Clinical trial NCT02282358
Conditions: Lymphoma Relapsed and Refractory Diffuse Large B-Cell Lymphoma and Follicular Lymphoma
Keywords: Mocetinostat 14-106
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2014-10-01; Completion date: 2023-05-26
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to learn if the study drug mocetinostat can slow the progression of cancer in people who have a mutation in CREBBP or EP300 in the genetic makeup of their cancer. The potential side effects of mocetinostat will also be studied.

Detailed description:

Arms: arm 1: Patients who harbor mutations for CREBBP and/or EP300 will be started on mocetinostat 70 mg orally three times per week on a 28 day schedule in cycle 1. The dose will be escalated in cycle 2 to 90 mg orally three times per week on a 28 day schedule if there are no grade 3 or higher drug related toxicities. Therapy will continue until disease progression, intolerable toxicities or death.
Interventions: intervention 1: Mocetinostat
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 14-106 A(7) 
Approval date: 24-Oct-2022 
 
 
MSK PROTOCOL COVER SHEET 
An Open-Label Phase II Study of Mocetinostat in Selected Patients with Mutations of 
Acetyltransferase Genes in Relapsed and Refractory Diffuse Large B-Cell Lymphoma and 
Follicular Lymphoma 
Principal Investigator/Department: Andrew Zelenetz, MD, PhD / Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
Page 1 of 56 
Version: 10/17/2022 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-106 A(7) 
Approval date: 24-Oct-2022 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 3 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................. 19 
4.1 
Design......................................................................................................................... 19 
4.2 
Intervention ................................................................................................................. 19 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 20 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 21 
6.1 
Subject Inclusion Criteria ............................................................................................. 21 
6.2 
Subject Exclusion Criteria ............................................................................................ 21 
7.0 
RECRUITMENT PLAN ..................................................................................................... 22 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 23 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 25 
10.0 EVALUATION DURING TREATMENT/INTERVENTION .................................................. 31 
11.0 TOXICITIES/SIDE EFFECTS ................................................................................................ 38 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....................... 42 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 45 
14.0 BIOSTATISTICS ................................................................................................................... 46 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES47 
15.1 Research Participant Registration .................................................................................... 47 
15.2 Randomization .............................................................................................................. 47 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 48 
16.1 Quality Assurance ....................................................................................................... 48 
16.2 Data and Safety Monitoring ......................................................................................... 48 
17.0 PROTECTION OF HUMAN SUBJECTS ........................................................................... 49 
17.1 Privacy ........................................................................................................................ 49 
17.2 Serious Adverse Event (SAE) Reporting ..................................................................... 49 
18.0 INFORMED CONSENT PROCEDURES .............................................................................. 51 
19.0 REFERENCES ...................................................................................................................... 51 
20.0 APPENDICES ....................................................................................................................... 53 


Memorial Sloan Kettering Cancer Center 
IRB Number: 14-106 A(7) 
Approval date: 24-Oct-2022 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title: An Open-Label Phase II Study of Mocetinostat in Selected Patients with Mutations of 
Acetyltransferase Genes in Relapsed and Refractory Diffuse Large B-Cell Lymphoma and Follicular 
Lymphoma 
Objectives: The purpose of this trial is to determine the therapeutic efficacy of mocetinostat in 
selected patients with CREBBP/EP300 alterations in relapsed and refractory DLBCL and FL. 
Patient Population: Patients with histologically confirmed relapsed or refractory diffuse large B cell 
lymphoma and follicular lymphoma with mutations of CREBBP or EP300. 
Study Design: This is an open label phase II study in patients with relapsed and refractory NHL in 2 
histologic subgroups: diffuse large B cell lymphoma and follicular lymphoma. Patients with mutations 
of CREBBP and/or EP300 will be eligible for the trial. Eligible patients will be be treated by 
mocetinostat and monitored for overall response, event free survival, and duration of response. 
Treatment Plan: Patients who harbor mutations for CREBBP and/or EP300 will be started on 
mocetinostat 70 mg orally three times per week on a 28 day schedule in cycle 1.  The dose will be 
escalated in cycle 2 to 90 mg orally three times per week on a 28 day schedule if there are no grade 
3 or higher drug related toxicities. Therapy will continue until disease progression, intolerable 
toxicities or death. 
Time to Completion: We anticipate that this study will enroll 10 patients in each cohort of follicular 
lymphoma and diffuse large B cell lymphoma. If 2 or more patients in each cohort show a response, 
we will enroll an additional 15 patients in that cohort for the second stage of the trial. Assuming a 
dropout rate of 10%, we plan to enroll 56 patients total, 28 patients in each cohort over 48 months. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1. PRIMARY OBJECTIVES 
 
 
Determine the efficacy as defined by overall response rate of Mocetinostat at one year in 
patients with relapsed/refractory DLBCL and FL who have inactivating mutations of 
acetyltransferase genes. 
2.2. SECONDARY OBJECTIVE 
 
 
Assess the event free survival of mocetinostat in this selected population 
 
Assess the duration of response of mocetinostat in this selected population 
 
Assess the safety and tolerability of mocetinostat in this selected population 
 
2. 3. EXPLORATORY ASSESSMENTS 
 
 
Correlation of myc and Bcl-2 positivity for treatment response 
 
Assessment of mechanisms of resistance to mocetinostat via genetic mutation analysis 
 
Assay T cell activation and exhaustion in the peripheral blood 


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IRB Number: 14-106 A(7) 
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Figure 2-1. Study design overview 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Rationale 
 
This is a single center, open label, single arm single step phase II study of mocetinostat in patients 
with relapsed and refractory DLBCL and FL harboring mutations in CREBBP and EP300 (Figure 2- 
1). The integrated assessment of CREBBP and EP300 mutations were chosen based on preclinical 
data suggesting patients harboring CREBBP or EP300 mutations may be more sensitive to HDAC 
inhibition[1]. The purpose of this study is to determine the therapeutic efficacy of mocetinostat in 
selected patients with CREBBP/EP300 alterations in relapsed and refractory DLBCL and FL. 
Approximately 30% of patients with DLBCL and FL harbor inactivating mutations in acetyltransferase 
genes which may make their disease more susceptible to HDAC inhibition. Mocetinostat has been 
previously shown to elicit modest responses of 15-17% in unselected DLBCL and FL patients[2]. 
Selection for populations of DLBCL and FL patients with increased sensitivity to HDAC inhibition 
may identify a population of patients with a heightened response to HDAC therapy.  The starting 
dose for mocetinostat for this study is based on the results of the prior phase II clinical trial assessing 
mocetinostat in DLBCL and FL. The starting dose will be 70 mg orally three times a week on a 28 
day schedule on cycle 1 followed by dose increase to 90 mg orally three times a week on a 28 day 
schedule if there are no grade 3 or higher drug related toxicities.  Dose reductions will be determined 
based on side effect profile. 
 
3.2. 
Background 
 
3.2.1. Overview of disease pathogenesis, epidemiology and current treatment 
 
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with 
differing patterns of behavior and responses to treatment[3]. NHL is the ninth and seventh most 
frequent cancer in males and females, respectively, with an incidence of approximately 69,000 new 
patients each year and 19,000 deaths each year in the United States (US) [4]. The incidence rises 
with age becoming an important cause of mortality and morbidity in adults. NHL can occur at any age 
and is clinically marked by enlarged lymph nodes, fever, and weight loss. Though considered a 
curable disease, about 50% of NHL patients are not cured with available therapy. The current 5-year 
and 10- year survival rates for lymphoma are 68% and 57%, respectively [4]. 
 
3.2.2. Rationale for HDAC inhibition in patients with CREBBP and EP300 alterations 
 
Diffuse Large B-cell Lymphoma (DLBCL) represents the most common form of B-cell non-Hodgkin 
Lymphoma (B-NHL), accounting for ~30% of the de-novo diagnoses and also arising as a frequent 
clinical evolution of Follicular Lymphoma (FL) [5]. The molecular pathogenesis of DLBCL is 


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associated with multiple genetic lesions that segregate in part with individual phenotypic subtypes, 
namely germinal-center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, suggesting the 
involvement of distinct oncogenic pathways [6, 7].  Genome-wide efforts toward the identification 
and functional characterization of the entire set of structural alterations present in the DLBCL 
genome are required for a complete understanding of its pathogenesis [8]. 
Combining next generation whole-exome sequencing analysis of 7 DLBCL cases and genome-wide 
high-density single nucleotide polymorphism (SNP) array analysis of 72 DLBCL cases identified 
>450 loci that are affected by somatic point mutations and/or by recurrent, focal gene copy number 
(CN) aberrations[1]. The most commonly independently validated mutations involved the 
acetyltransferase genes CREBBP (CBP) and EP300 (p300). CREBBP encodes a highly conserved 
and ubiquitously expressed nuclear phosphoprotein that, together with the closely related protein 
EP300, belongs to the KAT3 family of histone/protein lysine acetyltransferases[9, 10] (Figure 3-1). 
CREBBP and EP300 function as transcriptional coactivators for a large number of DNA-binding 
transcription factors involved in multiple signaling and developmental pathways, by modifying lysine 
residues on both histone and non-histone nuclear proteins [11, 12]. CREBBP and EP300 enhance 
transcription by multiple mechanisms, including targeted acetylation of chromatin [11, 12], 
acetylation of transcriptional activators (e.g., the tumor 
suppressors p53 and GATA1) [13-16], and acetylation- 
mediated inactivation of transcriptional repressors (e.g. 
the DLBCL-associated oncogene BCL6) [17]. 
Additionally, both molecules were found to exhibit 
ubiquitin ligase activity [18]. 
 
Previous extensive surveys in malignancies of 
epithelial origin have reported inactivating mutations of 
EP300 and CREBBP in exceedingly rare cases (<2% 
of primary biopsies) [19-21]. However, recurrent 
mutations of CREBBP are found in B-cell acute 
lymphoblastic leukemia [22] suggesting a specific role 
for CREBBP/EP300 inactivation in the pathogenesis of 
malignancies derived from B-lymphocytes. Overall, 
CREBBP/EP300 lesions are among the most frequent 
structural alterations yet detected in FL and DLBCL, 
thus representing an important feature of the 
pathogenesis of these common diseases. In DLBCL, 
CREBBP mutations and deletions typically caused the elimination or truncation of the HAT domain 
implicating functional significance. Of the mutations, 17 (50%) were inactivating events, including 
nonsense mutations (n=9), frameshift insertions/deletions (n=7) and mutations at consensus splice 
donor/splice acceptor sites (n=1), which generate aberrant transcripts carrying premature stop 
codons. The remaining variants included 3 in-frame deletions and 14 missense mutations, primarily 
within the HAT domain (Figure 3-2A). The lesions were predominantly monoallelic (n=33/39 cases) 
with rare instances of biallelic genetic lesions include the homozygous loss, a missense mutation 
with loss of heterozygosity (2 primary biopsies), biallelic nucleotide substitutions (2 cases), and a 
frameshift deletion with missense mutation of the second allele in the OCI-Ly8 cell line. 
Figure 3-1. Transcription regulation by 
CREBBP/EP300. Schematic representation of 
the promoter region of a gene, with the DNA 
wrapped around octamer nucleosomes, the 
histone proteins H2A, H2B, H3 and H4. A 
transcription factor dimer (TF), bound to the 
enhancer region (ENH), recruits remodeling 
factors (remodeler) and HATs, like CREBBP or 
p300 (CBP/p300), sometimes indirectly through 
other coactivators like the p160 proteins. CBP 
and p300 can make the DNA more accessible for 
other regulatory proteins by acetylating the 
histone tails (Ac). In addition, CBP and p300 can 
form a physical bridge between transcription 
factors and the general transcription factors 
(GTF) and RNA polymerase II (Pol II) [9] 


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Cumulatively, 29% of all DLBCL patients (n=39/134), corresponding to 41.5% of GCB- and 17% of 
ABC-DLBCL, harbor genomic alterations affecting the CREBBP gene (Figure 3-2B).  Mutations 
analogous to those found in DLBCL were frequent in FL (32.6%, with 16 events distributed in 15/46 
cases), but not in other lymphoma types such as Burkitt lymphoma, marginal zone lymphoma, and 
chronic lymphocytic leukemia, suggesting a specific role in the pathogenesis of these two diseases 
(Figure 3-2C,D). 
 
 
Mutational analysis of the EP300 gene in the same panel identified 19 sequence variants leading to 
frameshift mutations (n=4), nonsense mutations (n=2), missense or in-frame deletions (n=13) (Figure 
3-3A). These lesions were found in 10% of DLBCL (n=13/134) and 8.7% of FL samples (n=4/46), 
but were virtually absent in other B-NHLs (Figure 3-3A). Seven additional DLBCLs harbored 
monoallelic deletions spanning, although not limited to, the EP300 locus. Notably, structural 
alterations of CREBBP and EP300 co-exist in only a minority of the affected cases (n=6/53      
DLBCL and 0/19 FL) suggesting that inactivation of these loci is at least in part functionally 
equivalent. 
 
 
Overall ~39% of all DLBCL and at least 41% of FL cases (based on mutations only) display 
structural alterations of KAT3 family genes. One key observation is that CREBBP/EP300 lesions are 
mostly detected in heterozygosity, suggesting a haploinsufficent role in tumor suppression. This is 
supported by data demonstrating congenital heterozygous mutations of CREBBP/EP300 are 
Figure 3-2. CREBBP mutations in DLBCL and FL. A. Schematic diagram of the CREBBP 
gene (top) and protein (bottom). Exons are colour-coded according to the corresponding 
protein functional domains (CH, cysteine-histidine rich; KIX, CREB-binding; Bromo, 
bromodomain; HAT, histone acetyltransferase; Q, polyglutamine stretch). Colour-coded 
symbols depict distinct types of mutations. B. frequency of CREBBP structural 
alterations in DLBCL subtypes (mutations and deletions, combined). C. Distribution of FL 
associated point mutations along CREBBP gene and protein.D. Overall frequency of 
CREBBP mutations according to mutation type.[1] 


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sufficient to cause pathologic and developmental abnormalities including tumorigenesis [23], 
CREBBP heterozygote mice have de novo hematologic malignancies [24], and unlike ubiquitously 
expressed histone deacetylases, HAT cellular concentrations are tightly regulated therefore small 
dosage variations can have severe biological consequences [25]. 
 
 
 
 
 
 
 
Mutant CREBBP and EP300 proteins are deficient in acetylating BCL6 and p53, leading to 
constitutive activation of the oncoprotein and to decreased p53 tumor suppressor activity [1]. The 
balance between the activities of these two genes is critical for the regulation of DNA damage 
responses in mature germinal center cells during immunoglobulin gene remodeling [26, 27]. The 
consequences of BCL6 activity overriding p53 would be an increased tolerance for DNA damage in 
the context of diminished apoptotic and cell cycle arrest responses. The use of HDAC inhibitors in 
this HAT mutated population may contribute to re-establishing physiologic acetylation levels 
sensitizing the lymphoma to cellular apoptosis and cell cycle arrest [1]. Therefore, the efficacy of 
HDAC inhibitors should be selectively evaluated in patients with HAT mutations in CREBBP and 
EP300. 
 
 
3.2.3. Overview of Diffuse Large B-cell Lymphoma 
 
DLBCL comprises more than 30% of all newly diagnosed NHL cases. Majority (over 80%) are 
aggressive lymphomas, and more than half of these patients are older than 60 years. The advent of 
rituximab has significantly improved the outcomes for patients with DLBCL and approximately 50% 
of patients are cured with rituximab and chemotherapy. The remaining 50% of DLBCL patients, 
especially the poor risk patients with International Prognostic Index (IPI) ≥ 3 factors, will relapse or 
progress despite a good initial response to the front line immuno- chemotherapy. High-dose 
chemotherapy with autologous stem-cell transplantation (HDT/ASCT) is an established treatment 
option for poor-prognosis patients who are 65 or younger and refractory to front line therapy. 
Nevertheless, more than half of these patients will relapse following HDT/ASCT and die of the 
disease. The prognosis among patients who are not transplant candidates is even more dismal. 
Therefore, novel drug therapy with different mechanisms to prolong duration of disease remission in 
Figure 3-3. EP300 mutations in DLBCL and FL. A.  Schematic of the EP300 protein with key functional 
domains and color coded symbols indicating distinct types of mutational events. B. Frequency of EP300 
mutated samples in DLBCL, FL, Burkitt lymphoma (BL) and marginal zone lymphoma (MZL). [1] 


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poor risk patients and eventually to improve long term survival among these patients is a pressing 
need. 
3.2.4. Overview of Follicular Lymphoma 
 
FL is the second most common form of NHL prevailing in the United States representing 22% of all 
newly diagnosed cases of NHL. Despite an advanced stage, the clinical course of disease is usually 
indolent and patients are highly responsive to various combinations of standard chemotherapy 
drugs. The disease, however, is not curable with available treatment, and most patients tend to 
relapse after treatment with shorter intervals of remission in between. In approximately 30% of 
patients, the disease progresses more rapidly with transformation into DLBCL and early death. The 
molecular biology underlying this phenomenon and the factors associated with the risk of 
transformation are not entirely known. 
The incorporation of effective and well-tolerated monoclonal antibodies, such as rituximab, into 
chemo-immunotherapeutic strategies provided the first evidence that survival of these patients could 
be prolonged. A relatively small pivotal phase II study in 166 patients with relapsed FL resulted in 
rituximab being the first FDA approved monoclonal antibody for the treatment of cancer. The 
combination of rituximab and chemotherapy (R-Chemo) has resulted in greatly improved response 
rates, Event free survival and also overall survival, to such an extent that R-Chemo is now worldwide 
the standard induction treatment in first line as well as for relapsed advanced stage FL. 
Nevertheless, FL remains incurable and characterized by recurrent relapses requiring additional 
treatment. An increasing number of effective drugs are now being evaluated either alone or in 
combinations including the chemotherapy drugs bendamustine and bortezomib. More targeted 
agents include monoclonal antibodies and their derivatives such as drug- antibody conjugates and 
small molecular immunopharmaceuticals. Other agents inhibit various cellular pathways including 
those triggered by the B-cell receptor, including spleen tyrosine kinase (Syk) and Bruton’s tyrosine 
kinase, and other intracellular pathways such as the mTOR, phosphatidylinositol-3-Kinase (PI3K), 
and apoptosis, and drugs that target the tumor microenvironment. This abundance stresses the 
unremitting need for clinical trials aimed at answering the many open questions as to optimal 
treatment strategies in advanced FL[28]. 
 
3.2.5. Histone acetylation pathway 
 
Epigenetic events such as acetylation, methylation, ubiquitination and phosphorylation of histones 
control accessibility of chromatin structure for DNA transcription, replication, repair and cellular 
development. Deregulation of histone acetylation is rapidly being recognized as a hallmark of 
cancer. Human histone deacetylases are classified into four classes: class I comprised of HDAC 1, 
2, 3, and 8 are localized to the nucleus with ubiquitous tissue expression, class II comprised of 
HDAC 4, 5, 6, 7, 9, 10 with variable cellular localization, class III includes NAD-dependant 
homologues of yeast SIRT 1-7 not currently targeted by currently available HDAC inhibitors, and 
class IV comprised of HDAC 11 with properties of class I and class II HDAC [29]. Histone 
deacetylases (HDACs) remove acetyl groups from histone and non-histone proteins altering 
oncogenic genetic and protein expression profiles [29]. 


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Decreased major histocompatibility class II (MHCII) expression on the tumors in both DLBCL 
subtypes directly correlates with significant decreases in patient survival. One common mechanism 
accounting for MHCII downregulation in DLBCL is reduced expression of the MHC class II 
transactivator (CIITA), the master regulator of MHCII transcription. Furthermore, reduced CIITA 
expression in ABC DLBCL correlates with the presence of the transcriptional repressor positive 
regulatory domain-I-binding factor-1 (PRDI-BF1). Treatment of CIITA(-) or CIITA(low) GCB cells with 
several different histone deacetylase inhibitors (HDACi) activated modest CIITA and MHCII 
expression. However, CIITA and MHCII levels were significantly higher in these cells after exposure 
to the HDAC-1-specific inhibitor MS-275. These results suggest that CIITA transcription is repressed 
in GCB DLBCL cells through epigenetic mechanisms involving HDACs, and that HDAC inhibition can 
alleviate repression [30]. 
 
HDAC inhibition induces large scale epigenetic changes to multiple cancer signaling networks[31- 
33]. Thus far, two HDAC inhibitors, vorinostat and romidepsin, have been approved by the Federal 
Drug Administration (FDA) for treatment of cutaneous T cell lymphoma and peripheral T cell 
lymphoma. Clinical activity has also been observed in Hodgkin lymphoma [34-37], DLBCL [38], 
multiple myeloma [39, 40], and acute myeloid leukemia [41]. 
3.2.6. Overview of mocetinostat 
 
Mocetinostat (MGCD0103) is an oral second generation benzamide HDAC inhibitor that selectively 
inhibits HDAC 1, 2, 3 and 11 [42, 43]. Mocetinostat, an isotype selective HDAC inhibitor against 
HDAC1, HDAC2, HDAC3, HDAC11, has broad spectrum antitumor activity in vitro and in vivo. 
Mocetinostat induced hyperacetylation of histones, selectively induced apoptosis, and caused cell 
cycle blockade [43]. Mocetinostat exhibited potent anti-proliferative activity in cancer cell lines, but 
not in normal human cells, consistent with its proposed mechanism of action. In in vivo xenograft 
studies, mocetinostat inhibited tumor growth in prostate, NSCLC, colon cancers [42]. 
 
As of April 2013, mocetinostat has been evaluated in 13 clinical trials, including 440 clinical trial 
patients with the following malignancies: Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) 
[including diffuse large B-cell (DLBCL) and follicular lymphoma], acute myelogenous leukemia 
(AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), acute lymphoblastic 
leukemia (ALL), chronic myelogenous leukemia (CML) and advanced solid tumors including 
adenocarcinoma of the pancreas. 
The safety profile of mocetinostat has been defined based on clinical studies. Fatigue has been 
observed consistently throughout the mocetinostat clinical evaluation program and has been 
deemed a drug-related toxicity. Gastrointestinal (GI) toxicities such as anorexia, nausea, vomiting 
and diarrhea have been reported as related to mocetinostat. Associated conditions, including, but 
not limited to, dehydration, electrolyte abnormalities such as hypokalemia (in a few cases 
concomitant with QTc prolongation), hypotension, and syncope, also have been observed. Less 
frequently, cystitis symptoms (e.g., dysuria, pollakiuria, hematuria, urgency and bladder spasm) 
have been reported in some subjects that received multiple cycles of treatment. In addition, a 
potential association of mocetinostat treatment with pericardial events has been investigated. 
Consequently, current studies will include echocardiogram and ECG monitoring and will exclude 
patients at higher risk of pericardial events. Neutropenia and thrombocytopenia have been observed 
more frequently in subjects with a diagnosis of MDS, leukemia or lymphoma than in patients with 


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other types of cancer, or in combination with a myelosuppressive agent such as gemcitabine. 
Patients experiencing GI toxicity, cystitis symptoms, or pericardial events should be monitored 
appropriately. 
 
3.2.7. Preclinical Data 
 
Pharmacodynamics 
 
Mocetinostat was shown to be a selective, potent, and dose-dependent inhibitor of human Class I 
HDACs (isoforms 1, 2, and 3) and Class IV (isoform 11) (Table 3-1). There was weak or no activity 
against Class II HDACs or HDAC 8. A kinetic analysis using HDAC 1 demonstrated that 
mocetinostat is a potent competitive inhibitor, with a Ki of 645 nM. Binding was reversible, with high 
affinity and slow kinetics. In addition, mocetinostat induced acetylation of core histones H4 and H3 in 
human bladder carcinoma (T24) cells, with an EC50 of 0.4 μM and 0.2 μM, respectively. Acetylation 
of histones was also observed in A549 human non-small cell lung carcinoma cells and A2780-S 
human ovarian carcinoma cells. Core histone acetylation was dose-dependent and was correlated 
with HDAC inhibition. 
Mocetinostat induced cell cycle arrest of HCT116 human colon carcinoma cells in a dose-dependent 
manner. G2/M and sub-G1 accumulation was also observed in HeLa human cervical cancer cells 
and A549 human non-small cell lung carcinoma cells. These effects were shown to occur via a 
mechanism independent of tubulin polymerization. Exposure of HCT116 cells to mocetinostat at 
concentrations of 1 to 25 μM resulted in the dose-dependent induction of apoptosis. Dose- 
dependent apoptosis also was observed in both A549 human lung carcinoma cells and HeLa human 
cervical carcinoma cells at concentrations of 1 μM (the lowest concentration tested). Mocetinostat 
also induced significant apoptosis in several hematologic cancer cell lines, including Jurkat T-cell 
leukemia cells, MV-4-11 acute myeloid leukemia cells, U266B1 multiple myeloma cells, and HL60 
promyelocytic leukemia cells. Induction of apoptosis in all four hematologic cancer cell lines was 
dose-dependent. Expression of the tumor suppressor p21waf1/Cip1 was upregulated both at the level  
of transcription and at the level of translation. A concentration of 1 μM mocetinostat induced 
p21waf1/Cip1 expression at least 2-fold in HCT116 colon carcinoma cells. This effect was independent 
of p53 status: p21waf1/Cip1 induction was observed both in HeLa cervical cancer cells, which are 
p53-null, and in A549 lung carcinoma cells, which express wild type p53. 
Table 3-1. Biochemical inhibition of HDAC activity by mocetinostat 
 
Parameter 
Class I HDAC Isoforms 
Class II HDAC Isoform 
Class IV HDAC 
Isoforms 
1 
2 
3 
8 
4 
5 
6 
7 
11 
Inhibition (+/-) 
+ 
+ 
+ 
- 
- 
- 
- 
- 
+ 
IC50 (µM)
0.15
0.29
1.66
>20
15
>20
>20
>20
0.59
 
 
Mocetinostat had anti-proliferative pharmacodynamic activity against A549 lung cancer cells and 
Du145 prostate cancer cells (IC50 1.0 µM), but not against normal human cells (IC50 > 20 µM). 
Inhibition was independent of p53 status as A549 cells express p53, whereas Du145 cells are p53- 
null.  The anti-proliferative activity of mocetinostat was assessed against a variety of other human 
cancer cells with IC50 in lymphoma cell lines ranging 0.15 – 0.5 µM (Table 3-2). 


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Table 3-2. In Vitro Anti-proliferative Activity Against Various Human 
Lymphoma Cancer Cell Lines 
Lymphoma Cell Lines 
Subtype 
IC50 (µM) 
U937
Histiocytic lymphoma
0.15
HDLM-2
Hodgkin lymphoma
0.25
SP53
Lymphocytic lymphoma
0.32
L428
Hodgkin lymphoma
0.47
MINO
Mantle cell lymphoma
0.48
KM-H2
Hodgkin lymphoma
0.50
 
 
Nonclinical pharmacokinetics and metabolism 
 
Pharmacokinetic studies of orally administered mocetinostat (or its dihydrobromide salt) were carried 
out in female CD-1 mice, female Sprague−Dawley rats, and male beagle dogs. The oral 
bioavailability was 12% in mice and 47% in rats. Pharmacokinetic parameters in mice and rats were 
linear with the dose administered and independent of vehicles used. In dogs, pharmacokinetic 
parameters were nonlinear with the dose and dependent on the vehicles used. A wide range of 
bioavailability (1−92%) was observed in dogs. It was noted that a lower pH resulted in higher 
bioavailability. The compound was quickly absorbed, with a short Tmax across all species tested. 
The terminal phase elimination half-life for 8 administered iv was 0.6 h in mice, 0.7 h in rats, and 1.3 
h in dogs. The clearance in the mice (4.3 (L/h)/kg) was high, but the clearance in rats (1.7 (L/h)/kg) 
and dogs (2.0 (L/h)/kg) was reasonable. Steady state volume of distribution was low in mice (0.34 
L/kg) and higher in rats (0.91 L/kg) and dogs (0.80 L/kg)20. 
In vitro experiments also showed that mocetinostat binds to plasma proteins, and is relatively stable 
in the presence of liver microsomes (80 to 90% recovery). Mocetinostat was shown to be 
metabolized by CYP 3A4, and possibly CYP 2E1 and CYP 2C8, and to be a strong inhibitor of CYP 
2C9 and a weak inhibitor of CYP 3A4. In addition, mocetinostat induced CYP 1A2 (only at the 
highest concentration tested, 5 µM), but did not induce CYP 3A4. Mocetinostat was also shown to 
be transported by P-gp, as well as to be a P-gp inhibitor. 
 
Mocetinostat showed dose proportional PK except at very high doses and variable bioavailability 
across species. There was evidence of higher bioavailability with lower pH vehicles. In rats, females 
had higher exposure than males, but no gender differences were seen in dogs. Further information 
concerning the pharmacokinetic and pharmacodynamic properties of mocetinostat may be found in 
the Investigator Brochure. 
 
Safety pharmacology and toxicology 
 
The nonclinical safety profile of mocetinostat has been evaluated in a cardiovascular safety 
pharmacology study in dogs, in repeated dose toxicology studies in rats and dogs (for durations of 7 
days, 28 days, 13 weeks, and 26 weeks), and in genotoxicity studies. 
 
No evidence of mocetinostat-induced changes in cardiovascular or hemodynamic function was 
observed in the cardiovascular safety pharmacology, as well as in the repeated-dose toxicity 
studies. No adverse central nervous system (CNS) or respiratory effects have been observed in the 
repeated-dose toxicity studies. 


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Test article-related effects observed across the repeated-dose toxicology studies with mocetinostat 
in rats and dogs include reduced body weights and clinical pathology changes indicative of bone 
marrow suppression. Microscopic findings were observed in the liver, pancreas, spleen, thymus, and 
lung following daily administration. Histopathological changes were observed in the liver and corpora 
lutea of the rat and in the pancreas of the dog following administration 3 times a week. 
Mocetinostat was mutagenic in vitro in the bacterial reverse mutation assay only in 1 of the 
conditions tested (TA98 with S9 activation), but not in the in vitro mouse lymphoma forward mutation 
assay. Mocetinostat increased the incidence of micronucleated erythrocytes when orally 
administered to rats at doses of 500 to 2000 mg/kg.. 
 
3.2.8. Clinical Data 
 
Mocetinostat monotherapy and mocetinostat in combination with other anticancer agents have been 
evaluated as part of the clinical development program. Mocetinostat has been investigated in 440 
clinical trial patients with the following malignancies: Hodgkin Lymphoma, Non-Hodgkin Lymphoma 
(including DLBCL or follicular lymphoma), acute myeloid leukemia, myelodysplastic syndrome, 
chronic lymphocytic leukemia, acute lymphocytic leukemia and advanced solid tumors including 
adenocarcinoma of the pancreas. 
 
Pharmacodynamic biomarker 
 
Pharmacodynamic effects of mocetinostat have been examined by analyzing HDAC activity in 
peripheral blood WBCs from patients treated with mocetinostat. HDAC enzyme activity has been 
measured using a novel whole-cell enzyme activity assay. Briefly, in this assay, patients’ peripheral 
WBCs are incubated with a membrane-permeable HDAC substrate for 1 hour at 37ºC. The reaction 
is then stopped, cells are lysed, and the deacetylated product is cleaved, releasing a fluorescent 
moiety that can be quantified by fluorometry. Data obtained from a total of 25 patients with solid 
tumors in a phase I study of mocetinostat in advanced metastatic solid tumors or aggressive Non- 
Hodgkin Lymphoma showed HDAC activity is inhibited in a time- dependent and dose-dependent 
manner. Prolonged HDAC inhibition (48 to 72 hours after dosing) was observed for doses 56 
mg/m2. Similarly, prolonged HDAC inhibition was observed in peripheral blood mononuclear cells 
(PBMCs) from 9 patients with Hodgkin Lymphoma treated with 110 mg of mocetinostat. 
 
Human safety and tolerability data 
 
Four Phase I trials have evaluated mocetinostat monotherapy. Mocetinostat was not tolerated well 
by patients with advanced solid tumors when given daily as single oral dose of up to 17 mg/m2 for 
14 days followed by a 7-day rest period. The DLT at 17 mg/m2 administered daily was fatigue. 
Dose-limiting fatigue, as well as nausea, vomiting, and diarrhea also appeared to be the major 
adverse effects observed to date in the other Phase I, Phase I/II, and Phase II studies with one of 
the following treatment schedules: 3 times weekly dosing for 2 weeks followed by a 7-day rest 
period; 3-times-weekly dosing for 3 weeks with no rest period; or 3 times weekly dosing for 4 weeks 
with no rest period. 
 
The 3-times-weekly schedule appears to have improved tolerability compared with daily dosing, as 
higher MTDs have been observed with the former schedule. Studies with mocetinostat have 
escalated to a single-agent dose of 83 mg/m2 (average total daily dose = 160 mg) administered 3 


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times weekly without interruption. Treatment at this dose level was limited by GI toxicity. However, 
evaluation at 60 mg/m2 (average total daily dose = 110 mg) was initially determined to be the MTD 
according to protocol-defined criteria. 
 
In patients with relapsed or refractory NHL (DLBCL and FL), safety data is reported for 69 patients, 
41 patients with DLBCL and 28 patients in the FL cohort.  The median age of these patients was 61 
(range: 31 to 80). All patients had received prior cancer therapy. Mocetinostat was administered 
orally 3 times weekly for 4 consecutive weeks (28-day cycles). The starting dose was initially 110 
mg, and it was reduced to 85 mg for non-life-threatening toxicities (e.g., fatigue, GI effects). 
Following an interruption to enrolment due to investigation of a possible relationship between 
treatment with mocetinostat and the observation of pericardial events in some patients, enrolment 
was resumed at a dose of 70 mg three times weekly. The study was subsequently closed for 
administrative reasons. In an attempt to consolidate the multiple dosing regimens of mocetinostat, 
the MTD will be specified as 90 mg three times weekly. 
 
In addition to Phase I studies, the safety profile of mocetinostat has been evaluated as a single 
agent in Phase II studies. Four Phase II studies have evaluated mocetinostat as a monotherapy in 
the following populations: 1) Elderly, previously untreated patients with AML or MDS or adults with 
relapsed/refractory AML or high-risk MDS; 2) Patients with relapsed or refractory NHL; 3) Patients 
with refractory CLL; and 4) Patients with relapsed or refractory HL. The safety profile of mocetinostat 
has also been investigated in combination with other anticancer agents in Phase I/II and Phase II 
studies. Mocetinostat has been evaluated with Vidaza® (azacitidine) in patients with MDS, AML, HL, 
or NHL, with Gemzar® (gemcitabine) in patients with refractory solid tumors or pancreatic cancer, 
and with docetaxel in patients with solid malignancies. As of April 2013, mocetinostat has been 
evaluated in 440 patients in 13 clinical trials (analyses were performed based on 435 patients for 
whom sufficient information was captured in the database at the time of data cut). 
System organ classes (SOCs) with the most frequently reported AEs (≥20% of all patients for an 
SOC) across all studies are summarized in Table 3-3; individual events occurring in ≥10% of all 
patients in a preferred term category within those SOCs are also presented. Overall, the percentage 
of patients experiencing any AE was 99.3%. The most frequent AEs (occurring in ≥20% of patients 
in a preferred term category) were nausea (71%), fatigue (70%), diarrhea (57%), vomiting (49%), 
anorexia (36%), anemia (26%), constipation (25%), pyrexia (25%), thrombocytopenia (24%), 
decreased weight (23%), abdominal pain (22%), cough (21%), dyspnea (21%), and peripheral 
edema (20%). 
 
The most frequent AEs (occurring in ≥10% of patients in a preferred term category) considered 
related to study drug were the following: nausea (66%), fatigue (63%), diarrhea (50%), vomiting 
(44%), anorexia (31%), weight decreased (21%), anemia (21%), thrombocytopenia (20%), 
neutropenia (16%), abdominal pain (14%), decreased appetite (13%), asthenia (13%), constipation 
(12%), pyrexia (12%), dyspepsia (12%), headache (11%), dizziness (10%), and peripheral edema 
(10%). 
 
SOCs with the most frequently reported Grade 3/4 AEs (≥10% of all patients for an SOC) across all 
studies are summarized in Table 3-4; individual events occurring in ≥5% of all patients in a preferred 
term category within those SOCs are also presented. 


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Overall, the percentage of patients experiencing any Grade 3/4 AE was 81%. The most frequent 
Grade 3/4 AEs (occurring in ≥10% of all patients in a preferred term category) were fatigue (25%), 
thrombocytopenia (17%), neutropenia (16%), anemia (14%), and febrile neutropenia (12%). 
The most frequent Grade 3/4 AEs (occurring in ≥5% of all patients in a preferred term category) 
considered related to study drug were the following: fatigue (23%), neutropenia (14%), 
thrombocytopenia (14%), anemia (9%), nausea (8%), febrile neutropenia (7%), vomiting (5%), and 
anorexia (5%). 
 
SOCs with the most frequently reported SAEs (≥10% of all patients for an SOC) across all studies 
are summarized in Table 3-4; individual events occurring in ≥5% of all patients in a preferred term 
category within those SOCs are also presented. 
 
Overall, the percentage of patients experiencing any SAE was 59%. The most frequent SAEs 
(occurring in ≥5% of all patients in a preferred term category) were pneumonia (9%), febrile 
neutropenia (7%), AML (7%), dehydration (6%), fatigue (6%), and vomiting (5%). 
 
Pericarditis and pericardial effusion, with or without cardiac tamponade, have been reported 
following treatment with mocetinostat. These events have been associated with SAEs in 
approximately 4% of patients. The incidence is higher in populations with greater predilection for 
pericardial abnormalities, including Hodgkin lymphoma, but also AML and NHL.  Bladder toxicity 
resulting in dysuria and rarely hemorrhagic cystitis has been described in a few patients receiving 
mocetinostat. 


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Table 3-4. Most commonly reported grade 3/4 adverse events across all studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a No individual event occurred at a percentage ≥5%. 
Note: If the same event term was recorded multiple times for a patient, the patient was only counted once. 
 
 
Table 3-4. Most commonly reported serious adverse events across all studies 
System Organ Class/Preferred Term 
All Patients (N=435) 
Patients with at least one AE 
255 (58.6) 
Infections and infestations
99 (22.8)
Pneumonia 
37 (8.5) 
Gastrointestinal disorders
66 (15.2)
Vomiting 
21 (4.8) 
General disorders and administration site conditions
65 (14.9)
Fatigue 
25 (5.7) 
Blood and lymphatic system disorders
58 (13.3)
Febrile neutropenia 
30 (6.9) 
Neoplasms benign, malignant and unspecified
53 (12.2)
Acute myeloid leukemia
29 (6.7)
Note: If the same event term was recorded multiple times for a patient, the patient was only counted once. 
 
 
Toxicity 
 
Cardiac Arrythmias 
 
Grade 3 AEs of QTc prolongation (> 500 msec) were reported in 4 of 435 patients in clinical trials 
with mocetinostat; 3 of those 4 events were also reported as part of SAEs. Three of the 4 patients 
already had a prolonged QTc at baseline. Three of the events of QTc prolongation occurred in a 
setting of GI disturbances associated with dehydration and/or hypotension. In 2 cases, there was 
definite hypokalemia, with concomitant low magnesium in one patient, and in both cases, the QTc 
values decreased quickly to baseline levels after IV administration of potassium and magnesium. 
System Organ Class/Preferred Term 
All Patients (N=435) 
Patients with at least one AE 
350 (80.5) 
Blood and lymphatic system disorders
175 (40.2)
Thrombocytopenia 
72 (16.6) 
Neutropenia
69 (15.9)
Anemia
59 (13.6)
Febrile neutropenia
52 (12.0)
General disorders and administration site conditions
159 (36.6)
Fatigue 
108 (24.8) 
Asthenia
21 (4.8)
Gastrointestinal disorders
103 (23.7)
Nausea 
39 (9.0) 
Vomiting
23 (5.3)
Abdominal pain
21 (4.8)
Diarrhea
20 (4.6)
Infections and infestations
96 (22.1)
Pneumonia 
35 (8.0) 
Metabolism and nutrition disorders
93 (21.4)
Anorexia 
24 (5.5) 
Hypokalemia
22 (5.1)
Dehydration
21 (4.8)
Investigationsa 
58 (13.3) 
Respiratory, thoracic and mediastinal disorders
57 (13.1)
Dyspnea 
28 (6.4) 


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Concomitant treatment with drugs identified as having the potential to cause QTc prolongation may 
have been a factor in 2 patients. 
Although therapy with mocetinostat does not appear to be an obvious risk factor for development of 
QTc prolongation, ECG monitoring may be warranted in the settings of GI disturbances associated 
with dehydration and/or electrolyte abnormalities. 
 
Pericardial Events 
 
MethylGene/Mirati identified pericardial AEs by searching the SAE database, the clinical database 
for each study, searching CT scan reports, and prospective ECHOs. The total number of patients 
with pericardial findings was 45 (10.3%), with 19 patients having serious adverse events (4.3%) 
(Table 3-5).  An additional 26 on-study non serious pericardial findings (for a total of 45 pericardial 
findings) were identified by the Sponsor, including 6 incidental cases from database searches, 7 
incidental cases from CT scan review, and 13 cases from prospective echocardiographic monitoring. 
A fourteenth pericardial finding was identified through echocardiographic monitoring (non-serious 
trivial pericardial effusion), subsequent to the complete analysis of pericardial events. There were 
also 14 patients identified with pericardial findings at baseline. 
 
All retrospective review findings except 2, as well as all of the 13 prospective echocardiographic 
monitoring cases were reported as minimal, trivial, or small effusions, not requiring treatment or 
medical intervention. The information presented below is based on the initial 45 pericardial findings. 
These additional pericardial findings are of uncertain clinical relevance, because minimal (or trivial) 
effusions typically represent the normal amount of pericardial fluid in a disease-free state [44]; 
however, they were included in the analyses as a conservative measure. 
The types of pericardial events included pericarditis, pericardial effusion, and cardiac tamponade, 
with many patients having more than one of these three adverse events (Table 3-6). Of the 
pericardial adverse events, pericardial effusion was the most common.  The occurrence of 
pericardial AEs was similar for patients with NHL as it was for the overall population treated with 
mocetinostat (Table 3-7).  Most of the pericardial AEs (54.8%) and SAEs (73.7%) occurred during 
the first cycle of treatment. 
 
Table 3-5. Summary of Pericardial SAEs and Pericardial Findings Identified 
 
Method of Identification 
No. of Cases Identified 
Total No. of 
Patients 
Pre-Treatment 
On-Study 
No. Patients (%) 
No. Patients (%) 
Pharmacovigilance 
SAEs 
437 
- 
19 (4.3) 
Retrospective Review Findings 
Database Searches 
-
- 
6 (1.4) 
Radiographic Review 
199 
14 (7.0) 
7 (3.5) 
Prospective Echocardiographic Monitoring Findings 
Echocardiograms 
35 
- 
13(37.1) 
Total 
Total Pericardial SAEs 
437 
- 
19 (4.3) 


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Table 3-6. Nature of Pericardial Event 
Pericardial SAEs 
(N = 19) 
All Pericardial Findings 
(N = 44) 
No. 
% of 
Pericardial
SAE 
Patients 
% of 
Evaluable 
Population
No. 
% of 
Patients 
with 
Pericardial 
Findings 
% of 
Evaluable 
Population
Total No. of Patients with any Pericardial 
Term1 
19 
100 
4.4 
342 
77.3 
7.8 
No. of Patients with Pericarditis 
6 
31.6 
1.4 
6 
13.6 
1.4 
No. of Patients with Pericardial Effusions 
16 
84.2 
3.7 
312 
70.5 
7.1 
No. of Patients with Cardiac Tamponade 
8 
42.1 
1.8 
8 
18.2 
1.8 
Total No. of Pericardial Terms1 
30 
- 
- 
45 
- 
- 
1Includes the following terms: pericarditis, pericardial effusion, and cardiac tamponade. More than one event term could be 
attributed to the same patient. 
2 Pericardial effusion terms for 3 patients with pericardial effusion findings identified through echocardiographic monitoring were
not available from the database at the time of this analysis. There were 12 terms of pericardial effusion for the other pericardial 
findings captured in the database. 
 
 
Table 3-7. Summary of Pericardial Findings by Type of Malignancy 
 
 
Specified Patient 
Population by Type of 
Malignancy 
 
 
Study Nos. 
 
 
No. of 
Patients
Pericardial SAEs 
(N = 19) 
All Pericardial Findings 
(N = 44) 
 
N 
% of Specified 
Patient Population
 
N 
% of Specified 
Patient Population
Solid Tumors 
0103-001, 0103-002, 
0103-006, CL001 
114 
1 
0.9 
5 
4.4 
MDS, AML, & Other 
Leukemia 
0103-003, 0103-004, 
0103-005, 0103-007, 
0103-009, CL003 
 
177 
 
8 
 
4.5 
 
17 
 
9.6 
Hodgkin Lymphoma 
0103-010, CL002 
63 
6 
9.5 
13 
20.6 
Non-Hodgkin Lymphoma
0103-008, 
CL002 
80 
3 
3.8 
8 
10.0 
Other 
0103-006 
11 
1 
N/A 
1 
N/A 
Total Population 
435 
19 
4.4% 
44 
10.1% 
1 Although Study No. 0103-006 was performed with solid tumor patients, 1 patient was exceptionally admitted with 
cutaneous T-cell lymphoma (and had a pericardial SAE). 
 
 
Fatigue 
 
Fatigue has been observed consistently throughout the mocetinostat clinical evaluation program and 
has been deemed a drug-related toxicity. The etiology of fatigue is not yet understood. 
 
Gastrointestinal Toxicities 
Total Pericardial Findings1
437
14 (3.2)
45 (10.3)


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GI toxicities such as anorexia, nausea, vomiting and diarrhea have been reported as related to 
mocetinostat. Dehydration, electrolyte abnormalities (such as hypokalemia), hypotension and 
syncope also have been observed in connection with GI toxicity. 
 
Cystitis 
 
Cystitis symptoms (e.g., dysuria, pollakiuria, hematuria, urgency, and bladder spasm) have been 
reported in some subjects, most commonly after multiple cycles of treatment. 
 
Human pharmacokinetics and product metabolism 
 
The PK profile of mocetinostat has been evaluated in clinical trials, after both single or repeated 
dose administration. Plasma samples for PK analyses were collected over a 24-hour period 
following single and multiple doses. Plasma drug concentrations were determined using a validated, 
sensitive, LC-MS/MS assay. High PK variability was noted in initial studies with mocetinostat 
(administered with water). This variability was partly reduced through administration of mocetinostat 
with a low pH beverage. In general, mocetinostat was rapidly absorbed following administration with 
200 mL of a low pH beverage, with Cmax occurring 0.5 to 1.5 hours after dosing. Drug 
concentrations in plasma declined biphasically and remained quantifiable for 24 hours after dosing. 
The elimination half- life ranged from approximately 7 to 12 hours. As determined from Cmax and 
AUC values, exposure to mocetinostat following oral dosing appears to increase with doses up to 
110 mg. Some saturation of absorption may occur at higher doses. Mocetinostat did not appear to 
accumulate following multiple dosing, and its elimination half-life was approximately 10 hours. 
 
Pharmacodynamic effects of mocetinostat have been examined by analyzing HDAC activity in 
peripheral blood WBCs from patients treated with mocetinostat. HDAC enzyme activity has been 
measured using a novel whole-cell enzyme activity assay. Briefly, in this assay, patients’ peripheral 
WBCs are incubated with a membrane-permeable HDAC substrate for 1 hour at 37ºC. The reaction 
is then stopped, cells are lysed, and the deacetylated product is cleaved, releasing a fluorescent 
moiety that can be quantified by fluorometry. Data obtained from a total of 25 patients with solid 
tumors showed HDAC activity is inhibited in a time- dependent and dose-dependent manner. 
Prolonged HDAC inhibition (48 to 72 hours after dosing) was observed for doses • 56 mg/m2. 
Similarly, prolonged HDAC inhibition was observed in peripheral blood mononuclear cells (PBMCs) 
from 9 patients with Hodgkin Lymphoma treated with 110 mg of mocetinostat. 
 
Clinical Efficacy Data 
 
An open label phase II study evaluated mocetinostat as a monotherapy in non-Hodgkin lymphoma 
study (Table 3-8). The phase II study enrolled patients with DLBCL and FL with patients receiving 
mocetinostat at doses ranging from 70-110 mg three times per wk every 28 days. Sixty-nine patients 
were enrolled for treatment at starting doses of 85-110 mg with 41 patients with DLBCL and 28 
patients with FL. Median age was 62 years (range 32 to 81). Median duration of treatment was ~3 
months (range: <1 to 24). Objective response rate in DLBCL and FL, respectively, was 7/41 (17%; 
including 2 unconfirmed PRs) and 3/28 (11%; including 1 CR). Median time to response was 2.0 mos 
(range 1.7-21.0) and 5.3 mos (range 4.3-6.0) respectively. Stable disease was achieved by 13/41 
(32%) and 14/28 (50%), respectively, for a disease control rate of 49% and 61%, respectively.   
Mean duration of SD in patients with DBLCL was ~4.5 mos (range 2-12 mos), with 10 patients 


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remaining stable for ≥3 mos. Among FL patients, mean duration of SD was approximately 4.1 mos 
(range 1.7-13 mos), with 9 patients remaining stable for ≥3 mos. The FL CR occurred in a 62-year- 
old female with paratracheal, subcarinal and portal target lesions who achieved a PR after 4 cycles 
and CR after 12 cycles that persisted through the remaining 4 mos on study. Study drug was 
discontinued for adverse events in 19/69 (28%). Fatigue, weight loss or anorexia were most 
common (n=4 each). A total of 26 drug-related SAEs were reported among 12 patients (17%; 1-6 
events per pt). There were no drug related deaths. 
 
 
Table 3-8. Efficacy of Mocetinostat in DLBCL and FL 
Clinical Trial/Study 
Population 
Dosing Regimen 
Efficacy 
 
NCT00359086 
Phase II Study of 
MGCD0103 in Patients 
With Relapsed and 
Refractory Lymphoma 
 
Relapsed or 
refractory DLBCL 
or follicular 
lymphoma 
 
3 times/week for 4 weeks 
Starting dose: 110 mg, 
reduced to 85 mg 
28 day cycles 
ORR: 
DLBCL 17% (7/41) 
FL 10% (3/28) 
 
Disease control: 
DLBCL 49% (20/49) 
FL 61% (17/61) 
ORR (CR+PR), Disease control (CR+PR+SD) 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a phase II single center single stage clinical trial evaluating the efficacy of mocetinostat in a 
population of patients with DLBCL or FL with inactivating mutations of acetyltransferase genes 
CREBBP and/or EP300. 
A pre-screening evaluation of archival tumor biopsies from current relapse or fresh tumor biopsies is 
required for CREBBP and EP300 analysis.  Potential eligible patients will be asked to sign a 
“Molecular Pre-screening Informed Consent.” The patient’s archival tumor from the current relapse 
or a fresh tumor biopsy will be obtained. This will ensure that the CREBBP/EP300 molecular status 
of the tumor is known when the potential patient is screened for enrollment into the study. 
 
Twenty-eight patients will be enrolled in each cohort with an anticipated analysis of 25 patients in 
each cohort for a total of 50 evaluable patients. Patients will be started on mocetinostat and 
monitored for response by physican exam and imaging.  Treatment will be organized into cycles of 
28 days in all cohorts and patients will receive mocetinostat orally three times a week at 70 mg for 
cycle one and increased to 90 mg for cycle 2 onwards barring any grade 3 or higher drug related 
toxicities.  Treatment will continue until disease progression, intolerable toxicity, withdrawal of 
consent, or until other criteria for discontinuation are met, whichever comes first. 
 
4.3 
Intervention 
 
Mocetinostat will be administered as an oral therapeutic three times a week on a 28 day cycle. The 
starting dose will be 70 mg orally three times per week in cycle 1. The dose will be escalated in 
cycle 2 to 90 mg orally three times per week on a 28 day schedule if there are no grade 3 or higher 
drug related toxicities. Therapy will continue until disease progression, intolerable toxicities or death. 
Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for 


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Adverse Events (NCI CTCAE) Version 4.0.  Response to treatment will be determined according to 
Cheson criteria[45] initially every 8 weeks for 6 months, then every 12 weeks for 6 months and every 
4 months thereafter, until disease progression or prohibitive toxicity develops, whichever comes first. 
All patients benefiting from treatment at the time of final analysis will be permitted to continue study 
drug at investigator’s discretion until disease progression, intolerable toxicity or withdrawal of 
consent.Give a detailed explanation of the intervention to be conducted, the treatment plan and the 
rationale for its use. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1. 
Mocetinostat 
 
Mocetinostat will be supplied by MethylGene/Mirati Therapeutics.  The mocetinostat IND will be 
cross referenced between MSKCC and MethylGene/Mirati.  IND approval and activation is pending 
at MSKCC. 
 
5.2. 
Study drug preparation and dispensation 
 
Mocetinostat will be dispensed by an authorized person at MSKCC. Investigator staff will add the 
patient number on the label. Immediately before dispensing the package to the patient, investigator 
staff will detach the outer part of the label from the packaging and affix it to the source document 
(Drug Label Form) for that patient’s unique patient number. 
 
5.3. 
Study drug packaging and labeling 
 
Mocetinostat Finished Drug Product is supplied by MethylGene/Mirati in hard gelatin capsules. 
Initially, 10 mg and 25 mg unit dose strength capsules will be provided, each containing either 10 mg 
or 25 mg of Mocetinostat, calculated as free-base corrected for purity. Additional unit dose strengths 
may be added in the future. 
 
Medication labels comply, or will comply, with the legal requirements of the United States and will be 
printed in English. The storage conditions for study drug will be described on the medication label 
(currently 2-8°C – refrigerated storage). 
 
Mocetinostat, 10 mg and 25 mg unit dose strengths will be supplied in bulk bottles (48 count) for 
patient dispensing at clinical sites. The pharmacist will repackage bottles for each subject’s dose for 
dispensation. 
 
5.4. Study drug ingredients 
 
Study drug contains the free-base form of Mocetinostat (MGCD0103), mocetinostat dihydrobromide 
salt and inert excipients: microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, 
non-bovine magnesium stearate. 
5.5. Study drug disposal and destruction 
 
Study drug destruction at the investigational site will only be permitted if authorized by 
MethylGene/Mirati in a prior agreement and if permitted by local regulations. 


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6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
Patients eligible for inclusion in this study have to meet ALL of the following criteria: 
 
 
Patient has provided a signed study Informed Consent Form prior to performance of any study 
related procedurePatient is ≥ 18 years of age 
 
Patient has histologically confirmed diagnosis of diffuse large B cell lymphoma or follicular 
lymphoma harboring mutations in CREBBP or EP300 with relapsed or refractory disease 
 
Patients with diffuse large B cell lymphoma must have received at least two prior therapies and 
have received, declined or be ineligible for autologous or allogeneic stem cell transplant. 
 
Patients with follicular lymphoma must have received at least two prior therapies. 
 
Patients with either diffuse large B cell lymphoma or follicular lymphoma will be allowed to enroll 
after receiving only 1 prior therapy if they are felt to not be a candidate for further systemic 
chemotherapy. 
 
Patient has at least one measurable lesion (≥ 2 cm) according to Cheson criteria [45].  Patient 
has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
 
Patient has adequate bone marrow and organ function by: 
• 
Absolute neutrophil count (ANC) ≥ 1.0 x 109/L 
• 
Platelets ≥ 75 x 109/L (no platelet transfusion within past 14 days) 
• 
Hemoglobin (Hgb) ≥ 9.0 g/dL (no RBC transfusion within past 14 days) 
• 
International Normalized Ratio (INR) ≤ 1.5 
• 
Serum Creatinine ≤ 1.5 x upper limit of normal (ULN) 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 2.5 x ULN, or ≤ 
5.0 x ULN for patients with documented hepatic involvement 
• 
Serum bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN for patients with Gilbert Syndrome or documented 
hepatic involvement. 
 
Patients must have fully recovered from major surgery and from the acute toxic effects of prior 
chemotherapy and radiotherapy (residual grade 1 toxicity, e.g. grade 1 peripheral neuropathy, 
and residual alopecia are allowed) 
 
6.3 
Subject Exclusion Criteria 
 
Patients eligible for this study must NOT MEET ANY of the following criteria: 
 
 
Patient has received previous treatment with HDAC inhibitors 
 
Patient has evidence of graft versus host disease (GVHD) 
 
Patient has active or history of central nervous system (CNS) disease 
 
Patient has impaired cardiac function including any of the following: 
 
Presence or history of pericardial effusion (definitions are provided in Section 9.3.4) and/or 
pericarditis. 
 
Acute myocardial infarction, symptomatic angina pectoris ≤ 6 months prior to starting study 
drug 
 
Presence of congestive heart failure ≥ NYHA class 3 


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 
QTc > 480 ms on a screening ECG 
 
Screening LVEF < 45% by echocardiography or MUGA 
 
Uncontrolled cardiac arrhythmia including uncontrolled atrial fibrillation/atrial flutter/sinus 
tachycardia, complete left bundle branch block, congenital long QT syndrome 
 
Presence of permanent cardiac pacemaker 
 
Other clinically significant heart disease 
 
Subject is taking warfarin at start of treatment or within 6 months prior to start of study treatment. 
 
Patient has a concurrent malignancy or has a malignancy within 3 years of study enrollment 
(with the exception of adequately treated basal or squamous cell carcinoma or non- 
melanomatous skin cancer) 
 
Patient is concurrently using other approved or investigational antineoplastic agent 
 
Patient has received chemotherapy, targeted anticancer therapy, pelvic and/or para-aortic 
radiotherapy or has had major surgery ≤ 4 weeks (6 weeks for nitrosourea, monoclonal 
antibodies or mitomycin-C) prior to starting study drug or who have not recovered from side 
effects of such therapy 
 
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of mocetinostat (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or small bowel resection) 
 
Patient is currently receiving increasing or chronic treatment (> 10 days) with corticosteroids or 
another immunosuppressive agent. The following uses of corticosteroids are permitted: single 
dose, topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye 
drops or local injections (e.g., intra-articular). 
 
Patient has a history of non-compliance to medical regimen or inability to grant consent. 
 
Concomitant medications causing prolonged QT which cannot be discontinued or changed to a 
different medication prior to initiating study 
 
Patient is currently being treated with drugs known to be moderate or strong inhibitors or 
inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a 
different medication prior to starting study drug. Patients must have discontinued strong inducers 
for at least one week and must have discontinued strong inhibitors before the start of treatment. 
Note: the oral anti-diabetic drugs troglitazone and pioglitazone are CYP3A inducers. Refer 
Appendix A, Table 20-1 to 20-5 
 
Patient has a known history of HIV (testing not mandatory), active Hepatitis B or C infection 
 
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive serum hCG laboratory 
test (> 5 mIU/mL) 
 
Women of child bearing potential and men with reproductive potential, if they are unwilling to use 
adequate contraception while on study therapy and for 3 months thereafter 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited by the treating team of physicians and medical professionals. Patients will 
be treated by the lymphoma service at MSKCC. Given the diverse population of patients at 
MSKCC, we expect that minorities and women patients will have full access to this study and will be 


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fairly represented in the accrual. The study procedures and requirements will be clearly presented  
in the molecular prescreening consent form and the consent form and explained to all patients at the 
time the consent is obtained. The principle investigator, Dr. Andrew Zelenetz, MD, PhD, will be 
available to all patients for further questions and information through a contact number provided on 
the molecular prescreening consent and the therapeutic consent. 
7.1 
Molecular pre-screening 
 
Only patients with mutations in CREBBP or EP300 will be eligible for enrollment into this study.  For 
patients with documented mutation of CREBBP or EP300, molecular pre-screening will not be 
needed.  For patients with unknown CREBBP or EP300 status, tumor biopsies will be tested. Tumor 
mutational testing will be performed in the MSK Department of pathology Diagnositc Molecular lab 
using protocol 12-245. Mutational testing performed via the MSK-DMP on the IMPACT panel will 
require normal tissue/blood for germline comparision to identify mutations. 
 
Only patients that exhibit a CREBBP/EP300 mutation as described below (in addition to all other 
inclusion/exclusion criteria) will be eligible for subsequent study enrollment. We anticipate pre- 
screening approximately 100 patients in order to enroll 27 in each cohort. 
 
CREBBP and EP300 mutation is confirmed if: 
 
Direct sequencing results confirm the presence of a CREBBP or EP300 mutation (deletion, 
frameshift, nonsense, missense) affecting CREBBP or EP300 as previously described [1] or via 
corroboration with the COSMIC database. 
 
OR 
 
Should mutations be identified that have not been previously described, patients may be enrolled 
following discussion and agreement of the principle investigator on consultation with 
MethylGene/Mirati. The method used and the result should be entered into CRDB. 
 
8.0 
PRETREATMENT EVALUATION 
 
8.1. 
Screening 
 
After signing the main study informed consent form for the study, the remaining screening 
assessments will be done generally within 7 to 28 days prior to start of treatment (Table 8-1). Please 
note that the screening period must not exceed 28 days. 
 
 
Medical history and demographics 
 
Complete history and physical exam (including weight, pulse, blood pressure, temperature, 
ECOG performance status) 
 
Medication review 
 
Bloodwork 14 days prior to starting therapy: 
 
CBC with differential 
 
Comprehensive metabolic panel, LDH, magnesium, phosphorus 
 
Liver function tests 
 
Uric acid 


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 
Coagulation tests with PT/PTT and INR 
 
HIV testing 
 
Hepatitis B and C testing 
 
ECG 
 
Pregnancy test will be performed for women of child bearing potential 
 
Echocardiogram at baseline 
 
Evidence of disease evaluation within 28 days prior to starting treatment 
 
CT scan with contrast, unless contraindicated, of the chest, abdomen, and pelvis 
 
CT scan with contrast, unless contraindicated, of the neck as clinically indicated 
 
PET scan for patients with DLBCL 
 
MRI may be substituted for CT scan if patients are intolerant of CT scans with contrast 
 
Archival or fresh tumor biopsy for confirmation of CREBBP and/or EP300 mutation 


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9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1. 
Mocetinostat administration 
 
Mocetinostat will be administered on a three times per week dosing schedule. There will be no 
breaks between dosing cycles.  Mocetinostat will be initiated at 70 mg orally three times per week for 
cycle 1.  The dose will be increased to 90 mg orally three times per week 
 
The following general guidelines should be followed for mocetinostat administration: 
 
 
Patients should be instructed to take the dose of mocetinostat three times a week in the morning, 
at approximately the same time each day 
 
Mocetinostat should be taken at least 1 hour following a light breakfast. 
 
Patients should not eat for 2 hours after the administration of each mocetinostat dose. 
 
Mocetinostat should be taken with a low pH beverage (Table 9-1). Patients should swallow the 
capsules as a whole and not chew them. 
 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before 
the next scheduled dose. The occurrence and frequency of any vomiting during a treatment 
cycle must be noted in the adverse events section of CRDB. 
 
Table 9-1. List of low pH beverages 
Coca cola, diet cola 
Lime juice 
Cranberry juice 
Lemon juice 
Hawaiian Fruit Punch 
Orange juice 
Dr. Pepper Soda 
Orange soda 
Gatorade 
Pepsi cola, +/- caffeine 
 
9.2. 
Mocetinostat dose modification 
 
Patients will be initiated at 70 mg mocetinostat three times per week for 1 cycle and observed for 
toxicities. If there are no grade 3 or higher drug related toxicities, the dose will be increased to 90 mg 
starting cycle 2 if thre are no grade 3 or higher treatment related toxicities. 
 
Mocetinostat dose reduction will be administered at 20 mg below the current dose. For each patient, 
a maximum of 3 dose reduction (minimum dose of 35 mg three times per week) will be allowed after 
which the patient will be discontinued from treatment with mocetinostat (Table 9-2).  Once a dose 
has been reduced during a treatment cycle, re-escalation will not be permitted during any 
subsequent cycle.  If the administration of mocetinostat is interrupted for reasons other than toxicity, 
then treatment with the study drug may be resumed at the same dose. The same applies if the 
patient experienced an unacceptable toxicity not specifically described in Table 3-3 or Section 9.3, 
provided this toxicity resolved to ≤ CTCAE grade 1, unless otherwise specified. 
 
If treatment with the study drug is withheld for ≥21 consecutive days, then study drug must be 
permanently discontinued. Patients who permanently discontinue the study drug should have follow- 
up for 30 days after discontinuation of all study treatment or resolution of the AE to ≤ grade 1, 
whichever occurs first, that includes all study assessments appropriate to monitor the event. 


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Table 9-2. Dose modifications for mocetinostat 
Mocetinostat dose levels and reductions* 
Starting dose 0
70 mg three times per week
Escalation dose +1
90 mg three times per week
Dose level 0
70 mg three times per week
Dose level –1
50 mg three times per week
Dose level –2
35 mg three times per week**
*Dose reduction should be based on the worst preceding toxicity 
**Dose reduction below 35 mg 3x/week is not allowed. If a dose reduction below 35 mg 3x/week is required, the 
patient should be permanently discontinued from mocetinostat. 
 
 
9.3. 
Guidelines for dose reduction based on toxicities 
 
9.3.1. Management on non-hematologic toxicities 
 
In the case of drug-associated grade 3 non-hematologic toxicities experienced by the subject, hold 
treatment (one or both drugs if applicable) until toxicity is resolved to ≤ grade 1 or to baseline value.  
If further treatment is desired, treatment should then be resumed at the next lower dose level for the 
applicable drug(s). If the toxicity can be managed by routine supportive care, such as anti-emetics or 
electrolyte supplementation, then a dose reduction is not required. If there is no recovery within 21 
day the subject will go off protocol treatment, unless the clinical investigator in discussion with 
MethylGene/Mirati deems that it is in the best interest of the subject to resume treatment. If grade 3 
non-hematologic toxicity recurs following the first dose reduction, a second dose reduction of one 
dose level may be implemented following recovery to ≤ grade 1 or to baseline. However if grade 3 
non-hematologic toxicity again recurs, then the subject should be removed from protocol therapy. 
Subjects who experience grade 4 non-hematologic toxicities should have study treatment 
discontinued, unless the Investigator and the sponsor agree that the subject is benefiting from study 
treatment, in which case, treatment may be resumed at a lower dose level as described above 
following recovery. Dose reductions for lower-grade toxicities may also be implemented based on 
Investigator discretion; however the sponsor should be notified of such an event (Table 9-3). 
 
Table 9-3. Dose Modifications – Non-Hematologic Drug Related Toxicities1 
Occurrence 
Toxicity 
Treatment Delay 
Dose Modification 
1st Occurrence 
< Grade 3 
May be implemented based on Investigator and subject 
discretion; Sponsor should be notified
Grade 3 
Hold until ≤ Grade 1 or return 
to baseline
Then, resume at next lower 
dose level
Grade 3 toxicity manageable 
with routine supportive care
Hold until ≤ Grade 1 or return 
to baseline
Not required 
Grade 4 
-- 
Remove from Therapy 
2nd Occurrence 
Grade 3 
Hold until ≤ Grade 1 or return 
to baseline 
Then, resume at next lower 
dose level (e.g., 2nd dose 
reduction)
3rd Occurrence 
Grade 3 
-- 
Remove from Therapy2 
1For pericardial toxicity, see Section 6.2.2. 
2 Unless the Investigator and the sponsor agree that the subject is benefiting from study treatment, in which case, 
treatment may be resumed at the next lower dose level as described above following recovery.


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9.3.2. Management of Gastrointestinal Toxicity 
 
GI toxicities, such as anorexia, nausea, vomiting and diarrhea have been reported as probably 
related to mocetinostat. Associated conditions, including, but not limited to, dehydration, electrolyte 
abnormalities such as hypokalemia (sometimes with associated QTc prolongation), hypotension, 
and syncope have also been observed. Subjects experiencing GI toxicity should be closely 
monitored and treated as per guidelines mentioned below. 
 
For anorexia, dehydration, nausea, vomiting, or diarrhea that is grade 3 or 4, or is prolonged grade 2 
(more than 3 days), manage per institutional standard. Hold study treatment until resolution to grade 
1 or better. 
 
9.3.3. Management of Mocetinostat associated Cystitis 
 
In the event of a subject experiencing symptoms of cystitis (dysuria, pollakiuria, hematuria, urgency 
or bladder spasm) suspected to be mocetinostat related: 
 
Encourage adequate hydration. 
 
Conduct urinalysis, urine culture, blood urea nitrogen (BUN), creatinine and complete 
blood count (CBC). 
 
If clinically significant symptoms persist despite a negative work-up or treatment of an 
associated condition, hold study drug until resolution of clinically significant symptoms. 
 
Resume dosing of mocetinostat when medically appropriate at the same or a reduced 
dose level as per the Investigator’s judgment. 
9.3.4. Management of Pericardial toxicity 
 
Subjects will be assessed for evidence of pericardial events during scheduled visits according to the 
schedule in Table 10-1.  The following findings would heighten suspicion of pericardial effusion or 
pericarditis and prompt immediate evaluation by ECHO: 
 
Symptoms: shortness of breath, orthopnea, chest pain, dizziness, rapid pulse 
 
 
Clinical exam:  hypotension, jugular venous distension, pulsus paradoxus, faint heart sounds, 
friction rub, and/or arrhythmia 
 
ECG: sinus tachycardia, atrial fibrillation, atrial flutter, low voltage with non specific ST-T 
wave changes and ST elevation or PR depressions, arrhythmia 
 
Chest X-ray: widening cardiac silhouette 
 
ECHOs will categorize pericardial fluid as minimal (or trivial), small, moderate or large and will 
assess for hemodynamic compromise. 
 
Pericardial effusions will be assessed as follows (Table 9-4): 
 
 
Minimal (or trivial): A small echo-free space in the posterior atrioventricular groove that is 
visible only in systole when the heart has pulled away from the pericardium. Typically 
represents a normal amount of pericardial fluid in a disease-free state. 


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 
Small: <1 cm of posterior echo-free space, with or without fluid accumulation elsewhere, 
present throughout the cardiac cycle, including diastole (and not only systole). 
 
Moderate: 1 to 2 cm of echo-free space. Moderate effusions tend to be seen along the length 
of the posterior wall but not anteriorly. 
 
Large: >2 cm of maximal separation. Large effusions tend to be seen circumferentially. 
 
Hemodynamic compromise: RV compression, IVC dilation without respiratory variation, 
abnormal flow variation across the AV valves without respiratory variation, enlarged or 
collapsed ventricles.  RA diastolic collapse in isolation is too non-specific to signal 
hemodynamic compromise, but should be considered consistent with this diagnosis when 
accompanied by other findings 
 
Table 9-4. Pericardial Effusion Echocardiographic Assessment and Subject Management Guidelines 
 
Category 
Definitions 
Subject Management 
 
Increased ECHO and ECG monitoring1: 
-Weekly until the minimal (or trivial) effusion is 
 
 
Minimal (or trivial) 
 
 
 
 
 
 
 
 
Small 
 
 
 
 
 
Moderate 
A small echo-free space in the posterior 
atrioventricular groove that is visible only in 
systole when the heart has pulled away from the 
pericardium. Typically represents a normal 
amount of pericardial fluid in a disease-free state. 
 
 
 
 
 
<1 cm of posterior echo-free space, with or 
without fluid accumulation elsewhere, present 
throughout the cardiac cycle, including diastole 
(and not only systole). 
 
 
 
1 to 2 cm of echo-free space. Moderate effusions 
tend to be seen along the length of the posterior 
no longer present or has not progressed (to a 
small or greater effusion) over a period of 2 
weeks to validate the findings as non- 
pathologic or until the effusion has regressed 
(if sooner); 
- Regular schedule afterwards (i.e., prior to 
each subsequent cycle). 
Increased ECHO and ECG monitoring: 
-Weekly for the first month after the new 
pericardial effusions are first noted or until the 
effusion has regressed (if sooner). 
- Treatment for the effusion may be 
administered at the discretion of the 
Investigator. 
- Study drug will not be discontinued in these 
subjects, at the discretion of the investigator, 
unless the effusion progresses. 
 
Remove from study treatment; refer to 
  
wall but not anteriorly. 
cardiologist for follow up as clinically indicated, 
Large 
>2 cm of maximal separation. Large effusions 
tend to be seen circumferentially. 
RV compression, IVC dilation without respiratory 
variation, abnormal flow variation across the AV 
valves without respiratory variation, enlarged or 
until resolution or stabilization. 
Hemodynamic 
Compromise 
collapsed ventricles. RA diastolic collapse in 
isolation is too non-specific to signal 
hemodynamic compromise, but should be 
considered consistent with this diagnosis when 
accompanied by other findings 
Remove from study treatment; refer to 
cardiologist for follow up as clinically indicated, 
until resolution or stabilization. 
 
1 Subjects with ECHO findings of minimal (or trivial) effusion may be discontinued from the study at any time if judged in 
the subject’s best interest, following discussion between the Investigator and the Medical Monitor. 
 
 
Subjects who are found to have moderate or large pericardial effusions (as defined above)  and/or 
evidence of hemodynamic compromise (regardless of the size of the pericardial effusion) will be 
immediately removed from study treatment and will be managed according to the accepted standard 
of care at the discretion of the Investigator. Subjects should be referred to cardiologist for follow up 
as clinically indicated, until resolution or stabilization. 


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Subjects who are found to have de novo (i.e. not present at baseline) small pericardial effusions on 
study will be followed with weekly ECHOs and ECGs for the first month after the new pericardial 
effusions are first noted or until the effusion has regressed (if sooner). Treatment for the effusion 
may be administered at the discretion of the Investigator. Study drug will not be discontinued in 
these subjects, at the discretion of the investigator, unless the effusion progresses. 
Subjects presenting with de novo (i.e. not present at baseline) minimal or trivial pericardial effusions 
visualized by ECHO will be permitted to stay on study treatment since these findings would be 
considered to represent physiological levels of fluid and typically represents a normal amount of 
pericardial fluid in a disease-free state. However, such subjects will have increased safety 
monitoring, including weekly ECHOs and ECGs for 2 weeks to validate the finding as non-pathologic 
or until the effusion has regressed (if sooner), followed by a return to the regular schedule. 
In patients who develop a significant pericardial toxicity, blood will be collected and tested for anti- 
nuclear antibody (ANA) and anti-histone antibody testing. 
 
In exceptional circumstances where ECHO is not considered a technically optimal assessment of 
pericardial space (e.g., overweight subject), other methods (e.g., MRI) should be used for pericardial 
assessments. In such cases, the guidelines provided in Table 9-4 would not apply, and the 
evaluation should be performed in consultation with the Medical Monitor. In the event that a 
pericardial effusion is first identified by a method other than ECHO, efforts should be made to obtain 
an ECHO for assessment of effusion size. 
 
 
9.3.5. Management of chest pain 
 
Subjects who report chest pain, even without other complaints suggestive of pericarditis, effusion, 
hemodynamic compromise, or tamponade, will require careful questioning to characterize this 
symptom. Pericarditis typically presents with dull or sharp precordial or substernal pain that may 
radiate to the neck, trapezius ridge (especially the left), or shoulders. This pain ranges from mild to 
severe. Unlike ischemic chest pain, pain due to pericarditis is usually aggravated by thoracic motion, 
cough, breathing, or swallowing food and may be relieved by sitting up and leaning forward. 
Tachypnea and nonproductive cough may be present. Fever, chills, and weakness are common. 
 
If the subject’s symptoms suggest pericarditis, history and physical exam including careful 
auscultation for pericardial friction rub and an ECG should be performed. In the first stages of 
pericarditis, pericardial effusion may or may not be found on ECHO.  ECHO in a week or two may be 
more useful. 
 
9.4. 
Concomitant therapy 
 
9.4.1. Permitted concomitant therapy 
 
Supportive care/Palliative care:  Supportive and palliative care for disease related symptoms may 
be administered at the investigator’s discretion including the use of analgesics. 
Anti-emetics: Subjects should be premedicated for nausea and vomiting as these have been 
associated with the administration of mocetinostat. 


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Transfusions: Subjects may receive transfusions as necessary. 
 
9.4.2. Cautioned concomitant therapy 
 
CYP450 substrates:  In vitro human liver microsome assays demonstrated that mocetinostat had 
differing inhibitory effect on the metabolism of medications by cytochrome P450 CYP2C9 (strong 
inhibition for diclofenac but no inhibition for tolbutamide). In in vitro assays using specific chemical 
inhibitors and individual human recombinant CYP enzymes (cDNA expressed supersomes), 
mocetinostat was found to be metabolized mainly by CYP2E1 and to a lesser extent by CYP3A4 
and CYP2C8.  Caution should be used when mocetinostat is administered to Subjects taking 
medications metabolized by CYP2C9 or that inhibit or induce metabolism by CYP2E1.  See 
Appendix A, Table 20-1 and Table 20-2, for examples of medications of interest. If a subject is 
taking a drug on one these lists, it is encouraged to substitute a different medication if possible. 
Gastric acid inducers: Medications that directly increase gastric pH such as short-acting antacids 
should be avoided 4 hours before and 1 hour after administration of mocetinostat. Medications that 
affect gastric acid secretion, such as H2 antagonists or proton pump inhibitors will be allowed. 
QTc Prolongating medications: Patients currently receiving treatment with risk of prolonging QTc 
or inducing torsade de pointes are recommended to either discontinue or switch to a different 
medication prior to study enrollment.  Prohibited QTc prolonging medications are listed in Table 
20.4.  Concomitant use of potential QTc prolonging agents should be discussed with the sponsor 
and evaluated based on a case by case basis. 
Substrates and inhibitors of P-gp: Mocetinostat was shown to be a substrate and an inhibitor of 
P-gp. Therefore, P-gp sensitive substrates and strong inhibitors of P-gp should be used with caution 
(Table 20.3). 
Anti-coagulation: At the discretion of the investigator and under medical supervision, Subjects may 
continue to receive prophylactic dose levels of anti-coagulants (except warfarin and coumarin 
derivatives) and chronic supportive care agents (e.g. ESAs) established at least 4 weeks or more 
prior to first dose of study treatment and used in a consistent regimen unless reduced or 
discontinued. The investigator should take into consideration the use of anticoagulants in subjects 
at risk of bleeding due to low platelet count. 
9.4.3.  Prohibited concomitant therapy 
 
Other anticancer treatments: Other anti-cancer treatment including chemotherapy and 
radiotherapy are prohibited during this study. If such agents are required, then the patient must be 
discontinued from the study. 
Growth factor support: Prophylactic use of growth factor support to avoid anticipated study 
treatment side effects or as a substitute for a scheduled dose reduction. However they may be used 
in case of severe anemia (hemoglobin < 80 g/L or 8 g/dL) or neutropenia (< 1.0 x 109/L or 1000/ 
mm3) at discretion of the Investigator. Use of growth factors must be documented in CRDB. 


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Warfarin or coumarin derivatives: Therapeutic doses of warfarin or other coumadin derivatives 
anticoagulants are not permitted. Warfarin has a narrow therapeutic range and mocetinostat is 
possibly affected by CYP2C9, the main metabolizing enzyme of warfarin. 
Drugs with QTc prolonging activity: As listed in Table 20.4. This list is not comprehensive and 
any questions should be reviewed with the pharmacist and discussed with the sponsor. 
CYP3A4 inhibitors and inducers: As listed in Table 20.5. This list is not comprehensive and any 
questions should be reviewed with the pharmacist and discussed with the sponsor. 
Herbal medications/preparations: Hernal medications and preparations are not allowed 
throughout the study, as a potential drug- drug interaction is always possible. These herbal 
medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients should stop 
using these herbal medications at least 7 days prior to first dose of study treatment. 
Contraceptives: Hormonal contraceptives may be affected by cytochrome P450 interactions, and 
are therefore not considered effective for this study, since induction of CYP3A4 may not be excluded 
in patients receiving mocetinostat. 
Gastric acid inducers: Medications that directly increase gastric pH such as short-acting antacids 
should be avoided 4 hours before and 1 hour after administration of mocetinostat. Medications that 
affect gastric acid secretion, such as H2 antagonists or proton pump inhibitors will be allowed. 
Immunosuppressants: Chronic administration of corticosteroids (>10 days), patients receiving 
increasing corticosteroids or another immunosuppressive agent will be prohibited. The following 
uses of corticosteroids are permitted: single dose, topical applications (e.g., rash), inhaled sprays 
(e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular). 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1. Evaluation Summary Chart. 
 
Table 10-1 lists all of the assessments and indicates with an “X”, the visits when they are performed. 
All data obtained from these assessments must be supported in the patient’s source documentation. 
All visits can take place 3 days before or 3 days after the specified study visit (total window of 7 
days) except for the time window for the end of treatment and safety follow-up visit which is +7 days. 


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Table 10-1. Study flow and evaluation 
Evaluation Summary 
Day of Cycle 
Cycle 1 
Day 1 
(- 3 days) 
Cycle 
1 Day 
8 (+/- 
1 day) 
Cycle 1 
Day 15 
(+/- 1 
day) 
Cycle 1 
Day 22 
(+/- 1 
day) 
Cycle 2 
Day 1 
(+/- 3 
days) 
Cycle 2 
Day 15 
(+/- 1 
day) 
Cycle 3 
Day 1 
+ onward 
(+/- 3 days)
 
End of 
Study 
Treatment 
Mocetinostat 
Continuous dosing, three days per week by mouth 
Pill Diary Review 
X 
X 
X 
History+ Physical 
Toxicity 
Assessmenta, 
X 
Continuous Assessment 
X 
Medication review 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
Laboratory assessments 
Hematologyc 
X (- 7 
days) 
X 
X 
X 
X 
X 
Chemistryc 
X(-7 days) 
X 
X 
X 
X 
X 
DLBCL arm only: 
Chemistry specific to 
tumor lysis 
syndromed 
 
X( day 2, 3, 4 of cycle 1 only) 
Coagulation 
(PT/PTT) 
X (-7 days) 
As clinically indicated 
X 
Pregnancy test 
(serum); for WOCBP 
only 
 
X (-7 days) 
 
X 
 
X 
 
X 
Tumor assessments 
Radiographic 
assessmente 
 
 
 
X (-28 
days) 
X 
Q 8 wks for 
0-6 mo; 
Q 12 wk for 
6-12 mo; 
Q16 wk 
after 1 yr 
X 
Q 8 wks 
for 0-6 mo; 
Q 12 wk 
for 6-12 
mo; 
Q16 wk 
after 1 yr 
Bone Marrow biopsy 
As 
clinically 
indicated 
 
** At time of complete response if BM involved prior 
Safety assessments 
ECG 
X (-28 
days) 
X 
X 
(predose) 
X 
As clinically 
indicated 
X 
Cardiac imaging 
(ECHO) 
X (-28 
days) 
X 
X 
(predose) 
X 
As clinically 
indicated 
X 
Biomarkers 
CREBBP/EP300 
screening 
Pre- 
screening 
Collection of fresh 
tumor from 
biopsy/resection 
X 
(option 
al) 
X 
(optional) 
X 
(optional at 
relapse) 


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Research blood 
sample 
X (-7 days) 
X 
X 
a. Assessed including type, severity, timing and relationship to study drug using NCI common 
Toicity Criteria version 4.0 
b. Weight, blood pressure, pulse 
c. CBC with differential, Chemistry (Potassium, sodium, calcium, magnesium, chloride, 
inorganic phosphorus, ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, direct 
bilirubin, LDH, Gamma GT, Serum creatinine, urea or blood urea nitrogen (BUN), lipase, 
albumin, uric acid) 
d. Uric acid, potassium, sodium, calcium, inorganic phosphorus and serum creatinine 
e. CT scan with contrast, unless contraindicated, of the chest, abdomen, and pelvis, neck; PET 
scan for patients with DLBCL (combination PET/CT may be used); MRI may be substituted 
for CT scan if patients are intolerant of CT scans with contrast 
 
 
 
 
10.1.4. 
End of treatment evaluation (within 30 days of last dose of mocetinostat) 
 
 
MD visit, with history and physical exam including weight, blood pressre, pulse, ECOG 
performance status, and updated medication list. Concurrent medications will be reviewed for 
potential drug-drug interactions with study medications. 
 
Patient drug diary review 
 
Toxicity will be assessed and the type, severity, timing, and relationship of each adverse event to 
therapy will be determined as ther NCI Common Toxicity Criteria version 4.0. 
 
Blood work to be obtained will include: 
 
CBC with differential, Comprehensive metabolic panel, LDH, phosphorus, uric acid 
 
PT/PTT 
 
Serum pregnancy test for females of reproductive age 
 
ECG 
 
Echocardiogram 
 
Optional tumor biopsy 
 
10.2. Evidence of disease evaluation 
 
Patients will have evidence of disease evaluation at baseline using modified criteria for malignant 
lymphoma [45]. Response criteria will generally follow the CT scan recommendations as per the 
revised response criteria for malignant lymphoma [45]. Further clarification on these criteria has 
been published by [46]. MRI will be allowed only in those cases when CT scan cannot be performed. 
 
Clinical evaluation and tumor assessments will be performed periodically, as is indicated in Table 
10-1, based on physical examination, radiological evaluation and core bone marrow biopsy (only to 
confirm complete responses in patients with bone marrow tumor involvement prior to study 
treatment). Tumor assessments will be performed every 2 cycles/8 weeks for the first 6 months, 
every 3 cycles/12 weeks for the following 6 months, and every 4 cycles/16 weeks thereafter. Clinical 
suspicion of disease progression at any time will require a physical examination and radiological 


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confirmation to be performed promptly, rather than waiting for the next scheduled tumor 
assessment. In case of an unscheduled or delayed tumor assessment for any reason, subsequent 
tumor assessments must be performed according to the originally planned schedule from baseline. 
 
10.2.1. Physical Exam 
 
Tumor assessment by physical examination and evaluation of disease related B symptoms 
(unexplained fever of ≥ 38°C; unexplained, recurrent drenching night sweats; or unexplained loss of 
>10% body weight within the previous 6 months) will be performed and recorded following the 
schedule for radiological tumor assessments. 
 
10.2.2. Radiographic tumor assessment 
 
At screening, all patients must have a PET/CT scan with contrast of the Chest, Abdomen and Pelvis. 
The same type of PET/CT scan used at screening must be used for all subsequent assessments. 
CT scan with contrast of the Neck, Chest, Abdomen and Pelvis is allowed in lieu of PET/CT for 
patients with follicular lymphoma at the discretion of the treating physician. MRI with contrast will be 
allowed only in those cases when CT scan cannot be performed and will be used at baseline and all 
subsequent assessments in these patients. No modality change would be allowed during the study. 
Only in exceptional cases when a patient is known to have or determined during the study, to have 
intolerance to the CT scan contrast medium, a CT scan without contrast will be acceptable to avoid 
modality change. At screening, tumor assessments should preferably be performed ≤ 7 days prior to 
the first dose of mocetinostat, however tumor assessments ≤ 21 days prior to first dose of study drug 
will be acceptable. 
PET and CT Scans of the Chest/Abdomen and Pelvis will be performed every 8 weeks for the initial 
6 months, every 12 weeks for the subsequent 6 months and every 16 weeks thereafter. It may also 
be performed as clinically indicated. 
A sum of the product of diameters (SPD) for lesions measured prior to study treatment will be 
calculated and reported at baseline. Conventional CT and MRI should be performed with 
contiguous cuts of 7.5 mm or less in slice thickness. Spiral CT should be performed using a 5 mm 
or less contiguous reconstruction algorithm (this specification applies to tumors of the chest, 
abdomen and pelvis). 
If a very small lesion cannot be reliably measured because of its size, it is recommended to enter the 
minimum lesion size (i.e., 5 mm for spiral CT). In other cases where the lesion cannot be reliably 
measured for reasons other than its size (i.e., borders of the lesion are confounded by neighboring 
anatomical structures), no measurement should be entered and the lesion cannot be evaluated. 
 
Any measurable extranodal lesions (organs other than lymph nodes) that resolves from baseline 
(disappear completely) must be assigned a size of 0 mm when documenting in CRDB. An 
extranodal lesion must be ≥ 1 cm x 1 cm to be considered measurable. 
 
10.2.3. Bone marrow assessment 
 
Information on the patient bone marrow involvement prior to study entry must be present in his/her 
source documents. Prior tumor bone marrow involvement should be entered in CRDB. 


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Core bone marrow biopsy is required to confirm Complete Responses (at the first occurrence of 
radiological and clinical evidence of CR) in patients with bone marrow tumor involvement prior to 
study treatment who achieve Complete Response based on clinical and radiological evidence. The 
biopsy sample on which this determination is made must be adequate (with a goal of > 20 mm 
unilateral core). Bone marrow biopsy should be obtained no later than at the next visit immediately 
following clinical and radiological evidence of CR (i.e. < 28 days ± 7 days from the date of the 
radiological assessment, on which the CR is based on). 
 
10.3. Laboratory assessments 
 
The standard clinical laboratory analyses described below are to be performed by the study site’s 
local laboratories according to the Visit Schedule, outlined in Table 10-1. 
The investigator is responsible for reviewing all laboratory reports for patients in the study and 
evaluating any abnormalities for clinical significance. At any time during the study, abnormal 
laboratory parameters that are clinically relevant (e.g., require dose modification and/or interruption 
of study drug, lead to clinical symptoms or signs, or require therapeutic intervention), whether 
specifically requested in the protocol or not, must be recorded in CRDB. Laboratory data will be 
summarized using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
 
Local laboratory tests will be collected and analyzed on the scheduled day, even if study medication 
is being held. More frequent examinations may be performed at the investigator’s discretion if 
medically indicated; those results should be recorded in CRDB. 
 
Laboratory assessments performed as part of the screening evaluations and within 7 days of the first 
dose of study drug, will not be required to be repeated on Day1 of Cycle 1. 
In the event of grade 2, grade 3 or grade 4 hematological toxicities that require study drug dose 
modifications or interruptions, hematological tests must be repeated until recovery to the baseline 
value or grade 1. 
 
Hematology 
 
Hematology includes the following parameters: complete blood count consisting of a white blood cell 
(WBC) count with differential (total neutrophils [including bands], lymphocytes, monocytes, 
eosinophils, basophils), hemoglobin (Hgb), and platelet counts. 
Hematological tests will be performed at screening, on Cycle 1 Day 1 (prior to administration of the 
study drug) and repeated on Day 1 of every subsequent treatment Cycle and at the End of 
Treatment. Hematology test may also be performed as medically necessary. 
Clinical chemistry 
 
Clinical chemistry includes the following parameters: 
 
 
Potassium, sodium, calcium, magnesium, chloride, inorganic phosphorus 
 
ALT/SGPT, AST/SGOT, alkaline phosphatase, total bilirubin, direct bilirubin, LDH, Gamma 
GT 
 
Serum creatinine, urea or blood urea nitrogen (BUN), lipase, albumin, uric acid 


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Clinical chemistry will be performed at screening, on Cycle 1 Day 1 (prior to administration of study 
drug), repeated on Day 1 of every subsequent treatment cycle and at End of Treatment. Chemistry 
tests may also be performed as clinically indicated. Patients with diffuse large B-cell lymphoma will 
require additional evaluations of the following parameters on days 2, 3 and 4 in the first treatment 
cycle to monitor for TLS: 
 
 
Uric acid, potassium, sodium, calcium, inorganic phosphorus and serum creatinine 
 
Coagulation 
 
The coagulation profile includes partial thromboplastin time (PTT) and either prothrombin time (PT) 
or International normalized ratio (INR). Coagulation profile will be performed at screening, on Cycle 
1 Day 1 (prior to administration of study drug) and as clinically indicated. 
 
Pregnancy and assessment of fertility 
 
Pregnancy tests are indicated for all females of childbearing potential. Serum tests are required at 
screening, on Cycle 1 Day 1 (prior to administration of study drug) and repeated on Day 1 of every 
subsequent treatment cycle and at End of Treatment. Additional serum pregnancy tests should be 
performed as soon as indicated in case the patient is suspected to be pregnant. 
 
In case of pregnancy, the patient must immediately be withdrawn from study treatment. 
 
Note: Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
 
10.4. Cardiac assessments 
Electrocardiograms 
The study requires standard 12-lead digital ECG as indicated in Table 10-1. Pre-dose ECGs must be 
performed prior to any study drug administration on the respective days.  ECGs may be repeated 
more frequently at the investigator’s discretion if signs and symptoms of cardio-toxicity exist. If an 
ECG is performed for screening ≤ 7 days before the first dose of study treatment, it does not need to 
be repeated on Day 1 of Cycle 1.  Single ECG should generally be done prior to any blood draws. 
Clinically significant findings must be discussed with the principle investigator prior to enrolling the 
patient in the study. New or worsened clinically significant findings occurring after informed consent 
must be recorded in CRDB. 
Echocardiograms 
 
Echocardiogram (ECHO) will be used to assess LVEF at screening and obtain baseline presence of 
pericardial effusion at start of study. 


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Echocardiograms will be performed at screening, on Cycle 1 Day 1 (prior to administration of study 
drug), cycle 1 day 15, cycle 2 day 1, cycle 2 day 15 and repeated as clinically indicated and at End 
of Treatment. Echocardiograms may be repeated more frequently at the investigator’s discretion if 
signs and symptoms of cardio-toxicity exist. Alternatively, cardiac MRI may be utilized as clinically 
indicated. If an echocardiogram is performed for screening ≤ 7 days before the first dose of study 
treatment, it does not need to be repeated on Day 1 of Cycle 1. 
 
LVEF assessment and evaluation of pericardial effusions may be performed as clinically indicated at 
the investigator’s discretion if there are signs or symptoms of cardiotoxicity. In case of clinically 
significant abnormalities, they should be reported in CRDB. 
 
10.5. Biomarkers and exploratory assessments 
 
Tumor tissue samples will be collected pre-treatment with the purpose of investigating the effects of 
CREBBP/EP300 mutations in treatment response to HDAC inhibition. In addition, we will also 
identify risk factors for treatment response, and disease relapse. 
 
Correlation of myc and Bcl-2 positivity for treatment response 
o Concurrent expression of Myc and Bcl-2 in DLBCL portends an overall poorer 
prognosis largely the results of double hit biology [47, 48]. Concurrent expression of 
myc and Bcl-2 occurs in both germinal center and activated B cell DLBCL suggesting 
heterogenous molecular pathways may be responsible for myc deregulation. 
Modulation of epigenetic landscape with mocetinostat may provide a route to 
deregulate the dependent myc signaling via alteration of gene expression. The 
immunohistochemistry staining of the pre-treatment samples for myc (defined as 
≥40% of tumor cells staining positive) and Bcl-2 (defined as ≥ 70% of tumor cells 
staining positive) will be correlated to response to mocetinostat [47]. 
 
Determination of mechanisms of resistance to mocetinostat via mutational analysis 
o Inhibition of HDAC activity results in accumulation of acetylated proteins including 
histones, transcription factors, and heat shock proteins which alter their function 
leasing to global cellular changes to transcription, mitosis, and protein stability. 
These changes interfere with tumor cell proliferation, survival and cellular 
homeostasis contributing to an anti-tumor effect. As cancer cells adapt to this insult, 
several mechanism of resistance may develop including the increased rug efflux, 
HDAC overexpression or desensitization, alterations of stress response mechanisms 
and increased anti-apoptotic signaling[49]. We plan to compare pretreatment, on- 
treatment and post relapse samples for alterations in key genes known to be 
frequently mutated in B cell lymphomas. The genes are tabulated in Table 10-2. 
 
Table 10-2. Genetic mutations common in B cell lymphoma 
CREBBP 
EP300 
MLL2/3 
EZH2 
TP53 
KDM2B 
KIT 
PDGFRA 
MYC 
MyD88 
CD79B 
Beta-2-microglobulin 
TNFAIP3 
CARD11 
BCL-6 
PIM-1 
FOXO1 
NOTCH2 
CDKN2A 
REL 


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o During the study: The pre, during, and post- treatment tumor biopsy should be 
collected with patient’s consent as appropriate for patient safety.  At the end of 
treatment, collection of optional post-relapse tumor sample will provide a unique 
opportunity to investigate the potential mechanisms of resistance of mocetinostat in 
patients. If the patient consents and the circumstances are favorable, it is encouraged 
to collect a fresh frozen tumor biopsy at initial screening biopsy and tumor 
progression .This tumor biopsy should be collected regardless whether the pre- 
treatment tumor sample was collected or not. The tumor sample at disease 
progression should only be obtained as a core biopsy, if feasible.  During collection of 
the fresh biopsy, if the treating physician collects enough tumor tissue, the tumor 
should be divided into 2 passes. The first pass is formalin fixed and the second pass 
is snap frozen and will be used for biomarker analysis. 
 
 
Assay T cell activation and exhaustion in the peripheral blood 
o Peripheral blood samples from three timepoints (Cycle 1 Day 1 (pretreatment), Cycle 
1 Day 15, and Cycle 2 Day 1) will be used to perform preliminary analysis of T cell 
activation and exhaustion. Four vials of peripheral blood will be drawn into CPT (Cell 
Preparation Tubes) with Sodium Heparin (each tube is 2 ml tubes for a total of 8 ml) 
and banked at the Immune Monitoring Core Facility. 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
11.1. Adverse events 
 
11.1.1. Definitions and reporting 
 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent has 
been obtained. Abnormal laboratory values or test results occurring after informed consent 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, require therapy (e.g. hematologic abnormality that requires transfusion or hematological 
stem cell support), or require changes in study medication(s). 
 
Adverse events that begin or worsen after informed consent should be recorded in CRDB. 
Conditions that were already present at the time of informed consent should be recorded in the 
Medical History in CRDB. Adverse event monitoring should be continued for at least 30 days 
following the last dose of study treatment. Adverse events (including lab abnormalities that constitute 
AEs) should be described using a diagnosis whenever possible, rather than individual underlying 
signs and symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the severity of mild, 
moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 


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(death) will not be used in this study; rather, information about deaths will be collected though a 
Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during the 
study. Adverse events also may be detected when they are volunteered by the patient (subject) 
during the screening process or between visits, or through physical examination, laboratory test, or 
other assessments. As far as possible, each adverse event should be evaluated to determine: 
 
1. The severity grade (CTCAE Grade 1-4) 
 
2. Its duration (Start and end dates) 
 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) or its 
relationship to the study treatment (Reasonable possibility that AE is related: No, Yes, 
investigational treatment, Yes, the study treatment (non-investigational), Yes, both and/or 
indistinguishable) 
 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, temporarily 
interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy taken (no concomitant medication/non-drug therapy, concomitant 
medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 11.2.1 
 
All adverse events should be treated appropriately. If a concomitant medication or non-drug therapy 
is given, this action should be recorded in CRDB. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study treatment, the interventions required to 
treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate method 
(Cheson criteria), should not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease progression) will be reported as 
per usual guidelines used for such events with proper attribution regarding relatedness to the drug. 
11.1.2. Laboratory test abnormalities 
 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes in 
study treatment), should be recorded in CRDB. Whenever possible, a diagnosis, rather than a 
symptom should be provided (e.g. anemia instead of low hemoglobin). Laboratory abnormalities that 


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meet the criteria for Adverse Events should be followed until they have returned to normal or an 
adequate explanation of the abnormality is found. When an abnormal laboratory or test result 
corresponds to a sign/symptom of an already reported adverse event, it is not necessary to 
separately record the lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be reported 
as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a 
SAE unless it meets the definition of serious as defined below and/or as per investigator’s discretion. 
A dose hold or medication for the lab abnormality may be required by the protocol in which case the 
lab abnormality would still, by definition, be an adverse event and must be reported as such. 
 
11.2. Serious adverse events 
 
11.2.1. Definitions and reporting 
 
Serious adverse event (SAE) is defined as one of the following: 
 
 
Is fatal or life-threatening 
 
Results in persistent or significant disability/incapacity 
 
Constitutes a congenital anomaly/birth defect 
 
Is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. Hospitalization is 
defined as admission to the Emergency Room for more than 24 hours or hospital admission. 
 
Events not considered to be serious adverse events are hospitalization for: 
 
 
Hospitalization of subjects to receive study treatment 
 
Subjects admitted to a hospice or nursing home for elective non-specific, general care or 
social reasons/respite care 
 
Hospital admissions purely for the evaluation and treatment of febrile neutropenia 
 
Hospitalization for prescheduled or elective procedures (such as for pain management, 
disease staging/restaging procedures, or protocol-specific procedures) Routine treatment or 
monitoring of the studied indication, not associated with any deterioration in condition 
 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 
Treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of a SAE 
The following Special Reporting Events will be reported in the same manner as SAEs using the 
dedicated reporting forms: 
 
Overdose of mocetinostat is defined as any increase in dose (> 20%) or frequency (>20% 
increased frequency over one month period) over the planned dose and frequency. In the 
case of overdose, further administration of Investigational Product(s) will be suspended, the 
subject will be followed closely for potential side effects until resolution and a decision 
regarding resumption of dosing will be made in conjunction with MSKCC. 


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 
Pregnancy - Pregnant women are excluded from this study. In the case of an identified 
pregnancy of a female participant or female partner of a male participant, study treatment will 
be immediately discontinued and follow-up reports on the safety of the fetus and mother will 
be provided for the duration of the pregnancy. If the fetus is brought to term, information 
regarding its development may be requested up to 3 months after birth. 
 
Protocol specific SAE 
 
 
Drug-induced liver toxicity should be reported as an SAE, even when assessed non-serious 
by the investigator. 
 
Protocol exempt SAEs 
 
 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (Cheson criteria), should not be reported as a serious adverse event. 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient 
has provided informed consent and until at least 30 days after the patient has stopped study 
treatment must be reported to the IRB/PB and MethylGene/Mirati as soon as possible but no later 
than 5 calendar days. 
 
The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted electronically 
to the SAE office at sae@mskcc.org. The report should contain the following information: 
 
 
Subject name (report generated with initials if it will be sent outside MSKCC) 
 
Medical record number 
 
Disease/histology 
 
Protocol number and title 
Data needing to be entered: 
 
The date the adverse event occurred 
 
The adverse event 
 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
 
If the AE was expected 
 
The severity of the AE 
 
The intervention 
 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
For IND/IDE protocols: The CRDB AE report should be completed as above and the FDA assigned 
IND/IDE number written at the top of the report. 


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11.3. Documentation and reporting of Pericardial Events 
 
Since pericardial abnormalities (e.g., pericarditis, pericardial effusion and hemodynamic 
compromise) exist along a continuum with overlap between the clinical symptomatology and 
diagnoses, each pericardial AE (including grading of severity for each individual event) along the 
continuum should be captured separately (Table 11-1). 
 
 
Table 11-1. Definitions of Pericardial Events 
Event Term 
Definition 
Characteristics/Diagnosis 
Pericarditis 
Inflammation of the 
pericardium 
The major clinical manifestations of acute pericarditis include: 1) chest pain, 
2) pericardial friction rub, 3) ECG changes (with new widespread ST 
elevation or PR depressions), and 4) pericardial effusion. At least 2 of these 
features are usually considered necessary to make the diagnosis. 
Pericardial 
effusion 
Excess exudate, or fluid, in 
the pericardium 
Once a pericardial effusion is suspected, the diagnostic approach consists 
of 3 steps: 1) establish the presence of effusion, 2) assess the 
hemodynamic impact, and 3) establish the cause. Clinical evaluation and 
ECG findings may suggest the presence of a pericardial effusion, but 
imaging, usually ECHO, is required to establish a diagnosis.
Hemodynamic 
Compromise 
Mechanical compression of 
the heart by large amounts 
of fluid or blood within the 
pericardial space that limits 
the normal range of motion 
and function of the heart 
The diagnosis of hemodynamic compromise is based upon clinical and 
imaging evidence. The following physical findings 1) sinus tachycardia, 
2) elevated jugular venous pressure, and 3) pulsus paradoxus are 
suggestive of frank tamponade. ECHO or other imaging of the pericardium 
is essential to the diagnosis of hemodynamic compromise. 
 
 
All pericardial findings, regardless of seriousness and relationship to study medication, should be 
reported to the IRB/PB and MethylGene/Mirati. When reporting pericardial events, available ECHO 
results/reports (or other means of diagnosis if available) should also be provided.  All cardiac events, 
including pericardial findings will be reported to the DSMB to facilitate their ongoing evaluation of 
safety in subjects treated in this study. Serious pericardial AEs are to be reported according to the 
standard procedure for reporting of SAEs. 
11.4. Pregnancies 
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to the IRB/PB and MethylGene/Mirati within 24 hours of learning of its occurrence. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator 
to the oncology MethylGene/Mirati Drug Safety and Epidemiology Department (DS&E). Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the possible 
relationship to the MethylGene/Mirati study treatment of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The objective of this study is to determine the efficacy of mocetinostat in selected patients with 
CREBBP/EP300 mutations with DLBCL and FL. The primary efficacy endpoint is the overall 


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response rate at 1 year, defined as the proportion of patients with a best overall response of CR or 
PR according to Cheson criteria per Section 12.1. Secondary efficacy endpoints are duration of 
response and event free survival.  Duration of response is defined as the time from the date of first 
occurrence of CR or PR whichever is recorded first to the date of the first objectively documented 
progressive disease (PD) or death due to any cause.  Event free survival (EFS) is defined as the 
time from the date of treatment start to the date of the first documented progressive disease (PD) or 
death due to any cause 
 
12.1. Criteria for evaluation of response 
 
Response will be evaluated, using modified criteria for malignant lymphoma [45]. Response criteria 
will generally follow the CT scan recommendations as per the revised response criteria for malignant 
lymphoma [45].  Further clarification on these criteria has been published by [46]. MRI will be allowed 
only in those cases when CT scan cannot be performed. 
 
Clinical evaluation and tumor assessments will be performed periodically, as is indicated in Table 
10-1, based on physical examination, radiological evaluation and core bone marrow biopsy (only to 
confirm complete responses in patients with bone marrow tumor involvement prior to study 
treatment). Clinical suspicion of disease progression at any time will require a physical examination 
and radiological confirmation to be performed promptly, rather than waiting for the next scheduled 
tumor assessment. In case of an unscheduled or delayed tumor assessment for any reason, 
subsequent tumor assessments must be performed according to the originally planned schedule 
from baseline. 
 
12.1. Measurability of lesion for objective response 
 
 
Measurable disease: lesions that can be accurately measured in two dimensions by CT, MRI, 
plain x-ray of other conventional technique and have a greatest transverse diameter of 2 cm or 
greater. Splenomegaly alone is not sufficient to qualify as measurable disease.  PET scans 
alone are insufficient for evaluation of measurable disease. 
 
Non-measurable disease: All other lesions including unidimensional lesions, lesions too small to 
be considered measurable, pleural or pericardial effusions, ascites, bone disease, 
leptomeningeal disease, lymphangitis, pulmonitis, abdominal masses not confirmed by CT of 
disease documented only by indirect evidence (e.g. lab values). 
 
12.2. Objective disease response assessment 
 
Objective status is to be recorded at each evaluation according to the 2007 revised Cheson criteria 
[45]. All measurable lesions up to a maximum of 6 lesions (largest) should be identified as target 
lesions at baseline. If there are more than 6 measurable lesions, the remaining will be identified as 
non-target lesions and included as non-measurable disease. The 6 lesions should be selected 
according to the following features: they should be from disparate regions of the body and they 
should include mediastinal and retroperitoneal areas of disease if these sites have measurable 
lesions.  Measurements must be provided for target lesions, while presence or absence must be 
noted for non-target measurable and non-measurable lesions. 


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 
Complete response (CR): Complete disappearance of all measurable and non-measurable 
disease with the exception of the following. In patients with positive PET prior to therapy, a post 
treatment residual mass of any size is permitted as long as it is PET negative.  If the PET scan 
was negative prior to therapy, all nodal masses > 2 cm in greatest transverse diameter (GTD) at 
baseline must have regressed to ≤ 2 cm in GTD and all nodal masses > 1 cm and ≤ 2 cm in GTD 
and > 1 cm in their short axis before treatment must have regressed to ≤ 1 cm in their short axis. 
No new lymphoma lesions should be visible on PET scan or by any other imaging studies. The 
spleen and/or liver, if considered enlarged at baseline based on physical examination or imaging 
study (other than PET), must have regressed in size and must not be palpable. If bone marrow 
was positive at baseline, it must be negative based on biopsy and aspirate at the same site. 
Normalization of markers (i.e. LDH) definitely assignable to DLBCL or FL. Tumor measurements 
must be obtained by an imaging modality other than PET. All disease must be assessed using 
the same technique as baseline unless clinically contraindicated. 
 
Partial response (PR): Applies to patients with at least one lesion that does not qualify for a CR. 
For patients with measurable disease, ≥ 50% decrease in sum of the product of the diameters 
(SPD) of up to 6 dominant lesions identified at baseline.  No new lesions and in increase in the 
size of extranodal disease.  Extranodal disease (splenic and hepatic lesions) must have 
regressed by ≥ 50% in SPD. In patients with a positive PET scan prior to therapy, PET should 
be positive in at least one previously involved site. Tumor measurements must be obtained by 
an imaging modality other than PET. All disease must be assessed using the same technique 
as baseline unless clinically contraindicated. Patients who meet all other criteria but have new 
lesions observed on PET scan only (not confirmed on CT or other imaging studies) are 
considered partial responders. 
 
Stable disease (SD): Does not qualify for CR, PR, or relapsed/progressive disease. Tumor 
measurements must be obtained by an imaging modality other than PET.  Persistent 
abnormalities seen on CT scans must be FDG-avid on PET scans. All disease must be 
assessed using the same technique as baseline unless clinically contraindicated. 
 
Relapsed disease (after CR)/Progressive disease (after PR or SD): At least 50% increase in the 
SPD of target measurable nodal lesions over the smallest sum observed (over baseline if no 
decrease during therapy), or ≥ 50% increase in the GTD of any node > 1 cm in shortest axis, or ≥ 
50% increase in the SPD of other target measurable lesions (e.g. splenic or hepatic nodules) 
over the smallest sum observed.  Appearance of any new bone marrow involvement. 
Appearance of any new lesion > 2 cm in longest axis, or ≥ 50% increase in GTD of any 
previously involved node with a diameter ≤ 1 cm in the short axis such that its longest axis is not 
> 2 cm. Lymph nodes should be considered abnormal for relapse or progressive disease only if 
the long axis is > 2 cm, or if both the long and short axis are > 1 cm. In patients with a positive 
PET scan before therapy, lesions should be PET positive. Tumor measurements must be 
obtained by an imaging modality other than PET and preferably consistent throughout the study 
unless clinically contraindicated. Appearance of any new lesion on PET alone (not confirmed by 
CT or other imaging modality) is NOT considered relapse or progression. 
12.3. Best objective response 
 
 
CR: one objective status of CR documented before relapse 
 
PR: one objective status of PR documented before progression but not qualifying as a CR 


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 
Stable: at least one objective status of stable disease documented at least 6 weeks after 
registration, no qualifying as a CR or PR 
 
Increasing disease: objective status of progression within 12 weeks of registration not qualifying 
as CR, PR or SD 
 
Inadequate assessment, response unknown: progression greater than 12 weeks after 
registration and no other response category applies 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
13.1. Criterial for premature patient removal from study 
 
Patients may voluntarily withdraw from the study or be removed from the study at the discretion of 
the investigator at any time. Patients may be withdrawn from the study if any of the following occur: 
 
Progressive disease 
 
Unacceptable toxicities 
 
Protocol deviation 
 
Lost to follow-up 
 
Pregnancy 
 
Discovery of patient ineligibility 
 
Errors in treatment compliance 
 
Administrative problems 
 
In addition to the general study treatment withdrawal criteria, the following study specific criteria will 
also require premature study treatment discontinuation: 
 
Study treatment modifications that result in discontinuation 
 
Interruption of mocetinostat treatment for more than 21 days 
 
Use of prohibited medication 
 
Start of any other anti-neoplastic therapy 
 
If a study treatment withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from study treatment and record 
this information in CRDB. In case of withdrawal from study treatment, the patient needs to indicate 
on the informed consent form whether she is willing to continue with subsequent follow-up 
procedures 
 
13.2. Patient Followup 
 
Patients lost to follow up should be recorded as such in CRDB. For patients who are lost to follow- 
up, the investigator should show "due diligence" by documenting in the source documents steps 
taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
13.2.1. Safety followup 
 
All patients will be followed for adverse events and serious adverse events for at least 30 days 
following the last dose of mocetinostat. At the end of this period (between day 30 and day 37 after 


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last dose), the investigator should contact the patient to inquire about any AE observed/concomitant 
medication taken during this period. This could be done via either an office visit or a phone contact. 
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. In case the patient has any abnormal lab values at end of treatment that are considered 
clinically significant by the investigator, the patient needs to come to the site for repeat blood 
analysis until resolution or stabilization including at least a site visit with respective analyses 30-37 
days after end of treatment. 
If patients refuse to return for safety evaluation visits or are unable to do so, every effort should be 
made to contact them by telephone to determine their status. Attempts to contact the patient should 
be documented in the source documents (e.g., dates of telephone calls, registered letters, etc.). 
13.2.2. Efficacy followup 
 
Patients who discontinue study treatment for reasons other than disease progression, death start of 
new anti-neoplastic therapies, lost to follow-up, or withdrawal of consent to efficacy follow-up will 
continue to have radiological tumor assessments per Table 10-1 after end of treatment, or until 
disease progression, start of a new antineoplastic therapy, death, lost to follow-up, or withdrawn 
consent. 
At the time the patient discontinues the efficacy follow-up period or starts a new antineoplastic 
therapy, this will be recorded in CRDB. 
14.0 
BIOSTATISTICS 
 
The primary objective is to determine the efficacy of Mocetinostat in patients with relapsed/refractory 
DLBCL and FL who have inactivating mutations of acetyltransferase genes. To this end we will 
examine the endpoint of 1-yr overall response (complete response or partial response defined as per 
Cheson criteria further elaborated in Section 12.1). Currently this rate is around 15% for both 
lymphoma subtypes based on a previous study [2], and we expect to improve it to 40%. To this end 
we will use two parallel optimal Simon two-stage designs, one for each subtype, to test the rate of 
15% (lower than which will be unacceptable) vs 40% (higher than which will be acceptable). For 
each subtype, in the first stage, we will enroll 10 eligible patients. If 1 or 0 patients show response in 
a year, no additional patients will be enrolled and the regimen will be considered not promising. If 2 
or more patients show response, then an additional 15 patients will be enrolled for the second stage. 
Among the 25 patients, If 7 or more patients are able to show response then this treatment regimen 
will be declared effective. For this decision rule the type I error (declare Mocetinostat promising while 
it is actually not) rate is 6% and the type II error (declare Mocetinostat not promising while it actually 
is) rate is around 10%. The early stopping (i.e., stop after the first stage with 10 patients) probability 
is 0.54 when the true response rate is 15% or lower, and is 0.046 when the response rate is 45% or 
higher. If a patient died or progressed (and consequently received other treatments) within a year 
before showing any responses, or provided no information about the best response status, he/she 
will be recorded as a non-respondent patient. We expect the withdrawal/drop-out rate to be low 
(around 10%). However if such events occurred due to reasons unrelated with the disease and the 
patients had not shown any sign of response or progression, such patients will be replaced by new 
patients. 


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Due to the potential withdrawal we will enroll totally 56 patients (28 each subtype), and we expect to 
have 50 analyzable patients (25 each subtype) within 4 years. Note that only the first 25 analyzable 
patients, for each lymphoma subtype, will be counted towards the analysis of primary objective. For 
other objectives, all available patients will be used and the analysis will be done separately for each 
subtype. 
 
Event free survival (defined as time from the date of treatment start to the date of the first 
documented progressive disease (PD) or death due to any cause) rate using mocetinostat in this 
selected population will be estimated by the Kaplan-Meier method. For subjects achieving objective 
response as assessed by investigators, their duration of response is defined as the time from the 
date of first occurrence of CR or PR whichever is recorded first to the date of the first objectively 
documented progressive disease (PD) or death due to any cause. The duration of response will be 
assessed based on the sub-cohort of patients who showed responses also using Kaplan-Meier. To 
assess the safety and tolerability of mocetinostat, all toxicities related to the treatment will be 
tabulated and summarized by type and severity for illustration. Adverse events requiring 
discontinuation of study drug will be summarized and tabulated separately. 
 
Other exploratory objectives include correlation of myc and Bcl-2 positivity with treatment response, 
assessment of mechanisms of resistance to mocetinostat via  information on additional gene 
sequencing by IMPACT and Foundation Medicine, and analysis of T cell activation and exhaustion 
in the peripheral blood. For the former, myc and Bcl-2 positivity will be determined by IHC as binary 
factors which will be correlated with treatment response by Fisher’s exact test. The laboratory 
genetic mutation study will be mostly descriptive for future references. A panel of mutations included 
in Table 10-2 will be examined for their presence/absence before and after treatments. Analysis of T 
cell activation and exhaustion will be over 3 timepoints. Due to the expected small sub-sample size, 
we may only be able to summarize the T cell activation and exhaustion markers measurements. 
However, if there are >5 responders and >5 non-responders, then Wilcoxon rank sum tests will be 
used to preliminary assess the correlation between these markers and the response. 
 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
During the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am – 
5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic Registration 
System (http://ppr/). The completed signature page of the written consent/RA or verbal script/RA, a 
completed Eligibility Checklist and other relevant documents must be uploaded via the PPR 
Electronic Registration System. 
 
15.3 
Randomization 


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Randomization will not be necessary for this study.  After meeting inclusion and exclusion criteria, 
patients are eligible for this single arm open label study. 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordination of the activities of the study team. 
The Clinical Research Database (CRDB) will be used for data collection. The data will be reported 
to the institution (IRB) and the drug manufacturer (MethylGene/Mirati) as appropriate. 
Tumor slides will be stored in the pathology department. Results from laboratory studies will 
photomicrographs of immunohistochemical studies and computer files of sequencing data. These 
files will be stored on the Department of Medicine server.  Documentation linking patient identifiers, 
patient samples, and results will be securely maintained in the CRDB with access limited to study 
investigators. 
 
16.2 
Quality Assurance 
 
Routine registration reports will be generated to monitor patient accruals and completeness of 
registration data.  Routine data quality reports will be generated to assess missing data and 
inconsistencies.  Accrual rates, extent, and accuracy of evaluations and followup will be monitored 
periodically throughout the study period and potential problems will be brought to the attention of the 
study team for discussion and action. 
 
Random sample data quality and protocol compliance audits will be conducted by the study team at 
a minimum of twice a year and more frequently if indicated. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center were 
approved by the National Cancer institute in September 2001. The plans address the new policies 
set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data and 
Safety Monitoring of Clinical Trials” which can be found at:  
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1 
 
The MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research QA) and departmental procedures for quality control, and there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials programs. The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the 
Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Center’s 
Research Council and Institutional Review Board. 


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During the protocol development and review process, each protocol will be assessed for its level of 
risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the monitoring 
procedures will be established at the time of protocol activation. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits, and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities and side effects. 
Alternative treatment options, including non-protocol treatment options, will be discussed with the 
patient. It will be reviewed that participation in this clinical trial is voluntary and that the patient may 
withdraw consent at any time. The study is designed with careful safety monitoring for toxicities and 
regular physician visits.  Every effort will be made to keep study records private.  Neither the 
patient’s name nor anything else that could identify the patient will be used in any reports or 
publications that result from this study. Trained staff at MSKCC, the FDA, or the drug manufacturer 
MethylGene/Mirati, will be able to review the medical records if necessary. The financial cost of the 
study will be discussed with the patient and mocetinostat will be provided free of charge. 
17.2 
Privacy 
 
Medical information is confidential. The participant’s personal identity will not be used in reports that 
are written about the research. The MSKCC Institutional Review Board and Privacy Board (IRB/PB) 
will review all requests for research performed involving biospecimens ascertained through this 
protocol. Blood and tissue samples will be stored with a code linked to the patient’s medical record. 
With the permission of the IRB/PB, research studies on cellular, genetic, immunologic or other 
features of tumor or normal samples may be performed with sample information linked by codes to 
personal identifiers and no names attached to the samples. The results of any research using blood 
or tissues will not be placed in the medical record. The consent also indicates that samples and 
research information collected may be shared with other qualified researchers after de-identification. 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information pursuant 
to a completed and signed Research Authorization Form. The use and disclosure of protected 
health information will be limited to the individuals described in the Research Authorization Form. 
The Research Authorization Form must be completed by the Principle Investigator and approved by 
the IRB/PB. 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
Death 
 
A life-threatening adverse event 
 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
A congenital anomaly/birth defect 


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 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org. All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org. All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
 
Subject’s initials 
 
Medical record number 
 
Disease/histology (if applicable) 
 
Protocol number and title 
Data needing to be entered: 
 
The date the adverse event occurred 
 
The adverse event 
 
The grade of the event 
 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
 
If the AE was expected 
 
The severity of the AE 
 
The intervention 
 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
 
If an amendment will need to be made to the protocol and/or consent form 


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 
If the SAE is an Unanticipated Problem 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office. 
 
 
 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their 
inclusion in the study. Participants will also be informed that they are free to withdraw from the study 
at any time. All participants must sign an IRB/PB-approved consent form indicating their consent to 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization component 
of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
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20.0 
APPENDICES 


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Appendix A – Pharmacology 
 
20.1. List of drugs metabolized by CYP2C9 
 
This list of CYP2C9 metabolizers are to be used with caution is not comprehensive and any 
questions should be reviewed with the pharmacist and discussed with the principle investigator. 
 
Table 20-1. List of drugs metabolized by CYP2C9 
Non-steroidal anti- 
inflammatory 
Oral hypoglycemics 
Angiotensin II blockers
Others 
Celecoxib 
Glipizide 
Losartan 
Fluvastatin 
Diclofenac 
Rosiglitazone 
Irbesartan 
Phenytoin 
Ibuprofen 
Tolbutamide 
Sulfamethoxazole 
Naproxen 
Tamoxifen 
Piroxicam 
Torsemide 
Warfarin 
 
 
20.2. List of drugs inhibiting or inducing CYP2E1 
 
This list of CYP2E1 modulators are to be used with caution is not comprehensive and any questions 
should be reviewed with the pharmacist and discussed with the principle investigator. 
 
Table 20-2. List of drugs inhibiting or inducing CYP2E1 
Inhibitors 
Inducers 
Disulfiram 
Ethanol 
Isoniazid 
 
 
20.3. List of P-gp substrates to be used with caution 
 
This list of P-gp substrates to be used with caution is not comprehensive and any questions should 
be reviewed with the pharmacist and discussed with the sponsor. 
 
Table 20-3. List of P-gp substrates to be used with caution 
P-gp substrates 
Aliskiren 
Ambrisentan 
Colchicine 
Dabigatran 
Digoxin 
Everolimus 
Fexofenadine 
Imatinib 
Lapatinib 
Maraviroc 
Nilotinib 


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Posaconazole 
Ranolazine 
Saxagliptin 
Sirolimus 
Sitagliptin 
Tolvaptan 
 
 
20.4. List of prohibited QT prolonging drugs 
 
Table 20-4. List of prohibited QT prolonging drugs 
Drug 
QT risk(*) 
Comment 
Amiodarone 
known risk for TdP 
TdP risk regarded as low 
Arsenic trioxide 
known risk for TdP 
Chloroquine 
known risk for TdP 
Chlorpromazine 
known risk for TdP 
Disopyramide 
known risk for TdP 
Dofetilide 
known risk for TdP 
Haloperidol 
known risk for TdP 
When given intravenously or at higher-than- 
recommended doses, risk of sudden death, QT 
prolongation and torsades increases. 
Ibutilide 
known risk for TdP 
Methadone 
known risk for TdP 
Pentamidine 
known risk for TdP 
Pimozide 
known risk for TdP 
Sensitive CYP3A substrate with narrow therapeutic index 
Procainamide 
known risk for TdP 
Quetiapine 
possible risk for TdP 
Sensitive CYP3A substrate 
Quinidine 
known risk for TdP 
Sensitive CYP3A substrate 
Sotalol 
known risk for TdP 
Tacrolimus 
possible risk for TdP 
Sensitive CYP3A substrate with narrow therapeutic index 
Terfenadine 
Known risk for TdP 
Sensitive CYP3A substrate with narrow therapeutic index 
Thioridazine 
Known risk for TdP 
Vardenafil 
possible risk for TdP 
Sensitive CYP3A substrate 
(*) Classification according to the QTdrugs.org Advisory Board of the Arizona CERT 
 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co- 
administered with a potent inhibitor of the respective enzyme. 
 
 
 
 
 
 
 
 
20.5. List of prohibited CYP3A inhibitors and inducers 
 
This list of prohibited CYP3A inhibitors and inducers are not comprehensive and any questions 
should be reviewed with the pharmacist and discussed with the sponsor. 


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Approval date: 24-Oct-2022 
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Table 20.5. List of prohibited CYP3A inhibitors and inducers 
Strong CYP3A 
inhibitors 
Moderate CYP3A inhibitors 
Strong CYP3A 
inducers 
Moderate CYP3A 
inducers 
clarithromycin 
amprenavir 
carbamazepine * 
bosentan 
conivaptan 
aprepitant 
fosphenytoin * 
efavirenz 
grapefruit juice 
diltiazem 
nevirapine 
etravirine 
indinavir 
atazanavir 
oxacarbazepine* 
felbamate * 
itraconazole 
cimetidine 
phenobarbital * 
modafenil 
ketoconazole 
ciprofloxacin 
phenytoin * 
nafcillin 
lopinavir with ritonavir 
darunavir with ritonavir 
primidone * 
pioglitazone 
nefazodone 
elvitegravir 
rifabutin 
rufinamide * 
nelfinavir 
erythromycin 
rifampin 
talviraline 
posaconazole 
fluconazole # 
ritonavir 
tipranavir 
saquinavir 
schisandra sphenanthera 
St. John's Wort 
topiramate * (>200 mg/day) 
star fruit juice 
tipranavir with ritonavir 
telithromycin 
verapamil 
voriconazole 
# fluconazole inhibition is dose-dependent and use may be considered on a case by case basis 
* These drugs are Enzyme Inducing Anti-Epileptic drugs of Medicine’s “Clinically Relevant” Table; and from [50].