Clinical trial NCT02091063
Conditions: Lymphoma Lymphoid Malignancies
Keywords: hematologic malignancies hodgkin hodgkins non-hodgkin non-hodgkins mantle cell lymphoma follicular lymphoma lymphoid malignancies
Sponsor: Jennifer Amengual
Start date: 2014-04-02; Completion date: 2019-05-05
Enrollment: 23 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This will be an open-label, single agent, multi-institutional phase Ib/II study of ACY-1215 for the treatment of patients with relapsed or refractory lymphoid malignancies. The target population will include patients with histologically confirmed relapsed or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma, with an expansion cohort of patients with mantle cell lymphoma.

The phase Ib will be conducted to determine the safety and tolerability of two dosing schedules of ACY-1215 monotherapy in patients with lymphoid malignancies. Patients will be accrued simultaneously to two dose cohorts (Arm A and Arm B) of ACY-1215. Selection into each cohort will occur by alternation. All patients will take the prescribed dose of ACY-1215 orally for 28 consecutive days. Patients enrolled into Arm A will take ACY-1215 160 mg daily (QD), whereas patients enrolled into Arm B will take ACY-1215 160 mg twice daily (BID). ACY-1215 will be supplied as a liquid for oral administration (PO). Each dose will be administered at least 1 hour after ingestion of food followed by at least 4 ounces of water. Patients will be instructed not to ingest food or other oral medication for at least 2 hours after each ACY-1215 dose. Frequency in phase II will be determined based on Phase Ib results.

Detailed description:
The emergence of epigenetic therapies has identified pan-class deacetylase (DAC) inhibitors as effective therapeutic agents for the treatment of lymphoma. While pan-class DAC inhibitors have led to FDA indications, clinical activity has been limited to the T-cell derived malignancies. The mechanism of action remains largely unknown and off-target effects lead to side effects including fatigue, gastrointestinal disturbances, and cytopenias. Recently, the development of isoform selective DAC inhibitors have opened the opportunity to investigate their mechanism. It is now recognized that DAC inhibitors not only have epigenetic properties, but have direct effects on transcription factors (p53), oncogenes (Bcl6), and protein degradation pathways (aggresome). Proteolysis occurs primarily through the ubiquitin-proteosome pathway. In states where this pathway is physiologically overwhelmed or therapeutically inhibited, the aggresome sequesters proteins for degradation. DAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the aggresome for proteosome-independent proteolysis. Inhibition of the aggresome activates the unfolded protein response (UPR) pathway, a cellular quality control mechanism with two primary functions: (1) to promote survival during cellular endoplasmic reticulum (ER) stress by chaperoning proteins back for re-folding and halting further transcription until homeostasis is restored and (2) to signal CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) mediated apoptosis when homeostasis cannot be reestablished\[9\]. While most cells depend on both branches of the UPR to coordinate protein folding, lymphocytes physiologically down-regulate the UPR-apoptosis pathway, specifically CHOP, to allow for generation of high affinity antibodies. In addition to initiating genetic abnormalities (translocations and point mutations) lymphomas inherit this biology, and thus gain a survival advantage.

It has been shown ACY-1215, an Histone Deacetylase 6 (HDAC6)-selective, orally active small-molecule enzyme inhibitor has had single agent activity in a panel of lymphoma cell lines and mouse models, and marked synergistic activity with several agents such as bortezomib, carfilzomib, and ibrutinib, unpublished data. ACY-1215 has been studied in vivo in models of multiple myeloma and lymphoma with marked activity both as a single agent and in combination with bortezomib. Therefore ACY-1215 will be investigated for treatment of lymphoma as a single agent leading to future studies evaluating its effects in combination with other targeted agents known to be active in lymphoma and synergistic with ACY-1215.

Arms: arm 1: Participants will receive Phase Ib Arm A: ACY-1215 QD or Arm B: ACY-1215 BID. Once Phase I dosing schedule has been determined. 160 mg BID dosing will be administered for Phase II.
Interventions: intervention 1: ACY-1215
Intervention descriptions: intervention 1: All patients will take the oral ACY-1215 160mg for 28 consecutive days on a 28-day treatment cycle. Each dose will be administered at least 1 hour after ingestion of food and followed by at least 4 ounces of water. Patients will be instructed not to ingest food or other oral medication for at least 2 hours after each ACY-1215 dose.

Protocol documents:
Prot_SAP_000.pdf: 
TITLE:   
A Phase IbII, Open-label, Multicenter Study of the Selective HDAC6 Inhibitor, ACY-1215, 
for the Treatment of Patients with Relapsed or Refractory Lymphoid Malignancies 
Coordinating Center:  
Columbia University Medical Center (CUMC) 
Participating Centers: 
H. Lee Moffitt Cancer Center & Research Institute 
Principal Investigator/ 
Jennifer Amengual, MD 
Study Chair: 
Assistant Professor of Medicine and Experimental Therapeutics 
Center for Lymphoid Malignancies 
Herbert Irving Comprehensive Cancer Center 
Columbia University Medical Center 
jea2149@columbia.edu 
Co-Investigators: 
Owen A. O’Connor, MD, PhD 
Professor of Medicine and Experimental Therapeutics 
Director, Center for Lymphoid Malignancies 
owenoconnor@columbia.edu 
Changchun Deng, MD, Ph.D. 
Assistant Professor of Clinical Medicine 
CD2448@columbia.edu 
Ahmed Sawas, MD 
Instructor in Clinical Medicine 
AS4386@columbia.edu 
Bijal Shah, MD  
Site Principal Investigator 
H. Lee Moffitt Cancer Center & Research Institute 
Bijal.Shah@moffitt.org  
CUMC Protocol #: 
AAAM4054 
Protocol Type / Version # / Version Date: Amendment 3 Ph II / Version 6 /23November2016
NCT02091063


 
 
 
 
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PROTOCOL SYNOPSIS 
 
Title: 
 
A Phase Ib/II, Open-label, Multicenter Study of the Selective HDAC6 Inhibitor, ACY-
1215, for the Treatment of Patients with Relapsed or Refractory Lymphoid Malignancies  
 
Study Design: 
 
This will be an open-label, single agent, multi-institutional phase Ib/II study of ACY-
1215 for the treatment of patients with relapsed or refractory lymphoid malignancies.  
The target population will include patients with histologically confirmed relapsed or 
refractory non-Hodgkin’s lymphoma or Hodgkin’s lymphoma, with an expansion cohort 
of patients with mantle cell lymphoma. 
  
Phase Ib Objectives: 
 
 Establish the safety of 2 dose schedules of ACY-1215 in patients with relapsed or 
refractory lymphoid malignancies treated with ACY1215.   
 
Phase II Objectives: 
 
Primary Objectives 
 
 
 
 Determine the overall response rates (CR plus PR) in patients with relapsed or refractory 
lymphoid malignancies treated with ACY1215.   
 Determine the progression free survival (PFS) and Time to Treatment Failure (TTF) in 
patients with relapsed or refractory lymphoid malignancies treated with ACY1215.   
 Determine the duration of response (DOR) in patients with relapsed or refractory 
lymphoid malignancies treated with ACY1215. 
 
Secondary Objectives 
 
 Determine the safety and tolerability of ACY-1215 in patients with relapsed or refractory 
lymphoid malignancies. 
 Evaluate the pharmacokinetic (PK) profile of ACY-1215 as a single agent in patients 
with lymphoid malignancies. 
 Evaluate and compare pharmacodynamic (PD) endpoints with PK endpoints. Proposed 
PD markers of target effect in paired pre- and post ACY-1215 tissue biopsies peripheral 
blood, and serum samples would include: HDAC6, acetylated-α-tubulin, total 


 
 
 
 
iv 
polyubiquinated proteins, GRP-78, CHOP, XBP-1, IL6, IL10, STAT3, AKT, NFkB level 
of expression, and Treg levels 
 Conduct Magnetic Resonance Spectroscopy Imaging (MRS) for the detection of early 
signal of response and predict overall response.   
 
Target Population 
 
Patients with relapsed or refractory non-Hodgkin’s lymphoma and Hodgkin’s lymphoma 
 
Inclusion Criteria  
 
1. Patients must have histologically confirmed relapsed or refractory Non-Hodgkin’s 
Lymphoma or Hodgkin’s Lymphoma (WHO criteria), for which they are unwilling or 
unable to undergo an autologous stem cell transplant. Patients may have relapsed after 
prior stem cell transplant. 
2. Must have relapsed or refractory disease. No upper limit to number of prior therapies.  
3. Patients must have measurable disease  
4. Patients must be age ≥ 18. 
5. Patients must be ECOG performance status ≤ 2. (See definition in Appendix). 
6. Patients must have adequate organ and marrow function. 
7. Patients must utilize adequate contraception. 
8. Patients must have the ability to understand and sign informed consent. 
 
Exclusion Criteria 
 
1.  Prior Therapy 
a. Patients who have had chemotherapy or radiotherapy within 2 weeks of study 
drug treatment or those who have not recovered from adverse events due to agents 
administered   
b. No monoclonal antibody within 3 months unless evidence of disease progression. 
2. Patients may not be receiving any other investigational agents. 
3. Patients with known central nervous system metastases, including lymphomatous 
meningitis  
4. Any known cardiac abnormalities such as: 
- 
Congenital long QT syndrome 
- 
QTc interval ≥ 500 milliseconds; 
5. Uncontrolled inter-current illness 
6. Pregnant or nursing women  
7. Patient is known to be Human Immunodeficiency Virus (HIV)-positive  


 
 
 
 
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8. Patients with active Hepatitis A, Hepatitis B, or Hepatitis C infection 
9. Patient has a history of surgery that would interfere with the administration or absorption 
of the oral study drugs 
Treatment Plan 
 
Phase Ib: 
 
Patients will be accrued sequentially to two dose cohorts (Arm A and Arm B) of 
ACY1215.  Upon completion of enrollment of 3 patients to Arm A and a safety 
assessment has occurred, patients will be allowed to be enrolled to Arm B.  All patients 
will take the assigned dose of ACY1215 for 28 consecutive days.  Patients enrolled into 
Arm A will take ACY1215 160mg once daily, whereas patients enrolled into Arm B will 
take ACY1215 160mg twice daily. ACY-1215 will be supplied as a liquid for oral 
administration (PO).  Each dose will be administered at least 1 hour after ingestion of 
food followed by at least 4 ounces of water.  Patients will be instructed not to ingest food 
or other oral medication for at least 2 hours after each ACY-1215 dose. 
 
Phase II: 
 
All patients will take the assigned dose of ACY1215 for 28 consecutive days.  The 
schedule of ACY1215 will be determined based on the safety data from the Phase Ib.  
Recommended Phase II dose will be based on a discussion with the sponsor and 
collaborating investigators, with a pre-planned intent to select the schedule that allows 
the highest dose intensity safely.  ACY1215 will be supplied as a liquid for oral 
administration (PO).  Each dose will be administered at least 1 hour after ingestion of 
food followed by at least 4 ounces of water.  Patients will be instructed not to ingest food 
or other oral medication for at least 2 hours after each ACY-1215 dose. 
 
Duration of Treatment 
 
There is no limit to the number of cycles of therapy. Patients may continue on treatment 
until they develop progressive disease (PD) or experience an unacceptable toxicity that 
precludes further treatment. 
 
After discontinuation of therapy, patients will be followed on an every 3 month 
(+/- 1 week) basis for 1 year or until development of progressive disease or initiation of 
alternative therapy in order to determine the duration of response. 
 
Patients will be treated until one of the following events: 
 
 
Disease progression 
 
Unacceptable adverse event(s) 
 
Withdrawal of consent 


 
 
 
 
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 
General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
An event that in the judgment of the treating physician warrant’s discontinuation of 
therapy.  
 
Termination of the study 
 
Study Endpoints 
 
Phase Ib: 
 
 
The primary endpoint of the study is: 
 Establish the safety and tolerability of ACY1215 in two dosing schedules. 
 
 
Phase II:  
 
 
The primary endpoint of the study is: 
 The anti-tumor activity of ACY-1215, as measured by: 
o Objective response rate (complete response [CR] + partial response [PR]) assessed 
according to International Harmonization Project revised Criteria (2007)  
 
 
 
Secondary endpoints of the study are to: 
 Define the duration of response 
 Define the rate of progression free survival 
 Define safety and adverse events 
 Define the exposure response analyses including biomarkers relating to intracellular 
protein acetylation. 
 Describe the Single- and multiple-dose ACY-1215 pharmacokinetic profile. 
 Describe changes in MRS signals with response to study drug 
 
Sample Size 
 
Phase Ib: 
 
Three patients will be sequentially enrolled in one of two cohorts: Arm A and Arm B for a total 
of six patients (3 in each arm).  If ≤33% of patients (N≤1) experiences a dose limiting toxicity 
(DLT) in a cohort, the cohort will be expanded to 6 patients (3+3).  If there are ≤ 33% (N≤ 2 
DLTs), the cohort will be further expanded to a total of 10 patients (3+3+4).  The maximum total 
number of patients for both Arms A and B with full expansions will total of 20.   If more than 1/3 
or 2/6 patients experience a DLT, there will be no expansion. 
 
Phase II: 
 
Utilizing the Simon 2 Stage Minimax design, an estimated 40 patients will be needed to 
determine efficacy at a power of 0.80 and type I error of 0.05. For Stage I, 22 patients 


 
 
 
 
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will be enrolled of which 2 must achieve a response to allow for recruitment of patients 
into Stage 2.  Stage 2 will enroll 18 patients of which 8 responses would be needed to 
attain an efficacy of 25%. An expansion cohort of 20 patients with relapsed or refractory 
mantle cell lymphoma patients will be assessed to evaluate efficacy in this subtype. The 
total number of patients accrued to the Phase II component of the study will equal 60.   
 
Safety 
 
Patients will be monitored carefully for the development of adverse events as well as 
clinical and/or radiographic evidence of disease response.  Adverse events will be 
evaluated according to criteria outlined in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
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Figure 1: Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening: 
History, Physical, Performance Status, Blood tests, 
PET/CT scan, and biopsy for correlative studies 
Intervention: 
Evaluation in First Cycle: 
Safety Evaluations Days 1, 8, 15 
Laboratory Evaluation Days 1 
 
Evaluations in Future Cycles: 
Safety Evaluations Day 1 
Laboratory Evaluation Day 1 
PET/CT scan after cycles 2 and 6, then at the 
discretion of the treating physician with an interval 
not more than 6 months 
Discontinuation: 
Disease progression, undercurrent illness, 
unacceptable adverse events, pregnancy, patient 
decides to withdraw, general or specific changes in 
the patient’s condition that render them 
unacceptable for further treatment in the judgment 
of the investigator 
Phase Ib: 
Arm A: ACY-1215 160 mg PO daily days 1-28 
OR 
Arm B: ACY-1215 160 mg PO BID days 1-28 
Phase II: 
ACY-1215 160 mg PO days 1-28 
Schedule determined by Phase Ib results 


 
 
 
 
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TABLE OF CONTENTS 
 
Page 
1. OBJECTIVES ..........................................................................................................................1 
 
1.1  
Phase Ib…………………………..……………………….…………………………..1 
 
1.2  
Phase II…………………………………………………………...…………………..1 
 
 
 
2. BACKGROUND ......................................................................................................................1 
 
2.1 
Background on lymphoid Malignancies  ...................................................................1 
 
2.2 
ACY-1215......................................................................................................................2 
 
2.3  
Rationale for Phase Ib Study Design……………………………………………....11 
 
 
3. PATIENT SELECTION........................................................................................................12 
 
3.1  
Inclusion Criteria for Lymphoma  ...........................................................................12 
 
3.2  
Exclusion Criteria ......................................................................................................13 
 
3.3  
Inclusion of Women and Minorities .........................................................................13 
 
3.4  
Source of Patients.......................................................................................................13 
 
4. REGISTRATION PROCEDURES ......................................................................................13 
 
4.1 
General Guidelines ....................................................................................................13 
 
4.2 
Screening…………………………………………………………………………….14 
 
4.3 
Informed Consent ......................................................................................................15 
 
4.4 
Registration Process ..................................................................................................15 
 
4.5 
Withdrawal and Replacement of Patients………………………………….……..16 
 
5. TREATMENT PLAN ............................................................................................................16 
 
5.1  
Overall Plan and Design of Study  ...........................................................................16 
 
5.2  
Duration of Therapy ..................................................................................................22 
 
5.3 
Patient Adherence to Protocol Schedule ..................................................................22 
 
5.4  
Criteria for Removal from Study .............................................................................23 
 
5.5  
Duration of Follow Up ...............................................................................................23 
 
6. DOSING DELAYS/DOSE MODIFICATIONS ..................................................................23 
 
6.1  
Dose Delays .................................................................................................................23 
 
6.2  
Resuming Administration of Study Drug ................................................................23 
 
6.3 
Dose Modifications .....................................................................................................23 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................26 
 
7.1 
Safety Evaluation Procedures ...................................................................................27 
 
7.2 
Pregnancy   …………………………………………………………………………27 
 
7.3 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................28 
 
7.4 
Adverse Event Characteristics and Reporting ........................................................29 
 
 
8. CORRELATIVE STUDIES ..................................................................................................32 
 
8.1  
Pharmacokinetic Studies ...........................................................................................32 


 
 
 
 
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8.2  
Pharmacodynamic Studies ........................................................................................32 
 
8.3  
Optional Magnetic Resonance Spectroscopy Imaging ...........................................33 
 
9. STUDY CALENDAR ............................................................................................................36 
 
10. MEASUREMENT OF EFFECT ..........................................................................................37 
10.1 
Imaging Studies .........................................................................................................37 
10.2 
Bone Marrow Examination ......................................................................................37 
10.3 
Assessment of Disease Response……………….…………………………………..37 
10.4  
Response Criteria…………………………………………………………………..38 
 
11.  DATA REPORTING / REGULATORY REQUIREMENTS ..........................................40 
 
11.1 
Data Reporting ...........................................................................................................40 
 
11.2 
Data Safety Monitoring Board……………………………………………………..40 
 
11.3 
Investigator Reporting Responsibilities and Compliance………………………..40 
 
11.4 
Study Auditing………………………………………………………………………41 
 
11.5 
Protocol Amendments………………………………………………………………41 
 
 
12. STATISTICAL CONSIDERATIONS .................................................................................41 
 
12.1 
Statistical Methods .....................................................................................................41 
 
12.2 
Disposition of Patients ...............................................................................................42 
 
12.3 
Analysis of Primary and Secondary Endpoints ......................................................42 
 
12.4 
Demographics and Baseline Characteristic .............................................................43 
 
12.5 
Extent of Exposure…………………………………………………………………43 
 
12.6 
Concomitant Medications……………………………………………… …………43 
 
12.7 
Safety Analysis………………………………………………………………………43 
 
12.8 
Population for Analysis…………………………………………………………….44 
 
12.9 
Analysis Schedule………………………………   …………………………………45 
 
12.10 Procedures for Handling Missing, Unused, and Spurious Data  ………………..45 
 
12.11 Procedures for Reporting Deviations to Original Statistical Analysis   ………..45 
 
13. ACCRUAL RATE   ………………………………………………………………………..45 
 
14. ADMINISTRATIVE REQUIREMENTS…………………………………………………45 
 
14.1 
Good Clinical Practice…   …………………………………………………………45 
 
14.2 
Ethical Considerations   ……………………………………………………………46 
 
14.3 
Patient Information and Informed Consent  ……………………………………..46 
 
14.4 
Patient Confidentiality   ……………………………………………………………46 
 
14.5 
Protocol Compliance  ………………………………………………………………46 
 
14.6 
Direct Access to Source of Data  …………………………………………………..46 
 
14.7 
Case Report Form Completion ……………………………………………………47 
 
14.8 
Record Retention……………………………………………………………………47 
 
14.9 
Liability and Insurance…………………………………………………………….47 
 
14.10 Publication, Study Findings, and Use of Information……………………………48 


 
 
 
 
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15. REFERENCES .......................................................................................................................49 
 
APPENDIX……………………………………………………………………………………51 
 
  
 
 
 


 
 
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1. OBJECTIVES 
 
1.1 Phase Ib: 
 
1.1.1 Primary Objectives 
 Establish the safety of 2 dose schedules of ACY-1215 in patients with relapsed or 
refractory lymphoid malignancies treated with ACY1215.   
 
1.2 Phase II: 
 
1.2.1. Primary Objectives 
 
 
 
 Determine the overall response rates (CR plus PR) in patients with relapsed or refractory 
lymphoid malignancies treated with ACY1215.   
 Determine the progression free survival (PFS) and time to treatment failure (TTF)  in 
patients with relapsed or refractory lymphoid malignancies treated with ACY1215.   
 Determine the duration of response (DOR) in patients with relapsed or refractory 
lymphoid malignancies treated with ACY1215. 
 
1.2.2       Secondary Objectives 
 Determine the safety and tolerability of ACY-1215 in patients with relapsed or refractory 
lymphoid malignancies. 
 Evaluate the pharmacokinetic (PK) profile of ACY-1215 as a single agent in patients 
with lymphoid malignancies. 
 Evaluate and compare pharmacodynamic (PD) endpoints with PK endpoints. Proposed 
PD markers of target effect in paired pre- and post ACY-1215 tissue biopsies peripheral 
blood, and serum samples would include: HDAC6, acetylated-α-tubulin, total 
polyubiquinated proteins, GRP-78, CHOP, XBP-1, IL6, IL10, STAT3, AKT, NFkB level 
of expression, and Treg levels. 
 Conduct Magnetic Resonance Spectroscopy Imaging (MRS) for the detection of early 
signal of response and predict overall response. 
 
2. 
BACKGROUND 
 
2.1 
 Background on Lymphoid Malignancies 
 
Lymphoma is a heterogeneous group of malignancies that are derived from lymphocytes at 
different stages of development.  The 2008 World Health Organization (WHO) now recognizes 
nearly 70 subtypes of lymphoma, with many of these subtypes being further subdivided [1].   
These diseases include  some of the fastest growing cancers known to science (Burkitt’s 
lymphoma, lymphoblastic  lymphoma/leukemia) as well as some of the most indolent (small 
lymphocytic  lymphoma, follicular lymphoma, and marginal zone lymphoma).  This diversity of 
biology poses challenges in diagnosis, as well as identifying drugs that might be particularly 


 
 
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active in specific subtypes. 
In the United States, non-Hodgkin lymphomas represent 4-5% of all new cancer cases, and are 
the fifth leading cause of cancer death. According to Surveillance Epidemiology and End 
Results(SEER) registries, it is estimated that nearly 80,000 men and women will be diagnosed 
and over 20,000 will die of lymphoma in 2012[2].  It is estimated that about 9,000 of these cases 
with be diagnosed with Hodgkin lymphoma, while the remaining 70,000 will be diagnosed with 
non-Hodgkin lymphoma.  The overall survival in patients with Hodgkin lymphoma is 
approximately 90%, whereas for non-Hodgkin lymphoma is less than 70%.  An evaluation of the 
distribution of non-Hodgkin lymphoma subtypes was performed on the 114,548 cases of 
lymphoid neoplasms diagnosed between 1992-2001 in the SEER registries, of which 87,666 
were B-cell lymphoid neoplasms, 6,228 were considered T/Natural Killer (NK) cell neoplasms, 
and about 10,042 were attributed to Hodgkin’s disease [1].  As a group, the diffuse, large-cell 
lymphomas (DLBCL) account for approximately one-third of all NHLs. 
The International Prognostic Index, and subtype specific prognostic scores (for example FLIPI,  
MIPI, and IPSS) are used for prognostic purposes to risk stratify patients.  Despite many 
advances in the care of patients with lymphoma, many subtypes still carry a poor prognosis, and 
advances in treatment are still needed.  Patients with relapsed or refractory disease often develop 
resistance and do not respond to standard chemotherapy.  Novel therapies are needed to 
overcome this resistance, increase complete response rates, thus increase the chances to 
potentially bridge some patients to definitive therapy, like stem cell transplant.  For those 
patients where there is no curative option, an increasing number of patients are living with 
quiescent or stable disease due to the use of targeted therapies. 
 
2.2  
ACY-1215 
 
2.2.1 Overview 
The HDACs are a family of enzymes consisting of 4 distinct classes.  Class I (HDAC1, 2, 3, and 
8), Class IIa (HDAC4, 5, 7, and 9) and Class IIb (HDACs 6 and 10), Class III (sirtuins 1-7) and 
Class IV (HDAC11).  Classes I, II, and IV are zinc-dependent deacetylases, whereas Class III are 
dependent on the co-factor nicotinamide adenine dinucleotide (NAD). The function of HDACs 
has been largely attributed to their effects on gene transcription through modification of histone 
tail acetylation and regulation of chromatin condensation [3-5].  More recently, it has become 
apparent that HDACs play a critical role in the regulation and function of lysine acetylation of 
non-histone proteins through post-translational modifications affecting many cellular functions 
[6-8]. The breadth of post-translational regulation in many proteins of diverse functional roles is 
on a par with that achieved through phosphorylation/dephosphorylation of hydroxyl groups by 
kinases/phosphatases. Additionally, several HDACs, including HDAC6, are localized to the 
cytoplasm of cells while others can “shuttle” between the nucleus and cytoplasm [9-11].  
HDACs are thus substantially more diverse in their intracellular mechanisms of action than is 
implied by the “histone” in their name. 
The development of small-molecule HDAC inhibitors has previously focused on the 
antiproliferative effects of HDAC inhibition by modification of gene transcription.  This initial 
focus has led to the approval of 2 HDAC inhibitor drugs for the treatment of cutaneous T-cell 
lymphoma and peripheral T-cell lymphoma (vorinostat and romidepsin) [12-14].  Vorinostat, 
which belongs to the structurally class of HDACs referred to as hydroxamic acids,  were 


 
 
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previously considered to be nonselective across Class I and Class II, while the ortho 
aminoanilide inhibitors (e.g., MS-275, Syndax Pharmaceuticals) are relatively more semi-
selective for Class I.  Recently, it has been demonstrated that the hydroxamate-based inhibitors 
are relatively more selective for Class I and the Class IIb enzyme HDAC6, while having 
relatively less activity against  Class IIa HDAC enzymes[3]. 
HDAC6 has been shown to be crucial in the degradation of misfolded proteins aggregates as an 
alternative to the ubiquitin-proteasome degradation pathway[15].  Failure of a cell to remove 
accumulated misfolded protein aggregates leads to apoptosis.  HDAC6 mechanistically has 
two direct roles in aggresome formation[16,17]. The deacetylase activity of HDAC6 directly 
binds misfolded protein aggregates and tubulin, along which protein complexes are transported 
to the microtubule organizing center where aggresomes form.  HDAC6 acts as an adaptor protein 
binding polyubiquitinated proteins and dynein, an ATP dependent component of the motor 
complex that transports protein along the microtubules.  
Additionally, HDAC6 modulates the acetylation state of a number of other important proteins, 
one of which is GRP78, a molecular chaperone required for stability and function of numerous 
proteins[11, 17-19]. The unfolded protein response (UPR) is a critical mechanism employed by 
all cells to recognize the misfolded protein burden, and either chaperone these proteins to the 
aggresome or proteasome for processing, or alternatively, if the misfolded protein burden is too 
high, to initiate apoptosis.  Inhibition of HDAC6 leads to activation of the UPR and ultimately 
programmed cell death.   Increased acetylation of GRP78, enforced by inhibition of HDAC6, 
leads to its dissociation from its cognate inhibitors PERK, p-IRE-1, and ATF6, leading to the 
induction of CHOP-mediated cell death.  GRP78 (a heat shock protein and chaperone), PERK, p-
IRE-1, ATF6, and CHOP are thus all potential biomarkers of activity given their role as 
molecular regulators of the UPR.    HDAC6 appears to have a similar role in modulating the 
acetylation state of Hsp90, Hsp70 and other members of the heat shock protein family. 
In theory, the therapeutic index for compounds modulating protein disposal is influenced, at least 
to some extent, by the metabolic states and increased protein dynamics of the target cells.  
Malignancies derived from cells of the lymphoid lineage appear to be particularly sensitive to 
these types of strategies, given the approval of drugs like bortezomib in lymphoma and multiple 
myeloma.  Lymphocytes undergo somatic hypermutation and class switch recombination to 
generate specific antibodies.  These cells physiologically produce a large volume of proteins 
compared to other tissue types given their role in producing immunoglobulins. As such, the 
development of HDAC6 and other drugs affecting protein dynamics have had the most 
significant impact on diseases like myeloma and B-cell lymphomas.     
While the mechanisms of action of a drug like bortezomib are considered broad and at times 
difficult to precisely define, it is clear that the proteasome inhibitor appears to enhance the 
activity of virtually every drug it has been studied with.  One example is the incorporation of 
bortezomib with the regimen EPOCH for the treatment of activated B-cell like (ABC) diffuse 
large B-cell lymphoma, as recently demonstrated by Wilson et al[20]. Bortezomib has also been 
shown to be synergistic with pan-class HDAC inhibitors such as vorinostat in DLBCLand 
multiple myeloma [21,22] and in combination with romidepsin and belinostat in mantle cell 
lymphoma [23].  The evidence of anticancer activity of HDAC6 inhibitors in animal disease 
models, coupled with the evidence that HDAC6 -/- genetic knockout animals have a normal life 
span [24] whereas Class I -/- animals are nonviable, suggests that selective HDAC6 inhibitors 
have the potential for a substantially reduced side-effect profile versus current HDAC inhibitor 
drugs and drug candidates, while retaining the inhibition of the aggresome pathway and 


 
 
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potentiating the UPR leading to marked anticancer effectiveness. 
It has been shown ACY-1215, an HDAC6-selective, orally active small-molecule enzyme 
inhibitor has had single agent activity in a panel of lymphoma cell lines and mouse models, and 
marked synergistic activity with several agents such as bortezomib, carfilzomib, and ibrutinib, 
unpublished data.  ACY-1215 has been studied in vivo in models of multiple myeloma and 
lymphoma with marked activity both as a single agent and in combination with bortezomib [17].  
Therefore ACY-1215 will be investigated for treatment of lymphoma as a single agent leading to 
future studies evaluating its effects in combination with other targeted agents known to be active 
in lymphoma and synergistic with ACY-1215. 
 
2.2.2 Rationale for the Study 
 
Hypothesis and Preliminary Data 
The emergence of epigenetic therapies has identified pan-class deacetylase (DAC) inhibitors as 
effective therapeutic agents for the treatment of lymphoma. While pan-class DAC inhibitors 
have led to FDA indications, clinical activity has been limited to the T-cell derived malignancies.  
The mechanism of action remains largely unknown and off-target effects lead to side effects 
including fatigue, gastrointestinal disturbances, and cytopenias.  Recently, the development of 
isoform selective DAC inhibitors have opened the opportunity to investigate their mechanism.  It 
is now recognized that DAC inhibitors not only have epigenetic properties, but have direct 
effects on transcription factors (p53), oncogenes (Bcl6), and protein degradation pathways 
(aggresome) [5-8].  Proteolysis occurs primarily through the ubiquitin-proteosome pathway.  In 
states where this pathway is physiologically overwhelmed or therapeutically inhibited, the 
aggresome sequesters proteins for degradation.  DAC6 is a class IIb deacetylase that facilitates 
misfolded protein transport to the aggresome for proteosome-independent proteolysis. Inhibition 
of the aggresome activates the unfolded protein response (UPR) pathway, a cellular quality 
control mechanism with two primary functions: (1) to promote survival during cellular 
endoplasmic reticulum (ER) stress by chaperoning proteins back for re-folding and halting 
further transcription until homeostasis is restored and (2) to signal CHOP (C/EBP-homologous 
protein) mediated apoptosis when homeostasis cannot be reestablished[9].  While most cells 
depend on both branches of the UPR to coordinate protein folding, lymphocytes physiologically 
down-regulate the UPR-apoptosis pathway, specifically CHOP, to allow for generation of high 
affinity antibodies.  In addition to initiating genetic abnormalities (translocations and point 
mutations) lymphomas inherit this biology, and thus gain a survival advantage.  Given these 
principles, our hypothesis is: If lymphomas generate high levels of misfolded proteins, then 
pharmacologic up-regulation of the UPR through DAC6 inhibition, could lead to 
accumulation of misfolded proteins and ultimately increased apoptosis. 
 
ACY1215 is currently being evaluated in the clinical setting for the treatment of multiple 
myeloma.  Little is known about its effectiveness in lymphoma.  In preclinical models of 
lymphoma, we have demonstrated that selectively targeting DAC6 with ACY1215 inhibits 
sequestration of misfolded proteins by disrupting transport to the aggresome through acetylation 
of α-tubulin.  It also leads to the acetylation of the key ER-resident chaperone protein, GRP78.  
This releases and activates the UPR signaling protein, PERK, which in turn promotes 
transcription of the pro-apoptotic transcription factor, CHOP.  This dynamic process, under the 
influence of ACY1215, shifts toward the pro-apoptotic pathway and ultimately cell death.  
Interestingly, cells most sensitive to ACY1215 expressed higher baseline levels of pro-apoptotic 


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6
protein degradation pathways with both ACY1215 and bortezomib has synergistic antitumor 
activity in vitro and enhanced all effects on modulation of the UPR and apoptosis.   
 
In addition, MRS imaging will be compared to biomarker and clinical response data.  Tumor 
metabolism has long been of interest as a potential predictor of response to chemotherapy.  The 
intra-tumoral content of the phospholipid-related metabolites phosphoethanolamine (Etn-P) and 
phosphocholine (Cho-P) has been shown to be increased in clinically aggressive malignant 
disease and to decrease with clinical response to anticancer therapy, suggesting that phospholipid 
metabolism may be an intrinsic component of oncogenesis [25, 26] This is significant because 
molecular changes can be detected at a significantly earlier time points than clinical or standard 
radiologic response. Novel radiation-free imaging represents an opportunity to detect early 
signals of response.  Once validated, this modality could compliment standard imaging 
modalities adding another dimension of information.  
 
The approval of bortezomib in MCL provides a basis for further study of these approaches in this 
disease, potentially establishing future regulatory approaches combining ACY1215 plus 
bortezomib verses alone.  The proposed study will establish important single agent activity of 
ACY1215, and will pave the way for thinking about future combination studies, how to power 
them from a statistical perspective, and how to design potential regulatory studies in diseases like 
MCL.  Establishing biomarkers for response to this isoform selective DAC6 inhibitor will help 
elucidate the mechanism of action of ACY-1215 in lymphoma and might lead to understanding 
of the optimal patient populations to benefit from this therapy. 
 
2.2.3 Pharmaceutical Information 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7. 
 
2.2.4  ACY-1215 Chemical Structure 
 
Figure 3: Chemical Structure 
 
The molecular formula of ACY-1215 is C24H27N5O3, its molecular weight is 433.5, and its 
chemical 
name 
is: 
2-(Diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-pyrimidine-5-
carboxamide. 
2.2.5 Product description:   
ACY-1215 is a histone deacetylase (HDAC) inhibitor that has not been assigned either an 
International Nonproprietary Name (INN) or a United States Adopted name (USAN).  The active 
pharmaceutical ingredient is a white to off white crystalline solid with a melting point of 


 
 
7
approximately 192oC. ACY-1215 is highly soluble in dimethyl sulfoxide, soluble in methanol, 
and poorly soluble in acetone, chloroform, and water at less than 1 mg/mL. The label attached to 
each vial contains the appropriate information, including product name and amount, lot number, 
directions for storage, date of manufacture, name of Sponsor, and the following statement: 
“Caution: New Drug--Limited by Federal (or United States) law to investigational use.” 
Study drug labels will not contain any statement that is false or misleading in any manner or 
represent that the study drug is safe or effective for the purposes for which it is being 
investigated.   
 
2.2.6 Solution preparation: 
 
ACY-1215 will be supplied by Acetylon Pharmaceuticals as a liquid for oral administration in  
20mL clear type I glass vials.  Each vial will contain 15 mL of a 12 mg/mL solution for a total of  
180 mg per bottle.   
 
2.2.7 Storage requirements:  
ACY-1215 will be stored at -20ºC.  Additional storage conditions and dose preparation 
instructions will be provided in detail within the Pharmacy Manual. All study drug must be 
stored in a safe and locked place with no access by unauthorized personnel. 
 
2.2.8 Administration 
 
ACY-1215 should be handled in a manner consistent with recommended safe procedures for 
handling cytotoxic drugs.  
 
2.2.9 Supplier 
Acetylon Pharmaceuticals, INC will supply ACY-1215 to study participants at no charge. 
 
2.2.10 Agent Accountability 
Accountability for ACY-1215 at the study center is the responsibility of the Investigator.  The 
Investigator will ensure that the study drug is used only in accordance with this protocol.  Where 
allowed, the Investigator may choose to assign some of the drug accountability responsibilities to 
a pharmacist or other appropriate individual.  Drug accountability records indicating the drug’s 
delivery date to the study center, inventory at the study center, use by each patient, and return to 
Sponsor or designee (or disposal of the drug, if approved by Sponsor) will be maintained by the 
study center.  These records will adequately document that the patients were provided the doses 
as specified in the protocol and should reconcile all study drug received from Acetylon.  
Accountability records will include dates, quantities, batch/serial numbers, expiration dates (if 
applicable), and patient numbers.  The Sponsor or its designee will review drug accountability at 
the study center on an ongoing basis during monitoring visits. 
All unused and used study drug will be retained at the study center until inventoried by the 
monitor.  All used, unused or expired study drug will be returned to Acetylon or if authorized, 
disposed of at the study site and documented.  All material containing ACY-1215 will be treated 
and disposed of as hazardous waste in accordance with governing regulations. 


 
 
8
2.2.11  Pre-Clinical Pharmacology 
 
2.2.11.1 In Vitro Activity 
ACY-1215 is a potent inhibitor of HDAC6 activity (50% inhibitory concentration [IC50] 5.7 nM) 
and is ~10-fold less active against Class I HDAC enzymes, HDAC1, HDAC2 and HDAC3 and 
has minimal activity against other HDAC enzymes including HDAC4, 5, 7, 9, 11, and sirtuin 1 
and 2.  In addition the two major metabolites of ACY-1215 have minimal activity against 
HDAC6.  ACY-1215 in the submicromolar (µM) concentration range increases the level of 
acetylated -tubulin, a key therapeutic target of HDAC6 inhibition in multiple myeloma and 
lymphoma cells.  ACY-1215 can also increase the level of acetylated -tubulin in human 
peripheral mononuclear cells (PMBCs) in a dose-dependent and time-dependent manner.  
ACY-1215 can inhibit the growth of lymphoma cell lines (OCI-Ly1, OCI-Ly7, OCI-Ly10, Su-
DHL2, Su-HDL4, Su-DHL6, HBL-1, Jeko, JVM-2, Rec-1, Maver, HH, H9, Sup-T1, CCL-119), 
in the 0.3-2 µM concentration range.  The antiproliferative activity of ACY-1215 can overcome 
the growth supportive activity of growth factors such as Il-6 and IL-10, while having minimal 
impact on normal cells such activated PBMCs.  In addition ACY-1215 (0.2 -1.5 μM) displays 
synergistic antiproliferative activity in lymphoma cells with the proteosome inhibitor bortezomib 
(1 – 5nM).  At the molecular level the synergistic activity is demonstrated by the increase in 
molecular markers of apoptosis such as cleaved PARP and caspases, and increased levels of 
polyubiquitinated proteins, as well as substantially increasing the proportion of lymphoma cells 
in apoptosis (determined by propidium iodide and Annexin V staining).  In addition, there is 
modulation of the UPR response with increase of GRP78, PERK, p-eIF2a, p-IRE1, spliced XBP-
1 in cells treated with ACY-1215 alone and in combination with bortezomib.   
 
2.2.11.2  In Vivo Activity 
In the plasmacytoma mouse model of human MM, bortezomib was administered intravenously 
twice weekly and ACY-1215 was administered daily for 5 days each week over a period of two 
weeks to maintain exposure of the HDAC6 inhibitor during and after administration of 
bortezomib.  ACY-1215 at 50 and 75 mg/kg (once daily [QD] × 5) in combination with 
bortezomib at 0.5 mg/kg (2 × week), demonstrated significant suppression of tumor growth and 
increased median survival than either agent alone.  Further, ACY-1215 showed single agent 
activity in suppression of tumor growth at 50 mg/kg.  ACY-1215 as a single agent or in 
combination with bortezomib was well-tolerated and the MTD level of ACY-1215 is equal to or 
greater than 75 mg/kg in the plasmacytoma model.  
In a disseminated skeletal disease mouse model of multiple myeloma bortezomib was 
administered once per week and ACY-1215 was administered daily for 5 days each week with 
bortezomib delivered on Day 2 of each week over a two week period.  The combination of ACY-
1215 (10 – 75 mg/kg, QD × 5) and bortezomib (1 – 1.5 mg/kg, 1 × week) demonstrated 
significant suppression of tumor growth and increased median survival compared to either agent 
alone or vehicle.  Single agent activity of ACY-1215 was observed, but at a higher dose level of 
200 mg/kg compared to 50 mg/kg in the plasmacytoma model.  ACY-1215 was well-tolerated as 
a single agent in tumor bearing animals and in combination with bortezomib in preliminary 
safety studies in non-tumor bearing animals.  Variable incidence of toxicity resulting in 
premature death was observed in tumor bearing animals at higher dose levels of ACY-1215 (≥30 
mg/kg) in combination bortezomib (1 or 1.5 mg/kg).  These effects were observed in the first and 


 
 
9
second treatment cycles and only when disseminated tumor was present in animals, suggesting 
the toxicity may in part be related to the significant suppression of tumor growth.  Preliminary 
results comparing tumor bearing to non-tumor bearing animals suggest a greater impact on renal 
function in the former when treated with a high dose of ACY-1215 in combination with 
bortezomib.  Overall ACY-1215 had an MTD dose level of ~200 mg/kg as a single agent and 
MTD level of ≥10 mg/kg and <30 mg/kg in combination with bortezomib in animals bearing 
disseminated tumor. 
In a lymphoma xenograft model of diffuse large B-cell lymphoma (OCI-Ly10) mice treated with 
ACY-1215 50 mg/kg days 1-5, 8-12, 15-19 exhibited decreased tumor burden compared to 
control miceand equal delay of tumor growth compared to single agent bortezomib 0.5 mg/kg 
days 1, 8, 11..  Mice tolerated the therapy well with weight loss exceeding 10% within the first 5 
days of therapy which quickly resolved to baseline.  Mice treated with the combination of 
ACY1215 in combination with bortezomib had statistically significant synergistic tumor growth 
delay and a survival advantage after one cycle of therapy. 
 
2.2.12  Safety Pharmacology 
In an extensive survey of diverse enzyme functions, including kinases, receptors and ion 
channels, no significant interactions (inhibition > 50% at 10 µM) were noted, with the exception 
of a mild to moderate inhibition (IC50 1.3 µM) of the enzyme 5-lipoxygenase. 
ACY-1215 has no activity against the human ether-à-go-go related gene (hERG) channel in vitro 
at 10 µM and showed 18% inhibition at the solubility limit of ~62 µM, i.e. 12 – 60 fold higher 
than the expected efficacious concentration.  
In beagle studies,  dose levels of 10, 30, and 60 mg/kg of ACY1215 produced a moderate and 
transient rise in heart rate (19 – 24 bpm)with a modest  decrease in systolic pressure (5 - 15 mm 
Hg) observed at 0.5 - 11 hours post-dose for all 3 dose levels.  One beagle in the highest dose 
group (60 mg/kg) with the highest exposure and maximum concentrations (Cmax) levels of ACY-
1215 exhibited a QTcR prolongation 15 – 24 hours post-dose, with a maximal excursion of 32 
ms (13.4%), and an average excursion for the time period of 20 ms (8.3%) compared to pre-dose 
values.  Plasma levels of ACY-1215 during this period were at least 100-fold below the 
concentration of ~62 µM, where a minimal 18% inhibition of the hERG channel was observed.  
ACY-1215 did not elicit any changes in respiratory or central nervous system function. 
 
2.2.13  Pre-Clinical Pharmacokinetic Studies 
ACY-1215 is rapidly absorbed (time to maximum concentration [Tmax] ≤1 hour) following oral 
administration in the mouse, rat, and dog, with an oral bioavailability of 11% to 19% in rodents 
and approximately 45% in dogs.  Allometric scaling between species suggests the 
pharmacokinetic  profile of ACY-1215 in humans will be similar to that observed in dogs.  
Pharmacodynamic studies in mice with ACY-1215 demonstrated a reversible increase in levels 
of acetylated -tubulin, a biomarker of HDAC6 inhibition, in peripheral blood mononuclear cells 
(PBMCs).  ACY-1215 is classified as moderately permeable and is stable in human liver 
microsomes (half-life [t1/2] >45 minutes). 
Two major metabolites were identified in human S9 liver and intestinal microsomes, which were 
also present in plasma samples from toxicological studies rat and dog.  ACY-1215 and the 


 
 
10 
2 major metabolites have minimal potential to cause drug-drug interactions through inhibition or 
induction of CYP450 enzymes. 
 
2.2.14  Pre-Clinical Toxicology 
ACY-1215 administered by the oral route has been extensively studied in toxicological studies 
including pivotal 28 Day repeat-dose studies in rats and dogs.  Exposure in the dog for 
ACY-1215 was considerably higher than in rats by 21- to 31-fold due to higher bioavailability in 
the dog.  Severe toxicity has not been observed at any dose level after administration of 
ACY-1215 in rats and dogs.  
In the rat, a 28 Day repeat-dose study, which included a neurobehavioral functional observation 
battery and motor assessment, no significant findings were observed after administration of 
ACY-1215 at dose levels of 30, 60, and 120 mg/kg.  The no observed adverse effect level 
(NOAEL) in rat for the nominal dose is considered to be 120 mg/kg.  The NOAEL in the rat for 
the exposure level is considered to be 30 mg/kg due to the slight increase in exposure with 
increasing dose on Day 28. 
Significant toxicological findings were restricted to the pivotal dog 28 Day repeat-dose study and 
were generally minimal to mild in nature.  The findings were partially or fully recoverable 
following a 14-day recovery phase.  Slight decreases in body weight and minimal to mild 
decreases in red blood cell mass was observed at all 3 dose levels of 30, 60, and 120 mg/kg, 
while decreases in white blood cells, lymphocytes, and monocytes were observed in males.  The 
decreased red blood cell mass may reflect decreased hematopoiesis and/or increased turnover of 
red blood cells suggested by minimal to slight pigment deposition in the liver of some dogs.  
Marginal, non-adverse, though statistically significant from the control group, clinical chemistry 
changes were noted in both genders  in all dose groups, including a decrease in hepatic enzyme 
activities (alanine transaminase, alkaline phosphatase, and gamma-glutamyl transferase) and 
increases in triglyceride (males), total bilirubin (high dose male), albumin and total protein.  
Administration ACY-1215 at all dose levels was associated with decreased thyroid/parathyroid 
weights by 27-49% (males) and decreased thymus gland weights by 59-65% (females).  There 
were no histological correlates for the organ effects.  A NOAEL in the dog was not established 
due to the hematological findings and slight but statistically significant body weight effects, 
which were present at all dose levels.  
The mutagenic potential for ACY-1215 appears to be low.  ACY-1215 did not exhibit 
mutagenicity in either the Ames test or Chinese hamster ovary (CHO) micronucleus test.  
ACY-1215 did not display a mutagenic potential in the mouse lymphoma mutation assay, except 
with metabolic activation at concentrations 46- to 460-fold above the therapeutic range in 
cellular assays with MM cells.   
Detailed descriptions of findings from nonclinical studies of ACY-1215 are summarized in the 
Investigator’s Brochure. 
 
2.2.15 Clinical Data  
ACY-1215 monotherapy was administered at doses to 360 mg without any observed dose 
limiting toxicities..  Across all dose levels, the most common treatment-emergent adverse events 
reported among 15 patients treated with ACY-1215 monotherapy were elevated creatinine (5 
patients; 33%), anemia, fatigue, hypercalcemia, and upper respiratory infection (4 patients each; 


 
 
11 
27%), and cough, diarrhea, dizziness, and low white blood cell count (WBC) (3 patients each; 
20%).  Of these events, diarrhea and low WBC only occurred at doses ≥160 mg.  Grade 3 
adverse events that were considered by the investigator to be at least possibly related to study 
drug occurred at doses of 160 mg and 360 mg, and included anemia and decreased WBC and 
absolute neutrophil count; no Grade 4 events were reported.   
Pharmacokinetic analysis of ACY-1215 monotherapy revealed measurable levels of ACY-1215 
in all patients, with maximum plasma concentration (Cmax) levels ranging from 85±39  to 
503±195 ng/mL (0.2 to 1.2 μM) and area under the concentration curve from time 0 to the last 
time point of quantifiable drug concentration (AUClast) values ranged from 170±61 ng•h/mL to 
1093±357 ng•h/mL at dose levels of 40 to 360 mg.[1] Maximal plasma (Cmax) and exposure 
(AUC) levels were observed in patients treated at 160 mg (Cmax 626±150 ng/mL, and AUClast 
1074±439 ng•h/mL) and 240 mg (Cmax 719±329 ng/mL, and AUClast 1231±430 ng•h/mL), 
suggesting an exposure plateau was reached at dose levels ≥160 mg.[1] 
The drug was rapidly absorbed (Tmax ~1 hour) from the gastrointestinal tract.  The apparent 
elimination half-life was ~3 hours.  By 24 hours post-dose, drug levels ranged from ~1 ng/mL to 
below the lower limit of quantification (0.5 ng/mL).  There was no accumulation of drug 
observed over multiple days of administration [28] Overall drug exposure was similar for all 
doses greater than 160 mg.. 
Pharmacodynamic analyses in peripheral blood mononuclear cells (PBMCs) revealed acetylation 
of tubulin at starting at the 40mg dose and that this peaked to a   2-fold increase in acetylated 
tubulin, the pharmacological marker of HDAC6 inhibition, in all patients at doses of ≥160 mg.  
At doses higher than 160 mg, a modest increase in acetylated histones was demonstrated with 
ACY-1215 monotherapy.  
Taken together, the data show that exposures observed at ACY-1215 doses ≥160 mg achieve the 
target change in pharmacodynamic markers such as acetylated tubulin, while sparing acetylation 
of H3 (an off-target effect), and attain drug levels in the range where efficacy was observed in 
nonclinical studies[28] These drug levels plateaued at 160 mg so further increases in dosing did 
not lead to increased in drug exposure.  
Further information about ACY-1215 can be found in the investigator brochure. 
 
2.3 Rationale for Phase Ib Study Design 
 
Given that the experience of ACY-1215 monotherapy is limited and restricted to patients with 
multiple myeloma, a Phase Ib study will be performed exclusively in patients with lymphoma.  
In addition, in the previous Phase I myeloma experience the dosing schedule was on days 1-5, 8-
12 of a 21day cycle.  In the prior Phase I study, DLTs were never reached at the dose of 360 mg 
daily, although pharmacodynamics endpoints were met and the maximum plasma concentrations 
plateaued at 160 mg daily dosing.  This current study is designed to evaluate two dosing 
schedules of the recommended dose (see above Section 2.2.14) for safety and tolerability while 
maximizing intensity of exposure to the study drug.  Given the half-life of elimination ranges 
from 3-4 hours, dosing every 12 hours will be explored.  Patients of all lymphoma subtypes will 
be enrolled in order to broaden the experience with ACY-1215 monotherapy.   Three patients 
will be sequentially enrolled in one of two cohorts: Arm A and then after a safety assessment has 
occurred, Arm B for a total of six patients (3 in each arm).  If ≤33% of patients (N≤1) 
experiences a dose limiting toxicity (DLT) in a cohort, the cohort will be expanded to 6 patients 


 
 
12 
(3+3).  If there are ≤ 33% (N≤ 2 DLTs), the cohort will be further expanded to a total of 10 
patients (3+3+4).  The total number of patients for both Arms A and B with full expansions will 
total 20.   If more than 1/3 or 2/6 patients experience a DLT, there will be no expansion.  Safety 
data obtained from this Phase Ib will be analyzed by the sponsor and collaborating investigators 
to recommend a Phase II dose and schedule. 
 
 
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria for Lymphoma  
Patients meeting all of the following criteria will be considered eligible for enrollment in the 
study: 
1. Patients must have histologically confirmed relapsed or refractory non-Hodgkin’s 
lymphoma or Hodgkin’s lymphoma (WHO criteria), for which they are unwilling or 
unable to undergo an autologous stem cell transplant. Patients may have relapsed after 
prior stem cell transplant. 
2. Must have received first line chemotherapy. No upper limit to number of prior therapies.  
3. Patients must have measurable disease.  
4. Patients must be age ≥ 18. 
5. Patient has a Karnofsky Performance Status score of ≥70 or ECOG <2  
6. The patient or the patient’s legal representative is able to understand the risks of the study 
and provide signed informed consent and authorization to use protected health 
information (in accordance with national and local privacy regulations). 
7. Patient has adequate bone marrow reserve, as evidenced by: 
 Absolute neutrophil count (ANC) of ≥1.0109/L. 
 Platelet count of ≥50109/L. 
8. Patient has adequate renal function, as evidenced by a CR within the institutional limits 
of normal or a calculated creatinine clearance of ≥30 mL/min according to the Cockroft-
Gault equation. 
9. Patient has adequate hepatic function, as evidenced by serum bilirubin values <2.0 mg/dL 
and serum alanine transaminase (ALT) and/or aspartate transaminase (AST) values <3 × 
the upper limit of normal (ULN) of the local laboratory reference range.  (Patients with 
isolated elevations in alkaline phosphatase [ALP] <5 × ULN in the presence of bony 
disease are not excluded from participating in the study.) 
10. Females of childbearing potential must have a negative urine or serum pregnancy test 
within 7 days of (C1D1) and have adequate contraception.  (A female is considered to be 
NOT of childbearing potential if she has undergone bilateral oophorectomy or if she has 
been menopausal without a menstrual period for 12 consecutive months.) 
 
 
 
 
 
 


 
 
13 
3.2  Exclusion Criteria 
 
 
 
 
1. Prior Therapy 
a. Patients who have had chemotherapy or radiotherapy within 2 weeks of study 
drug treatment or those who have not recovered from adverse events due to agents 
administered   
b. No monoclonal antibody within 3 months unless evidence of disease progression. 
2. Patients may not be receiving any other investigational agents. 
3. Patients with known central nervous system metastases, including lymphomatous 
 meningitis  
4. Any known cardiac abnormalities such as: 
- 
Congenital long QT syndrome 
- 
QTc interval ≥ 500 milliseconds; 
5. Uncontrolled inter-current illness 
6. Pregnant or nursing women  
7. Patient is known to be Human Immunodeficiency Virus (HIV)-positive  
8. Active Hepatitis A, Hepatitis B, or Hepatitis C infection 
8.   Patient has a history of surgery that would interfere with the administration or absorption  
     of the oral study drugs  
 
3.3  
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
3.4  
Source of Patients 
This will be a multi-center study.  Each study center is required to obtain Institutional 
Review Board (IRB) approval to conduct the study before enrollment of patients may 
commence.  Patients meeting the entrance criteria who are known or referred to the study 
center will be eligible for enrollment. 
4. REGISTRATION PROCEDURES 
 
4.1       General Guidelines 
 
Eligible patients will be entered on study by the coordinating center study team at 
Columbia University Medical Center (CUMC). Subsites will fax or PDF/e-mail their 
signed eligibility checklist to the coordinators at CUMC.  Once received, CUMC will 
confirm eligibility, enter the patient into the CUMC Cancer Center database and assign a 
study ID number to each patient.  CUMC will provide the subsite with the information 
and the patient will be enrolled to the study. 
 
Following enrollment, patients should begin protocol treatment within 10 days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator. If a 


 
 
14 
patient does not receive protocol therapy within the specified timeframe, the patient’s 
enrollment on the study may be canceled.   
 
4.2 
Screening 
 
All potential study patients will be screened and eligibility determined prior to 
enrollment.  Unless otherwise specified, the following procedures and evaluations will be 
performed as noted in the study calendar (Section 9) prior to the start of study drugs 
(cycle 1, dose 1): 
 
1) Obtain written informed consent and privacy authorization prior to initiating any 
protocol-required procedure that is not considered standard of care 
2) Review eligibility criteria 
3) Review medical chart for past medical/surgical history 
4) Record medications and prior treatment regiments 
5) Record response to prior treatment regimen 
6) Document histopathology from: 
i. 
Original diagnosis 
ii. 
Tumor biopsy in the relapsed setting (if applicable) 
7) Documentation of known measurable disease parameters by the following 
procedures: 
i. 
CT of neck, chest, abdomen, and pelvis (PET/CT optional) 
ii. 
Skin exam 
iii. 
Other imaging techniques documenting disease site other than neck, chest,           
abdomen, and pelvis, if applicable 
8) Obtain a 12-lead electrocardiogram (ECG) and calculate the QTc interval.  
9) Perform a comprehensive physical examination 
10)  Assess and record ECOG or Karnofsky Performance Status 
11)  Local laboratory: Collect blood for hematology (CBC with differential counts), 
chemistry (Na, K, Cl, HCO3, BUN, creatinine, glucose, calcium, magnesium, 
including serum β-human chorionic gonadotropin [β-hCG] pregnancy test for women 
who are not postmenopausal or surgically sterile [within 7 days prior to cycle 1, dose 
1 and again within 24 hours prior to first dose of the study drugs.), liver function tests 
(total protein, Albumin, AST, ALT, total bilirubin, direct bilirubin, alkaline 
phosphate). 
12) Calculate creatinine clearance using the glomerular filtration rate (GFR) according to 
the Cockroft and Gault Equation, only if screening serum creatinine is > Upper Limit 
of Normal: GFR* = (140 – age [years]) x actual body weight (kg)72 x serum 
creatinine       *For female patients, multiply by 0.85 
13) Urinalysis 
 
4.3 
Informed Consent 
 


 
 
15 
4.3.1  Study Informed Consent 
 
Study personnel must obtain documented consent from each potential patient prior to conducting 
any study related procedures and enrolling the patient to the clinical study.  Any procedures/tests 
performed prior to giving written informed consent may be used provided that these tests are 
considered part of standard care. Consent must be documented on the IRB approved consent 
form by obtaining the dated signature both of the patient and of the investigator conducting the 
consent discussion.  If the patient is unable to sign the consent form, then oral consent, attested to 
by the dated signature of an impartial witness (someone not involved with the conduct of the 
study), is the required alternative. 
 
If the patient is illiterate, an impartial witness should be present during the entire informed 
consent reading and discussion.  Afterward, the patient should sign and date the informed 
consent, if capable.  The impartial witness should also sign and date the informed consent along 
with the individual who read and discussed the informed consent (i.e., study staff personnel). 
 
The information from the consent form should be translated and communicated to the subject in 
language understandable to the subject.  When the study participant is non-English the consent 
form must be read accurately in its entirety by a qualified professional translator.   The translator 
will provide a written statement indicating that the consent form has been accurately translated 
from the accompanying English version, and that the study participant consents to participation.  
The professional translator will sign the consent form as an impartial witness. 
 
A copy of the signed and dated consent form should be given to the patient before participation 
in the study. 
 
 
The initial informed consent form and any subsequent revised written informed consent 
form, and written information will receive IRB approval prior to implementation.  The patient or 
his/her legally acceptable representative will be informed in a timely manner if new information 
becomes available that may be relevant to the patient’s willingness to continue participation in 
the trial.  The communication of this information will be documented. 
 
4.4 
Registration Process 
 
To register a patient, the following documents should be completed by a member of the research 
staff and sent to the study coordinator at CUMC: 
 Eligibility Screening Worksheet  
 Copy of required laboratory and imaging tests 
 
The Study Coordinator will verify eligibility.  To complete the registration process, the 
Coordinator will: 
 Assign a patient study number 
 Register the patient on the study 
 Confirm registration with the Principal Investigator 
 


 
 
16 
No patient may be enrolled or begin treatment prior to registration and assignment of a patient 
number. Patients who are registered but not treated will be replaced.  Investigators will be 
notified by CUMC when enrollment in the initial part of the study(stage 1) is closed and 
enrollment into the next parts of the study (stage 2 and expansion cohort) can begin. 
Investigators will be notified by CUMC or the Sponsor if the study is placed on administrative 
hold, when it is completed, or is closed to further patient enrollment. 
 
4.5 Withdrawal and Replacement of Patients 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The Investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
 Progression of Disease. 
 Occurrence of an unacceptable adverse event. 
 Patient requires use of an unacceptable concomitant medication. 
 General or specific changes in the patient’s condition unacceptable for further treatment in 
the judgment of the Investigator. 
 Non-compliance. 
 Patient withdrawal of consent. 
 Patient no longer meets the protocol entrance criteria. 
 Sponsor request. 
At the time of withdrawal, all study procedures outlined for the End of Study Visit should be 
completed.  The primary reason for a patient’s withdrawal from the study is to be recorded in the 
patient’s chart and the CRF. 
Patients who discontinue from the study will not be replaced. 
Patients who miss >10% of planned dose will be censored for response assessment, but not for 
toxicity, and will be replaced for adequate response assessment. 
 
5. 
TREATMENT PLAN 
 
5.1 
Overall Design and Plan of the Study 
 
5.1.1 Phase Ib: 
 
This is a Phase Ib two-arm multicenter, open-label study in patients with relapsed/refractory 
lymphoma.  The phase Ib will be conducted to determine the safety and tolerability of two 
dosing schedules of ACY-1215 monotherapy in patients with lymphoid malignancies.  Patients 
will be accrued sequentially to two dose cohorts (Arm A and then after a safety assessment has 
occured, Arm B) of ACY1215.  All patients will take the assigned dose of ACY1215 orally for 
28 consecutive days.  Patients enrolled into Arm A will take ACY1215 160 mg daily, whereas 
patients enrolled into Arm B will take ACY1215 160 mg twice daily. ACY-1215 will be 
supplied as a liquid for oral administration (PO).  Each dose will be administered at least 1 hour 
after ingestion of food followed by at least 4 ounces of water.  Patients will be instructed not to 
ingest food or other oral medication for at least 2 hours after each ACY-1215 dose. Three 


 
 
17 
patients will be sequentially enrolled in one of two cohorts: Arm A and then after a safety 
assessment has occurred, Arm B for a total of six patients (3 in each arm).  If ≤33% of patients 
(N≤1) experiences a dose limiting toxicity (DLT) in a cohort, the cohort will be expanded to 6 
patients.  If there are ≤ 33% (N≤ 2 DLTs), the cohort will be further expanded to a total of 10 
patients (3+3+4).  The total number of patients for both Arms A and B with full expansions will 
total of 20.   If more than 1/3 or 2/6 patients experience a DLT, there will be no expansion.  
Safety data obtained from this Phase Ib will be analyzed by the sponsor and collaborating 
investigators to recommend a Phase II dose. 
 
5.1.2 Phase II: 
 
This is a phase II, single-arm, multicenter, open-label study in patients with relapsed or 
relapsed/refractory lymphoma.  Utilizing the Simon 2 Stage Minimax design, an estimated 40 
patients will be needed to determine efficacy at a power of 0.80 and type I error of 0.05. Using 
this design, there will be an early stopping rule if <10% achieve a response in Stage 1.  Twenty-
two (N= 22) patients will be accrued to Stage 1, of which 2 patients are required to achieve a 
response to allow accrual to Stage 2. Patients accrued to Stage 1 of the Phase II will be of all 
lymphoid malignancy subtypes including those with mantle cell lymphoma (MCL).  Eighteen 
patients (N=18) will be treated in Stage 2, of which 8 responses would be needed to attain an 
efficacy of at about 25%.  The safety, tolerability, single- and multiple-dose PK, 
pharmacodynamics, and anti-tumor activity of ACY-1215 also will be evaluated.  
Simultaneously in Stage 2, an additional cohort of 20 mantle cell lymphoma patients will be 
assessed to evaluate for a signal of efficacy in this subtype.  These patients will be enrolled in 
parallel to the phase II study. Assuming success in Stage I, enrollment to Stage 2, and expansion 
of MCL cohort, the total number of patients will be 60 (Stage 1 N=22, Stage 2 N=18, MCL 
focused Expansion Phase N=20). 
 
5.1.3 Treatment plan common to both Phase Ib and Phase II: 
After executing written informed consent, patients will be evaluated for study eligibility during 
the Screening period within the Screening period before Cycle 1, Day 1 [C1D1].  Patients 
determined to be eligible will be treated on study.   Patients will be evaluated on Days 1, 8, and 
15 of Cycle 1.  
On study drug administration days that coincide with scheduled study center visits, ACY-1215 
will be administered at the study center. 
 
 One cycle of therapy is comprised of 28 or 56 doses of ACY-1215.  
 Administration of the study drugs will be allowed within 48 hours of the scheduled 
dates. 
 Missed doses will not be made up.  
Patients will be evaluated for disease response with CT or PET/CT after cycles 2 and 6, then at 
the investigators discretion with intervals no more than 6 months.   Patients who withdraw from 
the study will be required to have an End of Study Visit 4 weeks (+/- 7 days) after the last study 
drug dose.  After discontinuation of therapy, patients will be followed on an approximately every 
3 month basis (+/- 1 week) until development of PD or initiation of alternative therapy in order 
to determine the duration of response. 


 
 
18 
Safety will be evaluated during the study by documentation of AEs and SAEs, clinical laboratory 
tests (hematology, clinical chemistry, and urinalysis), physical examinations, vital sign 
measurements, and 12-lead ECGs.   
The anti-tumor activity of ACY-1215 will be determined by CT or PET/CT and assessment of 
disease response will be evaluated using the International Harmonization Project revised Criteria 
(2007) [27].   
Exposure-response of ACY-1215 including biomarkers relating to intracellular protein 
acetylation, IL6 and IL10 secretion, and markers of the UPR will be analyzed as a function of 
treatment and response.   
Serial blood samples will be collected for determination of the single- and multiple-dose PK of 
ACY-1215.  Patients will receive ACY-1215 160mg orally (PO) for 28 consecutive days per 
cycle according to schedule determined by the Phase Ib.  There will be no limit to the number of 
cycles patients will receive.   
 
Table 1: Regimen Description 
 
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
Frequency 
 
Schedule 
Cycle 
Length  
ACY-1215 
None 
160mg 
(1 vial) 
PO 
Once daily vs. 
Twice daily 
Days 1-28 
28 days 
 
5.1.2 Regimen Description and Guidelines for Drug Administration 
 
Treatment will be administered on an outpatient basis. All patients will take the oral ACY-1215 
160mg for 28 consecutive days on a 28-day treatment cycle.  Frequency in phase II will be 
determined based on Phase Ib results.  ACY-1215 will be supplied as a liquid for oral 
administration (PO).  Each dose will be administered at least 1 hour after ingestion of food and 
followed by at least 4 ounces of water.  Patients will be instructed not to ingest food or other oral 
medication for at least 2 hours after each ACY-1215 dose. Reported adverse events and potential 
risks for oral ACY-1215 are described in Section 7.  Appropriate dose modifications are 
described in Section 6.  No investigational or commercial agents or therapies other than those 
described may be administered with the intent to treat the patient's malignancy. 
 
5.1.2.1 Rationale for the Dose Selected  
 
In this study, ACY-1215 will be examined as a single agent administered by the oral route 28 
consecutive days of a 28 day cycle in patients with relapsed and/or relapsed-refractory 
lymphoma to assess clinical response, safety, tolerability, PK and PD of ACY-1215.   
 
The rationale of the dosing schedule of ACY 1215 is based on results from a Phase I 
monotherapy trial in which no maximally tolerated dose (MTD) was established when ACY-
1215 was dosed once daily on days 1-5 and days 8-13 of a 21 day cycle up to a dose of 360 mg. 
Pharmacokinetics were similar at doses of 160 mg (Cmax 626 +/- 150 ng/mL and AUC0-∞ 1300 
+/- 533 ng*h/mL) to higher doses. The half-life of elimination ranged from 3-4 hours and  no 


 
 
19 
accumulation of drug was observed.  Dosing at 160 mg and above demonstrated acetylation of 
tubulin, the pharmacodynamic marker of HDAC6 inhibition, in peripheral mononuclear cells for 
all patients in these cohorts. Doses above 160 mg lead to off target effects demonstrated by 
acetylation of histone 3 and increased toxicities.  Given the relatively short  half-life (~3 h) and 
safety profile of ACY-1215, twice daily dosing will also be explored to maximize the dose 
intensity while limiting the toxicity. Twice daily administration of ACY-1215 at 160 mg is 
expected to approximately double the daily exposure (AUC) to ~4000 ng·h/mL with a minimal 
impact on maximal plasma levels and no anticipated accumulation, since >95% of the 
administered dose will have been cleared before the next dose administration.  28-day repeat 
dose GLP toxicology studies in dogs showed that exposure levels of 15,000-26,800 ng·h/mL 
were attained with minimal to mild changes in blood cell parameters and minimal changes in 
body weight that were partially to fully recoverable. Twice daily dosing is therefore not 
anticipated to change the safety profile of ACY-1215. Accordingly, once daily and BID dosing at 
160 mg will be explored in the Phase 1b section of the trial. 
 
5.1.2.2 Rationale and Justification of the Study Design 
 
The trial design is based on existing data recently obtained from a Phase 1-2 study of ACY1215 
in patients with multiple myeloma. In nonclinical studies, ACY-1215 has been shown to induce 
cellular cytotoxicity in MM and lymphoma cells as a single agent.  Thus, the anti-tumor activity 
of ACY-1215 will be studied in patients with lymphoma.  
 
Given that the experience of ACY-1215 monotherapy is limited and restricted to multiple 
myeloma patients only, a Phase Ib study will be performed.  In prior Phase I study, dose limiting 
toxicities were never reached, although pharmacodynamics endpoints were met and 
pharmacokinetic profile plateaued at 160 mg daily dosing.  This current study is designed to 
evaluate two dosing schedules of the recommended dose (160 mg see above Section 2.2.14) for 
safety and tolerability while maximizing intensity of exposure to the study drug.   It will inform 
the final dosing schedule to be used in the Phase II. The total possible number of patients to be 
accrued to the Phase Ib is 20 if each cohort is expanded to 10 patients.  
The Phase II study will be designed to determine the efficacy of ACY-1215 in lymphoid 
malignancies and incorporated an expansion cohort of patients with mantle cell lymphoma.  The 
minimum number of patients to be treated in stage 1 of the Phase II part is consistent with this 
standard minimax Simon-2stage design.  In order to ensure the safety of patients, the Sponsor 
personnel, the Study Chair, and Investigators will review all safety data from the first stage 
before enrollment of additional patients into stage 2 and the expansion cohort. The expansion 
cohort of patients with mantle cell lymphoma was chosen to obtain early activity and response 
data in this specific subtype.  This subtype was chosen given its sensitivity to bortezomib, a drug 
which inhibits catabolism of unfolded proteins and which has single agent activity in mantle cell 
lymphoma.   
 
5.1.3 Required Blood Parameters and Other Investigations Prior to Each Treatment 
Before the start of each treatment cycle, patients should be reassessed and the following criteria 
must be fulfilled: 
 
 Karnofsky Score > 70 or ECOG Performance Status < 2 


 
 
20 
 ANC >  1000/dL 
 Platelet count ≥ 50,000  
 Serum creatinine concentration ≤ 2.0 × ULN or ≤ baseline, or creatinine clearance 
>30 ml/min 
 AST (SGOT) and ALT (SGPT) ≤3.0 × ULN or ≤3.0 × ULN in presence of 
demonstrable liver metastases 
 Bilirubin concentration ≤2.0 × ULN  
 Recovery of any drug-related non-hematological toxicity to Grade 1 or less, unless 
otherwise indicated 
 
5.1.4 Dose-Limiting Toxicity 
 
A dose limiting toxicity (DLT) is defined as any toxicity not specifically included in section 
5.1.4 that occurs within cycle 1.  DLT is also defined as any toxicity, occurring up to 7 days after 
completion of cycle 1 that results in a delay of initiating cycle 2.   For patients who discontinue 
study drug administration after Cycle 1, DLT will be defined as any toxicity not specifically 
included in section 5.1.4 that occurs within 30 days of the last dose of drug on study, in cycle 1 
that is not related to disease progression. 
 
DLTs include: 
 
Hematologic dose-limiting toxicity will be defined as either Grade 4 neutropenia that does not 
resolve to ≤ Grade 2 within ≤ 7 days, any Grade 4 thrombocytopenia, or any Grade 5 
hematologic toxicity. At least three patients in each cohort must be evaluable for hematologic 
toxicity.  
 
Non-hematologic dose-limiting toxicity will be defined as any Grade 3, 4 or 5 non-hematologic 
toxicity, with the exception of: 
 Grade 3 nausea or Grade 3 vomiting that occurs in the setting of inadequate compliance 
with supportive care measures specified in Section 5.1.7 and lasts for less than 48 
hours. 
 Grade 3 diarrhea that occurs in the setting of inadequate compliance with supportive 
care measures specified in Section 5.1.7 and lasts for less than 48 hours.   
 Grade 3 dehydration that occurs in the setting of inadequate compliance with 
supportive care measures specified in Section 5.1.7 and lasts for less than 48 hours. 
 Grade 3 acidosis or alkalosis that responds to medical intervention by returning to ≤ 
Grade 2 within 48 hours. 
 Isolated (i.e. no other abnormalities) Grade 3 elevation of liver function tests (LFTs) 
without associated clinical symptoms, lasting for ≤ 5 days in duration. 
 Isolated (i.e. no other abnormalities) Grade 3 elevation of amylase without associated 
clinical symptoms, lasting ≤5 days 
 Grade 
3 
hypocalcemia, 
hypokalemia, 
hypomagnesemia, 
hyponatremia, 
or 
hypophosphatemia that responds to medical intervention. 


 
 
21 
 Grade 3 hypercholesterolemia. 
 Grade 3 hypertriglyceridemia 
 Grade 2 Alopecia 
 Grade 3 Constipation 
 Grade 3 Fatigue  
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6.3. 
 
5.1.5 Prophylactic Medicines and Supportive Care 
All prescription and non-prescription medications including pharmacologic doses of vitamins, 
herbal medicines, or other non-traditional medicines, taken from thirty days prior to the first dose 
of ACY-1215 through the End of Study Visit must be recorded in the CRF. 
Patients will be permitted to receive appropriate supportive care measures as deemed necessary 
by the treating physician including but not limited to the items outlined below:   
 
 Diarrhea: Diarrhea should be treated promptly with appropriate supportive care, 
including loperamide.  Loperamide should not be taken prophylactically. Patients 
should be instructed to begin taking loperamide at the first sign of: 1) poorly formed 
or loose stool, 2) occurrence of more bowel movements than usual in one day or 3) 
unusually high volume of stool.  Loperamide should be taken in the following 
manner: 4 mg at first onset of diarrhea, then 2 mg after each unformed stool.  The 
daily dose of loperamide should not exceed 16 mg/day.  Loperamide should be 
deferred if blood or mucus is present in the stool or if diarrhea is accompanied by 
fever. In this setting, appropriate diagnostic microbiologic specimens should be 
obtained to exclude an infectious etiology. Patients should also be advised to drink 
liberal quantities of clear fluids.  
  
 Nausea/vomiting: ACY-1215 is not emetogenic.  Standard institutional guidelines 
for anti-emetics will be used. Nausea and vomiting should be treated aggressively, 
with agents such as prochlorperazine, metoclopramide, 5-HT-3 inhibitors, or 
benzodiazepines.  Patients should be strongly encouraged to maintain liberal oral 
fluid intake during therapy. Patients who experience indigestion or gastroesophageal 
reflux symptoms may be treated with Proton Pump Inhibitors (PPIs) as well as H2 
blockers as clinically indicated.  High dose steroids (> 10 mg QD of predisone 
equivalent) are to be avoided as an anti-emetic therapy.   
 
 Growth Factors: Patients who have pre-existing chronic anemia prior to receiving 
ACY-1215 may continue to receive erythropoietin or darbepoietin.  After initiating 
treatment, anemia may be managed with growth factors according to the ASCO 
guidelines: 2006 Update of Recommendations for the Use of White Blood Cell 
Growth Factors: An Evidence-Based Clinical Practice Guideline 
http://www.jco.org/cgi/content/full/24/19/3187.    
Post cycle 1, colony stimulating growth factors (e.g., filgrastim, peg-filgrastim, and 
sargramostim) may be used in patients who experience hematological toxicity per 


 
 
22 
American Society of Clinical Oncology (ASCO) guidelines.  Furthermore, patients 
who are not receiving such prophylaxis who experience febrile neutropenia (a DLT if 
occurring in Cycle 1) may receive treatment with colony stimulating factors at the 
Investigator’s discretion.  Neulasta should not be administered given that there is no 
data for co-admnistration of ACY-1215 with neulasta. 
 
 Thrombocytopenia: Transfusion of platelets may be used if clinically indicated. 
Dose modification for thrombocytopenia is allowed in a manner consistent with the 
guidelines for dose modification (Section 6). 
 
5.1.6 Excluded Medications and Substances 
The following medications and supportive therapies and procedures are prohibited during the 
study: 
 Any investigational agent other than ACY-1215, including agents that are commercially 
available for indications other than lymphoma that are under investigation for the 
treatment of lymphoma. 
 Any anti-neoplastic treatment with activity against lymphoma other than study drug. 
 
5.2  
Duration of Therapy 
 
Treatment may continue until one of the following criteria applies: 
 
 Disease progression 
 Unacceptable adverse event(s), DLTs 
 Withdrawal of consent 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 An event that in the judgment of the treating physician warrant’s discontinuation of 
therapy 
 Termination of the study 
5.3 
Patient Adherence to Protocol Schedule 
 
All patients are required to adhere to the protocol-specified visit schedule.  If the patient misses 
the D1 visit of any cycle, attempts should be made to reschedule the visit within the following 
2 days.  Failure to attend scheduled study visits may result in discontinuation from the study. 
 
Patients will be required to maintain a log of the precise time at which they had last ingested 
food prior to taking ACY-1215, the time at which they took study drug, and the time at which 
they next ingested food. 
 
5.4 
Criteria for Removal from Study 
 
Patients will be removed from treatment when any of the criteria listed in Section 5.2 applies. 
The reason for study removal and the date the patient was removed must be documented in the 
patient’s chart and the CRF. 


 
 
23 
 
Subjects/patients may withdraw at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a subject/patient may be withdrawn 
by the investigator if he/she violates the study plan or for administrative and/or other safety 
reasons. The investigator or study coordinator will notify the appropriate parties within 2 
business days when a subject has been discontinued/ withdrawn due to an adverse event (Section 
7).  When a subject discontinues/withdraws prior to study completion, all applicable activities 
scheduled for the end of study visit should be performed at the time of discontinuation. Any 
adverse events present at the time of discontinuation/withdrawal will be followed until 
resolution. 
 
5.5 
Duration of Follow Up 
 
Patients will have an end of study visit 4 weeks +/- 7 days after their last dose of drug to evaluate 
safety.  Patients will be further followed every three months after the 4-week safety evaluation 
for one year, or until they develop a POD or begin a new treatment for their disease, for 
evaluation of delayed toxicity. Patients removed from study for unacceptable adverse events will 
be followed until resolution or stabilization of the adverse event. 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1  
Dose Delays 
 
 Study drugs will be held until adverse event returns to ≤ Grade 2. 
 If interruption lasts for more than 14 days, study treatment will be discontinued. 
 In patients who miss >10% of planned dose in the Phase II, but not the Phase Ib, data 
will be censored for response, but not for toxicity, and patients will be replaced for 
adequate response assessment. 
 
6.2  
Resuming Administration of Study Drug  
 
For toxicities that can be treated or prevented, such as nausea, vomiting, diarrhea and 
neutropenia, mucositis, treatment may be resumed at the previous dose once supportive measures 
have been instituted and toxicity recovers to Grade 2 or less.   
 
6.3 
Dose Modifications 
 
Dose escalation will not be allowed in any patient at any time. Before each scheduled study drug 
dose administered in the clinic, the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s).  
Toxicities are to be graded according to the NCI CTCAE, Version 4.0.  The Investigator is to 
assess the relationship of a toxicity to each study drug.  If a toxicity is considered to be related to 
a particular drug(s), then the dose of the drug(s) to which the toxicity is considered related may 
be modified per the applicable algorithm in the following subsections.  Conversely, if the toxicity 
is considered unrelated to a particular drug(s), then no modification of that drug(s) is required. 
 


 
 
24 
6.3.1 ACY-1215 Dose Modifications   
 
In general, if study drug has been held and the toxicity does not resolve, as defined above, then 
drug must be discontinued. Note:  Dose reductions should not be performed for alopecia or for 
nausea or vomiting that was not treated with aggressive anti-emetic support. Dose modifications 
are described in detail in the table below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2: Dose Modifications for ACY1215 


 
 
25 
Dose Modifications for ACY1215 
CTCAE Grade or Abnormal Value 
1) ACY1215 
Thrombocytopenia 
Grade 1 (75 x 109/L -  LLN) 
Grade 2 (50 -  75 x 109/L) 
Maintain dose level 
2) Maintain dose level 
Grade 3 or 4 thrombocytopenia: 
 
 
 
OR 
 
 
Thrombocytopenia that requires 
platelet transfusion or recurrent 
Grade 3 or 4 thrombocytopenia 
 
Hold subsequent doses of therapy until 
thrombocytopenia returns to ≤Grade 2 or baseline 
and continue at full dose 
 
 
 
 
Hold subsequent doses of therapy until 
thrombocytopenia returns to ≤Grade 2 or baseline 
and permanently reduce dose of ACY1215 to 
75% of dose.  If the same toxicity recurs despite 
dose reduction, reduce by an additional 25%. 
 
Neutropenia (ANC) 
3) Grade 1 (1.5 x 109/L -  LLN) 
4) Grade 2 (1.0 -  1.5 x 109/L) 
5) Maintain dose level 
6) Maintain dose level 
7) Grade 3 and 4 neutropenia:  
 
 
 
 
8) Hold subsequent doses of therapy until 
specific cytopenia returns to ≤Grade 1 or 
baseline and continue at full dose 
 
 
9) Febrile Neutropenia 
Febrile (≥38.5ºC) Grade 4 
neutropenia or recurrent Grade 3 
or 4 neutropenia:  
10) Hold subsequent doses of therapy until 
neutropenia returns to ≤Grade 1 or baseline 
and permanently reduce dose of ACY1215 to 
75% of dose.  If the same toxicity recurs 
despite dose reduction, reduce by an 
additional 25%. 
11) All Other Non-Hematologic Drug Toxicities (not mentioned in previous 
tables) 
Grade 1 or 2: 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
12) Maintain dose level 
 
Hold treatment with ACY1215 until toxicity returns 
to ≤Grade 1 or baseline, then restart therapy at 
full dose.  If Grade 3 toxicity recurs, reduce dose 
of by 25%.  This is a permanent dose reduction. 
 
Grade 4 toxicity:  Hold treatment with ACY1215 
until toxicity returns to ≤Grade 1 or baseline, and 
then restart therapy at 25% dose reduction.  This 
is a permanent dose reduction  
 
 
 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 


 
 
26 
7.1 
Safety Evaluation Procedures 
 
7.1.1 Adverse Event Reporting 
 
An adverse event is defined as any unfavorable and unintended change in the structure, function, 
or chemistry of the body temporally associated with the use of the study drugs, whether or not 
considered related to the use of the product. Any worsening (i.e., any clinically significant 
adverse change in frequency and/or intensity) of a preexisting condition that is temporally 
associated with the use of the study drugs product, is also an adverse event. 
 
Adverse events may occur in the course of receiving study drugs or within the follow-up period 
specified by the protocol, as well as from overdose (whether accidental or intentional), from 
abuse, and from withdrawal. 
 
Adverse events will be graded and recorded throughout the study according to NCI-CTCAE, 
version 4.0.  Toxicities will be characterized in terms including duration, intensity, and time to 
onset.  Safety endpoints will include all types of adverse events, in addition to laboratory safety 
assessments, ECOG performance scale status, ECGs, and vital signs. 
 
The investigator must assess all abnormal laboratory results for their clinical significance.  If any 
abnormal laboratory result is considered clinically significant, the investigator must provide 
details about the action taken with respect to the test drug and about the patient’s outcome. 
 
The following safety evaluations will be performed during patient screening and at defined 
points during the course of the study: 
 Vital signs 
 Laboratory studies complete blood count (CBC), serum chemistry, urinalysis,  
 
 coagulation studies (PT/PTT), pregnancy test, LDH 
 Electrocardiograms (ECG) 
 Physical examinations 
 Performance Status Evaluation using the ECOG scale 
 Adverse event monitoring using the NCI CTCAEv4.0 
 
The Study Calendar (Section 9) provides specific details on collection time points.  
 
Serious Adverse Event (SAE) Definition  
A serious adverse event is one that at any dose (including overdose): 
Results in death 
Is life-threatening1 
Requires inpatient hospitalization or prolongation of existing hospitalization 
Results in persistent or significant disability or incapacity2 
Is a congenital anomaly or birth defect 
Is an important medical event3 
 
 1“Life-threatening” means that the subject was at immediate risk of death at the time of the serious adverse event; it 
does not refer to a serious adverse event that hypothetically might have caused death if it were more severe. 


 
 
27 
2“Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability to 
carry out normal life functions. 
3Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
situations where none of the outcomes listed above occurred.  Important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above should also usually be considered serious.  Examples 
of such events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.  A new diagnosis of cancer during the course of a treatment should be considered as medically 
important.  
 
Note: Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations; for example, important medical events may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent one of the outcomes listed in the definition above. Any 
adverse event is considered a serious adverse event if it is associated with clinical signs or 
symptoms judged by the investigator to have a significant clinical impact. 
Hospitalizations that do not meet these criteria are: 
 
 
Social reason in the absence of an AE 
 
Surgery or procedure planned prior to entry into the trial 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7) and the characteristics of an observed AE (Section 7) will 
determine whether the event requires expedited (via AdEERS) in addition to routine reporting.    
 
Ongoing monitoring of the clinical safety data in this trial will be performed consistent with 
procedures outlined in the DSMC charter. This review will pay particular attention to Grade 3 or 
4 adverse events, serious adverse events (SAEs), adverse events that lead to discontinuation and 
adverse events that lead to dose reduction. Should the incidence of any particular adverse event, 
or combination of events, rise to a level of clinical concern the DSMC will be notified for 
possible review of the emergent adverse events. 
 
7.2 Pregnancy 
Pregnancies occurring while the patient is receiving ACY-1215 or within 30 days after the 
patient’s last dose of ACY-1215 will not be considered serious, but are to be reported using the 
same procedures as for SAEs described in Section 7.3.  There are no adequate and well-
controlled studies of this agent in pregnant women. 
Women of child bearing potential will be advised to avoid becoming pregnant while receiving 
treatment with ACY-1215 .  Women enrolled in this study should either be post-menopausal, 
free from menses for > 1 years, surgically sterilized, or willing to use 2 adequate barrier methods 
of contraception to prevent pregnancy or agree to abstain from heterosexual activity throughout 
the study, starting with visit 1.  Women of child-bearing potential must have a negative serum 
pregnancy test (-hCG) within 7 days prior to receiving the first dose of ACY-1215.  Men 
enrolled in the study must also agree to an adequate method of contraception for the duration of 
the study. 


 
 
28 
If a patient inadvertently becomes pregnant while on study, the patient will immediately be 
removed from the study and the drugs will be discontinued and the investigator must notify the 
Study Chair of the outcome within 5 days. The patient should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling.  Investigators will follow the patient monthly and document the patient’s status until 
the pregnancy has been completed or terminated.  The outcome of the pregnancy will be reported 
to appropriate parties within 24 hours if the outcome is a serious adverse event (i.e. death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). If a male patient’s partner becomes pregnant on study, the pregnancy will be reported 
to appropriate parties 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should report it as such.  
Furthermore, all neonatal deaths that occur within 30 days of birth should be reported, without 
regard to causality, as SAEs.  In addition, any infant death after 30 days that the Investigator 
suspects is related to the in utero exposure to the study drug should also be reported. 
 
7.3 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for ACY-1215  
 
7.3.1. Clinical Trials Experience 
 
To date, 15 patients have been treated with ACY-1215 monotherapy, at doses of 40, 80, 160, 
240, 360 mg (n = 3, 3, 4, 3, and 2, respectively).Eighteen patients have been treated with ACY-
1215 in combination including 9 patient receiving ACY1215 in combination with bortezomib 
and 9 in combination with lenalidomide. 
 
Of the 15 patients who received monotherapy with ACY1215, the median duration of therapy 
ranged from 1.7 weeks to 12.3 weeks with a maximum of 29.5 weeks.  These patients all had a 
diagnosis of multiple myeloma and 93% had at least 1 AE that were reported as mild to moderate 
and unrelated to the study drug.  The most common AE, regardless of the dose, were blood 
creatinine increase (33%), fatigue, hypercalcemia, and upper respiratory infections (27%), and 
anemia, cough diarrhea, and dizziness (20%).  Diarrhea occurred only at doses >/= 160 mg. 
 
7.3.2 Serious Adverse Reactions 
 
AEs that were assessed by the investigator as Grade 3 or 4 and possibly related to study drug 
were seen at doses >/= 160 mg and were all hematologic abnormalities, including anemia (160 
mg) and neutropenia (360 mg).  None of these events were a dose limiting toxicity based on 
protocol definitions. 
 
Two of the 15 patients (13%) experienced an SAE including Grade 5 (fatal) cardiac arrest at the 
dose level 40 mg and chronic obstructive pulmonary disease at 160 mg dose level.  Neither event 
was considered by the investigator to be study drug related. 
 
 
7.3.3 Discontinuations 
 


 
 
29 
No patients discontinued ACY1215 monotherapy because of an AE. 
 
7.3.4 Dose Modifications 
 
No DLTs were reported in any patient treated with ACY1215 monotherapy at doses up to 360 
mg, and an MTD of ACY-1215 was not defined. 
 
7.4  
Adverse Event Characteristics and Reporting 
 
7.4.1 Procedures for Evaluating AEs and SAEs 
Each patient must be carefully monitored for the development of any adverse events.  This 
information should be obtained in the form of non-leading questions (e.g., “How are you 
feeling?”) and from signs and symptoms detected during each examination, observations of 
study personnel, and spontaneous reports from patients.   
All adverse events (serious and non-serious) spontaneously reported by the patient and/or in 
response to an open question from study personnel or revealed by observation, physical 
examination or other diagnostic procedures will be recorded in the CRF.  Any clinically relevant 
deterioration in laboratory assessments or other clinical findings is considered an adverse event 
and must be recorded in the CRF.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
 
7.4.2 AE and SAE Reporting 
All SAEs that occur during the course of the study must be reported to the Sponsor Investigator – 
Jennifer Amengual at the contact information below.  The Sponsor Investigator will notify INC Drug 
Safety (on behalf of Acetylon) within 1 working day, of all serious adverse events and expedited 
safety reports submitted to relevant regulatory authorities, as per the contact information below.  All 
SAEs must be reported whether or not considered causally related to the study drug.  SAE forms 
will be provided to each clinical study site.  The information collected will include patient 
number, a narrative description of the event and an assessment by the Investigator as to the 
severity of the event and relatedness to study drug.  A sample of the SAE form can be found in 
the study manual.  Follow-up information on the SAE may be requested by CUMC and 
Acetylon. 
 
 
 
 
INC Drug Safety on behalf of Acetylon  - Drug Safety Reporting Contact Information 
INC 24 Hour SAE Reporting 
E-mail:  incdrugsafety@incresearch.com 
Fax:  1 (877) 464-7787 
 
If there are serious, unexpected adverse drug reactions associated with the use of the study drug, 
the Sponsor will notify the appropriate regulatory agency(ies) and all participating Investigators 
Jennifer Amengual, MD 
212-326-5720 


 
 
30 
on an expedited basis.  It is the responsibility of the Investigator to promptly notify the 
Institutional Review Board (IRB) of all unexpected serious adverse drug reactions involving risk 
to human patients.  An unexpected event is one that is not reported in the Investigator’s 
Brochure. 
7.4.3 AE and SAE Definitions 
 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.   A copy of the CTCAE version 4.0 can be found 
online (see http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf.).   
 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.2 above) for 
expedited reporting purposes only.   
 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.4.4 Report of Adverse Events to the Institutional Review Board 
Reportable information should always be reported by the PI directly to the IRB within 5 working 
days from when the PI learns of the event or new information.    
7.4.5 Investigator Reporting to the FDA 
The investigator is responsible for reporting any SAEs to the FDA.  Serious adverse events 
(SAEs) that are unlisted/unexpected, and at least possibly associated to the drug, and that have 
not previously been reported in the Investigators brochure, or reference safety information 
document should be reported promptly to the Food and Drug Administration (FDA) by telephone 
(1-800-332-1088), fax (1-800-FDA-0178).  Fatal or life threatening SAEs that meet the criteria 
for reporting to the FDA must be reported to the FDA within 7 calendar days after awareness of 
the event.  All other SAEs that meet the criteria for reporting to the FDA must be reported to the 
FDA within 15 calendar days after awareness of the event.  A clear description of the suspected 
reaction should be provided along with an assessment as to whether the event is drug or disease 
related.    
7.4.6 Adverse event updates/IND safety reports 
Acetylon shall notify the Investigator via an IND Safety Report of the following information: 
 
 
Any AE associated with the use of drug in this study or in other studies that is both 
serious and unexpected. 
 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 


 
 
31 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected 
AE(s) or significant risks to subjects. 
 
The Investigator must keep copies of all AE information, including correspondence with 
Acetylon and the IRB/EC, on file (see Section 14.8 for records retention information). 
 
7.4.7   Expedited Reporting Guidelines  
 
Note:  All deaths on study require expedited reporting regardless of causality.  Attribution 
to treatment or other cause must be provided. 
 
 
Expedited AE reporting timelines defined: 
 “1 business day; 5 calendar days” – The investigator must initially report the AE 
within 1 business day of learning of the event followed by a complete report 
within 5 calendar days of the initial 24-hour report. 
 “10 calendar days” - A complete report on the AE must be submitted within 10 
calendar days of the investigator learning of the event.  
 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions.   
 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported if the event occurs following treatment. 
 
7.4.8 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol, certain AEs/grades are exceptions to the Expedited Reporting Guidelines and 
do not require expedited reporting.  The following AEs must be reported through the routine 
reporting mechanism (Section 7): 
 
Table 3: CTCAE AE Reporting Exclusions 
 
CTCAE Category 
 
Adverse Event 
 
Grade 
Hospitalization/  
Prolongation of  
Hospitalization 
 
Attribution 
Blood/Bone 
Marrow 
Neutropenia <7 days without  
fever 
4 
No 
Yes 
Blood/ Bone 
Marrow 
Thrombocyotopenia <7 days  
without bleeding 
4 
No 
Yes 
 
7.4.9 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.   
 
For 30 days subsequent to study completion or withdrawal, new onset adverse events will be 
captured.  Follow up of these events will follow the same procedure as described above for AEs 
observed during the study period. 
 


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33 
 
Tumor Tissue Biopsies: The biopsies will be performed by a surgeon if necessary, or by 
interventional radiology.  A cytopathologist will evaluate the biopsy for tumor cells 
microscopically at the time of the biopsy.  If multiple lymph nodes are available, the safest 
lymph node will be selected. The choice of core biopsy versus incisional or excisional biopsy 
will be made based on safety, accessibility, and likelihood of being pathologic.  A biopsy 
confirming recurrent or refractory disease is mandatory for participation in study.  The second 
biopsy is encouraged, but is not mandatory. Correlative studies will be performed on de-
identified tissue samples. Tissue will be labeled only with the protocol-specific unique identifier.  
If the patient has a single target lesion, this lesion will not be eligible for correlative biopsy. 
 
8.2.2 Handling of Specimens 
 
All biopsies will be snap-frozen and sent to Surgical Pathology, flagged for use in the protocol.  
Paraffin blocks will be made to confirm histological diagnosis, and appropriate 
immunohistochemical staining will be performed. Remaining tissue will be used for the 
pharmacodynamic analysis.  
 
Samples from collaborating institutions may be processed and stored with batched delivery at 
completion of accrual.  All correlative studies will occur once all the samples have been 
received.  Details regarding obtaining, processing, handling, and shipping samples will be 
outlined in the provided laboratory manual. 
 
8.2.3 Serum collection 
 
Serum will be collected to assess for changes in IL6 and IL10 secretion following administration 
of study drug. After centrifuge, serum will be stored in polypopylene screw to tube at -80oC until 
evaluation. 
 
 
 
9. Study Calendar 
 
Baseline evaluations are to be conducted as indicated in the table below, prior to start of protocol 
therapy.  Scans must be done <4 weeks prior to the start of therapy.  In the event that the 
patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. 
 
 
 
 
 
 
 
 
 
 
 


 
 
34 
 
 
 
 
 
 
 
Table 4. Study Calendar 
 
Cycle 
 
                      1 
     
2 - onward 
 
 
 
Screening 
Day 1 
Day 2 
Day 8 
Day 15 
    Day 1 
End of Treatmentj 
End of Study (4 weeks 
after last dose) k 
Follow-up 
Eligibility & 
Safety 
Monitoring 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
Xe 
 
 
 
 
 
 
 
 
Demographics 
Xe 
 
 
 
 
 
 
 
 
Medical History 
Xe 
 
 
 
 
 
 
 
 
Concurrent 
Medications 
Xf  
Xh 
 
 
 
X 
X 
X 
X 
Physical exam 
Xf  
Xh 
 
 
 
X 
X 
X 
X 
Vital Signs, 
weight 
Xf 
X 
 
 
 
X 
X 
X 
X 
Performance 
Status  
Xf 
X 
 
 
 
X 
X 
X 
X 
CBC w/ 
differential 
Xf 
Xh 
 
 
 
X 
X 
X 
X 
Chemistriesa 
Xf 
Xh 
 
 
 
X 
X 
X 
X 
EKG 
Xe 
X 
 
 
 
 
 
 
 
Toxicity 
Assessment 
 
 
X 
X 
X 
X 
   X 
X 
X 
Serum -hCG 
Xf 
X 
 
 
 
X 
X 
 
 
Urinalysis 
Xe 
Xh 
 
 
 
X 
 
 
 
Creatinine 
clearance 
X 
X 
 
 
 
X 
 
 
 
Efficacy 
Measurements 
 
 
 
 
 
 
 
 
 
CT (PET/CT 
optional) 
Xe 
 
 
 
 
 
 
 
 
Bone Marrow 
Biopsy 
Xc 
 
 
 
 
 
 
 
 
Lymph Node 
Assessment 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
a) Chemistries include: Chem, Mg, K, Hepatic Function Panel, and LDH.   
b) CT (PET optional) to occur within 7 days prior to starting cycle 3.  The CT will be repeated per investigator 
discretion but at least every six months, PET/CT is optional.   
c) Bone Marrow biopsy will be required after cycle 2 for patients with bone marrow involvement at baseline who have 
a complete response by imaging and physical exam 
d) PK for ACY-1215:  See section 8 for details. 
e) To be done within 4 weeks of treatment start date 
f) To be done within 1 week of treatment start date 
g) To be performed at the discretion of the treating investigator 
h) Not necessary if conducted within 72 hours of screening assessment 
i) To be performed on C1D1 pre-dose  
j) Follow-up visits will be every 3 months for 1 year, until the development of progressive disease or until the patient 
begins a new treatment for their disease.  . 
k) May be done +/- 7 days 
ALL SCHEDULED EVENTS +/- 2 DAYS 
 
 


 
 
35 
 
10. 
Measurement of Effect 
 
The following section describes the anti-tumor measurements that will be obtained during the 
study.  Response will be evaluated with physical exam, computerized tomography (CT) and 
optional Positron emission tomography (PET) scans, and tissue biopsies as defined by the 
guidelines of the International Harmonization Project Group 2007 Revised Response Criteria 
[27]. 
10.1 Imaging Studies 
CT, and optional PET scans are to be performed during Screening and within 7 days prior to 
starting Cycle 3.  The CT, and optional PET scans will be done at Investigator’s discretion 
thereafter, but not longer than every 6 months.  Either CT or PET/CT scan may utilized, at the 
discretion of the investigator. 
Other appropriate imaging studies (e.g., MRI, CT, X-ray) to document sites of disease are to be 
performed during Screening per standard of care, as determined by the Investigator.  Appropriate 
imaging studies are to be repeated as necessary to confirm CR. 
10.2 Bone Marrow Examination 
Optional bone marrow aspiration and trephine biopsy are to be performed for patients during 
Screening.  Bone marrow aspiration and biopsy are to be repeated during treatment as clinically 
indicated, at the Investigator’s discretion, and in order to confirm CR.   
 
10.3 
Assessment of Disease Response 
 
After discontinuation of therapy, patients are to have disease response assessed at the discretion 
of the treating physician, but not longer than every 6 months. Bone Marrow biopsy will be 
required after cycle 2 for patients with bone marrow involvement at baseline who have a 
complete response by imaging and physical exam 
10.3.1 Definitions 
Evaluable for objective response.  Patients who have received at least one day of therapy, and 
have had their disease re-evaluated will be considered evaluable for response.  These patients 
will have their response classified according to the definitions stated below.  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered. 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
two dimension (longest diameter to be recorded) as >20 mm with conventional techniques 
(PET/CT, MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements will be 
recorded in millimeters (or decimal fractions of centimeters).  Tumor volume will be recorded as 
the sum of the product of the diameters (SPD) of the largest predominant target lesions.  
 
FDG avidity is based on comparison with background tissues.  There is no specific SUV value 
that is considered a cut-off. 
 
Non-measurable disease (evaluable disease).  All other lesions (or sites of disease), including 


 
 
36 
small lesions (<10 mm using spiral CT scan), are considered non-measurable disease.  Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), 
and cystic lesions are all non-measurable. 
 
Target lesions.  All measurable lesions up to a maximum of 6 lesions total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their SUV avidity (High SUV lesions will be 
prioritized, even if not the largest lesions) and size (lesions with the largest SPD diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or clinically).  
An SPD for all target lesions will be calculated and reported as the baseline sum SPD.  The 
baseline sum SPD will be used as reference by which to characterize the objective tumor 
response based on CT criteria. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 6 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.  
 
10.3.2 Methods for Evaluation of Measurable Disease in Lymphoma 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by  
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
CT, PET/CT and MRI: These techniques should be performed with cuts of 10 mm or less in slice 
thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and neck tumors and 
those of extremities usually require specific protocols. 
 
Ultrasound (US): Will not be used for disease assessment 
 
 
 
 
10.4 
Response Criteria 
 
10.4.1 Evaluation of Measurable Disease in Lymphoma  


 
 
37 
 
Table 5 outlines the response criteria used to evaluate disease response to therapy. 
 
Table 5 : Response Criteria for NHL 
Response 
Definition 
Nodal Masses 
Spleen/Liver 
Bone Marrow CR 
CR 
Disappearance of all 
evidence 
of disease 
a) FDG-avid or PET positive 
prior to therapy; mass 
of any size permitted if PET 
negative 
(b) Variably FDG-avid or PET 
negative; regression to 
normal size on CT 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared on 
repeat 
biopsy; if 
indeterminate 
by morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable 
disease and no new 
sites 
50% decrease in SPD of up to 6 
largest dominant 
masses; no increase in size of 
other nodes 
(a) FDG-avid or PET positive 
prior to therapy; one or 
more PET positive at previously 
involved site 
(b) Variably FDG-avid or PET 
negative; regression on CT 
50% decrease in 
SPD of nodules 
(for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of 
liver or spleen 
Irrelevant if positive 
prior 
to therapy; cell type 
should be specified 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET positive 
prior to therapy; PET 
positive at prior sites of disease 
and no new sites 
on CT or PET 
(b) Variably FDG-avid or PET 
negative; no change in 
size of previous lesions on CT 
 
 
Relapsed or 
PD 
Any new lesion or 
increase 
by   50% of 
previously 
involved sites from 
nadir 
Appearance of a new lesion(s)   
1.5 cm in any axis, 
  50% increase in SPD of more 
than one node, 
or   50% increase in longest 
diameter of a 
previously identified node   1 
cm in short axis 
Lesions PET positive if FDG-
avid lymphoma or PET 
positive prior to therapy 
50% increase 
from 
nadir in the SPD 
of 
any previous 
lesions 
New or recurrent 
involvement 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, 
computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, 
progressive disease. 
 
10.4.2 Response Definitions 
 
Complete Response (CR): Disappearance of all non-target lesions by PET/CT 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 


 
 
38 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
10.4.3 Evaluation of Best Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
10.4.4    Overall Response Rate 
 
Overall Response Rate (OR) = CR + PR based on evaluation of best response in each patient. 
 
11.  
Data Reporting / Regulatory Requirements 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
11.1 
 Data Reporting 
 
11.1.1.1 
Monitoring 
 
The Institutional Review Board (IRB) at each respective institution will monitor this study. 
 
11.1.2 Responsibility for Data Submission 
 
The Study Coordinator is responsible for compiling data for all participants and for providing the 
data to the Study Chair for review.   
 
11.2  Data Safety Monitoring Board  
 
The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center’s 
Data Safety Monitoring Board (DSMB) will oversee conduct of the study, patient safety and all  
interim analyses as specified in the data analysis plan.  Detailed guidelines regarding the  
structure, function and decision-making mechanisms for the Data Safety Monitoring Board are  
provided in the DSMB charter. 
11.3 Investigator Reporting Responsibilities and Compliance 
The conduct of the study will comply with all FDA safety reporting requirements.   
 
During the course of the study, the Sponsor may determine that certain safety reports are 
required to comply with regulations.  The Sponsor is responsible for submission of such reports 
to their IND.  The Investigator may receive a letter called an “IND Safety Report” from this 
study and/or other Acetylon sponsored studies (cross reports). These reports are required to be 
submitted to the IRB/EC. 


 
 
39 
 
11.4  Study auditing 
 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) 
and in the US Code of Federal Regulations. 
 
Investigators must enter study data onto CRFs or other data collection system.  The Investigator 
will permit study-related audits by CUMC, Acetylon or its representatives, IRB/EC review, and 
regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the facilities where 
the study took place, to source documents, to CRFs, and to all other study documents. 
 
11.5     Protocol amendments 
 
Any amendment to this protocol must be agreed to by the Principal Investigator and reviewed by 
CUMC and Acetylon.  Amendments should only be submitted to IRB/EC after consideration 
from CUMC and Acetylon review.  Written verification of IRB/EC approval will be obtained 
before any amendment is implemented.   
 
12.  
Statistical Considerations 
 
12.1 
Statistical Methods 
 
12.1.1 Phase Ib: 
 
The study will follow the similar principles of a standard 3+3 dose escalation study in which less 
than one third of patients enrolled to a particular Arm must not have a dose limiting toxicity to 
allow for expansion. Three patients will be sequentially enrolled in one of two cohorts: Arm A 
and then after a safety assessment has occurred, Arm B for a total of six patients (3 in each arm).  
If ≤33% of patients (N≤1) experiences a dose limiting toxicity (DLT) in a cohort, the cohort will 
be expanded to 6 patients.  If there are ≤ 33% (N≤ 2 DLTs), the cohort will be further expanded 
to a total of 10 patients (3+3+4).  The total number of patients for both Arms A and B with full 
expansions will total of 20.   If more than 1/3 or 2/6 patients experience a DLT, there will be no 
expansion.  Safety data obtained from this Phase Ib will be analyzed by the sponsor and 
collaborating investigators to recommend a Phase II dose. 
 
12.1.2 Phase II: 
 
The study will employ the minimax Simon 2-stage design.  In Stage 1, 22 patients will be 
enrolled.  If <2 patients experience an objective tumor response (defined as CR, or PR, as 
outlined by the 2007 International Harmonization Project criteria), the study will be 
discontinued.  If 2 or more of the first 22 patients experiences CR, or PR, additional 18 patients 
will be enrolled in Stage 2.  Enrollment into Stage 2 will begin only after least 2 objective 
response have been observed in Stage 1.  (Enrollment into Stage 2 need not be delayed until the 
response status of all 22 Stage 1 patients is known.)  The design parameters are as follows:  
 
 0.15:  unacceptable response rate. 


 
 
40 
 0.25:  target response rate. 
 α =0.05:  the probability of declaring the drug effective when the true response 
probability is less or equal to 0.15. 
 β=0.20:  the probability of declaring the drug as not effective when its true response 
probability is as large or larger than the target response rate 0.30. 
Once enrollment begins for stage 2 of the study, an additional 20 patients will be enrolled per 
lymphoma subtype, specifically Mantle Cell Lymphoma. Therefore the total number of patients 
estimated to be enrolled is 60. 
12.2 Disposition of Patients 
Patients who are screened for study entry and do not meet the eligibility criteria will be listed.  
Reasons for study discontinuation after the start of study treatment will be tabulated. 
12.3 
Analysis of Primary and Secondary Endpoints  
 
12.3.1 Phase Ib 
 
12.3.1.1 Primary Objective: Safety and tolerability of ACY-1215 monotherapy 
 
Analysis of dose limiting toxicities will be assessed for Arm A and Arm B of the Phase Ib.  If 
more than 1/3 or 2/6 patients experience a DLT, enrollment into the cohort will be stopped. 
Safety data obtained from this Phase Ib will be analyzed by the sponsor and collaborating 
investigators to recommend a Phase II dose. 
 
12.3.2 Phase II 
 
12.3.2.1 Primary Objective: Activity Analysis  
Efficacy endpoints in this study include defining the proportion of patients with disease response 
(CR+PR). 
CR, PR, and SD are to be determined according to the International Harmonization Project 
revised Criteria (2007), Patients who discontinue the study before response evaluation will be 
considered un-evaluable.  
In the expansion cohort, analysis for activity in mantle cell lymphoma will be measured for 
proportion of patients with disease response (CR+PR) determined according to the International 
Harmonization Project revised Criteria (2007). Patients who discontinue the study before 
response evaluation will be considered un-evaluable. 
For responding patients, the duration of response and time to progression will be reported on a 
per-patient basis.   
Data that may further characterize the activity of ACY-1215 will be summarized and assessed 
for a potential dose-response relationship. 
Overall response rates will be estimated upon completion of the study along with exact 95% 
confidence intervals.  
 
12.3.2.2 Secondary Objectives 
 


 
 
41 
Pharmacokinetic Analysis 
Study drug serum concentrations will be determined at all pre- and post-dose timepoints.  
Parameters to be calculated based on a non-compartmental model approach include: 
 Cmax. 
 Minimum observed serum concentration (Cmin). 
 Tmax. 
 Area under the serum concentration time curve (AUC), for time 0 to the last observed value 
and to the last measurable value, and from time 0 extrapolated to infinity. 
 Half-life (t1/2). 
ACY-1215 serum levels will be tabulated as single- and multiple-PK doses and results will be 
presented. 
Pharmacodynamic Analysis 
Details regarding the analysis of pharmacodynamic data will be included in the statistical 
analysis plan. 
 
 
12.4 Demographics and Baseline Characteristics 
Demographic and baseline disease characteristic data summarization will be performed in order 
to descriptively assess the outcomes related to lymphoma subtype.  Data to be tabulated will 
include at least demographic features such as sex, age and race, height, and weight as well as 
disease-specific status and medical history. 
12.5 Extent of Exposure 
Descriptive statistics for patients treated in and completing each treatment cycle, including the 
number of doses missed or held and dose reductions required, will be presented for each 
treatment cycle.  Furthermore, descriptive statistics for the number of doses received, percent of 
expected dose received, and actual dose received will be summarized by treatment cycle.  A 
tabular summary and listing of drug administration and dose intensity by treatment cycle and a 
by-patient listing of the date and time of each study drug dose and the dose administered also 
will be presented.   
12.6 Concomitant Medications 
A tabulation of all concomitant medications will be produced, with concomitant medications 
coded using the World Health Organization (WHO) drug dictionary.  All concomitant 
medications administered will be presented in a data listing.   
12.7 Safety Analysis 
Safety evaluations will be based on the incidence, intensity, and type of adverse events, and 
changes in the patient’s physical examination findings, vital signs, ECG findings, and clinical 
laboratory results.  Safety variables will be tabulated and presented for all patients who receive 
any amount of study drug and have follow-up safety data.  Summarization will focus on 
occurrence rates of: any serious adverse events; treatment-emergent adverse events by system 
organ class (SOC) and preferred term; discontinuation rates of study therapy due to adverse 
event or toxicity based on clinical laboratory assessment and rates of hematologic toxicity.  The 


 
 
42 
frequency of DLT by dose cohort also will be summarized.   
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
for purposes of summarization.  All adverse events occurring on study will be listed in by-patient 
data listings.  Treatment-emergent events will be tabulated, where treatment-emergent is defined 
as any adverse event that occurs after administration of the first dose of study drug and through 
30 days after the last dose of study drug, any event that is considered drug-related regardless of 
the start date of the event, or any event that is present at Baseline but worsens in intensity or is 
subsequently considered drug-related by the Investigator.   
Events that are considered related to treatment (possibly or probably drug-related) will also be 
tabulated; it should be noted, however, that without a control the primary safety conclusions 
must be based on overall incidence rates, not those considered treatment-related.   
A tabulation will also be provided that enumerates adverse events by maximum severity.   
Deaths, serious adverse events, and events resulting in study discontinuation will be tabulated.   
Change from Baseline in clinical laboratory parameters will be summarized across time on study, 
and the frequency of clinically significant abnormal laboratory values will be tabulated.  Shift 
tables will be produced for selected laboratory parameters, to include at least hemoglobin, WBC 
count, ANC, absolute lymphocyte count, platelet count, AST, ALT, bilirubin, creatinine, ALP, 
and electrolytes.  These tables will summarize by cycle the number of patients with each baseline 
CTCAE grade and changes to the maximum CTCAE grade in the cycle. 
Changes in vital sign parameters (including systolic and diastolic blood pressure, heart rate, 
respiration rate, and temperature) will be summarized over time in a similar fashion to laboratory 
parameters, and any abnormal values will be tabulated.  Changes in ECG findings will be 
presented in data listing format. 
Karnofsky/ECOG performance status will be summarized for changes from Baseline to the Final 
Study Visit; Karnofsky/ECOG performance status on D1 of each treatment cycle will be 
presented in data listing format. 
Additional safety analyses may be determined at any time without prejudice, in order to most 
clearly enumerate rates of toxicities and to define further the safety profile of ACY-1215. 
 
12.8      Populations for Analysis 
Patients will be evaluable for response in the context of the Simon 2-stage methodology. 
Safety analyses will be performed on the safety population, defined as all patients who receive 
any amount of study drug.   
The evaluation of drug-specific toxicity will be based on data from patients who receive  1 dose 
of ACY-1215.   
12.9 
Analysis Schedule 
 
12.9.1 Interim Analysis 
 
12.9.1.1 Phase Ib 
 
Upon enrollment of three patients into Arm A and then after a safety assessment has occurred,  


 
 
43 
Arm B, no additional patients will be accrued until completion of cycle one to adequately 
evaluate for dose limiting toxicities.  Following determination of <1/3 of patients experiencing a 
DLT 3 additional patients will be enrolled for a total of 6 patients per Arm.  If < 1/3 or < 2/6 
patients experience a DLT, planned accrual will expand to a maximum of 10 patients in each 
arm.  The Phase II study will not begin until all 10 patients have completed one full cycle of 
therapy. 
 
12.9.1.2 Phase II 
Interim analysis will be performed following accrual of the first 22 patients to ensure a response 
rate of at least 10% to proceed to stage 2 of accrual.  An early stopping rule will be in effect if 
<10% of patients achieve a response.  If >10% achieve a response, Stage 2 will proceed. 
12.9.2   Final Analysis 
A final analysis is planned after all enrolled patients either complete 6 cycles of study treatment, 
or their final study visit, or following early withdrawal from the study.   
12.9.3 Addendum 
An addendum to the final analysis will be prepared when all patients have withdrawn from the 
study.  
12.10 Procedures for Handling Missing, Unused, and Spurious Data 
All available safety, PK, pharmacodynamic, and activity data will be included in data listings 
and tabulations.  No imputation of values for missing data will be performed. 
12.11 Procedures for Reporting Deviations to Original Statistical Analysis Plan 
A formal statistical plan for the analysis and presentation of data from this study will be prepared 
before database lock.  Deviations from the statistical analyses outlined in this protocol will be 
indicated in this plan; any further modifications will be noted in the final clinical study report. 
 
13.  
Accrual Rate 
 
We estimate accrual of an average of 6 patients per month across the study centers, with a goal 
of completing accrual within 12-18 months. 
 
14. Administrative Requirements  
 
14.1 Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonization 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
Investigator will be thoroughly familiar with the appropriate use of the study drug as described in 
the protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations.   
14.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 


 
 
44 
Helsinki (see Appendix).  The IRB will review all appropriate study documentation in order to 
safeguard the rights, safety, and well-being of the patients.  The study will only be conducted at 
sites where IRB approval has been obtained.  The protocol, Investigator’s Brochure, informed 
consent, advertisements (if applicable), written information given to the patients (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB by the Investigator. 
14.3 Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative prior to study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent will comply 
with ICH-GCP and all applicable regulatory requirement(s). 
14.4 Patient Confidentiality 
In order to maintain patient privacy, all CRFs, study drug accountability records, study reports, 
and communications will identify the patient by initials and the assigned patient number.  The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authority(ies) access to the patient’s original medical records for verification of data gathered on 
the CRFs and to audit the data collection process.  The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
14.5 Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by Acetylon, 
and given approval/favorable opinion by the IRB and the appropriate regulatory authority(ies).  
Modifications to the protocol should not be made without agreement of both the Investigator and 
Acetylon.  Changes to the protocol will require written IRB approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients.  The IRB may provide, if applicable regulatory authority(ies) permit, expedited review 
and approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB.  Acetylon will submit all protocol modifications to the regulatory 
authority(ies) in accordance with the governing regulations.  
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the study coordinator at CUMC, the Sponsor or designee, if 
circumstances permit, to discuss the planned course of action.  Any departures from the protocol 
must be fully documented in the CRF and source documentation.   
14.6 Direct Access to Source Data 
Monitoring and auditing procedures developed by CUMC, the Sponsor or designee will be 
followed, in order to comply with GCP guidelines.   
The study will be monitored by CUMC, Acetylon or its designee.  Monitoring will be done by 
personal visits from a representative of CUMC, the Sponsor (site monitor) and will include on-
site review of the CRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed.  The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. 
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, telephone, and facsimile). 


 
 
45 
All unused study drug and other study materials are to be returned to Acetylon after the clinical 
phase of the study has been completed. 
Regulatory authorities, the IRB, and/or Acetylon’s clinical quality assurance group may request 
access to all source documents, CRFs, and other study documentation for on-site audit or 
inspection.  Direct access to these documents must be guaranteed by the Investigator, who must 
provide support at all times for these activities. 
14.7 Case Report Form Completion 
CUMC will provide the study centers with CRFs for each patient. 
CRFs will be completed for each study patient.  It is the Investigator’s responsibility to ensure 
the accuracy, completeness, and timeliness of the data reported in the patient’s CRF.  Source 
documentation supporting the CRF data should indicate the patient’s participation in the study 
and should document the dates and details of study procedures, adverse events, and patient 
status.   
The Investigator, or designated representative, should complete the CRF pages as soon as 
possible after information is collected, preferably on the same day that a patient is seen for an 
examination, treatment, or any other study procedure.  Any outstanding entries must be 
completed immediately after the final examination.  An explanation should be given for all 
missing data. 
The Investigator must sign and date the Investigator’s Statement at the end of the CRF to endorse 
the recorded data.   
CUMC will retain the originals of all CRFs.  The Investigator will retain a copy of all completed 
CRF pages. 
14.8 Record Retention 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).  Records will be retained for at least two years after the last marketing 
application approval or two years after formal discontinuation of the clinical development of the 
investigational product or according to applicable regulatory requirement(s).  If the Investigator 
withdraws from the responsibility of keeping the study records, custody must be transferred to a 
person willing to accept the responsibility.  The Sponsor must be notified in writing if a custodial 
change occurs. 
14.9 Liability and Insurance 
Acetylon has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating persons and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards. 
14.10 Publication of Study Findings and Use of Information 
All information regarding ACY-1215 supplied by the Sponsor to the Investigator is privileged 
and confidential information.  The Investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from Acetylon.  It is understood that 
there is an obligation to provide CUMC and the Sponsor with complete data obtained during the 
study.  The information obtained from the clinical study will be used towards the development of 
ACY-1215 and may be disclosed to regulatory authority(ies), other Investigators, corporate 


 
 
46 
partners, or consultants as required.   
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal.  A Publications Committee, 
comprised of Investigators participating in the study and representatives from Acetylon, as 
appropriate, will be formed to oversee the publication of the study results, which will reflect the 
experience of all participating study centers.  Subsequently, individual Investigators may publish 
results from the study in compliance with their agreement with the Sponsor. 
A pre-publication manuscript is to be provided to Acetylon at least 30 days prior to the 
submission of the manuscript to a publisher.  Similarly, the Sponsor will provide any company 
prepared manuscript to the Investigators for review at least 30 days prior to submission to a 
publisher. 
 
 


 
 
47 
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Atlanta, GA. 
28. 
Acetylon Pharmaceuticals, Inc.  Investigator’s Brochure for ACY-1215, Version 2.0, 
24 January 2012. 
29. Amengual JE, Johannet PM, Jones SS, O’Connor OA. Dual Targeting of Protein Degradation 
Pathways with the Selective HDAC6 Inhibitor Rocilinostat (ACY-1215) and Bortezomib, 
Demonstrates Synergistic Antitumor Activity in Preclinical Models of Lymphoma. Blood (ASH 
Annual Meeting Abstracts – Poster Presentation), Dec 2012; Abstract 1650. 
 
 
 
 


 
 
49 
APPENDIX 
 
Karnofsky Performance Status Scale 
The following table presents the Karnofsky performance status scale: 
Points 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self unable to carry on normal activity or to do active work 
60 
Required occasional assistance but is able to care for most of his/her needs 
50 
Required considerable assistance and frequent medical care 
40 
Disabled; required special care and assistance 
30 
Severely disabled; hospitalization indicated.  Death not imminent 
20 
Very sick; hospitalization necessary; active support treatment necessary 
10 
Moribund; fatal processed progressing rapidly 
0 
Dead 
Source:  Mor V, Laliberte L, Morris JN, Wiemann M.  The Karnofsky Performance Status Scale:  an examination of its reliability 
and validity in a research setting.  Cancer 1984;53:2002-2007. 
 
ECOG PS 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 


 
 
50 
Creatinine Clearance Calculation 
Calculate creatinine clearance for males and females as follows: 
In males: 









dL
mg
creatinine
kg
weight
age
/
72
140



 
In females: 









85
.0
/
72
140




dL
mg
creatinine
kg
weight
age
 
 
New York Heart Association Classification of Heart Failure 
Class 
Symptomatology 
I 
No symptoms.  Ordinary physical activity such as walking and climbing stairs does 
not cause fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity.  Walking or climbing stairs rapidly, 
walking uphill, walking or stair climbing after meals, in cold weather, in wind or 
when under emotional stress causes undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity.  Walking one to two blocks on 
the level and climbing more than one flight of stairs in normal conditions causes 
undue fatigue or dyspnea. 
IV 
Symptoms at rest.  Inability to carry on any physical activity without fatigue or 
dyspnea. 
 
Toxicity Grading Scale 
The NCI CTCAE, Version 4.0, can be accessed using the following link:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
 


 
 
51 
Declaration of Helsinki 
World Medical Association Declaration of Helsinki: 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, 
Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th 
WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 52nd 
WMA General Assembly, Edinburgh, Scotland, October 2000 
INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human subjects.  Medical research involving human subjects includes 
research on identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people.  The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the patient's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the patient." 
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
5. In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the 
aetiology and pathogenesis of disease.  Even the best proven prophylactic, diagnostic, 
and therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human beings 
and protect their health and rights.  Some research populations are vulnerable and need 
special protection.  The particular needs of the economically and medically 
disadvantaged must be recognized.  Special attention is also required for those who 
cannot give or refuse consent for themselves, for those who may be subject to giving 
consent under duress, for those who will not benefit personally from the research and for 
those for whom the research is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration. 
 


 
 
52 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
10. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
11. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation. 
12. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
13. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol.  This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
Investigator, the Sponsor or any other kind of undue influence.  This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed.  The committee has the right to monitor ongoing 
trials.  The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events.  The researcher should also submit to 
the committee, for review, information regarding funding, Sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
14. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration. 
15. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  
The responsibility for the human subject must always rest with a medically qualified 
person and never rest on the subject of the research, even though the subject has given 
consent. 
16. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the subject or to others.  This does not preclude the participation of healthy volunteers in 
medical research.  The design of all studies should be publicly available. 
17. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can 
be satisfactorily managed.  Physicians should cease any investigation if the risks are 
found to outweigh the potential benefits or if there is conclusive proof of positive and 
beneficial results. 
18. Medical research involving human subjects should only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the subject.  This is 
especially important when the human subjects are healthy volunteers. 
19. Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
20. The subjects must be volunteers and informed participants in the research project. 
21. The right of research subjects to safeguard their integrity must always be respected.  
Every precaution should be taken to respect the privacy of the subject, the confidentiality 


 
 
53 
of the patient's information and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
22. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail.  The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal.  After ensuring that the subject has understood the information, the physician 
should then obtain the subject's freely-given informed consent, preferably in writing.  If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
23. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress.  In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
24. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the Investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law.  
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
25. When a subject deemed legally incompetent, such as a minor child, is able to give assent 
to decisions about participation in research, the Investigator must obtain that assent in 
addition to the consent of the legally authorized representative. 
26. Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population.  The 
specific reasons for involving research subjects with a condition that renders them unable 
to give informed consent should be stated in the experimental protocol for consideration 
and approval of the review committee.  The protocol should state that consent to remain 
in the research should be obtained as soon as possible from the individual or a legally 
authorized surrogate. 
27. Both authors and publishers have ethical obligations.  In publication of the results of 
research, the Investigators are obliged to preserve the accuracy of the results.  Negative as 
well as positive results should be published or otherwise publicly available.  Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared 
in the publication.  Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
28. The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value.  
When medical research is combined with medical care, additional standards apply to 
protect the patients who are research subjects. 


 
 
54 
29. The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods.  This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 
30. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by 
the study. 
31. The physician should fully inform the patient which aspects of the care are related to the 
research.  The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician's judgement it offers hope of saving life, re-establishing 
health or alleviating suffering.  Where possible, these measures should be made the 
object of research, designed to evaluate their safety and efficacy.  In all cases, new 
information should be recorded and, where appropriate, published.  The other relevant 
guidelines of this Declaration should be followed.