
In addition, the Participating Institutions must report the serious adverse events to the Protocol 
Chair and the Coordinating Center (Lead Institution) following the DFCI IRB SAE Reporting 
Requirements. 
 
The Lead Institution will maintain documentation of all Adverse Event Reporting and be 
responsible for communicating all SAEs to all Participating sites. 
 
7.3 Guidelines for Processing IND Safety Reports  
 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to 
notify the FDA and all participating investigators of any serious and unexpected adverse 
experiences that are possibly related to the investigational agent. In compliance with these FDA 
regulations, the Protocol Chair is responsible for reviewing all IND Safety Reports and forwarding 
the IND Safety Reports to the Participating Institutions.  The investigators are to file a copy with 
their protocol file and send a copy to their IRB according to their local IRB’s policies and 
procedures. 
 
 
8.0 PROTOCOL VIOLATIONS AND DEVIATIONS 
 
Neither the FDA nor the ICH GCP guidelines define the terms “protocol violation” or “protocol 
deviation.”  All DF/HCC Protocol Chairs must adhere to those policies set by the DFCI IRB, the 
definitions for protocol violation and deviation as described by the DFCI IRB will be applied for 
reporting purposes for all institutions participating in the DF/HCC Multi-center Protocol.  
   
8.1 Definitions 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a subject who does not meet all inclusion/exclusion criteria. 
 
 
 


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Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB prior 
to its initiation or implementation.  
 
 
8.2 Reporting Procedures 
 
The Protocol Chair: is responsible for ensuring that clear documentation is available in the 
medical record to describe all protocol exceptions, deviations and violations. The Protocol Chair 
will also be responsible for ensuring that all protocol violations/deviations are promptly reported 
per DFCI IRB guidelines.  
 
 
Participating Institutions: Protocol deviations require prospective approval from DFCI IRB. 
The Participating institution must submit the deviation request to the Protocol Chair or designee, 
who will submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation 
should be submitted to the participating site’s own IRB, per its institutional policy. 
A copy of the participating institution’s IRB report and determination will be forwarded to the 
DF/HCC Lead Institution or designee by mail, facsimile, or via e-mail within 10 business days 
after the original submission.  
 
All protocol violations must be sent to the DF/HCC Lead Institution Protocol Chair or designee 
in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the participating 
institution, the DF/HCC Lead Institution or designee will submit the report to the Protocol Chair 
for review. Subsequently, the participating institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
 
9.0 QUALITY ASSURANCE 
 
The quality assurance process for a clinical trial research study requires verification of protocol 
compliance and data accuracy. As the Coordinating Center, the DF/HCC Lead Institution or designee 
with the aid of the QACT provides quality assurance oversight for the DF/HCC Multi-center Protocol. 
 
9.1 Ongoing Monitoring of Protocol Compliance 
 
 
All data submitted to the DF/HCC QACT will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements.  Monitoring will begin at the time of 
participant registration and will continue during protocol performance and completion.  The Lead 
Institution or designee and if applicable QACT Data Analysts assigned to the Protocol will perform 
the ongoing protocol compliance monitoring with the support of the participating institution’s 
Coordinators, the Principal Investigators, and the Protocol Chair.  
 
9.2 Evaluation of Participating Institution Performance 
 
 


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9.2.1 
Eligibility Checklist  
Eligibility criteria are checked on a protocol-specific eligibility checklist and faxed to the DF/HCC 
QACT prior to registration on protocol.  The checklist and informed consent document are reviewed 
by a DF/HCC QACT Protocol Registrar before the participant can be registered on a protocol.  The 
DF/HCC QACT cannot make exceptions to the eligibility requirements. 
 
9.2.2 Accrual of Eligible Participants 
Annual accrual rates for eligible participants enrolled onto therapeutic clinical trials is calculated for 
each institution. Institutions are expected to maintain the minimum annual average accrual as defined 
by the protocol grant or contract.  
 
9.3 On-Site Auditing 
 
9.3.1 DF/HCC Sponsored Trials 
On-site monitoring will occur on an as-needed basis. At a minimum, the DF/HCC Lead 
Institute, or designee, will visit each participating twice a year while patients are receiving 
treatment. 
 
The participating institutions may be required to submit subject source documents to the 
DF/HCC Lead Institution or designee for monitoring.  
 
9.3.2 Participating Institution 
It is the participating institution’s responsibility to notify the DF/HCC Lead Institution or 
designee of all scheduled audit dates (internal or NCI) and re-audit dates (if applicable), 
which involve the DF/HCC Multi-Center Protocol. All institutions will forward a copy of 
final audit and/or re-audit reports and corrective action plans (if applicable) to the DF/HCC 
Lead Institution or designee within 12 weeks after the audit date.  
 
9.3.3 Coordinating Center (Lead Institution or designee)  
The Protocol Chair will review all DF/HCC Multi-Center Protocol Final Audit reports and 
corrective action plans if applicable. The Lead Institution or designee must forward these 
reports to the DF/HCC QACT per DF/HCC policy for review by the DF/HCC Audit 
Committee. Based upon the audit assessments the DF/HCC Audit Committee could accept 
or conditionally accept the audit rating and final report. Conditional approval could require 
the Protocol Chair to implement recommendations or require further follow-up.  For 
unacceptable audits, the Audit Committee would forward the final audit report and corrective 
action plan to the DFCI IRB as applicable. 
 
9.4 Sub-Standard Performance 
 
The Protocol Chair, and the DFCI IRB is charged with considering the totality of an institution’s 
performance in considering institutional participation in the DF/HCC Multi-Center Protocol. 
 
9.4.1 Corrective Actions 
Institutions that fail to meet the performance goals of accrual, submission of timely accurate 


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data, and adherence to protocol requirements will be recommended for a six- month 
probation period. Such institutions must respond with a corrective action plan and must 
demonstrate during the probation period that deficiencies have been corrected, as evidenced 
by the improved performance measures. Institutions that fail to demonstrate significant 
improvement will be considered by the Protocol Chair for revocation of participation.