Conditions: Multiple Myeloma
Keywords: Multiple Myeloma Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Blood Protein Disorders Hematologic Diseases Dexamethasone Dexamethasone acetate Pomalidomide
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 103
Healthy volunteers: no

Brief summary:
Phase 1b: To evaluate the side effects and determine the best dose of ACY-1215 in combination with Pomalidomide and low-dose dexamethasone in patients with relapsed-and-refractory multiple myeloma.

Phase 2: To determine the overall response rate of ACY-1215 in combination with Pomolidomide and low-dose dexamethasone in patients with relapsed-and-refractory multiple myeloma

Detailed description:

Arms:
arm 1: ACY-1215 (Ricolinostat) in combination with pomalidomide and dexamethasone

Interventions: intervention 1: ACY-1215 (Ricolinostat) in combination with pomalidomide and dexamethasone
Intervention descriptions: intervention 1: ACY-1215 (Ricolinostat) 160mg QD Days 1-21 with pomalidomide 4mg QD Days 1-21 and dexamethasone 40mg QD Days 1,8,15,22 of a 28-day cycle

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Phase 1B/2 Multi-Center, Open Label, Dose-Escalation Study to Determine the Maximum Tolerated 
Dose, Safety, and Efficacy of ACY-1215 (RICOLINOSTAT) in Combination With Pomalidomide and 
Low-Dose Dexamethasone in Patients With Relapsed and Refractory Multiple Myeloma 
 
NCT Number: NCT01997840 
Document Date (Date in which document was last revised): 12 July 2016 


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CLINICAL STUDY PROTOCOL 
Protocol ACE-MM-102 
EudraCT Number: 2014-002338-29 
 
A PHASE 1B/2 MULTI-CENTER, OPEN LABEL, DOSE- ESCALATION 
STUDY TO DETERMINE THE MAXIMUM TOLERATED DOSE, 
SAFETY, AND EFFICACY OF ACY-1215 (RICOLINOSTAT) IN 
COMBINATION WITH POMALIDOMIDE AND LOW-DOSE 
DEXAMETHASONE IN PATIENTS WITH RELAPSED-AND- 
REFRACTORY MULTIPLE MYELOMA 
 
This study will be conducted according to the protocol and in compliance with 
Good Clinical Practice, the ethical principles stated in the Declaration of Helsinki, 
and other applicable regulatory requirements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Sponsor: 
Acetylon Pharmaceuticals, Inc. 
Seaport Center 
70 Fargo Street, Suite 205 
Boston, MA 02210-2138 
Document Version (Date): 
Original (15 August 2013) 
Amendment (7 April 2014) 
Amendment 2 (21 Aug 2014) 
Amendment 2.1 Greece (16 Jan 2015) 
Amendment 3 (09 February 2015) 
Amendment 4 (12 July 2016) 


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CONFIDENTIALITY NOTE:Acetylon 
The information contained in this document is privileged and confidential. Any distribution, copying, or 
disclosure is strictly prohibited unless such disclosure is required by federal regulations or state law. 
Persons to whom the information is disclosed must know that it is confidential and that it may not be 
further disclosed by them. 


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STUDY PERSONNEL AND ADMINISTRATIVE STRUCTURE 
 
Study Sponsor: 
Acetylon Pharmaceuticals, Inc. 
Seaport Center 
70 Fargo Street, Suite 205 
Boston, MA 02210-2138 
Sponsor Contact: 
 
Clinical Project Manager 
Telephone: 
Fax: 
E-mail: 
Sponsor Medical Monitor: 
Acetylon Pharmaceuticals, Inc. 
Telephone (office): 
Telephone (mobile): 
E-mail: 
CRO Safety Monitor: 
 
Medical Officer 
INC Safety Monitor 
Telephone: 
E-mail: 
Fax: 
SAE Reporting: 
24-Hour SAE Reporting 
E-mail: 
Fax: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol ACE-MM-102 
ACY-1215 
12 July 2016 
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INVESTIGATOR STATEMENT 
 
I understand that all documentation provided to me by Acetylon Pharmaceuticals, Inc., or its 
designated representative(s) concerning this study that has not been published previously will be 
kept in the strictest confidence. This documentation includes the study protocol, investigator 
brochure, case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board or Independent Ethics Committee (IRB/IEC). No changes will be 
made to the study protocol without the prior written approval of Acetylon Pharmaceuticals, Inc., 
and the IRB/IEC, except where necessary to eliminate an immediate hazard to the patient. 
I have read, understood, and agree to abide by all the conditions and instructions contained in 
this protocol. 
Investigator Name 
Investigator Signature 
Date 
 
 
 
 
 
 
 
 
Investigational site or name of institution and location (printed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Study Protocol ACE-MM-102 
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CLINICAL STUDY SYNOPSIS 
 
Protocol Title: 
A Phase 1b/2 Multicenter, Open Label, Dose-Escalation Study to Determine 
the Maximum Tolerated Dose, Safety, and Efficacy of ACY-1215 
(Ricolinostat) in Combination with Pomalidomide and Low-dose 
Dexamethasone in Patients with Relapsed-and-Refractory Multiple Myeloma 
Protocol Number: 
ACE-MM-102 
EudraCT Number: 
2014-002338-29 
Study Phase: 
1b/2 
Lead Investigator: 
Telephone: 
Fax: 
E-mail: 
Number of Study 
Centers: 
Approximately 19 
Indication: 
The treatment of multiple myeloma (MM) patients who have received at least 
2 prior therapies, including a proteasome inhibitor and an 
immunomodulatory agent, and who are refractory to the most recent therapy. 
Study Duration: 
Patients are to receive study treatment until documented progressive disease 
(PD) or unacceptable toxicity. 
Objectives: 
Primary: 
Phase 1b: 
• 
To determine the maximum tolerated dose (MTD), or if not 
present, the recommended Phase 2 dose and schedule of 
ACY-1215 administered in combination with pomalidomide and 
low-dose dexamethasone in patients with relapsed-and-refractory 
MM. 
Phase 2: 
• 
To determine the efficacy of ACY-1215 administered in 
combination with pomalidomide and low-dose dexamethasone as 
treatment for patients with relapsed-and-refractory MM as 
assessed by overall response rate. 
Secondary: 
Phase 1b and Phase 2: 
• 
To evaluate the safety of ACY-1215 administered in 
combination with pomalidomide and low-dose dexamethasone as 
treatment for patients with relapsed-and-refractory MM. 
Phase 1b: 
• 
To assess the pharmacokinetics (PK) of ACY-1215 administered 
in combination with pomalidomide and low-dose dexamethasone 
in patients with relapsed-and-refractory MM. 
 
 
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• 
To assess the PK of pomalidomide administered in combination 
with ACY-1215 and low-dose dexamethasone in patients with 
relapsed-and-refractory MM. 
• 
To assess the pharmacodynamics of ACY-1215 administered in 
combination with pomalidomide and low-dose dexamethasone in 
patients with relapsed-and-refractory MM. 
Exploratory: 
Phase 2: 
• 
To explore the relationship between response to treatment and 
any cytogenetic abnormalities. 
Study Endpoints: 
Primary: 
Phase 1b: 
• 
MTD and schedule, or if not present, the recommended Phase 2 
dose and schedule of ACY-1215 administered in combination 
with pomalidomide and dexamethasone. 
Phase 2: 
• 
Objective response to treatment as assessed by site Investigators 
using the International Myeloma Working Group (IMWG) 
Uniform Response criteria. 
Secondary: 
Efficacy: 
Phase 1b and Phase 2: 
• 
Time to response (TTR). 
• 
Duration of response (DOR). 
• 
Time to progression (TTP). 
• 
Progression-free survival (PFS). 
• 
Objective response to treatment as blindly assessed by the 
Central Adjudication Committee using IMWG criteria and dates 
of PD. 
Safety: 
Phase 1b and Phase 2: 
• 
Safety (type, frequency, and severity of adverse events [AEs] 
and relationship of AEs to study drug) 
Pharmacokinetics: 
Phase 1b: 
• 
Plasma levels of ACY-1215 to assess the single and multiple- 
dose PK of ACY-1215 in combination with pomalidomide and 
low-dose dexamethasone. 
• 
Plasma levels of pomalidomide to assess the PK of 
pomalidomide in combination with ACY-1215 and low-dose 
dexamethasone. 
Pharmacodynamics: 
Phase 1b: 
• 
Exposure-response of ACY-1215 in combination with 
pomalidomide and low-dose dexamethasone, including 
biomarkers relating to intracellular protein acetylation. 
 
 
 
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ACY-1215 
12 July 2016 
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Exploratory: 
Phase 2: 
• 
Explore the relationship between response to treatment and any 
cytogenetic abnormalities. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12 July 2016 
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Study Design: 
This is a Phase 1b/2, multi-center, single-arm, open-label, dose-escalation 
study that will evaluate the safety and efficacy of oral (PO) ACY-1215 in 
combination with PO pomalidomide and low-dose PO dexamethasone in 
patients with relapsed-and-refractory MM. Eligible patients must have a 
documented diagnosis of MM and have relapsed-and-refractory disease. 
Patients must have relapsed after having achieved at least stable disease (SD) 
for at least one cycle of treatment to at least one prior regimen and then 
developed PD. Patients must also have documented evidence of PD during 
or within 60 days (measured from the end of the last cycle) of completing 
treatment with the last anti-myeloma drug regimen used just prior to study 
entry (refractory disease). Patients must also have undergone prior treatment 
with at least 2 cycles of lenalidomide and at least 2 cycles of bortezomib 
(either in separate regimens or within the same regimen) and have 
measurable disease. This study will consist of a Phase 1b ACY-1215, 
pomalidomide and low dose dexamethasone dose-finding segment and a 
Phase 2 segment. The Phase 1b segment will determine the starting dose and 
schedule to be used in the Phase 2 segment of the study. All patients will 
receive ACY-1215 in combination with pomalidomide and dexamethasone 
administered orally in 28-day treatment cycles unless an alternative schedule 
is identified in Part 1b. 
Potentially eligible patients will sign informed consent form (ICF) prior to 
undergoing any study-related procedures. Patients will undergo screening 
assessments for protocol eligibility within 28 days of study start (Cycle 1, 
Day 1 [C1D1]). 
For all patients who enroll into either the Phase 1b or Phase 2 segment of this 
study, study visits and serial measurements of safety and efficacy will be 
performed as outlined in the Schedule of Assessments. In addition, all 
patients will be given aspirin 81 or 325 mg daily (commercial supply) as 
prophylactic anti-thrombotic treatment unless contraindicated. If aspirin is 
contraindicated, patients will receive another form of anti-thrombotic therapy 
according to hospital guidelines or physician preference. All patients will be 
monitored for signs and symptoms of venous thromboembolism (VTE) while 
on pomalidomide; diagnostic algorithms will be provided (Appendix 9.1). 
Tumor response, including PD, will be assessed according to the consensus 
recommendations based on the IMWG1 criteria, published by Rajkumar et 
al., in Blood in 2011, which includes the category of minimal response (MR) 
(as defined by the European Group for Blood and Marrow Transplantation 
[EBMT] criteria) for relapsed refractory MM. In order to assess response to 
treatment, M-protein component is to be measured in serum and urine, 
FreeLite™ testing is to be performed and, as applicable, bone marrow 
aspirate and biopsies, and appropriate imaging studies (e.g., computed 
tomography [CT], magnetic resonance imaging [MRI]) are to be performed. 
 
 
 
1Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus 
recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop 
Consensus Panel 1. Blood 2011. 117: 4691-4695. 
 
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Patients who are determined to have PD at any time are to be discontinued 
from the study. 
The severity of AEs will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 4.0. 
Clinical laboratory tests are to be performed locally. In addition, a central 
laboratory will analyze duplicate samples of serum immunoglobulin levels, 
serum and urine protein electrophoresis of myeloma (M)-protein component 
(SPEP, UPEP), serum and urine immunofixation (IFE) studies, and serum 
free light chain (SFLC) analysis. A bone marrow aspirate will be centrally 
analyzed for fluorescence in situ hybridization (FISH)/cytogenetics. 
In the Phase 1b segment, blood samples will be collected from all patients for 
the assessment of PK for ACY-1215. Blood samples will also be collected 
from patients at participating sites in the Phase 2 segment for sparse PK 
sampling. Pharmacodynamic evaluations will also be performed in the 
Phase 1b segment and will include the assessment of the exposure-response 
relationship of ACY-1215 in combination with pomalidomide and low-dose 
dexamethasone and potential biomarkers of response. 
Exploratory assessments will include the evaluation of the relationship 
between response and cytogenetic abnormalities. 
Patients who withdraw from the study are to be followed up either in person 
or by phone 30 days (± 3 days) after the last dose of study drug. Upon 
discontinuation from study treatment for PD or any other reason, patients 
will be assessed 3 times per year (e.g., April, August, and December), for up 
to 1 year, for survival, subsequent anti-myeloma therapies, and monitoring of 
second primary malignancies as outlined in Table 1. Patients who 
discontinue study treatment due to reasons other than PD will also be 
followed for efficacy assessments (assessment of response, extramedullary 
plasmacytoma assessment, quantitative serum immunoglobulin levels, SPEP 
and UPEP of M-protein levels, serum and urine IFE, and SFLC analysis) 
until PD, death, or initiation of an alternate MM therapy, whichever occurs 
first. Serious adverse events (SAEs) will be collected from C1D1 through 
the first 30 days of follow-up. Females of childbearing potential (FCBP) 
with regular or no menstruation will be required to have a final pregnancy 
test at study treatment discontinuation, and at Day 28 following study 
treatment discontinuation. Females with irregular menstruation must have a 
pregnancy test at study treatment discontinuation, and at Day 14 and Day 28 
following study treatment discontinuation. 
PHASE 1b SEGMENT 
Identification of MTD and schedule 
Patients who have completed all screening assessments and meet all 
eligibility criteria, may enter the Phase 1b segment of the study. The 
Phase 1b segment of the study will follow a standard 3 + 3 dose escalation 
design and will include assessment of the safety of treatment between each 
dose cohort by the Safety Review Committee (SRC). The SRC will be 
comprised of the Study Investigators, the Sponsor Medical Monitor, and the 
Safety Monitor. Safety assessments will be conducted in real-time by the 
 
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SRC after the first 3 patients have completed Cycle 1. Dose escalations or 
expansion of a dose cohort will occur only with full approval of the SRC. 
The initial dose and schedule of ACY-1215 to be administered in this study 
is based on a dose and schedule similar to the ones explored in Study 
ACE-MM-101, which is evaluating ACY-1215 in combination with 
lenalidomide and dexamethasone: ACY-1215 160 mg once daily (QD) on 
Days 1 to 21 of a 28-day cycle. Pomalidomide will be administered based on 
the current approved dose and schedule: 4 mg PO QD on Days 1 to 21 of a 
28-day cycle. The starting dose of dexamethasone will be 40 mg PO QD on 
Days 1, 8, 15, and 22 of a 28-day cycle for patients who are ≤ 75 years of 
age. For patients who are > 75 years of age, the starting dose of 
dexamethasone will be 20 mg PO QD on Days 1, 8, 15, and 22 of each 28- 
day cycle. Complete blood counts (CBCs) will be monitored every 7 days 
(weekly) for Cycle 1, every 14 days for Cycle 2, and on Day 1 of each cycle 
beginning with Cycle 3. A guideline for the reduction of the dose of ACY- 
1215 for dose-limiting toxicities (DLTs) is provided in Section 5.2.8.1. 
Dose-Level Groups 
 
Dose 
Levela 
N 
ACY-1215 
Pomalidomide 
Dexamethasoneb 
-2 
3-6 
160 mg QD on 
Days 1-5, and 
8-12 
4 mg QD 
Days 1-21 
40 mg QD 
Days 1, 8, 15, 22 
-1 
3-6 
160 mg QD on 
Days 1-5, 
8-12, and 15-19 
4 mg QD 
Days 1-21 
40 mg QD 
Days 1, 8, 15, 22 
1 
3-6 
160 mg QD on 
Days 1-21 
4 mg QD 
Days 1-21 
40 mg QD 
Days 1, 8, 15, 22 
2 
3-6 
240 mg QD on 
Days 1-21 
4 mg QD 
Days 1-21 
40 mg QD 
Days 1, 8, 15, 22 
3 
3-6 
160 mg BID on 
Days 1-21 
4 mg QD 
Days 1-21 
40 mg QD 
Days 1, 8, 15, 22 
Key: BID = twice daily, QD = once daily. 
Note: treatment cycle is 28 days. 
a 
Patients will be initially enrolled at Dose Level 1. If 2 or more patients experience a 
DLT within the 28-day cycle, patients will be subsequently enrolled at Dose Level -1. If 
2 or more patients experience a DLT at Dose Level -1 within the 28-day cycle, patients 
will subsequently be enrolled at Dose Level -2 
b 
Patients ≤ 75 years of age will receive 40 mg of dexamethasone; patients > 75 years of 
age will receive 20 mg. 
 
Based on emerging data from ongoing studies of ACY-1215, intermediate 
dose levels and schedules may be added, or dose levels eliminated, and the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will 
be notified. 
Definition of Dose Limiting Toxicity (DLT): 
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. If a toxicity is not classified in the CTCAE, then it should be 
classified according to the criteria presented in Section 6.1.8.4. 
 
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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. For toxicities observed that may be attributable to 
pomalidomide (see Table 6) or dexamethasone (see Table 8), dose reductions 
should be attempted with these treatments prior to reducing the dose of 
ACY-1215. 
The following AEs occurring during Cycle 1 that are considered by the 
Investigator to be ACY-1215-related will be considered to be DLTs: 
Hematologic toxicity: 
• 
Grade 4 neutropenia (absolute neutrophil count 
[ANC] < 500/μL) lasting > 5 days, or 
• 
Febrile neutropenia (fever ≥ 38.5° C and ANC < 1,000/μL), or 
• 
Grade 4 thrombocytopenia (platelet count < 25,000/μL), or 
Grade 3 or 4 ACY-1215-related non-hematologic toxicity: 
• 
All other Grade 3 or 4 non-hematologic toxicities with the 
exception of: 
o Grade 3 or 4 nausea, vomiting or diarrhea (Patients must 
have received optimal symptomatic treatment for 
Grade 3 or 4 nausea, vomiting, or diarrhea to be 
considered a DLT). 
o Grade 4 transaminitis (serum transaminase > 20 × upper 
limit of normal [ULN]) is a DLT, while Grade 3 
transaminitis (serum transaminase >5 × ULN) must be 
present for ≥ 7 days to be considered a DLT. 
o Other asymptomatic Grade 3 and 4 laboratory 
investigations, excluding cardiac function tests, may be 
evaluated by the SRC to determine whether dose cohorts 
should be expanded. 
• 
Delay of the start of Cycle 2 by > 7 days due to ACY-1215- 
related AE 
No dose modifications for ACY-1215 are to be performed in Cycle 1. After 
Cycle 1, patients who are unable to tolerate ACY-1215 treatment may have 
the dose reduction steps presented below until a tolerable dose is achieved. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ACY-1215 Dose Modifications 
 
Dose 
level 
Starting dose of 
ACY-1215 
1st dose reduction 
2nd dose 
reduction 
-2 
160 mg QD on Days 1-5, 
and 8-12 
80 mg QD on Days 1-5, 
and 8-12 
NA 
-1 
160 mg QD on Days 1-5, 
8-12, and 15-19 
80 mg QD on Days 1-5, 
8-12, and 15-19 
NA 
1 
160 mg QD on Days 1-21 
80 mg QD on Days 1-21 
NA 
2 
240 mg QD on Days 1-21 
160 mg QD on Days 1-21 
80 mg QD on 
Days 1-21 
3 
160 mg BID on Days 1-21 
160 mg QD on Days 1-21 
80 mg QD on 
Days 1-21 
Determination of MTD: Dose escalation rules 
Study drug doses will be escalated sequentially after the SRC reviews safety 
data collected during Cycle 1 from patients at the current dose level to 
confirm any DLTs that were experienced and to make a determination 
regarding enrollment in the next dose cohort. 
The following dose escalation rules will be used: 
• 
If none of the 3 patients experiences a DLT within the first 
28-day cycle, and pending SRC review as described above, then 
an additional 3 patients will be enrolled into the next higher dose 
level. 
• 
If one of the 3 initial patients in a Dose-Level Group experiences 
a DLT within the first 28-day cycle, then an additional 3 patients 
will be enrolled into that Dose-Level Group. 
• 
If 2 or more patients within the expanded dose cohort experience 
a DLT within the first 28-day cycle, then the MTD has been 
exceeded and no further dose escalations will occur. 
• 
If no more than one of the 6 patients experiences a DLT within 
the first 28-day cycle, then the next dose cohort of 3 patients will 
be enrolled at the next higher dose level. 
The MTD will be defined as the highest dose level at which no more than 1 
of 6 patients experiences a DLT within the first 28-day cycle. If no more 
than 1 of these 6 patients experiences a DLT within the first 28-day cycle, 
then the last dose level enrolled to meet these criteria may be identified as the 
recommended dose for the Phase 2 segment of the study. 
Teleconferences or email communication between the Sponsor or designee 
and the clinical study sites will occur weekly to monitor for DLTs and to 
communicate enrollment to the next dose level. 
Patients who discontinue from the study for reasons other than DLT (e.g., 
non-compliance, patient request) before completing Cycle 1 will be replaced. 
The use of hematopoietic growth factors will not be permitted during 
screening in the Phase 1 or Phase 2 segments of the study or in Cycle 1 of the 
Phase 1b segments of the study; however, they will be permitted in Cycle 2 
and subsequent cycles. 
 
 
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Patients may not be enrolled in more than 1 dose cohort. Patients enrolled 
into the Phase 1b segment of the study cannot be enrolled into the Phase 2 
segment upon discontinuation from Phase 1b. 
Confirmation of the Safety of the MTD 
Following the identification of the MTD or identification of the 
recommended Phase 2 dose, up to 6 additional patients may be enrolled at 
this dose. When all 6 patients have completed the 28-day cycle at the MTD, 
the SRC will review all Phase 1b safety data to determine the recommended 
dose of ACY-1215 to be used in the Phase 2 segment of the study. For all 
patients enrolled in the Phase 1b MTD segment, following the completion of 
Cycle 1, efficacy assessments will be conducted every cycle for the duration 
of the treatment period. 
PHASE 2 SEGMENT 
When the SRC has determined a recommended Phase 2 dose of ACY-1215, 
the Phase 2 segment will be initiated. Treatment will continue until PD or 
toxicity requiring removal from study. 
Study Day 1 is defined as the first day the patient receives study drug. 
Based on findings from the Phase 1 segment of the study and as 
recommended by the SRC, the ACY-1215 dose and schedule to be 
administered in the Phase 2 segment will be 160 mg PO QD on Days 1 to 21 
of a 28-day cycle. Pomalidomide will be administered based on the current 
approved dose and schedule: 4 mg PO QD on Days 1 to 21 of a 28-day 
cycle. The starting dose of dexamethasone will be 40 mg QD on Days 1, 8, 
15 and 22 of each 28-day cycle for patients who are ≤ 75 years of age. For 
patients who are > 75 years of age, the starting dose of dexamethasone is 
20 mg QD on Days 1, 8, 15, and 22 of each 28-day cycle. CBC will be 
conducted every 7 days for Cycle 1, every 14 days for Cycle 2, and on Day 1 
of each cycle beginning with Cycle 3. 
The use of bisphosphonates is permitted. The use of hematopoietic growth 
factors will not be permitted during screening in the Phase 1 or Phase 2 
segments of the study or in Cycle 1 of the Phase 1b segment of the study; 
however, they will be permitted in Cycle 2 and subsequent cycles. 
Treatment with myeloid growth factors is encouraged when 
ANC < 1,000/µL. 
Dose Interruption and Modification: 
Dose interruption and reduction for ACY-1215, pomalidomide, and 
dexamethasone due to DLTs can be found in Section 5.2.8. 
Central Response 
Adjudication 
Committee: 
An Independent Central Adjudication Committee will be performing a blind 
review of the myeloma response data (i.e., laboratory data and radiographic 
data) to determine response to treatment and dates of PD for each study 
patient. Their assessments of response and dates of PD will be evaluated as a 
secondary endpoint. 
Number of Patients 
Planned: 
Up to 30 patients are planned to be enrolled in the Phase 1b segment and up 
to 95 patients are planned to be enrolled in the Phase 2 segment. 
Diagnosis and Main 
Criteria for Inclusion: 
Patients meeting the following criteria are to be enrolled in the study: 
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1. Must be able to understand and voluntarily sign an ICF. 
2. Must be ≥ 18 years of age at the time of signing the ICF. 
3. Must be able to adhere to the study visit schedule and other protocol 
requirements. 
4. Must have a documented diagnosis of MM and have relapsed-and- 
refractory disease. Patients must have received at least 2 lines of prior 
therapies. Patients must have relapsed after having achieved at least SD 
for at least one cycle of treatment to at least one prior regimen and then 
developed PD. Patients must also have documented evidence of PD 
during or within 60 days (measured from the end of the last cycle) of 
completing treatment with the last anti-myeloma drug regimen used just 
prior to study entry (refractory disease). 
5. Must have undergone prior treatment with at least 2 cycles of 
lenalidomide and at least 2 cycles of a proteasome inhibitor (either in 
separate regimens or within the same regimen). 
6. Must not be a candidate for autologous stem cell transplant (ASCT), has 
declined the option of ASCT, or has relapsed after prior ASCT. 
7. Must have measurable levels of myeloma paraprotein in 
serum (≥ 0.5 g/dL) or urine (≥ 0.2 g/24 hours). Nonsecretory myeloma 
and serum free light chain (SFLC)-only myeloma are excluded. 
8. Must have Eastern Cooperative Oncology Group (ECOG) performance 
status score of 0, 1, or 2. 
9. FCBP must have a negative serum or urine pregnancy test (must be 
serum for study participants in Canada), as described in Appendix 9.3 for 
the POMALYST REMS™ program (in the United States [US]) and 
Appendix 9.4 for the RevAid® program (in Canada). FCBP and males 
must either commit to continued abstinence from heterosexual 
intercourse or must abide by birth control requirements as described in 
Appendix 9.3 for the POMALYST REMS™ program (in US) and 
Appendix 9.4 for the RevAid® program (in Canada). The European 
Pomalidomide Pregnancy Prevention Risk Management Plans are 
described in Appendix 9.5. 
10. Must agree to refrain from donating blood while on study drug and for 
28 days after discontinuation from this study. 
11. Must agree not to share study medication with another person. 
12. Must be able to take acetylsalicylic acid (ASA) (81 or 325 mg) daily as 
prophylactic anticoagulation. Patients intolerant to ASA may use low 
molecular weight heparin. Lovenox is recommended. Coumadin will be 
allowed provided the patient is fully anticoagulated, with an international 
normalized ratio (INR) of 2 to 3. 
13. Must be registered into the mandatory POMALYST REMS™ program, 
and be willing and able to comply with the requirements of the 
POMALYST REMS™ program (or RevAid® for study participants in 
Canada). 
Exclusion Criteria: 
Patients meeting any of the following criteria will be excluded from 
enrollment in the study: 
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Acetylon Pharmaceuticals, Inc. 


Clinical Study Protocol ACE-MM-102 
ACY-1215 
12 July 2016 
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1. Any serious medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the patient from signing the ICF, including 
nonsecretory myeloma or SFLC-only myeloma. 
2. Any serious concurrent medical conditions, laboratory abnormality, or 
psychiatric illness that might make the patient non-evaluable, put the 
patient’s safety at risk, or prevent the patient from following the study 
requirements. 
3. Pregnant or lactating females. 
4. Prior therapy with histone deacetylase (HDAC) inhibitor or 
pomalidomide. 
5. Any of the following laboratory abnormalities: 
• 
ANC < 1,000/µL (hematopoietic growth factors will not be permitted 
during screening in the Phase 1 or Phase 2 segments of the study or 
in Cycle 1 of the Phase 1b segment of the study) in either segment of 
the study. 
• 
Platelet count < 75,000/µL for patients in whom < 50% of bone 
marrow nucleated cells are plasma cells, and < 50,000/µL for 
patients in whom ≥ 50% of bone marrow nucleated cells are plasma 
cells. 
• 
Hemoglobin < 8g/dL (< 4.9 mmol/L; prior red blood cell [RBC] 
transfusion is permitted). 
• 
Creatinine clearance < 45 mL/min according to Cockcroft-Gault 
formula. If creatinine clearance calculated from the 24-hour urine 
sample is ≥ 45 mL/min, patient will qualify for the study. 
• 
Serum glutamic oxaloacetic transaminase (SGOT)/aspartate 
aminotransferase (AST), or serum glutamic pyruvic transaminase 
(SGPT)/alanine aminotransferase (ALT) > 3.0 × ULN. 
• 
Serum total bilirubin > 2.0 mg/dL 
6. Prior history of malignancies, other than MM, unless the patient has been 
free of the disease for ≥ 3 years. Exceptions include the following: 
• 
Basal or squamous cell carcinoma of the skin 
• 
Carcinoma in situ of the cervix or breast 
• 
Incidental histologic finding of prostate cancer (TNM stage of T1a or 
T1b) 
7. Corrected QT interval using Fridericia’s formula (QTcF) 
value > 480 msec at screening; family or personal history of long QTc 
syndrome or ventricular arrhythmias including ventricular bigeminy at 
screening; previous history of drug-induced QTc prolongation or the 
need for treatment with medications known or suspected of producing 
prolonged QTc intervals on electrocardiogram (ECG). 
8. Positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) 
and known or suspected active hepatitis C virus (HCV) infection. 
9. Hypersensitivity to thalidomide, lenalidomide, or dexamethasone (such 
as Steven Johnson Syndrome). Hypersensitivity, such as rash, that can 
be medically managed is allowable. 
 
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ACY-1215 
12 July 2016 
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10. Peripheral neuropathy ≥ Grade 2 despite supportive therapy. 
11. Radiotherapy or systemic therapy (standard or an investigational or 
biologic anticancer agent) within 14 days of initiation of study drug 
treatment. 
12. Current enrollment in another clinical study involving treatment and/or is 
receiving an investigational agent for any reason 
13. Inability or unwillingness to comply with birth control requirements or 
any of the POMALYST REMS™ or RevAid® (region-specific), per 
Appendix 9.3 and Appendix 9.4, respectively, or to the European 
Pomalidomide Pregnancy Prevention Risk Management Plans, per 
Appendix 9.5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
Acetylon Pharmaceuticals, Inc. 


Clinical Study Protocol ACE-MM-102 
ACY-1215 
12 July 2016 
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Test Products, Doses, 
and Mode of 
Administration: 
All patients will receive ACY-1215 in combination with pomalidomide and 
dexamethasone in 28-day treatment cycles. 
Acetylon will supply liquid ACY-1215 in appropriately sized vials for PO 
administration to investigational pharmacies. Pomalidomide will be 
provided at 4, 3, 2, and 1 mg for PO administration. Sites in the US and 
Canada will utilize commercial supply of PO dexamethasone. Acetylon will 
supply dexamethasone to sites in the European Union (EU). All sites will 
utilize commercial supply of aspirin or other anti-thrombotics or anti- 
coagulants. 
All patients will receive ACY-1215 in combination with pomalidomide and 
dexamethasone. On ACY-1215 administration days, pomalidomide and 
dexamethasone are to be taken immediately after ACY-1215. If the patient is 
receiving ACY-1215 twice daily (BID), pomalidomide and dexamethasone 
are to be taken immediately after the first (a.m.) dose of ACY-1215 only. 
Phase 1b (MTD) Segment: 
The starting dose of ACY-1215 (Dose Level 1) will be 160 mg QD, 
administered on Days 1-21 of a 28-day cycle in combination with the labeled 
dose of pomalidomide and dexamethasone. If that dose is tolerated per SRC 
safety review, 240 mg QD on the same days will be explored (Dose Level 2). 
If Dose level 2 is well tolerated, Dose Level 3 of 160 mg BID will be 
explored. If Dose Level 1 is not tolerated, the schedule will be modified 
(Dose Level -1) to 160 mg ACY-1215 QD on Days 1-5, 8-12, and 15-19. If 
Dose Level -1 is not tolerated, the schedule will be modified (Dose Level -2) 
to 160 mg ACY-1215 QD on Days 1-5, and 8-12. 
Phase 2 Segment: 
The ACY-1215 dose and schedule to be administered in the Phase 2 segment 
will be 160 mg PO QD on Days 1 to 21 of a 28- day cycle, as recommended 
by the SRC. 
Phase 1b and Phase 2 Segments: 
All patients will receive pomalidomide 4 mg PO QD on Days 1 to 21 of a 
28 day cycle in combination with dexamethasone (40 mg PO for patients 
≤ 75 years of age or 20 mg for patients > 75 years of age) on Days 1, 8, 15, 
and 22 of a 28-day cycle. Patients should take pomalidomide at the same 
time each day, immediately following ACY-1215 dosing when applicable. 
Pomalidomide should be taken without food, at least 2 hours before or 
2 hours after a meal. Doses of ACY-1215 will be administered at least 1 
hour after ingestion of food and followed by 4 ounces of water. Patients will 
be instructed not to ingest food or other oral medication, other than 
pomalidomide and dexamethasone, for at least 2 hours after each dose of 
ACY-1215. 
 
 
 
 
 
 
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Acetylon Pharmaceuticals, Inc. 


Clinical Study Protocol ACE-MM-102 
ACY-1215 
12 July 2016 
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Assessments: 
Efficacy: 
• 
Myeloma paraprotein (serum-M and urine M-protein; quantified 
by SPEP and UPEP, respectively) 
• 
Serum and urine immunoglobulins (IFE) 
• 
SFLCs 
• 
Bone marrow aspiration/biopsy 
• 
Skeletal survey and other imaging studies 
• 
Extramedullary plasmacytoma assessments 
• 
Disease response assessment (per IMWG criteria) 
Safety: 
• 
Vital signs 
• 
Physical examinations 
• 
ECOG performance status 
• 
Clinical laboratory evaluations 
• 
Pregnancy testing/counseling 
• 
12-Lead ECG 
• 
VTE monitoring 
• 
Concomitant medications and procedures 
• 
AEs 
• 
Secondary primary malignancies 
Exploratory: 
• 
Cytogenetic abnormalities 
• 
Blood samples for the assessment of the PK of ACY-1215 and 
potential biomarkers in patients with relapsed-and-refractory 
MM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Acetylon Pharmaceuticals, Inc. 


Clinical Study Protocol ACE-MM-102 
ACY-1215 
12 July 2016 
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Statistical Methods: 
Justification of Sample Size: 
Phase 1b (MTD): Using a 3+3 design, the total number of patients required 
for the MTD phase will range from 9 to 30. 
Phase 2: The reference response rate is assumed to be 0.29. For a study 
with a sample size of 66, a one-sided 0.05 level test with power of 80% 
would be adequate to detect the response rate of 0.29 against 0.44. 
Assuming a 10% drop out rate, a study of 75 patients would be sufficient. In 
order to have a robust study, a single interim analysis will be conducted 
when there are 30 evaluable patients. The SRC will use the totality of 
information from the interim analysis to recommend whether the study 
should proceed as planned, be terminated for superiority or futility, or 
extended to allow for 86 evaluable patients. Assuming a 10% dropout rate, a 
study with n=95 would be sufficient. 
Statistical analysis: 
Interim analysis: 
The interim analysis with the first 30 evaluable patients will be conducted 
using a one-sided 95% CI estimate for the response rate. If the lower bound 
of the 95% CI estimate with the 30 patients is ≥ 29%, the SRC may 
recommend either terminating the study at the interim based on treatment 
superiority, or continuing the study as planned. If the lower bound is < 29%, 
various predicted lower bounds of one-sided 95% CIs for the response rate 
will be constructed to further guide the SRC’s recommendation. For 
example, assuming a true response rate of 44% for the remaining 36 patients, 
the expected lower bound of one-sided 95% CI with 66 evaluable patients 
will be calculated. If the expected lower bound is ≥ 29%, the SRC may 
recommend continuing the study as planned. If the expected lower bound 
with 66 evaluable patients is < 29%, another simulation will be run with 86 
evaluable patients. If the resulting lower bound is acceptable (e.g., close to 
or ≥ 29%), the SRC may recommend expanding the sample size by 
20 patients. If the resulting lower bound is not acceptable (e.g., < 29%), the 
SRC may recommend terminating the study for futility. In addition, the 
expected lower bound of the one-sided 95% CI when the true response rate is 
equal to the observed value at the interim analysis will be calculated. The 
resulting scenario will be similar to the previous one: if the expected lower 
bound is ≥ 29%, the SRC may recommend continuing the study as planned, 
if the lower bound is < 29%, the SRC may recommend expanding the sample 
size by 20 patients. Additional simulations with other possible response rates 
(for example, assuming a 40% response rate), with or without adaptation, 
will also be conducted; the SRC will review all simulation results to make a 
recommendation at the interim. Furthermore, with the potential adaptations 
at the interim, we find via an extensive simulation study the final CI estimate 
would have the accurate coverage level. Therefore, no statistical penalty or 
adjustment will be needed for the final inferential statistical procedure for the 
response rate. 
Demographic, Disposition, Study Medication: 
The baseline (C1D1) characteristics of patients enrolled in each dose cohort, 
the Phase 1b MTD segment and the Phase 2 segment, will be summarized. 
 
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Acetylon Pharmaceuticals, Inc. 


Clinical Study Protocol ACE-MM-102 
ACY-1215 
12 July 2016 
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An accounting will be made of the study course for all patients who received 
study drug for each dose cohort and, in particular, the number of patients 
who died or withdrew during treatment will be specified and reasons for 
withdrawal categorized. Study drug administration will be summarized for 
each dose cohort. Information on dose reductions will be summarized. 
Safety Analysis: 
Safety data for the Phase 1b MTD segment will be summarized when all 
patients have completed the first 28-day cycle (Cycle 1). 
Safety data for the Phase 2 segment, as well as for patients from the Phase 1b 
segment who continued treatment following the completion of the first cycle, 
will be analyzed when all patients have completed 48 weeks of the study or 
have discontinued the study. 
All patients who received at least one dose of study medication will be 
included in the safety analyses. SAEs, treatment-emergent AEs, frequency 
of DLTs, vital sign measurements, clinical laboratory information, and 
concomitant medications will be tabulated and summarized for each dose 
cohort when appropriate. Patient incidence rates of all AEs (including 
serious, Grade 3/4, treatment-related, and events requiring the 
discontinuation of investigational product), will be tabulated by system organ 
class (SOC), preferred term, and severity using Medical Dictionary for 
Regulatory Activities (MedDRA) terms and NCI CTCAE Version 4.0 
severity grades. 
Death, SAEs, and AEs resulting in study discontinuation will also be 
summarized. AEs leading to dose reduction or interruption will also be 
tabulated. 
All other measurements will be summarized using means, standard 
deviations, medians, minimum, and maximum. Graphical displays will be 
provided where useful in the interpretation of results. 
Efficacy Analysis: 
Efficacy analysis will be performed on both the Intent-to-Treat (ITT) 
Population and Efficacy Evaluable (EE) Population. The ITT Population 
will include all treated patients, and the EE Population will include all 
patients who meet eligibility criteria, receive at least 14 doses of study drug 
(i.e., ACY-1215, pomalidomide and low-dose dexamethasone), and have at 
least 1 post-baseline efficacy assessment. The primary analysis will be based 
on the EE population, and will use the Investigator-assessed response data 
evaluated according to consensus recommendations based on the IMWG 
criteria. Response rate will be percent of patients who achieve at least partial 
response (PR) at the recommended Phase 2 dose. Percent of patients 
achieving MR or better will also be collected as clinical benefit response. 
PFS will be defined as the time from first dose of study treatment to the first 
documentation of PD or death from any cause during study. OS will be 
defined as the time from first dose of study treatment to death from any 
cause. For responders, TTR and response duration will be analyzed. TTR 
will be defined as the time from first dose of study treatment to the first 
documentation of response (either PR or complete response [CR]). DOR 
 
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Acetylon Pharmaceuticals, Inc. 


Clinical Study Protocol ACE-MM-102 
ACY-1215 
12 July 2016 
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will be defined as the time from the first PR or CR to the first documentation 
of PD or death, whichever occurs earlier. 
For data obtained from patients treated at doses of ACY-1215 not selected as 
the MTD, a case-by-case description of myeloma response (per IMWG 
criteria) will be provided. For the 12 patients who initiate ACY-1215 at the 
recommended Phase 2 dose level, response rates together with CIs will be 
provided. Kaplan-Meier curves will be used to characterize the time-to-event 
curves (PFS, OS, response duration) when there is censoring; univariate 
summary statistics will be provided for TTR. 
For the Phase 2 segment, a 0.95 CI for the response rate will be constructed 
for evaluating the efficacy of ACY-1215. Kaplan-Meier curves will be 
constructed to characterize PFS, OS, and DOR. One sample standard 
inferences for PFS, OS, and DOR will be made accordingly. 
Pharmacokinetic Analysis 
Study drug serum concentrations of ACY-1215 and pomalidomide will be 
determined at all pre- and post-dose time points specified in the Schedule of 
Assessments. Parameters to be calculated based on a non-compartmental 
model approach will include maximum serum concentration (Cmax), time to 
Cmax (Tmax), area under the concentration-time curve from time zero to the 
last quantifiable value (AUC0-last), AUC from time zero to infinity (AUC0-∞), 
and serum half-life (t1/2). ACY-1215 and pomalidomide serum levels and 
non-compartmental PK parameters will be tabulated by dose cohort using 
descriptive statistics. Tabulated single- and multiple-PK dose results will be 
presented. 
Pharmacodynamic Analysis 
The fold change between pre- and post-dose time points in the levels of 
acetylated histones and acetylated tubulin will be determined in peripheral 
blood mononuclear cells (PBMCs). The resulting data may be used to 
generate a PK/pharmacodynamic model(s) of the relationship of changes in 
acetylated histones and/or tubulin with the plasma levels of ACY-1215 over 
time. A summary report will be generated of the pharmacodynamic analysis 
and results from PK/pharmacodynamic modeling. 
Schedule of 
Assessments 
The Schedule of Assessments is presented in Table 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ACY-1215 
09 February16 Jan 2015 
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Table 1: 
Schedule of Assessments 
 
Procedure 
Screening 
Treatment/Follow Up 
Screening 
Disease 
30 Days 
(Within 28 Days 
Cycle 1 
Progression/ 
After Study 
of Cycle 1, 
Day 1/ 
Cycle 1 
Cycle 1 
Cycles 2 
Treatment 
Treatment 
3 Times per 
Day 1) 
Baseline 
Day 2/ 
Days 8, 15, 22 
and on, Day 1 
Discontinuation1 
Discontinuation2 
Year3 
Visit Window 
± 2 
Days 
± 3 
Days 
± 3 
Days 
± 3 
Days 
± 7 
Days 
Informed Consent 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Inclusion/Exclusion Criteria 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Confirmation of Diagnosis 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Prior Anti-myeloma Therapies 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Demographics 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Medical and Surgical History 
(including MM history) 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Review Concomitant Medications 
X 
X 
X 
X 
X 
X 
-- 
-- 
Measurement of Vital Signs4 
X 
X 
-- 
-- 
X 
X 
-- 
-- 
Physical Examination 
X 
-- 
-- 
-- 
-- 
X 
-- 
-- 
ECOG Performance Score 
X 
X 
-- 
X 
X 
-- 
-- 
Bone Marrow Aspiration and/Biopsy5 
(diagnosis and cytogenetics) 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Serum Chemistry6 
X 
X 
-- 
-- 
X 
X 
-- 
-- 
Haematology7 
X 
X 
X 
X 
X 
Cycle 2 Day 15 
X 
-- 
-- 
Quantitative Serum Immunoglobulin 
Levels8 
X 
X 
-- 
-- 
X 
X 
-- 
-- 
 
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Clinical Study Protocol ACE-MM-102 
ACY-1215 
09 February16 Jan 2015 
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Procedure 
Screening 
Treatment/Follow Up 
Screening 
Disease 
30 Days 
(Within 28 Days 
Cycle 1 
Progression/ 
After Study 
of Cycle 1, 
Day 1/ 
Cycle 1 
Cycle 1 
Cycles 2 
Treatment 
Treatment 
3 Times per 
Day 1) 
Baseline 
Day 2/ 
Days 8, 15, 22 
and on, Day 1 
Discontinuation1 
Discontinuation2 
Year3 
Visit Window 
± 2 
Days 
± 3 
Days 
± 3 
Days 
± 3 
Days 
± 7 
Days 
Protein Electrophoresis 
(serum and 24-hour urine)9 
X 
X 
-- 
-- 
X 
X 
-- 
-- 
SFLC Analysis 
(serum)10 
X 
X 
-- 
-- 
X 
X 
-- 
-- 
Immunofixation Studies 
(serum and 24-hour urine)11 
X 
X 
-- 
-- 
X 
-- 
-- 
-- 
Urinalysis12 
X 
X 
-- 
-- 
X 
X 
-- 
-- 
Pregnancy Test for FCBP13 
X 
X 
-- 
X 
X 
X 
X 
-- 
Pregnancy Counseling14 
X 
X 
-- 
-- 
X 
X 
X 
-- 
Skeletal Survey15 
X 
-- 
-- 
-- 
-- 
X 
-- 
-- 
Extramedullary Plasmacytoma 
Assessment16 
X 
X 
-- 
-- 
X 
X 
-- 
-- 
12-Lead Electrocardiogram17 
X 
X 
-- 
Day 8 
X 
X 
-- 
-- 
Serology (HIV, HBsAg, HCV) 
X 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
Assessment of Response18 
-- 
-- 
-- 
-- 
X 
X 
-- 
-- 
VTE Monitoring19 
-- 
X 
X 
X 
X 
X 
-- 
-- 
Adverse Events20 
-- 
X 
X 
X 
X 
X 
X 
-- 
Assessment of Second Primary 
Malignancy21 
-- 
X 
-- 
-- 
X 
X 
X 
X 
Study Drug (ACY-1215) 
Administration22 
-- 
X 
-- 
-- 
X 
-- 
-- 
-- 
 
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CONFIDENTIAL 
Acetylon Pharmaceuticals, Inc. 


Clinical Study Protocol ACE-MM-102 
ACY-1215 
09 February16 Jan 2015 
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Procedure 
Screening 
Treatment/Follow Up 
Screening 
Disease 
30 Days 
(Within 28 Days 
Cycle 1 
Progression/ 
After Study 
of Cycle 1, 
Day 1/ 
Cycle 1 
Cycle 1 
Cycles 2 
Treatment 
Treatment 
3 Times per 
Day 1) 
Baseline 
Day 2/ 
Days 8, 15, 22 
and on, Day 1 
Discontinuation1 
Discontinuation2 
Year3 
Visit Window 
± 2 
Days 
± 3 
Days 
± 3 
Days 
± 3 
Days 
± 7 
Days 
Pomalidomide23 
-- 
X 
-- 
-- 
X 
-- 
-- 
-- 
Dexamethasone24 
-- 
X 
-- 
X 
X 
-- 
-- 
-- 
Survival 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
X 
Subsequent Anti-myeloma Therapies 
-- 
-- 
-- 
-- 
-- 
-- 
X 
X 
PK/Pharmacodynamic Blood 
Sampling25, 26 
-- 
X 
X 
Day 8 
-- 
-- 
-- 
-- 
1 
Patients who discontinue from study treatment for reasons other than PD will continue to be followed for efficacy measurements (assessment of response, extramedullary plasmacytoma assessment, 
quantitative serum immunoglobulin levels, serum and urine protein electrophoresis of M-protein component, and serum free light chain [SFLC] analysis) until PD, death, or initiation of an alternate MM 
therapy, whichever occurs first. 
2 
Pregnancy tests may be conducted locally for patients who are unable to attend the 30 day follow-up visit at the study center; all other assessments may be conducted via phone. 
3 
Patients will be followed 3 times per year, for up to 1 year, for survival, subsequent anti-myeloma therapies, and monitoring of second primary malignancy. Subsequent therapies should be collected until 
death or the end of the 1year follow-up period. Survival follow-up may be done via phone. 
4 
Vital signs will include weight, height (screening only), blood pressure (BP), temperature, and heart rate. 
5 
A bone marrow aspirate is to be performed at screening and a sample sent for central cytogenetic and fluorescence in situ hybridization (FISH) analysis (a bone marrow biopsy is needed only if the 
marrow is unable to be aspirated). A bone marrow biopsy/aspirate may be done as clinically indicated, at the discretion of the treating physician for assessment of disease. 
6 
Serum chemistry (glucose, calcium, albumin, total protein, sodium, potassium, magnesium, phosphorus, chloride, blood urea nitrogen, uric acid, alkaline phosphatase [ALP], creatinine, carbon dioxide, 
total bilirubin, lactate dehydrogenase [LDH], aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma-glutamyl transpeptidase [GGT]) will be performed at screening, on Day 1 of 
every cycle beginning with Cycle 1 Day1, PD, and at study treatment discontinuation. 
7 
Hematology will include hematocrit, hemoglobin, red blood cell (RBC) count, international normalized ratio (INR), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), white blood cell 
(WBC) count with differential, platelet count, reticulocyte count, and mean corpuscular volume. Complete blood count (CBC) will be conducted every 7 days for Cycle 1, every 14 days for Cycle 2 
(Cycle 2, Day 15), and on Cycle Day 1 of every cycle beginning with Cycle 3. INR will be measured at screening and on Day 1 of every cycle for patients on coumadin. 
8 
Quantitative serum immunoglobulin levels will be obtained at screening, at Day 1 of each treatment cycle, PD, and at study treatment discontinuation. 
9 
Serum and 24-hour urine samples for M-protein analysis (see Section 6.2.1) will be collected from all patients at screening, on Day 1 of every cycle, at PD, and at study treatment discontinuation. 
10 
Serum samples for SFLC analysis (see Section 6.2.2) will be collected from all patients at screening, on Day 1 of every cycle, PD, and at study treatment discontinuation. 
11 
IFE studies will be performed at screening, Day 1 of each treatment cycle, and to confirm CR (undetectable M-protein by protein electrophoresis in urine and serum will trigger the central laboratory to 
perform IFE studies in urine and serum). 
12 
Urinalysis will include specific gravity, pH, glucose, bilirubin, protein, ketones, and microscopic analysis (casts, RBCs, and WBCs). 
13 
Pregnancy tests (serum or urine test with a sensitivity of at least 25 mIU/mL) must occur 10 - 14 days and again within 24 hours prior to initiation of study drug for study participants in the US (see 
Appendix 9.3 for the POMALYST REMS™ program, or 7 – 14 days and again within 24 hours prior to initiation of study drug for study participants in Canada (see Appendix 9.4 for the RevAid® 
program). FCBP with regular or no menstruation must have a pregnancy test weekly for the first 4 weeks and then every 4 weeks while on therapy (including breaks in therapy); at study treatment 
discontinuation, and at Day 28 following study treatment discontinuation. Females with irregular menstruation must have a pregnancy test weekly for the first 4 weeks and then every 14 days while on 
therapy (including breaks in therapy), at study treatment discontinuation, and at Day 14 and Day 28 following study treatment discontinuation. For additional information, including acceptable forms of 
 
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Clinical Study Protocol ACE-MM-102 
ACY-1215 
09 February16 Jan 2015 
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birth control, see Appendix 9.3 for the POMALYST REMS™ program, Appendix 9.4 for the RevAid® program, and Appendix 9.5 for the European Pomalidomide Pregnancy Prevention Risk 
Management Plans. 
14 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted on Day 1 of every cycle (or at a minimum of every 28 days), and at study treatment discontinuation. 
Additional pregnancy counseling may be performed; see Appendix 9.3 and Appendix 9.4 for requirements of the POMALYST REMS™ and RevAid® programs, respectively. See Appendix 9.5for the 
European Pomalidomide Pregnancy Prevention Risk Management Plans. 
15 
Skeletal survey to be performed at screening (or within 60 days of Study Day 1), and later, when clinically indicated. 
16 
Assessment/measurement required only if present or if clinically indicated. Plasmacytomas that can be assessed clinically are to be assessed everycycle. Plasmacytomas that are assessed by radiography 
will be assessed at screening, Day 1 of every treatment cycle, at study treatment discontinuation, and to assess best response. 
17 
Single 12-lead ECGs will be performed at screening, pre-dose on Day 1 of every treatment cycle, pre-dose Day 8 (Cycle 1, only for Phase 1b), at the Investigator’s discretion, and at study treatment 
discontinuation. Corrected QT interval at screening (QTcF) must be < 480 msec at screening. Additional ECGs may be taken at any time point at the Investigator’s discretion. 
18 
Response will be assessed every cycle while on study drug treatment, and at study treatment discontinuation. Screening labs do not need to be repeated at C1D1 if they have been completed within 14 
days. Assessment of response will include measurement of serum M-protein by electrophoresis, SFLC analysis, and IFE studies (see footnotes 10-12). 
19 
VTE assessment will be performed at each visit during study treatment and at study treatment discontinuation. 
20 
AEs will be assessed starting at baseline (C1D1). AEs that lead to study treatment discontinuation should be followed until resolution or stabilization. Serious adverse events (SAEs) will be assessed 
until 30 days after study treatment discontinuation. 
21 
Second primary malignancies will be monitored as events of interest and must be reported as SAEs regardless of the dose cohort the patient is in. This includes any second primary malignancy, regardless 
of causal relationship to study drug (ACY-1215, pomalidomide, dexamethasone), occurring at any time for the duration of the study, from the time of signing the informed consent up to the time all 
patients have been followed for at least 1 year post the 30 day discontinuation visit or have died. Events of second primary malignancy are to be reported using the SAE report form and must be 
considered an “Important Medical Event” even if no other serious criteria apply; these events must also be documented in the appropriate page(s) of the case report form (CRF) and patient’s source 
documents. Documentation on the diagnosis of the second primary malignancy must be provided at the time of reporting as an SAE (e.g., any confirmatory histology or cytology results, X-rays, 
computed tomography [CT] scans, etc.). 
22 
ACY-1215 will be administered on Day 1 of each 28-day cycle. For patients enrolled in Dose Level 1, the starting dose of ACY-1215 will be 160 mg QD on Days 1-21 of a 28-day cycle. Patients 
enrolled in Dose Level 2 will receive 240 mg QD on Days 1-21 of each 28-day cycle. Patients enrolled in Dose Level 3 will receive 160 mg BID on Days 1-21 of each 28-day cycle. In the Phase 2 
segment, the ACY-1215 dose and schedule is 160 mg PO QD on Days 1 to 21 of a 28-day cycle. 
23 
Pomalidomide will be administered 4 mg PO on Days 1-21 of each 28-day cycle. 
24 
Dexamethasone will be administered once weekly on Days 1, 8, 15, and 22 of each 28-day cycle. Patients who are ≤ 75 years of age will receive 40 mg QD, and patients who are > 75 years, will receive 
20 mg QD. 
25 
Serial blood samples for PK assessments are to be collected from all US and Canada patients during Cycle 1 of the Phase 1b segment and at participating sites in the Phase 2 segment at the following time 
points: 
• 
Phase 1b, C1D1: pre-dose, 0.5, 1, 2, 4, and 6 hours post dose 
• 
Phase 1b, C1D2: 24 hours post dose 
• 
Phase 1b, C1D8: pre-dose, 0.5, 1, 2, 4, and 6 hours post dose 
• 
Phase 2, C1D1:  pre-dose, 0.5 and 1hour post dose 
• 
Phase 2, C1D22: 24 hours post morning dose of Day 21 
• 
Phase 2, Day 1 of C2-6: at least 1 hour post dose 
26 
Pharmacodynamic blood samples from all patients during Cycle 1 of the Phase 1b segment will be collected on Day 1 at the following time points: 
• 
Phase 1b, C1D1: pre-dose, 0.5, 1, 2, 4, and 6 hours post dose 
• 
Phase 1b, C1D2: 24 hours post dose. 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ADLs 
Activities of daily living 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASA 
Acetylsalicylic acid 
ASCO 
American Society of Clinical Oncology 
ASCT 
Autologous stem cell transplant 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration time curve 
AUC0-last 
AUC from time zero to the last quantifiable value 
AUC0-∞ 
AUC from time zero to infinity 
β2M 
Serum beta-2 microglobulin 
BID 
Twice daily 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
C 
Cycle 
C1D1 
Baseline (Cycle 1 Day 1) 
CBC 
Complete blood count 
CHO 
Chinese hamster ovary 
Cmax 
Maximum serum concentration 
CR 
Complete response 
CRF 
Case report form 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
DST 
Dexamethasone suppression test 
DVT 
Deep venous thrombosis 
EBMT 
European Group for Bone and Marrow Transplant 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EE 
Efficacy Evaluable 
EU 
European Union 
FCBP 
Female of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
GCSF 
Granulocyte colony-stimulating factor 
GGT 
Gamma-glutamyl transpeptidase 
HBsAg 
Hepatitis B surface antigen 
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Abbreviation 
Definition 
HCV 
Hepatitis C virus 
HDAC 
Histone deacetylase 
hERG 
human Ether-à-go-go Related Gene 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IC50 
50% Inhibitory Concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFE 
Immunofixation 
IgA 
Immunoglobulin A 
IgD 
Immunoglobulin D 
IgE 
Immunoglobulin E 
IGF-1 
Insulin-like growth factor 1 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL-6 
Interleukin-6 
IMiD 
Immunomodulatory inhibitors 
IMWG 
International Myeloma Working Group 
INR 
International normalized ratio 
IRAC 
Independent Response Assessment Committee 
IRB 
Institutional Review Board 
ISS 
International Staging System 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Multiple myeloma 
MR 
Minimal response 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
Natural killer 
NOAEL 
No observed adverse effect level 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic 
PO 
Orally/Oral administration 
PR 
Partial response 
QD 
Once daily 
RBC 
Red blood cell 
RSS 
Radiographic skeletal survey 
SAE 
Serious adverse event 
SD 
Stable disease 
SFLC 
Serum free light chain 
SGOT 
Serum glutamic oxaloacetic transaminase 
 
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Abbreviation 
Definition 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System organ class 
SPEP 
Serum protein electrophoresis 
SRC 
Safety Review Committee 
t1/2 
Serum half-life 
Tmax 
Time to maximum serum concentration 
TNF-α 
Tumor necrosis factor alpha 
TTP 
Time to progression 
TTR 
Time to response 
ULN 
Upper limit of normal 
UPEP 
Urine protein electrophoresis 
US 
United States 
VGPR 
Very good partial response 
VTE 
Venous thromboembolism 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION .......................................................................................................... 35 
1.1. 
ACY-1215 ............................................................................................................ 36 
1.1.1. 
Pharmacology ........................................................................................ 38 
1.1.2. 
Nonclinical Pharmacokinetics ............................................................... 40 
1.1.3. 
Toxicology ............................................................................................ 40 
1.1.4. 
Clinical Data.......................................................................................... 41 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 43 
2.1. 
Study Objectives ................................................................................................. 43 
2.1.1. 
Primary Objectives ................................................................................ 43 
2.1.2. 
Secondary Objectives ............................................................................ 44 
2.1.3. 
Exploratory Objective ........................................................................... 44 
2.2. 
Study Endpoints ................................................................................................. 44 
2.2.1. 
Primary Endpoints ................................................................................. 44 
2.2.2. 
Secondary Endpoints ............................................................................. 44 
2.2.3. 
Exploratory Endpoint ............................................................................ 45 
3. 
INVESTIGATIONAL PLAN ........................................................................................ 45 
3.1. 
Overall Design and Plan of the Study ............................................................... 45 
3.2. 
Rationale for the Study ...................................................................................... 48 
3.3. 
Rationale for the Dose and Schedule Selected ................................................. 49 
3.4. 
Justification of the Study Design ....................................................................... 49 
3.5. 
Study Termination ............................................................................................. 49 
4. 
Study Population ............................................................................................................ 51 
4.1. 
Number of Patients ............................................................................................ 51 
4.2. 
Inclusion Criteria ............................................................................................... 51 
4.3. 
Exclusion Criteria .............................................................................................. 52 
4.4. 
Source of Patients ............................................................................................... 53 
4.5. 
Patient Identification and Registration ............................................................ 53 
4.6. 
Withdrawal and Replacement of Patients ........................................................ 54 
4.7. 
Patient Management .......................................................................................... 54 
4.8. 
Safety Review Committee .................................................................................. 55 
4.9. 
Independent Response Assessment Committee ............................................... 55 
4.10. Investigator Compliance .................................................................................... 56 
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5. 
Study Treatments ........................................................................................................... 56 
5.1. 
Study Drug Supply and Storage ....................................................................... 56 
5.1.1. 
ACY-1215 ............................................................................................. 56 
5.1.2. 
Pomalidomide and Dexamethasone ...................................................... 56 
5.2. 
Study Drug Dose and Administration .............................................................. 56 
5.2.1. 
ACY-1215 ............................................................................................. 57 
5.2.2. 
Pomalidomide ....................................................................................... 57 
5.2.3. 
Dexamethasone ..................................................................................... 58 
5.2.4. 
Planned Study Drug Doses .................................................................... 58 
5.2.5. 
Dose Escalation Procedure .................................................................... 59 
5.2.6. 
Dose-limiting Toxicity .......................................................................... 60 
5.2.7. 
Maximum Tolerated Dose ..................................................................... 60 
5.2.8. 
Dose Modifications ............................................................................... 61 
5.3. 
Blinding, Packaging, and Labeling ................................................................... 66 
5.3.1. 
Blinding and Breaking the Blind .......................................................... 66 
5.3.2. 
Packaging and Labeling ........................................................................ 66 
5.4. 
Assessment of Treatment Compliance ............................................................. 66 
5.4.1. 
ACY-1215 ............................................................................................. 66 
5.4.2. 
Pomalidomide ....................................................................................... 67 
5.4.3. 
Dexamethasone ..................................................................................... 67 
5.5. 
Study Drug Accountability ................................................................................ 67 
5.6. 
Prior and Concomitant Treatment ................................................................... 67 
5.6.1. 
Permitted Medication ............................................................................ 67 
5.6.2. 
Excluded Medication and Substances ................................................... 68 
6. 
STUDY ASSESSMENTS ............................................................................................... 71 
6.1. 
Safety Measurements ......................................................................................... 71 
6.1.1. 
Demographics and Medical History ...................................................... 71 
6.1.2. 
Physical Examination ............................................................................ 71 
6.1.3. 
Vital Signs ............................................................................................. 71 
6.1.4. 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status ..................................................................................................... 71 
6.1.5. 
12-Lead Electrocardiogram ................................................................... 71 
6.1.6. 
VTE Monitoring .................................................................................... 72 
6.1.7. 
Clinical Laboratory Tests ...................................................................... 72 
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6.1.8. 
Adverse Events ..................................................................................... 75 
6.2. 
Efficacy Measurements ...................................................................................... 79 
6.2.1. 
Myeloma  Protein  Measurements  and  Serum 
Immunoglobulins .................................................................................. 79 
6.2.2. 
FreeLite™ Testing ................................................................................ 79 
6.2.3. 
Bone Marrow Examination ................................................................... 79 
6.2.4. 
Skeletal Survey and Other Imaging Studies .......................................... 79 
6.2.5. 
Extramedullary Plasmacytoma Assessments ........................................ 80 
6.2.6. 
Assessment of Disease Response .......................................................... 80 
6.2.7. 
Survival ................................................................................................. 80 
6.3. 
Pharmacokinetic Measurements ....................................................................... 81 
6.4. 
Pharmacodynamic Assessments ........................................................................ 81 
7. 
STATISTICAL PROCEDURES ................................................................................... 81 
7.1. 
Sample Size Estimation ...................................................................................... 81 
7.2. 
Probability of Dose Escalation .......................................................................... 82 
7.3. 
Populations for Analysis .................................................................................... 82 
7.4. 
Procedures for Handling Missing, Unused, and Spurious Data .................... 82 
7.5. 
Analysis Schedule ............................................................................................... 82 
7.5.1. 
Interim Analysis .................................................................................... 82 
7.5.2. 
Final Analysis ....................................................................................... 83 
7.5.3. 
Addendum ............................................................................................. 83 
7.6. 
Statistical Methods ............................................................................................. 83 
7.6.1. 
General Methods ................................................................................... 83 
7.6.2. 
Disposition of Patients .......................................................................... 83 
7.6.3. 
Demographics and Baseline Characteristics ......................................... 83 
7.6.4. 
Extent of Exposure ................................................................................ 83 
7.6.5. 
Concomitant Medications ..................................................................... 84 
7.6.6. 
Safety Analysis ..................................................................................... 84 
7.6.7. 
Efficacy Analysis .................................................................................. 85 
7.6.8. 
Pharmacokinetic Analysis ..................................................................... 85 
7.6.9. 
Pharmacodynamic Analysis .................................................................. 85 
7.6.10. Procedures for Reporting Deviations to Original Statistical 
Analysis Plan ......................................................................................... 85 
8. 
ADMINISTRATIVE REQUIREMENTS .................................................................... 86 
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8.1. 
Good Clinical Practice ....................................................................................... 86 
8.2. 
Ethical Considerations ....................................................................................... 86 
8.3. 
Patient Information and Informed Consent .................................................... 86 
8.4. 
Patient Confidentiality ....................................................................................... 86 
8.5. 
Protocol Compliance .......................................................................................... 86 
8.6. 
Direct Access to Source Data ............................................................................. 87 
8.7. 
Case Report Form Completion ......................................................................... 87 
8.8. 
Record Retention ................................................................................................ 87 
8.9. 
Liability and Insurance ...................................................................................... 88 
8.10. Publication of Study Findings and Use of Information................................... 88 
9. 
APPENDICES ................................................................................................................ 89 
9.1. 
VTE Algorithms ................................................................................................. 90 
9.2. 
Toxicity Grading Scale ....................................................................................... 91 
9.3. 
POMALYST REMS™ Program (United States) ............................................ 92 
9.4. 
RevAid®  Complete  Guide  for  Health  Care  Practitioners 
(Canada) .............................................................................................................. 93 
9.5. 
European Pomalidomide Pregnancy Prevention Risk 
Management Plans ............................................................................................. 94 
9.5.1. 
Pregnancy Prevention Risk Management Plans ............................... 94 
9.6. 
International Myeloma Working Group Response Criteria ........................ 104 
9.7. 
European Group for Blood and Bone Marrow Transplantation: 
Definition of Minimal Response ...................................................................... 106 
9.8. 
Eastern  Cooperative  Oncology  Group  (ECOG)  Performance 
Status ................................................................................................................. 107 
9.9. 
Skeletal (Bone) Survey Films ........................................................................... 108 
9.10. Declaration of Helsinki .................................................................................... 109 
10. 
REFERENCES ............................................................................................................. 110 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF TABLES IN THE TEXT 
Table 1: 
Schedule of Assessments ................................................................................................. 22 
Table 2 
Planned Dose Escalation .................................................................................................. 58 
Table 3 
ACY-1215 Dose Modifications ....................................................................................... 61 
Table 4 
Dose Modification Instructions for ACY-1215 for Hematologic Toxicities .................... 62 
Table 5: 
Dose  Modification  Instructions  for  ACY-1215  for  Non-hematologic 
Toxicities ......................................................................................................................... 62 
Table 6 
Dose  Modification  Instructions  for  Pomalidomide  for  Hematologic 
Toxicities ......................................................................................................................... 63 
Table 7 
Dose Modification Instructions for Pomalidomide for Non-hematologic 
Toxicities ......................................................................................................................... 63 
Table 8 
Dexamethasone Dose Modifications................................................................................ 65 
Table 9 
Dose Reduction Steps for Dexamethasone (≤ 75 years of age) ....................................... 65 
Table 10 
Dose Reduction Steps for Dexamethasone (> 75 years of age) ....................................... 66 
Table 11 
Probabilities of Dose Escalation ...................................................................................... 82 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF FIGURES IN THE TEXT 
Figure 1 
In Vitro Activity of ACY-1215 in Combination with Lenalidomide 
±Dexamethasone in MM1.S Cells ................................................................................... 39 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. 
INTRODUCTION 
Multiple myeloma (MM), a plasma cell dyscrasia, is the most common primary malignancy of 
the bone marrow.[1,2] The etiology of myeloma is largely unknown, although genetic 
predisposition and environmental factors have been speculated. MM arises from malignant 
plasma cells that clonally expand and accumulate in the bone marrow.[3] These clonal 
antibody-producing plasma cells produce high levels of monoclonal immunoglobulins, most 
commonly immunoglobulin G (IgG) (50-60%) and immunoglobulin A (IgA) (20-25%), and less 
frequently immunoglobulin M (IgM), immunoglobulin D (IgD), and immunoglobulin E 
(IgE).[4] 
MM accounted for an estimated 20,180 (1.3%) new cancer cases in the United States (US) in 
the year 2010, including 11,170 cases in men (1.4%) and 9,010 (1.2%) cases in women.[5] 
Patients afflicted with MM are likely to suffer from bone pain and skeletal fragility.[6] 
Plasmacytomas are osteolytic in nature and are most often confined to the central skeleton, 
skull, and femur, and rarely involve distal bones and soft-tissues.[7] Production and secretion of 
cytokines such as interleukin-6 (IL-6) are thought to play a role in the stimulation of the plasma 
cells, increase in osteoclast activity, and possibly suppression of osteoblast activity resulting in 
retarded bone regeneration.[3,6] Lesions caused by osteoclastic bone destruction are replaced 
by the expanding malignant cell mass. The pattern of bone destruction is most often focal but 
may also be generalized in approximately 15% of patients.[7] Common methods of imaging 
include radiographic skeletal survey (RSS) for skull, rib, femur, and humerus, and magnetic 
resonance imaging (MRI) for spinal and pelvic bone lesions.[8,9] To protect patients from 
developing skeletal-related problems, most myeloma patients receive intravenous 
bisphosphonates either alone or with their other anti-myeloma therapies.[6,10,11] 
Since 1975, the Durie-Salmon classification system has been widely used for disease diagnosis 
and staging. Stages I, II, and III are defined by criteria for bone lesion status, hemoglobin, 
serum calcium, and monoclonal protein (M-protein) levels and subcategorized as A or B 
depending on renal function. A clear correlation between disease stage and survival duration 
has been demonstrated.[12] The criteria for diagnosis, staging, risk stratification, and response 
assessment of MM, as described by Kyle and Rajkumar, has been widely used as well.[13] A 
variety of other prognostic markers and indicators have been studied, including plasma cell 
labeling index, serum beta-2 microglobulin (β2M), C-reactive protein (CRP), plasmablast 
morphology, cytogenetics, and bone marrow angiogenesis.[14,15] More recently, an 
International Staging System (ISS) was established based on the combination of levels of serum 
β2M and albumin among MM patients at diagnosis [16], which has been validated as an 
effective predictor of overall survival (OS) for MM patients. 
Although MM is currently not curable, it is considered treatable.[17] The death rate due to the 
disease has declined by ~10% from 1990 to 2006, with an improvement in the 5-year survival 
rate from 29% in 1984 to 1986 to 37% in 1999 to 2005.[5] These improvements in survival 
have resulted in large part from major increases over the past several years in response rates to 
treatment with lenalidomide, a thalidomide analogue, and bortezomib, a reversible proteasome 
inhibitor, each of which are also often used in combination with the generic drug 
dexamethasone.[18] However, the rate of complete responses (CR) in relapsed disease, and 
particularly in refractory relapsed disease, remains relatively low, with substantial room for 
improvement. 
 
 
 
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1.1. 
ACY-1215 
Histone deacetylases (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), 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 also dependent on the cofactor nicotinamide adenine dinucleotide.[19] 
The function of HDACs has until recently been associated with gene transcription through 
modification of histone tail acetylation and regulation of chromatin dynamics. However it has 
become apparent that HDACs play a critical role in the regulation and function of lysine 
acetylation of nonhistone proteins in most, if not all, major cellular functions.[20] The breadth 
of posttranslational regulation in many proteins of diverse functional roles is on par with that 
achieved through phosphorylation/dephosphorylation of hydroxyl groups by 
kinases/phosphatases.[21,22] Additionally, several HDACs, including HDAC6, are localized to 
the cytoplasm of cells while others can “shuttle” between the nucleus and cytoplasm. HDACs 
are thus substantially more diverse in their intracellular mechanisms of action than is implied by 
the “histone” in their name.[19] 
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, vorinostat and romidepsin, with several other drug candidates also in clinical studies 
because of their potential for the treatment of various cancers.[23] The approved agents and 
development candidates that are structurally categorized as hydroxamates were previously 
considered to be nonselective across Class I and Class II, while the ortho aminoanilide inhibitors 
(e.g., entinostat [SNDX-275], Syndax Pharmaceuticals) are semi-selective for Class I. Recently 
it has been demonstrated that the hydroxamate-based inhibitors are selective for Class I and the 
Class IIb enzyme HDAC6, but they do not significantly inhibit Class IIa HDAC enzymes.[24] 
HDAC6 has been shown to be crucial in the autophagic degradation of poly-ubiquitinated 
protein aggregates and misfolded proteins which is an alternative to the proteasome degradation 
pathway.[25,26,27] Autophagy requires the formation of autophagasomes containing aggregated 
protein that fuse with lysosomes to digest the protein. Failure by a cell to remove accumulated 
misfolded protein aggregates leads to apoptosis. HDAC6 mechanistically has two direct roles in 
aggresome formation. First, the deacetylase activity of HDAC6 is required, and the likely 
substrate is α-tubulin. Tubulin is a key component of microtubules, along which protein 
complexes are transported to the microtubule organizing center where aggresomes form. 
Second, HDAC6 acts as an adaptor protein binding poly-ubiquitinated proteins and dynein, a 
component of the motor complex that transports protein along the microtubules. 
Additionally, HDAC6 regulates function through modulating the acetylation state of a number 
of other important proteins, one of which is Hsp90, a molecular chaperone required for stability 
and function of numerous proteins.[28] Increased acetylation of Hsp90 decreases the functional 
activity of the chaperone and results in increased levels of poly-ubiquitinated protein complexes. 
Development of Hsp90 inhibitors has been an active area to discover new antitumor agents (e.g., 
geldanamycin) and analogs thereof.[29] HDAC6 appears to have a similar role in modulating 
the acetylation state of Hsp70 and other members of the heat shock protein family. 
MM, a blood plasma cell malignancy is characterized by excessive production of 
immunoglobulins. The proteasome inhibitor bortezomib has been shown in vitro to trigger 
apoptosis in MM cells through protein accumulation.[30,31] Patients with MM relapse or 
become refractory to bortezomib treatment potentially due in part to the alternative aggresome 
 
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pathway being utilized for protein degradation.[32] Immunomodulatory inhibitors (IMiD) have 
well established clinical activity in myeloma and are considered standard therapy for patients 
with relapsed disease. One such agent is pomalidomide, a derivative of thalidomide, with 
higher potency and reduced toxicity. Pomalidomide is generated through modification of the 
thalidomide structure consisting of an amino group addition at the 4 position of the phthaloyl 
ring. The result is the generation of a thalidomide analog that is up to 50,000 times more potent 
at inhibiting tumor necrosis factor alpha (TNF-α) in vitro than its predecessor. 
Clinical experience with pomalidomide includes Study CC-4047-MM-003, a Phase 3, 
randomized, multicenter, open-label study of pomalidomide plus low-dose dexamethasone 
therapy versus high-dose dexamethasone alone in previously treated adult patients with relapsed 
and refractory multiple myeloma.[33] Enrolled patients had received at least 2 prior treatment 
regimens, including both lenalidomide and bortezomib, and demonstrated disease progression 
on the last therapy. A total of 455 patients were randomized to treatment in a 2:1 ratio. The 
primary endpoint of the study, progression-free survival (PFS), was met as PFS was 
significantly longer with the pomalidomide plus low-dose dexamethasone arm compared with 
the high-dose dexamethasone alone, exceeding the pre-specified difference (observed hazard 
ratio [HR] 0.45 versus planned 0.67). The difference in overall survival (OS) between the 
2 treatment arms was also statistically significant (HR 0.53 [95% CI: 0.37, 0.74], p < 0.001) 
exceeding the pre-specified OS difference (observed HR 0.53 versus planned 0.67). 
Study CC-4047-MM-002 was a Phase 1b/2, multicenter, randomized, open-label, 
dose-escalation study to determine the maximum tolerated dose (MTD) and evaluate safety and 
efficacy of pomalidomide alone and in combination with low-dose dexamethasone.[34] 
Enrolled patients included those with relapsed/refractory MM who had received prior treatment 
that included lenalidomide and bortezomib and were refractory to their last treatment. A total of 
221 patients were randomized in a 1:1 ratio. Median PFS was 10.7 weeks (95% CI: 8.3, 16.1) 
for patients in the pomalidomide group and 16.6 weeks (95% CI: 14.1, 21.1) for patients in the 
pomalidomide plus dexamethasone group. Median OS was 59.3 weeks (95% CI: 41.6, NE) for 
patients in the pomalidomide group and 62.6 weeks (95% CI: 53.6, NE) for patients in the 
pomalidomide plus dexamethasone group. 
Study IFM 2009-02 was a Phase 2, multicenter, randomized, open-label study to evaluate the 
safety and efficacy of 2 regimens of oral pomalidomide in combination with low-dose 
dexamethasone.[35] Patients with relapsed/refractory MM who had received prior treatment 
with lenalidomide and bortezomib and had been non-responsive or refractory to the last course 
of treatment with both drugs were enrolled. Patients were randomized to treatment in a 1:1 ratio 
to Arm A or Arm B. Median PFS was 25.1 weeks (95% CI: 16.3, 41.7) for Arm A and 
25.1 weeks (95% CI: 13.3, 36.0) for Arm B. Median OS was 58.4 weeks (95% CI: 38.7, 60.6) 
for Arm A and 66.4 weeks (95% CI: 39.9, NE) for Arm B. 
Preclinical studies and clinical studies in patients with refractory/relapsed MM, have been 
conducted to evaluate the potential synergistic effect of Class I HDAC + HDAC6 inhibitors, 
vorinostat and panobinostat, in combination with bortezomib and/or with lenalidomide and 
dexamethasone.[36,37,38,39,40] However, nonselective Class I HDAC inhibitors as well as the 
ortho amino anilide inhibitors, such as entinostat (Syndax Pharmaceuticals), that are semi- 
selective for Class I HDACs (i.e., excluding HDAC6) exhibit similar side-effect profiles 
regardless of their ability to inhibit HDAC6.[41,42,43,44,45] Taken together, 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 [46] whereas Class I -/- 
animals are nonviable [19], suggests that selective HDAC6 inhibitors have the potential for a 
 
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substantially reduced side-effect profile versus current HDAC inhibitor drugs and drug 
candidates, while retaining the inhibition of the aggresome pathway and Hsp90 and thus 
potential anticancer effectiveness. 
Based on this work, ACY-1215 (Ricolinostat), an HDAC6-selective, orally active small- 
molecule enzyme inhibitor, will be investigated for treatment of MM. In the current study, 
ACY-1215 will be evaluated in combination with the commercially-available thalidomide 
analog pomalidomide plus dexamethasone. 
1.1.1. 
Pharmacology 
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 2 major metabolites of ACY-1215 have minimal activity 
against HDAC6. ACY-1215 in the submicromolar (µM) concentration range increases the level 
of acetylated α-tubulin, a key therapeutic target of HDAC6 inhibition in MM cells. ACY-1215 
can also increase the level of acetylated α-tubulin in human peripheral mononuclear cells 
(PBMCs) in a dose-dependent and time-dependent manner. 
ACY-1215 can inhibit the growth of MM cell lines (MM.1S, OPM1, RPMI 8226, MM.1R, LR5, 
OPM2, INA6 and U266), including drug resistant cell lines and primary cells from MM patients 
in the 1-6 µM concentration range. The antiproliferative activity of ACY-1215 can overcome 
the growth supportive activity of growth factors such as IL-6 and insulin-like growth factor 1 
(IGF-1) and bone marrow stroma from MM patients, while having minimal impact on normal 
cells such activated PBMCs. In vitro data with cultured MM1.S cells demonstrated that the 
presence of ACY-1215 enhances the activity of lenalidomide in a dose-dependent manner both 
with and without dexamethasone (50 nM) (see Figure 1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 1 
In Vitro Activity of ACY-1215 in Combination with Lenalidomide 
±Dexamethasone in MM1.S Cells 
 
 
 
 
 
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1.1.1.1. 
Safety Pharmacology 
There were no significant interactions (inhibition > 50% at 10 µM) against an extensive panel of 
enzymes, including kinases, receptors and ion channels 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 the dog at ACY-1215 dose levels of 10, 30, and 60 mg/kg, a moderate and transient rise in 
heart rate (19 – 24 bpm) and decrease in systolic pressure (5 - 15 mmHg) was observed at 
0.5 - 11 hours post-dose for all 3 dose levels. One dog in the high dose group (60 mg/kg) with 
the highest exposure and maximum serum 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 
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. 
1.1.2. 
Nonclinical Pharmacokinetics 
ACY-1215 is rapidly absorbed (time to maximum serum concentration [Tmax] ≤1 hour) 
following oral administration (PO) to 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 pharmacokinetics (PKs) of ACY-1215 in humans will be similar to that in dogs. 
Pharmacodynamic studies in mice with ACY-1215 demonstrated a reversible increase in levels 
of acetylated α-tubulin, a biomarker of HDAC6 inhibition, in PBMCs. ACY-1215 is classified 
as moderately permeable and is stable in human liver microsomes (serum half-life [t1/2] 
> 45 minutes). 
Two major inactive 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 2 major metabolites have minimal potential to cause drug-drug interactions through 
inhibition or induction of CYP450 enzymes. 
ACY-1215 was detected in feces and urine mainly in the 0-8 hour period following oral 
administration of a single dose (30 mg/kg) in rat. The 2 major metabolites (ACY-161-344 and 
ACY-161-349) were found predominately in feces at 4-24 hour post-dose of ACY-1215. 
Preliminary results following a single dose of radiolabeled (14C) ACY-1215 in rat confirmed the 
observation that ACY-1215 and metabolites were predominately excreted in the feces (87%) 
compared to urine (9.1%) by 72 hours post-dose. In addition, 85% and 98% of radiolabeled 
material (feces, urine and cage wash) was excreted by 24 hours post-dose versus 98% by 
72 hours post-dose, respectively. 
1.1.3. 
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. 
 
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In the rat 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 decrease in body weight and minimal to mild 
decrease in red blood cell (RBC) mass was observed at all 3 dose levels of 30, 60, and 
120 mg/kg, and decreases in white blood cells (WBCs), lymphocytes, and monocytes were 
observed in males. The decreased RBC mass may reflect decreased hematopoiesis and/or 
increased turnover of RBCs suggested by minimal to slight pigment deposition in the liver of 
some dogs. Marginal, non-adverse, yet statistically significant from the control group, serum 
chemistry changes were noted in both sexes in all dose groups, including a decrease in hepatic 
enzyme activities (alanine aminotransferase [ALT], alkaline phosphatase [ALP], and gamma- 
glutamyl transferase [GGT]) and increases in triglyceride (males), total bilirubin (high dose 
male), albumin and total protein. Administration of 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 
mutagenic ability in in vitro assays including the Ames test and the 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. In addition, ACY-1215 did not 
exhibit mutagenic potential in the GLP in vivo micronucleus and comet assay in rats. 
Detailed descriptions of findings from nonclinical studies of ACY-1215 are summarized in the 
Investigator’s Brochure.[47] 
1.1.4. 
Clinical Data 
To date, clinical data are available from 61 patients with MM, of whom 15 were treated with 
ACY-1215 monotherapy at doses up to 360 mg and 46 were treated with ACY-1215 in 
combination with other anti-neoplastic agents in 2 ongoing clinical studies. Of the 46 patients 
receiving combination therapy, 25 received ACY-1215 in combination with bortezomib and 
dexamethasone and 21 received ACY-1215 in combination with lenalidomide and 
dexamethasone. 
1.1.4.1. 
Safety 
Review of safety data from patients treated with ACY-1215 monotherapy or in combination with 
bortezomib/dexamethasone or lenalidomide/dexamethasone has shown ACY-1215 to be generally 
well tolerated and to have a manageable safety profile. 
ACY-1215 monotherapy at doses up to 360 mg was well tolerated, no deaths or other serious 
adverse events (SAEs) were considered by the Investigator to be related to ACY-1215, and no 
adverse events (AEs) reported were considered to represent dose-limiting toxicities (DLTs). 
Across all dose levels, common treatment-emergent adverse events reported among 46 patients 
 
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treated with ACY-1215 monotherapy included elevated blood creatinine (33%), fatigue, 
hypercalcemia, and upper respiratory infection (27% each); and anemia, cough, diarrhea, and 
dizziness (20% each). Of these events, diarrhea occurred at doses ≥ 160 mg, and no dose 
relationship was apparent with regard to the occurrence of the other AEs. Most AEs reported 
were Grade 1 and 2 in intensity and unrelated to ACY-1215. Grade 3 AEs that were considered 
to be at least possibly related to ACY-1215 were hematologic in nature and included anemia, 
leukopenia, and neutropenia. 
Safety data from patients treated with ACY-1215 on a Day 1-5 and Day 8-12 schedule, in 
combination with bortezomib, have shown ACY-1215 to be generally well tolerated.[48] The 
most common AEs seen to date with ACY-1215 in combination with 
bortezomib/dexamethasone included thrombocytopenia (40%); anemia, blood creatinine 
increased, diarrhea, and fatigue (36% each); hypokalemia (28%); decreased appetite (24%); 
ALT increased, amylase increased, cough, hypophosphatemia, and peripheral neuropathy (20% 
each). Most AEs were Grade 1 or 2 in intensity and unrelated to ACY-1215. Grade 3 or 4 AEs 
considered related to ACY-1215 among patients receiving ACY-1215 plus 
bortezomib/dexamethasone included elevated amylase, elevated lipase, hypophosphatemia, 
hyponatremia, anemia, worsening anemia, thrombocytopenia, worsening thrombocytopenia, 
decreased platelets, neutropenia, decreased WBC, fatigue, diarrhea and stomach pain/cramps. 
One DLT (amylase increased) was observed during a patient’s first cycle. In this study, one 
death (due to pulmonary embolism) was reported, for a 
 patient with chronic atrial 
fibrillation and bilateral ankle edema who was receiving ACY-1215 160 mg in combination 
with bortezomib 1.3 mg/m2/dexamethasone 20 mg; the Investigator considered the event 
possibly related to ACY-1215. 
In a second clinical study (ACE-MM-101), 21 patients were treated with escalating doses of 
ACY-1215 in combination with lenalidomide/dexamethasone on two different schedules. The 
most common AEs reported to date include fatigue (57%); upper respiratory tract infection 
(38%); diarrhea, anemia, and thrombocytopenia (29% each); and neutropenia, headache, and 
hypophosphatemia (24% each). Most AEs were Grade 1 or 2 and assessed by the Investigator as 
unrelated to ACY-1215. Of all Grade 3 and 4 AEs, 2 events of neutropenia were considered by 
the Investigator to be possibly related to ACY-1215 and probably related to lenalidomide (1 was 
also deemed possibly related to dexamethasone); all other Grade 3 and 4 events were considered 
unrelated to ACY-1215. To date, one SAE of hypercalcemia and one event of interest, a 
secondary malignancy, have been reported, and both were assessed as unrelated to ACY-1215. 
No deaths or other SAEs have been reported among patients receiving ACY-1215 in 
combination with lenalidomide/dexamethasone; however, 1 DLT of syncope has been identified 
to date. 
1.1.4.2. 
Efficacy 
Anti-tumor activity of ACY-1215 may be preliminarily demonstrated in patients treated with 
ACY-1215 monotherapy at doses of 40, 160, or 240 mg in that 6 of 15 patients experienced 
stable disease. ACY-1215 in combination with bortezomib/dexamethasone yielded an overall 
response rate (i.e., ≥ PR) in 47% of 17 evaluable patients and 32% of 25 patients in the Intent- 
to-Treat (ITT) Population. ACY-1215 in combination with lenalidomide/dexamethasone 
yielded an overall response rate (≥ PR) of 65% and a clinical benefit (stable disease or better) of 
100% has been seen in 20 evaluable patients. Some patients in both combination studies have 
had responses even if previously refractory to the combination agent. 
 
 
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1.1.4.3. 
Pharmacokinetics 
Preliminary PK analysis of ACY-1215 monotherapy revealed measurable levels of ACY-1215 
in all patients, with Cmax levels ranging from 85±39 ng/mL to 503±195 ng/mL (0.2 to 1.2 μM) 
and area under the plasma concentration curve from time 0 to the last time point of quantifiable 
drug concentration (4 hours post-dose) (AUC0-4) values ranged from 170±61 ng•h/mL to 
1093±357 ng•h/mL at dose levels of 40 to 360 mg.[49] Maximal plasma (Cmax) and exposure 
(AUC) levels observed in patients treated at 160 mg (Cmax 626±150 ng/mL, and AUC0-4 
1074±439 ng•h/mL) and 240 mg (Cmax 719±329 ng/mL, and AUC0-4 1231±430 ng•h/mL) were 
similar, suggesting an exposure plateau was reached at dose levels ≥ 160 mg.[49] The drug was 
rapidly absorbed (Tmax ~1 hour) from the gastrointestinal tract. The apparent elimination half- 
life was ~3 hours, and by 24 hours post-dose, drug levels ranged from ~1 ng/mL to below the 
lower limit of quantification (0.5 ng/mL). No accumulation was observed over multiple days of 
administration, and drug exposures at ≥ 160 mg were similar.[49] Since drug is rapidly cleared, 
twice daily dosing is being explored in ongoing studies. 
A comparison of preliminary PK data of ACY-1215 alone and coadministered in combination 
with bortezomib 1.0 and 1.3 mg/m2 on Days 1 and 11 of Cycle 1 and in combination with 
lenalidomide 15 and 25 mg on Days 1 and 8 in Cycle 1 suggest that the PK profile of 
ACY-1215 was not substantially altered by coadministration of bortezomib or lenalidomide. 
1.1.4.4. 
Pharmacodynamics 
Pharmacodynamic analyses in PBMCs revealed at least a 2-fold increase in acetylated tubulin, 
the pharmacological marker of HDAC6 inhibition, in all patients at ACY-1215 monotherapy 
doses of ≥ 160 mg. Additionally, a modest increase in acetylated histones was seen at an 
ACY-1215 monotherapy dose of 240 mg; at lower dose levels of 40 and 80 mg, 1 and 2 
patients, respectively, had a measurable increase in acetylated tubulin in PBMCs.[49] 
The data show that exposures observed at ACY-1215 doses ≥ 160 mg are likely to achieve the 
target change in pharmacodynamic markers and attain drug levels in the range where efficacy 
was observed in nonclinical studies (see Investigator’s Brochure, [47]). 
Further information about ACY-1215 can be found in the investigator brochure. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objectives of this study are the following: 
Phase 1b: 
• To determine the MTD dose, or if not present, the recommended Phase 2 dose and 
schedule of ACY-1215 administered in combination with pomalidomide and low-dose 
dexamethasone in patients with relapsed-and-refractory MM. 
Phase 2: 
• To determine the efficacy of ACY-1215 administered in combination with 
pomalidomide and low-dose dexamethasone as treatment for patients with relapsed-and- 
refractory MM as assessed by overall response rate. 
 
 
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2.1.2. 
Secondary Objectives 
The secondary objectives of this study are the following: 
Phase 1b and Phase 2: 
• To evaluate the safety of ACY-1215 administered in combination with pomalidomide 
and low-dose dexamethasone as treatment for patients with relapsed-and-refractory MM. 
Phase 1b: 
• To assess the PK of ACY-1215 administered in combination with pomalidomide and 
low-dose dexamethasone in patients with relapsed-and-refractory MM. 
• To assess the PK of pomalidomide administered in combination with ACY-1215 and 
low-dose dexamethasone in patients with relapsed-and-refractory MM. 
• To assess the pharmacodynamics of ACY-1215 administered in combination with 
pomalidomide and low-dose dexamethasone in patients with relapsed-and-refractory 
MM. 
2.1.3. 
Exploratory Objective 
The exploratory objective of this study is the following: 
Phase2: 
• To explore the relationship between response to treatment and any cytogenetic 
abnormalities. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoints include the following: 
Phase 1b: 
• MTD dose and schedule, or if not present, the recommended Phase 2 dose and schedule 
of ACY-1215 administered in combination with pomalidomide and dexamethasone. 
Phase 2: 
• Objective response to treatment as assessed by site Investigators using International 
Myeloma Working Group (IMWG) Uniform Response criteria. 
2.2.2. 
Secondary Endpoints 
The secondary endpoints include the following: 
Efficacy 
Phase 1b and Phase 2: 
• Time to response (TTR). 
• Duration of response (DOR). 
• Time to progression (TTP). 
• Progression-free survival (PFS). 
 
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• Objective response to treatment as blindly assessed by the Central Adjudication 
Committee using IMWG criteria and dates of progressive disease (PD). 
Safety 
Phase 1b and Phase 2: 
• Safety (type, frequency, and severity of AEs and relationship of AEs to study drug) 
Pharmacokinetics 
Phase 1b: 
• Plasma levels of ACY-1215 to assess the single and multiple-dose PK of ACY-1215 in 
combination with pomalidomide and low-dose dexamethasone. 
• Plasma levels of pomalidomide to assess the PK of pomalidomide in combination with 
ACY-1215 and low-dose dexamethasone. 
Pharmacodynamics 
Phase 1b: 
• Exposure-response of ACY-1215 in combination with pomalidomide and low-dose 
dexamethasone, including biomarkers relating to intracellular protein acetylation. 
2.2.3. 
Exploratory Endpoint 
The exploratory endpoint is the following: 
Phase 2: 
• To explore the relationship between response to treatment and any cytogenetic 
abnormalities. 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Design and Plan of the Study 
This is a Phase 1b/2, multi-center, single-arm, open-label, dose-escalation study that will 
evaluate the safety and efficacy of PO ACY-1215 in combination with pomalidomide and low- 
dose PO dexamethasone in patients with relapsed-and-refractory MM. Eligible patients must 
have a documented diagnosis of MM and have relapsed-and-refractory disease. Patients must 
have relapsed after having achieved at least stable disease (SD) for at least one cycle of 
treatment to at least one prior regimen and then developed PD. Patients must also have 
documented evidence of PD during or within 60 days (measured from the end of the last cycle) 
of completing treatment with the last anti-myeloma drug regimen used just prior to study entry 
(refractory disease). Patients must also have undergone prior treatment with at least 2 cycles of 
lenalidomide and at least 2 cycles of bortezomib (either in separate regiments or within the same 
regimen) and have measurable disease. 
This study will consist of a Phase 1b ACY-1215, pomalidomide and low dose dexamethasone 
dose-finding segment and a Phase 2 segment. The Phase 1b segment will determine the starting 
dose and schedule to be used in the Phase 2 segment of the study. All patients will receive 
ACY-1215 in combination with pomalidomide and dexamethasone administered orally in 
28-day treatment cycles unless an alternative schedule is identified in Part 1b. 
The study will employ a sequential group dose-escalation design to determine the DLT and 
MTD of ACY-1215 in combination with pomalidomide and dexamethasone, all administered 
 
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PO. The safety, tolerability, single- and multiple-dose PK, pharmacodynamics, and anti-tumor 
activity of ACY-1215 in combination with pomalidomide and dexamethasone also will be 
evaluated. 
• ACY-1215: 
• Dose Level -2: ACY-1215 160 mg once daily (QD) on Days 1-5, and 8-12 of a 
28-day cycle. 
• Dose Level -1: ACY-1215 160 mg QD on Days 1-5, 8-12, and 15-19 of a 28-day 
cycle. 
• Dose Level 1: ACY-1215 160 mg for 21 consecutive days of a 28-day cycle. 
• Dose Level 2: ACY-1215 240 mg QD for 21 consecutive days of a 28-day cycle. 
• Dose Level 3: ACY-1215 160 mg twice daily (BID) for 21 consecutive days of a 
28-day cycle. 
• Pomalidomide: 
• QD on Day 1 to 21 of a 28-day cycle. The starting dose of pomalidomide is 4 mg. 
• Dexamethasone: 
• QD on Days 1, 8, 15, and 22 of a 28-day cycle. Patients ≤ 75 years of age will 
receive dexamethasone at a dose of 40 mg/day. Patients > 75 years of age will 
receive dexamethasone at a dose of 20 mg/day. 
The planned dose escalation is presented in Table 2 in Section 5.2.4. 
Initially, 3 patients will be enrolled into a Dose-Level Group as specified above. If none of the 
3 patients experiences a DLT (as defined in 5.2.6) within the first 28-day cycle, the study will 
proceed with dose escalation to the next higher Dose-Level-Group following safety data review 
by the Safety Review Committee (SRC). Dose escalations or expansion of a dose cohort will 
occur only with full approval of the SRC. The SRC will be comprised of the Study 
Investigators, the Safety Monitor, and the Sponsor Safety Medical Monitor (Section 4.8). If one 
of the 3 initial patients in a Dose-Level Group experiences a DLT within the first 28-day cycle, 
then an additional 3 patients will be enrolled into that Dose-Level Group. If 2 or more patients 
within the expanded dose cohort experience a DLT within the first 28-day cycle, then the MTD 
has been exceeded and no further dose escalations will occur. If no more than 1 of the 6 
patients experiences a DLT within the first 28-day cycle, then the next dose cohort of 3 patients 
will be enrolled at the next higher dose level. Following the identification of the MTD, or 
recommended Phase 2 dose, up to 6 additional patients may be enrolled at this dose. 
The MTD will be defined as the highest dose level at which no more than 1 of 6 patients 
experiences a DLT within the first 28-day cycle. If no more than 1 of these 6 patients 
experiences a DLT within the first 28-day cycle, then the last dose level enrolled to meet these 
criteria may be identified as the recommended dose for the Phase 2 segment of the study. 
After provision of written informed consent, patients are to be evaluated for study eligibility at 
screening within 28 days of study start, Cycle 1 Day 1 (C1D1). Patients who are determined to 
be eligible based on screening assessments, will be enrolled in the study on C1D1, which is the 
first day of study drug administration. 
For all patients who enroll into either the Phase 1b or Phase 2 segment of this study, study visits 
and serial measurements of safety and efficacy will be performed as outlined in Table 1. In 
 
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addition, all patients will be given aspirin 81 or 325 mg daily (commercial supply) as 
prophylactic anti-thrombotic treatment unless contraindicated. If aspirin is contraindicated, 
patients will receive another form of anti-thrombotic therapy according to hospital guidelines or 
physician preference. All patients will be monitored for signs and symptoms of venous 
thromboembolism (VTE) while on pomalidomide; diagnostic algorithms are provided 
(Appendix 9.1). The study will conclude 30 days after the last enrolled patient discontinues 
from the study due to disease progression or treatment discontinuation. 
Patients are to be evaluated for disease response after every cycle and at study treatment 
discontinuation, starting with Cycle 1. The severity of AEs will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 4.0 (Appendix 9.2). Patients who withdraw from the study are to be followed up either 
in person or by phone 30 days (±3 days) after the last dose of study drug. If patients are treated 
with an alternate MM therapy before the 30 day visit, assessments for the 30 day visit should be 
performed prior to initiation of the alternate therapy. Upon discontinuation from study 
treatment for PD or any other reason, patients will be assessed 3 times per year (e.g., April, 
August, and December), for up to 5 years, for survival, subsequent anti-myeloma therapies, and 
monitoring of second primary malignancies as outlined in Table 1. Patients who discontinue 
study treatment due to reasons other than PD will also be followed for efficacy assessments 
(assessment of response, extramedullary plasmacytoma assessment, quantitative serum 
immunoglobulin levels, serum and urine protein electrophoresis of myeloma [M]-protein levels 
[SPEP, UPEP], serum and urine immunofixation [IFE] studies, and serum free light chain 
[SFLC] analysis) until PD, death, or initiation of an alternate MM therapy, whichever occurs 
first. Subsequent therapies should be collected until death or end of 1 year follow up period. 
Survival follow up may be done via phone. Serious adverse events (SAEs) will be collected 
from C1D1 through the first 30 days of follow-up. Females of childbearing potential (FCBP) 
with regular or no menstruation will be required to have a final pregnancy test at study treatment 
discontinuation, and at Day 28 following study treatment discontinuation. Females with 
irregular menstruation must have a pregnancy test at study treatment discontinuation, and at 
Day 14 and Day 28 following study treatment discontinuation. 
Safety is to be evaluated during the study by documentation of AEs, including SAEs, clinical 
laboratory tests (hematology, serum chemistry, and urinalysis), physical examinations, vital sign 
measurements, performance status, and 12-lead electrocardiograms (ECGs). All safety and 
efficacy laboratory tests will be analyzed by local laboratories. A central laboratory will 
analyze duplicate samples of serum immunoglobulin levels, SPEP and UPEP of M-protein 
levels, serum and urine IFE studies, and SFLC analysis. A bone marrow aspirate sample will be 
centrally analyzed for fluorescence in situ hybridization (FISH)/cytogenetics. Results from the 
central efficacy analysis will not be shared with sites. 
Second primary malignancies will be monitored as events of interest and should be included as 
part of the assessment of AEs throughout the course of the study. Investigators are to report any 
second primary malignancies as SAEs regardless of causal relationship to study drugs, occurring 
at any time for the duration of the study, from the time of signing the informed consent up to the 
time all patients have been followed for at least 1 year from randomization or have died. 
The anti-tumor activity of ACY-1215 in combination with pomalidomide and dexamethasone 
will be determined by assessment of disease response using the consensus recommendations 
based on the IMWG criteria, published by Rajkumar et al., in Blood in 2011, which includes the 
category of minimal response (MR) (as defined by European Group for Blood and Marrow 
Transplantation [EBMT] criteria) for relapsed refractory MM (Appendix 9.5, 
 
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Appendix 9.7).[50,53] In order to assess response, M-protein component is to be measured in 
serum and urine, FreeLite™ testing is to be performed and, as applicable, bone marrow aspirate 
and biopsies, and appropriate imaging studies (e.g., computed tomography [CT], MRI) are to be 
performed. Patients who are determined to have PD at any time are to be discontinued from the 
study. 
In the Phase 1b segment, blood samples will be collected from all patients for the assessment of 
PK for ACY-1215. Blood samples will also be collected from patients at participating sites in 
the Phase 2 segment for sparse PK sampling. Pharmacodynamic evaluations will also be 
performed in the Phase 1b segment and will include the assessment of the exposure-response 
relationship of ACY-1215 in combination with pomalidomide and low-dose dexamethasone and 
potential biomarkers of response. Exploratory assessments will include the evaluation of the 
relationship between response and cytogenetic abnormalities, including biomarkers relating to 
intracellular protein acetylation. 
3.2. 
Rationale for the Study 
Pomalidomide is approved for patients with MM who have received at least 2 prior therapies 
including lenalidomide and bortezomib and have demonstrated disease progression on or within 
60 days of completion of the last therapy.[51] Pomalidomide, an analogue of thalidomide, is an 
immunomodulatory agent with antineoplastic activity. Apoptotic activity and inhibition of 
proliferation has been observed for pomalidomide in in vitro cellular assays using hematopoietic 
tumor cells. In addition, pomalidomide inhibited the proliferation of lenalidomide-sensitive 
MM cell lines and synergized with dexamethasone in both lenalidomide-sensitive and 
lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide enhanced T cell- 
and natural killer (NK) cell-mediated immunity and inhibited production of pro-inflammatory 
cytokines (e.g., TNF-α and IL-6) by monocytes. Pomalidomide demonstrated anti-angiogenic 
activity in a mouse tumor model and in the in vitro umbilical cord model.[51] 
Combination treatment of MM cells with ricolinostat and pomalidomide resulted in synergistic 
decreases in cellular viability in vitro. Time course studies demonstrated accumulation of cell 
cycle arrest in cells after prolonged exposure to pomalidomide, as well as progressive induction 
of apoptosis in these cells. Notably, though, combination treatment with ricolinostat plus 
pomalidomide resulted in synergistic increases in the percentage of MM cells undergoing 
apoptosis. Furthermore, at the molecular level, MM cells are known to be dependent on 
expression of the MYC and IRF4 transcription factors. Both ricolinostat and pomalidomide as 
single agents reduced expression of the critical genes MYC and IRF4, which were reduced even 
further upon combination treatment.[52, 53] 
In vitro data with cultured MM1.S cells demonstrated that the presence of ACY-1215 enhances 
the activity of lenalidomide in a dose-dependent manner both with and without dexamethasone. 
Safety data thus far in 15 patients treated with ACY-1215 monotherapy and 46 patients treated 
with ACY-1215 in combination with dexamethasone and either bortezomib or lenalidomide 
have shown ACY-1215 to be generally well tolerated and to have a manageable safety profile. 
Preliminary evidence of anti-tumor activity has been demonstrated in patients treated either with 
ACY-1215 monotherapy or combination therapy including SD in 6 patients treated with the 
former regimen. These data, and the potential for reduced side effects with a selective HDAC6 
inhibitor with reduced activity against Class I epigenetic HDAC enzymes, support the rationale 
for clinical investigation of ACY-1215 in combination with pomalidomide/dexamethasone 
therapy in MM. 
 
 
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3.3. 
Rationale for the Dose and Schedule Selected 
In this study, ACY-1215 will be administered PO for 21 consecutive days for 3 consecutive 
weeks (Days 1 through 21) with cycles repeating every 28 days in patients with relapsed and/or 
relapsed-refractory MM. As monotherapy, exposures achieved with 160 mg doses of 
ACY-1215 were sufficient to increase acetylated tubulin levels by 3-fold in PBMCs (a marker 
of HDAC6 inhibition) in 3 of 3 patients per dose cohort. Accordingly, a 160 mg dose is likely 
to be a biologically relevant dose. The initial dose and schedule of ACY-1215 to be 
administered in this study is based on a dose and schedule equivalent to that established in 
Study ACE-MM-101, which is evaluating ACY-1215 in combination with lenalidomide and 
dexamethasone. In the ACE-MM-101 study, ACY-1215 is well-tolerated in combination with 
lenalidomide with no DLTs or ACY-1215 related Grade 3 or 4 toxicities when administered at 
160 mg for 5 out of 7 days for 2 weeks of a 28-day cycle. Dose escalation is ongoing in both 
magnitude and duration of dose administration. 
Based on findings from the Phase 1 segment of the study and as recommended by the SRC, the 
ACY-1215 dose and schedule to be administered in the Phase 2 segment will be 160 mg PO QD 
on Days 1 to 21 of a 28-day cycle. 
3.4. 
Justification of the Study Design 
Goals of Phase 1 studies include establishment of an MTD and determination of a recommended 
range of doses for evaluation in future clinical studies based on PK and pharmacodynamic 
effects [54,55,56]; the primary objectives of the current study are consistent with those typical of 
Phase 1 studies. 
The Phase 1b segment of the study will employ a standard 3+3 dose escalation design, the most 
common dose escalation method for conducting Phase 1 oncology studies.[57] The minimum 
number of patients to be treated at each dose level is consistent with this standard dose 
escalation design. In order to ensure the safety of patients, an SRC consisting of Sponsor 
personnel including the Sponsor Medical Monitor, the Sponsor Safety Monitor, and 
Investigators will review safety data from all patients enrolled in each dose cohort to confirm 
any DLTs that were experienced and make a determination regarding enrollment in the next 
dose cohort. 
Sparse PK sampling in Phase 2 will be analyzed to determine relationship of drug exposure to 
response and potential adverse events. 
3.5. 
Study Termination 
If the Sponsor or Investigator discovers conditions arising during the study that suggest the 
study should be halted, then study termination can occur only after appropriate consultation 
between the Sponsor and Investigators. Conditions that may warrant study termination include, 
but are not limited to: 
• The discovery of any unexpected, significant, or unacceptable risk to the patients 
enrolled in the study. 
• Failure of the Investigator to enter patients at an acceptable rate. 
• Insufficient adherence to the protocol requirements. 
• A decision on the part of the Sponsor to suspend or discontinue development of study 
drug. 
 
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Should the study be closed prematurely, all study materials must be returned to the Sponsor or 
designee. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. 
STUDY POPULATION 
4.1. 
Number of Patients 
Based on the dose escalation scheme, a total of up to 125 patients are planned to be enrolled, 
including up to 30 patients in the Phase 1b segment and up to 95 patients in the Phase 2 
segment. 
4.2. 
Inclusion Criteria 
Patients meeting all of the following criteria are to be enrolled in the study. 
1. Must be able to understand and voluntarily sign an informed consent form (ICF). 
2. Must be registered into the mandatory POMALYST REMS™ program, and be willing and 
able to comply with the requirements of the POMALYST REMS™ program (or RevAid® 
for study participants in Canada). 
3. Must be ≥ 18 years of age at the time of signing the ICF. 
4. Must be able to adhere to the study visit schedule and other protocol requirements. 
5. Must have a documented diagnosis of MM and have relapsed-and-refractory disease. 
Patients must have received at least 2 lines of prior therapies. Patients must have relapsed 
after having achieved at least SD for at least one cycle of treatment to at least one prior 
regimen and then developed PD. Patients must also have documented evidence of PD 
during or within 60 days (measured from the end of the last cycle) of completing treatment 
with the last anti-myeloma drug regimen used just prior to study entry (refractory disease). 
6. Must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 
2 cycles of a proteasome inhibitor (either in separate regimens or within the same regimen). 
7. Must not be a candidate for autologous stem cell transplant (ASCT), has declined the option 
of ASCT, or has relapsed after prior ASCT. 
8. Must have measurable levels of myeloma paraprotein in serum (≥ 0.5 g/dL) or urine 
(≥ 0.2 g/24 hours). Nonsecretory myeloma and SFLC-only myeloma are excluded. 
9. Must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, 
or 2. 
10. FCBP must have a negative serum or urine pregnancy test (must be serum for study 
participants in Canada), as described in Appendix 9.3 for the POMALYST REMS™ 
program (in the US) and Appendix 9.4 for the RevAid® program (in Canada) FCBP and 
males must either commit to continued abstinence from heterosexual intercourse or must 
abide by birth control requirements as described in Appendix 9.3 for the POMALYST 
REMS™ program (in US) and Appendix 9.4 for the RevAid® program (in Canada). The 
European Pomalidomide Pregnancy Prevention Risk Management Plans are described in 
Appendix 9.5. 
11. Must agree to refrain from donating blood while on study drug and for 28 days after 
discontinuation from this study. 
12. Must agree not to share study medication with another person. 
13. Must be able to take acetylsalicylic acid (ASA) (81 or 325 mg) daily as prophylactic 
anticoagulation. Patients intolerant to ASA may use low molecular weight heparin. 
 
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Lovenox is recommended. Coumadin will be allowed provided the patient is fully 
anticoagulated, with an international normalized ratio (INR) of 2 to 3. 
4.3. 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from enrollment in the study: 
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the patient from signing the ICF, including nonsecretory myeloma or SFLC-only 
myeloma. 
2. Any serious concurrent medical conditions, laboratory abnormality, or psychiatric illness 
that might make the patient non-evaluable, put the patient’s safety at risk, or prevent the 
patient from following the study requirements. 
3. Pregnant or lactating females. 
4. Prior therapy with HDAC inhibitor or pomalidomide. 
5. Any of the following laboratory abnormalities: 
• ANC < 1,000/µL (hematopoietic growth factors will not be permitted during screening 
in the Phase 1 or Phase 2 segments of the study or in Cycle 1 of the Phase 1b segment of 
the study). 
• Platelet count < 75,000/µL for patients in whom < 50% of bone marrow nucleated cells 
are plasma cells, and < 50,000/µL for patients in whom ≥ 50% of bone marrow 
nucleated cells are plasma cells 
• Hemoglobin < 8 g/dL (< 4.9 mmol/L; prior RBC transfusion is permitted) 
• Creatinine clearance < 45 mL/min according to Cockcroft-Gault formula. If creatinine 
clearance calculated from the 24-hour urine sample is ≥ 45 mL/min, patient will qualify 
for the study. 
• Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST), or 
serum glutamic pyruvic transaminase (SGPT)/ALT > 3.0 × upper limit of normal 
(ULN). 
• Serum total bilirubin > 2.0 mg/dL 
6. Prior history of malignancies, other than MM, unless the patient has been free of the disease 
for ≥ 3 years. Exceptions include the following: 
• Basal or squamous cell carcinoma of the skin 
• Carcinoma in situ of the cervix or breast 
• Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b) 
7. Corrected QT interval using Fridericia’s formula (QTcF) value > 480 msec at screening; 
family or personal history of long QTc syndrome or ventricular arrhythmias including 
ventricular bigeminy at screening; previous history of drug-induced QTc prolongation or the 
need for treatment with medications known or suspected of producing prolonged QTc 
intervals on ECG. 
 
 
 
 
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8. Positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) and known or 
suspected active hepatitis C virus (HCV) infection. 
9. Hypersensitivity to thalidomide, lenalidomide, or dexamethasone (such as Steven Johnson 
Syndrome). Hypersensitivity, such as rash, that can be medically managed is allowable. 
10. Peripheral neuropathy ≥ Grade 2 despite supportive therapy. 
11. Radiotherapy or systemic therapy (standard or an investigational or biologic anticancer 
agent) within 14 days of initiation of study drug treatment. 
12. Current enrollment in another clinical study involving treatment and/or is receiving an 
investigational agent for any reason. 
13. Inability or unwillingness to comply with birth control requirements or any of the 
POMALYST REMS™ or RevAid® requirements (region-specific), per Appendix 9.3 and 
Appendix 9.4, respectively, or to the European Pomalidomide Pregnancy Prevention Risk 
Management Plans, per Appendix 9.5. 
4.4. 
Source of Patients 
This will be a multi-center study. Each study center is required to obtain Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) approval to conduct the study before 
enrollment of patients may commence. Patients at the study center meeting the entrance 
criteria, or referred to the study center will be eligible for enrollment. 
4.5. 
Patient Identification and Registration 
To ensure accurate and timely monitoring of patient enrollment, the following procedures will 
be implemented: 
• Patients who are candidates for enrollment into the study will be evaluated for eligibility 
by the Investigator to ensure that the entrance criteria (see Sections 4.2 and 4.3) have 
been satisfied and that the patient is eligible for participation in this clinical study. 
• The patient will be assigned a sequential and unique patient number. Once a patient 
number has been assigned, it cannot be reused. 
• The Investigator or the Investigator’s research staff will provide eligibility information 
to Acetylon. As confirmation, Acetylon will provide the Investigator with written 
verification of each patient’s registration. No patient may be enrolled or begin treatment 
prior to Acetylon registration. 
• Patients who are registered but not treated will be replaced. Patients who discontinue 
from the study before completing Cycle 1 for reasons other than DLT also are to be 
replaced. 
• Investigators will be notified by Acetylon when enrollment in a given dose cohort is 
closed and enrollment into the next dose cohort can begin. 
• Investigators will be notified by Acetylon if the study is placed on administrative hold, 
when it is completed, closed to further patient enrollment, or unexpected AEs occur. 
 
 
 
 
 
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4.6. 
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: 
• Non-adherence to the POMALYST REMS™ or RevAid® Programs, 
• Progressive Disease 
• Determination of PD requires two consecutive assessments of disease 
progression. There is no specific requirement for the timing of these two 
assessments, 
• Occurrence of an unacceptable AE, 
• Pregnancy, 
• 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 (see Sections 4.2 and 4.3), 
• Sponsor request. 
At the time of withdrawal, all study procedures outlined in the Schedule of Assessments 
(Table 1) post-treatment follow-up visit (i.e., pregnancy test for FCBP, pregnancy counseling, 
AE evaluation, assessment of second primary malignancy, etc.) should be completed if possible. 
The primary reason for a patient’s withdrawal from the study is to be recorded in the electronic 
case report form (eCRF). 
Patients who discontinue from the study for reasons other than DLT (e.g., non-compliance, 
patient request) before completing Cycle 1 will be replaced. 
4.7. 
Patient Management 
This study will be conducted on an outpatient basis. 
Patients will be evaluated for study eligibility at screening, within 28 days before the first study 
drug dose. All patients must provide written informed consent before any samples are collected 
or evaluations are performed in this study. If patients have had recent scans, bone marrow 
biopsy, or blood test for other purposes prior to enrollment, these tests may be used for 
determination of eligibility if they were performed within the 28-day period before Baseline 
(C1D1, before study drug administration). Patients who are determined to be eligible will be 
enrolled in the study at Baseline. Patients will be evaluated at the study center on Days 1, 2, 8, 
15, and 22 of Cycle 1. During Cycle 2, patients will be evaluated at the study center on Days 1 
and 15. For all subsequent cycles, patients will be evaluated at the study center on Day 1. 
Patients who withdraw from the study are to be followed up either in person or by phone 30 
days (± 3 days) after the last dose of study drug. If patients are treated with an alternate MM 
therapy before the 30 day visit, assessments for the 30 day visit should be performed prior to 
initiation of the alternate therapy. 
 
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Patients are to receive study treatment until development of PD or an unacceptable toxicity that 
cannot be managed by dose reduction alone precludes further treatment. Upon discontinuation 
from the study for PD or any other reason, patients will be assessed 3 times per year (e.g., April, 
August, and December), for up to 1 years for survival, subsequent anti-myeloma therapies, and 
monitoring of second primary malignancies as outlined in Table 1. SAEs will be collected from 
C1D1 through the first 30 days of follow-up. Subsequent therapies should be collected until 
death or end of the 1 year follow-up period. Survival follow up may be done via phone, when 
relevant. Patients who discontinue study treatment due to reasons other than PD will also be 
followed for efficacy assessments (see Section 6.2) until PD, death, or initiation of an alternate 
MM therapy, whichever occurs first. 
Patients who have been contacted at least 3 times without success (at least 1 month apart) 
should be sent a certified letter. If no contact is established, the patient will be deemed lost to 
follow up. A similar process will be followed for patients being followed up by phone. All 
attempted contact should be documented in the patient’s medical chart. 
4.8. 
Safety Review Committee 
An SRC will be involved in the conduct of this study. The SRC will be comprised of the Study 
Investigators, the Sponsor Medical Monitor, and the Safety Monitor. The SRC has the 
responsibility for monitoring the clinical study’s progress and the safety of the participating 
patients. The SRC will evaluate study conduct during the course of the clinical study based 
upon data defined in the SRC Charter for this clinical study. Safety assessments will be 
conducted in real-time by the SRC after the first 3 patients have completed Cycle 1. Dose 
escalations or expansion of a dose cohort will occur only with full approval of the SRC. 
The SRC will review safety data from all patients enrolled in each dose cohort to confirm any 
DLTs that were experienced and make a determination regarding enrollment in the next dose 
cohort. Each of the first 3 patients in the dose cohort must have completed Cycle 1 (28-day 
cycle) to be eligible for SRC review and for a decision to be made regarding enrollment into the 
next dose level. If a DLT necessitates enrollment of additional patients into a dose cohort, the 
SRC will review all of the safety data for that dose cohort after those additional patients have 
completed Cycle 1 through Day 21. Based on evaluation of the data, the SRC may decide that 
enrollment at an alternate starting dose or an intermediate dose level not specified in this 
protocol may take place. If this occurs, the IRB/IEC will be informed of the intermediate dose 
level(s) or alternate dosing regimen. 
The SRC will also review all Phase 1b safety data to determine the recommended dose of 
ACY-1215 to be used in the Phase 2 segment of the study. The SRC may decide that 
enrollment at an intermediate starting dose or alternate dosing regimen not specified in this 
protocol may take place. If this occurs, the IRB/IEC will be informed immediately of the 
intermediate dose level(s) or alternate dosing regimen. 
4.9. 
Independent Response Assessment Committee 
The Independent Response Assessment Committee (IRAC) will be composed of 
3 hematologists with expertise and experience in the diagnosis and management of multiple 
myeloma and a biostatistician. The IRAC will review, at ad hoc and scheduled meetings, all 
efficacy data in a blinded manner (independent of investigator-reported response) and provide 
verifiable and objective assessment of each patient’s disease response. Patient data will be 
displayed using a unique number for each patient. 
 
 
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IRAC meetings will be convened when sufficient data becomes available for 30 enrolled 
patients, as well as prior final analysis, and intermittently as appropriate. The IRAC will 
determine disease response according to the following categories as specified in the IMWG 
(Appendix 9.5) and EBMT (Appendix 9.7) criteria. The IRAC will also make a disease 
response determination at 28-day intervals (study visits) up to and including the discontinuation 
from treatment visit. 
4.10. 
Investigator Compliance 
Study centers that deviate significantly from the protocol without prior approval from the 
Sponsor and regulatory authorities may be discontinued from the study. The Investigator at 
each study center is responsible for ensuring the accuracy and completeness of all research 
records, the accountability of study drug, and the conduct of clinical and laboratory evaluations 
as outlined in the protocol. 
5. 
STUDY TREATMENTS 
5.1. 
Study Drug Supply and Storage 
All study drugs must be stored in a safe and locked place with no access by unauthorized 
personnel. 
5.1.1. 
ACY-1215 
ACY-1215 will be supplied by the Sponsor as a liquid (12 mg/ml) for PO administration in 
20 mL glass vials. ACY-1215 will be stored in the pharmacy at -20ºC. Additional storage 
conditions and dose preparation instructions will be provided in detail within the Pharmacy 
Manual. 
5.1.2. 
Pomalidomide and Dexamethasone 
Pomalidomide will be provided at 4, 3, 2, and 1 mg for PO administration. Pomalidomide will 
be dispensed by pharmacists to patients for the duration of their participation in this study at no 
charge to them or their insurance providers, through the region-specific POMALYST REMS™ 
or RevAid®program. Patients will have to be registered in such a program and follow the 
required procedures to receive pomalidomide supply. Only enough pomalidomide for one cycle 
of therapy will be supplied to the patient every cycle. Pomalidomide capsules are to be stored, 
per the package insert [51,58]. 
For sites in the US and Canada, dexamethasone for PO administration will be supplied from 
commercially-available sources as 4 mg compressed tablets. (Dexamethasone tablets at 
strengths other than 4 mg may be used, as necessary.) Acetylon will supply dexamethasone to 
sites in the EU. Dexamethasone tablets are to be stored at room temperature between 68° to 
77ºF (20° to 25ºC) away from light and moisture. 
5.2. 
Study Drug Dose and Administration 
All patients will receive ACY-1215 in combination with pomalidomide and dexamethasone. On 
ACY-1215 administration days, pomalidomide and dexamethasone are to be taken immediately 
after ACY-1215. If the patient is receiving ACY-1215 BID, pomalidomide and dexamethasone 
are to be taken immediately after the first (a.m.) dose of ACY-1215 only. Study Day 1 is 
defined as the first day the patient receives study drug. 
 
 
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5.2.1. 
ACY-1215 
ACY-1215 will be administered orally QD or BID at least 1 hour after ingestion of food and 
followed by 4 ounces of water. Patients will be instructed not to ingest food or other PO 
medication, other than pomalidomide and dexamethasone, for at least 2 hours after each 
ACY-1215 dose. On study center visit days requiring PK/pharmacodynamic blood draws, 
ACY-1215 must be taken in the study center. On other study drug administration days that 
coincide with scheduled study center visits, ACY-1215 may be administered at the study center 
or at home. If ACY-1215 is being given BID, pomalidomide and dexamethasone are to be 
given with the first dose of ACY-1215. The ACY-1215 BID, doses should be taken 
approximately every twelve hours. A plus or minus 2 hour window is acceptable for BID 
dosing. 
One cycle of therapy is comprised of either 21 doses every 28 days (QD), or 42 doses every 
28 days (BID). 
Phase 1b Segment: 
Study Day 1 is defined as the first day the patient receives study drug. Patients in the Phase 1b 
segment of the study will receive single 160 mg QD doses of ACY-1215 for 21 consecutive 
days of a 28-day treatment cycle (Dose Level 1). Dose escalations will follow as outlined in 
Table 2. If that dose is tolerated per SRC safety review, 240 mg QD on the same days will be 
explored (Dose Level 2). If Dose level 2 is well tolerated, Dose Level 3 of 160 mg BID will be 
explored. If Dose Level 1 is not tolerated, the schedule will be modified (Dose Level -1) to 160 
mg ACY-1215 QD on Days 1-5, 8-12, and 15-19. If Dose Level -1 is not tolerated, the schedule 
will be modified (Dose Level -2) to 160 mg ACY-1215 QD on Days 1-5, and 8-12. 
Based on emerging data from ongoing studies of ACY-1215, intermediate dose levels and 
schedules may be added, or dose levels eliminated, and the IRB/IEC will be notified. 
Investigators should consider providing prophylaxis for tumor lysis, including hydration, prior 
to administration of ACY-1215. 
Phase 2 Segment: 
Based on findings from the Phase 1 segment of the study and as recommended by the SRC, the 
ACY-1215 dose and schedule to be administered in the Phase 2 segment will be be 160 mg PO 
QD on Days 1 to 21 of a 28- day cycle as recommended by the SRC. Treatment will continue 
until PD or toxicity requiring removal from study. 
5.2.2. 
Pomalidomide 
Pomalidomide (POMALYST®) will be provided to research patients for the duration of their 
participation in this study at no charge to them or their insurance providers. Pomalidomide will 
be provided in accordance with the Celgene Corporation’s POMALYST REMS™ or RevAid® 
program. Per the standard POMALYST REMS™ and RevAid®program requirements, all 
physicians who prescribe pomalidomide for research patients enrolled into this study, and all 
research patients enrolled into this study, must be registered in and must comply with all 
requirements of the POMALYST REMS™ and RevAid® program. Drug will be shipped to the 
patient’s home or to the study site (in Canada only) for Investigational New Drug studies. Only 
enough pomalidomide for one cycle of therapy will be supplied to the patient each cycle. This 
is in accordance with the POMALYST REMS™ and RevAid®programs. 
Pomalidomide (POMALYST®) will be administered based on the current approved dose and 
schedule: 4 mg PO QD on Days 1 to 21 of a 28-day cycle (see Table 2). Pomalidomide 
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capsules should be swallowed whole, and should not be broken, chewed or opened. Patients 
should take pomalidomide at the same time each day, immediately following ACY-1215 dosing 
when applicable. Pomalidomide should be taken without food, at least 2 hours before or 2 hours 
after a meal. If a dose of pomalidomide is missed, it should be taken as soon as possible on the 
same day. If it is missed for the entire day, it should not be made up, rather it should be taken at 
the next scheduled time point. Patients who take more than the prescribed dose of 
pomalidomide should be instructed to seek emergency medical care if needed and contact study 
staff immediately. Pomalidomide will be sent to the patients’ home or to the study site (in 
Canada only) via the POMALYST REMS™ and RevAid®programs (see Appendix 9.3 and 
Appendix 9.4, respectively). 
5.2.3. 
Dexamethasone 
All patients will receive dexamethasone, which will be taken PO QD on Days 1, 8, 15, and 22 of 
each 28-day cycle (see Table 2). For patients ≤ 75 years of age, the starting dose of 
dexamethasone will be 40 mg; for patients who are > 75 years of age, the starting dose of 
dexamethasone will be 20 mg. 
5.2.4. 
Planned Study Drug Doses 
The planned study drug doses for the combination regimen are shown in Table 2. 
Table 2 
Planned Dose Escalation 
 
Phase 1b 
Dose 
Levela 
N 
ACY-1215 
Pomalidomide 
Dexamethasoneb 
-2 
3-6 
160 mg QD on Days 1-5, 
and 8-12 
4 mg QD 
Days 1-21 
40 mg QD 
Days 1, 8, 15, 22 
-1 
3-6 
160 mg QD on Days 1-5, 
8-12, and 15-19 
4 mg QD 
Days 1-21 
40 mg QD 
Days 1, 8, 15, 22 
1 
3-6 
160 mg QD on Days 1-21 
4 mg QD 
Days 1-21 
40 mg QD 
Days 1, 8, 15, 22 
2 
3-6 
240 mg QD on Days 1-21 
4 mg QD 
Days 1-21 
40 mg QD 
Days 1, 8, 15, 22 
3 
3-6 
160 mg BID on Days 1-21 
4 mg QD 
Days 1-21 
40 mg QD 
Days 1, 8, 15, 22 
Key: BID = twice daily, QD = once daily. 
Note: treatment cycle is 28 days. 
a 
Patients will be initially enrolled at Dose Level 1. If 2 or more patients experience a DLT within the 28-day cycle, 
patients will subsequently be enrolled at Dose Level -1. If 2 or more patients experience a DLT at Dose Level -1 within 
the 28-day cycle, patients will subsequently be enrolled at Dose Level -2 
b 
Patients ≤ 75 years of age will receive 40 mg of dexamethasone; patients > 75 years of age will receive 20 mg. 
 
Based on the interim evaluation of the safety and tolerability data of the previous dose level, it 
may be decided to investigate an intermediate dose level not specified in Table 2 (as applicable) 
(see Section 5.2.5). If this occurs, the IRBs/IECs will be informed of the intermediate dose 
level(s). 
The SRC will review safety data after the first 3 patients have completed Cycle 1 and make the 
determination to initiate enrollment of another 3 patients into the next dose level. Based on 
these evaluations the SRC may decide that enrollment at an alternate starting dose or an 
intermediate dose level not specified in this protocol may take place. If this occurs, the 
 
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IRB/IEC will be informed immediately of the alternate starting dose or intermediate dose 
level(s). 
5.2.5. 
Dose Escalation Procedure 
Study drug doses will be escalated sequentially after the SRC reviews safety data from all 
patients enrolled in each dose cohort to confirm any DLTs that were experienced and make a 
determination regarding enrollment in the next dose cohort. Each of the first 3 patients in the 
dose cohort must have completed Cycle 1 (28-day cycle) to be eligible for SRC review and for a 
decision to be made regarding enrollment into the next dose level (see Section 4.8). Based on 
the interim evaluation of the safety and tolerability data of the previous dose level, it may also 
be decided that escalation will take place at an intermediate dose level not specified in Table 2 
(as applicable). If this occurs, the IRBs/IECs will be informed of the intermediate dose level(s). 
The SRC may be convened earlier at the discretion of the Sponsor if important safety issues 
arise requiring the attention of the committee. 
Determination of MTD: Dose escalation rules 
Three patients are to be enrolled in each Dose-Level Group. After 3 patients have completed 
Cycle 1 (28-day cycle) and: 
• If none of the 3 patients experiences a DLT within the first 28 day cycle, and pending 
SRC review as described above, then an additional 3 patients will be enrolled into the 
next higher dose level. 
• If one of the 3 initial patients in a Dose-Level Group experiences a DLT within the first 
28-day cycle, then an additional 3 patients will be enrolled into that Dose-Level Group. 
• If 2 or more patients within the expanded dose cohort experience a DLT within the first 
28-day cycle, then the MTD has been exceeded and no further dose escalations will 
occur. 
• If no more than one of the 6 patients experiences a DLT within the first 28-day cycle, 
then the next dose cohort of 3 patients will be enrolled at the next higher dose level. 
The MTD will be defined as the highest dose level at which no more than 1 of 6 patients 
experiences a DLT within the first 28-day cycle. If no more than 1 of these 6 patients 
experiences a DLT within the first 28-day cycle, then the last dose level enrolled to meet these 
criteria may be identified as the recommended dose for the Phase 2 segment of the study. 
Teleconferences or email communication between the Sponsor or designee and the clinical 
study sites will occur weekly to monitor for DLTs and to communicate enrollment to the next 
dose level. 
Patients who discontinue from the study for reasons other than DLT (e.g., non-compliance, 
patient request) before completing Cycle 1 will be replaced. 
The use of hematopoietic growth factors will not be permitted during screening in the Phase 1 or 
Phase 2 segments of the study or in Cycle 1 of the Phase 1b segment of the study; however, they 
will be permitted in Cycle 2 and subsequent cycles. The use of bisphosphonates is permitted. 
Patients may not be enrolled in more than 1 dose cohort. Patients enrolled into the Phase 1b 
segment of the study cannot be enrolled into the Phase 2 segment upon discontinuation from 
Phase 1b. 
 
 
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Complete blood counts will be monitored at least every 14 days during Cycle 2 and then at least 
at the first day of every cycle thereafter. 
5.2.6. 
Dose-limiting Toxicity 
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. If a toxicity is not classified in the CTCAE, 
then it should be classified according to the criteria presented in Section 6.1.8.4. 
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. For toxicities observed that may be attributable to pomalidomide 
(see Table 6) or dexamethasone (see Table 8), dose reductions should be attempted with these 
treatments prior to reducing the dose of ACY-1215. 
The following AEs occurring during Cycle 1 that are considered to be ACY-1215-related will 
be considered to be DLTs: 
Hematologic toxicity: 
• Grade 4 neutropenia (ANC < 500/μL), lasting > 5 days, or 
• Febrile neutropenia (fever ≥ 38.5° C and ANC < 1,000/μL), or 
• Grade 4 thrombocytopenia (platelet count < 25,000/μL), or 
Grade 3 or 4 ACY-1215-related Non-hematologic toxicity: 
• All other Grade 3 or Grade 4 non-hematologic toxicity with the exception of: 
• Grade 3 or 4 nausea, vomiting or diarrhea (Patients must have received optimal 
symptomatic treatment for Grade 3 or 4 nausea, vomiting, or diarrhea to be 
considered a DLT). 
• Grade 4 transaminitis (serum transaminase > 20 × upper limit of normal [ULN]) is a 
DLT, while Grade 3 transaminitis (serum transaminase > 5 × ULN) must be present 
for ≥ 7 days to be considered a DLT. 
• Other asymptomatic Grade 3 and 4 laboratory investigations, excluding cardiac 
function tests, may be evaluated by the SRC to determine whether dose cohorts 
should be expanded. 
• Delay of the start of Cycle 2 by > 7 days due to ACY-1215-related AE. 
Toxicity management procedures for ACY-1215 are presented in Table 4 and Table 5. No dose 
modifications for ACY-1215 are to be performed in Cycle 1. 
5.2.7. 
Maximum Tolerated Dose 
The DLT dose level is defined as the dose level of ACY-1215+pomalidomide+dexamethasone 
at which ≥ 2 of up to 6 patients experience a DLT. The MTD is defined as the dose level of 
ACY-1215+pomalidomide+dexamethasone immediately below the DLT dose level. Following 
the identification of the MTD, or recommended Phase2 dose, up to 6 additional patients may be 
enrolled at this dose. When all 6 patients have completed the 28-day cycle at the MTD, the 
 
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SRC will review all Phase 1b safety data to determine the recommended dose of ACY-1215 to 
be used in the Phase 2 segment of the study. 
5.2.8. 
Dose Modifications 
Before each scheduled study drug dose administered in the clinic, the patient will be evaluated 
for possible DLTs that may have occurred after the previous dose(s) as described in 
Section 5.2.6. 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 instructions outlined 
in Section 5.2.8.1, Section 5.2.8.2, and Section 5.2.8.3. Conversely, if the toxicity is considered 
unrelated to a particular drug(s), then no modification of that drug(s) is required. 
No dose modifications for ACY-1215 are to be performed in Cycle 1. After Cycle 1, patients 
who are unable to tolerate ACY-1215 treatment may have the dose reduction steps presented 
below until a tolerable dose is achieved. 
5.2.8.1. 
ACY-1215 
Patients must remain on their assigned ACY-1215 dose in Cycle 1 during the dose escalation 
phase of the study, or be withdrawn from the study. If toxicity attributable to pomalidomide or 
dexamethasone is seen during Cycle 1, dose reductions may be made as described in Table 6 
and Table 8. Patients should receive 80% of planned doses to be evaluable for SRC review. 
For toxicities observed that may be attributable to pomalidomide (see Table 6) or 
dexamethasone (see Table 8), dose reductions should be attempted with these treatments prior to 
reducing the dose of ACY-1215. 
After Cycle 1, patients who are unable to tolerate ACY-1215 treatment may have the dose 
reduction steps presented in Table 3 until a tolerable dose is achieved. 
Table 3 
ACY-1215 Dose Modifications 
 
Dose level 
Starting dose ofACY-1215 
1st dose reduction 
2nd dose reduction 
-2 
160 mg QD on Days 1-5, and 8- 
12 
80 mg QD on Days 1-5, and 8- 
12 
NA 
-1 
160 mg QD on Days 1-5, 8-12, 
and 15-19 
80 mg QD on Days 1-5, 8-12, 
and 15-19 
NA 
1 
160 mg QD on Days 1-21 
80 mg QD on Days 1-21 
NA 
2 
240 mg QD on Days 1-21 
160 mg QD on Days 1-21 
80 mg QD on Days 1-21 
3 
160 mg BID on Days 1-21 
160 mg QD on Days 1-21 
80 mg QD on Days 1-21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 4 
Dose Modification Instructions for ACY-1215 for Hematologic Toxicities 
 
Toxicity 
Dose Modification 
Neutropenia (1st occurrence): 
• 
ANC < 500/μL or febrile neutropenia 
(fever ≥ 38.5°C and ANC < 1,000/μL) 
• 
ANC return to ≥ 500/μL 
Interrupt ACY-1215 treatment, follow CBC weekly. 
Resume ACY-1215 at one dose level lower than at the 
time of the first occurrence per Table 3. 
For the second occurrence of neutropenia (each 
subsequent drop of ANC <500, interrupt and follow as 
above and resume at one dose level below the current 
dose. 
Thrombocytopenia (1st occurrence): 
• 
Platelets < 25,000/μL 
• 
Platelets return to ≥ 50,000/μL 
Interrupt ACY-1215 treatment, follow CBC weekly. 
Resume ACY-1215 at one dose level lower than at the 
time of the first occurrence per Table 3. 
For the second occurrence of thrombocytopenia (each 
subsequent drop of platelets <25,000), interrupt and 
follow as above. When platelet count returns to 50,000, 
resume at one dose level below the current dose. 
Table 5: 
Dose Modification Instructions for ACY-1215 for Non-hematologic 
Toxicities 
 
Toxicity 
Dose Modification 
Grade 1 or Grade 2 
Continue current ACY-1215 dose regimen at the 
discretion of the investigator. 
Grade 3 Non-hematologic1 
Hold ACY-1215 dose until value(s) return to ≤Grade 2; 
initiate therapy at one dose level lower than at the time 
of the first occurrence per Table 3. 
5.2.8.2. 
Pomalidomide 
Toxicities considered related to pomalidomide are to be managed as shown in Table 6 and Table 
7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 6 
Dose Modification Instructions for Pomalidomide for Hematologic Toxicities 
 
Toxicity 
Dose Modification 
Neutropenia 
Grade 4 neutropenia (ANC < 500/μL) or 
Febrile neutropenia (fever ≥38.5°C and ANC 
< 1,000/μL) 
Hold the pomalidomide dose for remainder of 
cycle. If the patient was not receiving 
Granulocyte colony-stimulating factor (GCSF) 
therapy, initiate GCSF therapy at the discretion 
of the treating physician. On Day 1 of next 
cycle, continue GCSF as needed and maintain 
dose of pomalidomide if neutropenia was the 
only DLT (except during the first cycle for 
patients enrolled into the MTD segment of the 
study). Otherwise, decrease pomalidomide by 
one dose level at start of next cycle. (Note, 
ANC must be ≥ 500/µL in the US and Canada 
and ≥ 1,000/μL in the EU to restart dosing) 
Grade 4 Thrombocytopenia 
(Platelets < 25,000/μL) 
Hold the dose for remainder of cycle. Decrease 
pomalidomide by one dose level when dosing 
is resumed at next cycle. (Note, platelet count 
must recover to ≥ 50,000/μL to restart dosing) 
 
 
Table 7 
Dose Modification Instructions for Pomalidomide for Non-hematologic 
Toxicities 
 
Toxicity 
Dose Modification 
Rash = Grade 3 
Hold pomalidomide dose for remainder of cycle. 
Decrease by one dose level when dosing restarted at 
next cycle (rash must resolve to ≤ Grade 1). 
Rash = Grade 4 or Blistering 
Discontinue pomalidomide dose and discontinue 
patient from study. 
Constipation 
≥ Grade 3 
Hold pomalidomide dose for remainder of cycle. 
Initiate bowel regimen. Decrease pomalidomide by 
one dose level when dosing restarted at next cycle 
(constipation must resolve to ≤ Grade 2). 
VTE 
≥ Grade 3 
Hold pomalidomide dose for remainder of cycle. 
Initiate anti-coagulation treatment. Maintain 
pomalidomide dose level when dosing restarted at 
next cycle at discretion of treating physician. 
Hypo/hyperthyroidism ≥ Grade 2 
Hold dose for remainder of cycle. Initiate 
appropriate medical therapy. Maintain dose level 
when dosing restarted at next cycle at discretion of 
treating physician. 
Peripheral Neuropathy = Grade 3 
Hold pomalidomide dose for remainder of cycle. 
Decrease pomalidomide by one dose level when 
dosing restarted at next cycle (neuropathy must 
resolve to ≤ Grade 1). 
Peripheral Neuropathy = Grade 4 
Discontinue pomalidomide and discontinue patient 
from study. 
 
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For all other ≥ Grade 3 pomalidomide-related AEs, hold treatment and restart treatment at 1 mg 
less than the previous dose when toxicity has resolved to ≤ Grade 2 at the discretion of the 
Investigator. 
Instructions for Initiating a New Pomalidomide Cycle 
To initiate a new cycle of pomalidomide, ANC must be ≥ 500/µL in the US and Canada and 
≥ 1,000/μL in the EU, the platelet count must be ≥ 50,000/μL, and non-hematologic AEs must 
have recovered as outlined in Table 7. 
If recovery from toxicities is prolonged beyond 14 days, then the dose of pomalidomide or 
dexamethasone will be decreased by one dose level. 
If the treatment has been interrupted and the next cycle is delayed beyond 29 days after Day 1 of 
the prior cycle, then Day 1 of the next cycle will be defined as the first day that the treatment is 
resumed. 
5.2.8.3. 
Dexamethasone 
Toxicities considered to be related to dexamethasone are to be managed as shown in Table 8. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 8 
Dexamethasone Dose Modifications 
 
Category 
Toxicity 
Grade 
Dose Change 
Gastrointestinal 
Dyspepsia, gastric 
or duodenal ulcer, 
or gastritis 
Grade 1-2 
(requiring medical 
management) 
Treat with H2 blockers, sucralfate, omeprazole, or 
other comparable medications (i.e. proton pump 
inhibitors). 
If symptoms persist despite treatment, decrease the 
dexamethasone dose by 1 level. 
≥Grade 3 
(requiring 
hospitalization or 
surgery) 
Interrupt dexamethasone until symptoms are 
adequately controlled. 
Thereafter, resume dexamethasone reduced by one 
level with concomitant H2 blockers, sucralfate, or 
omeprazole. 
If symptoms persist despite above measures, 
permanently discontinue dexamethasone. 
Acute pancreatitis 
≥Grade 3 
Permanently discontinue dexamethasone. 
Cardiovascular 
Edema 
≥ Grade 3 
(limiting function 
and unresponsive 
to therapy or 
anasarca) 
Treat with diuretics as needed and decrease 
dexamethasone by one level. 
If edema persists despite above measures, decrease 
by another level. 
If symptoms persist despite a second reduction, 
discontinue dexamethasone. 
Neurology 
Confusion or 
mood alteration 
≥ Grade 2 
(interfering with 
function ± 
interfering with 
activities of daily 
living [ADLs]) 
Interrupt dexamethasone for up to 2 weeks until 
symptoms resolve. 
If symptoms resolve, restart dexamethasone at 
dose decreased by one level. 
If symptoms persist despite above measures, then 
permanently discontinue dexamethasone. 
Musculoskeletal 
Muscle weakness 
≥ Grade 2 
(symptomatic and 
interfering with 
function ± 
interfering with 
ADLs) 
Decrease dexamethasone dose by one level. 
If symptoms persist despite a dose reduction, 
decrease by another level. 
If symptoms persist despite above measures, 
permanently discontinue dexamethasone. 
Metabolic 
Hyperglycemia 
≥ Grade 3 
Administer insulin or oral hypoglycemics as 
needed. 
If hyperglycemia is not controlled despite 
treatment, decrease dexamethasone by one level 
until levels are satisfactory. 
The dexamethasone dose reduction steps are summarized in Table 9 and Table 10. 
Table 9 
Dose Reduction Steps for Dexamethasone (≤ 75 years of age) 
 
Dose Level 
Dose (Days 1, 8, 15, and 22) 
Starting Dose 
40 mg 
Dose Level -1 
20 mg 
Dose Level -2 
10 mg 
Note: Dexamethasone should be discontinued if patient is unable to tolerate 10 mg dose. Patients may continue on ACY-1215 
and pomalidomide until PD. 
 
 
 
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Table 10 
Dose Reduction Steps for Dexamethasone (> 75 years of age) 
 
Dose Level 
Dose (Days 1, 8, 15, and 22) 
Starting Dose 
20 mg 
Dose Level -1 
12 mg 
Dose Level -2 
8 mg 
Note: Dexamethasone should be discontinued if patient is unable to tolerate 8 mg dose. Patients may continue on ACY-1215 
and pomalidomide until PD. 
 
5.3. 
Blinding, Packaging, and Labeling 
5.3.1. 
Blinding and Breaking the Blind 
This is single arm open label study; blinding methods are not applicable. 
5.3.2. 
Packaging and Labeling 
As stated previously, ACY-1215 will be supplied by the Sponsor as a liquid (12 mg/ml) for PO 
administration in 20 mL glass vials. Additional storage conditions and dose preparation 
instructions will be provided in detail within the Pharmacy Manual. 
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 
region-specific regulatory information. 
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. 
Pomalidomide will be provided at 4, 3, 2, and 1 mg for PO administration. Pomalidomide will 
be dispensed to patients for the duration of their participation in this study at no charge to them 
or their insurance providers, through the region-specific POMALYST REMS™ or 
RevAid®program (see Appendix 9.3 and Appendix 9.4, respectively). Pomalidomide capsules 
are to be stored, per the package insert [51, 58]. 
Dexamethasone will be packaged and labeled by the manufacturers according to their standard 
practices. 
5.4. 
Assessment of Treatment Compliance 
5.4.1. 
ACY-1215 
Study center pharmacy personnel will prepare individual patient doses to be administered either 
during scheduled study center visits or by the patient at home. 
On ACY-1215 administration days that coincide with study center visits, the ACY-1215 dose 
prepared by pharmacy personnel will be ingested by the patient at the study center. Prior to 
leaving the study center, the required number of doses of ACY-1215 prepared by pharmacy 
personnel will be dispensed to patients for ingestion at home on non-clinic dosing days. 
Each time ACY-1215 is dispensed to a patient, study personnel will record the date dispensed, 
amount dispensed, and the recorder’s initials. When the patient returns used and unused study 
drug containers, study personnel are to record the date returned, amount returned, the recorder’s 
initials, and any comments. A diary will be provided to patients on C1D1 in order to document 
the date and time of each ACY-1215 dose for all treatment cycles. Following Cycle 1, the 
Investigator will confirm treatment compliance with the patient at each visit. 
 
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5.4.2. 
Pomalidomide 
The date pomalidomide is administered and any changes in the dose will be documented in the 
eCRF. Date and time of all pomalidomide doses will be record in patient diaries. 
5.4.3. 
Dexamethasone 
The date dexamethasone is administered and any changes in dose will be documented in the 
eCRF. Date and time of all dexamethasone doses will be record in patient diaries. 
5.5. 
Study Drug Accountability 
Accountability for ACY-1215 (all centers), pomalidomide, and dexamethasone (EU only) 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 study 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 (or unless appropriately documented according to site procedure). 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 study drug will be treated and disposed of as 
hazardous waste in accordance with governing regulations. 
5.6. 
Prior and Concomitant Treatment 
All prescription and non-prescription medications, including pharmacologic doses of vitamins, 
herbal medicines, or other non-traditional medicines, taken within 28 days prior to the first dose 
of ACY-1215 through the final visit (30 days [±3 days] after the last dose of study drug) must 
be documented in the eCRF. 
5.6.1. 
Permitted Medication 
Supportive therapy for MM (e.g., erythropoietin) that is ongoing at Baseline will be permitted 
during the treatment phase of the study. The following medications and supportive therapies are 
examples of support therapies that may be used during the study: 
• Antiemetics and Antidiarrheals: Antiemetic treatments may be used at the Investigator’s 
discretion and in accordance with the American Society of Clinical Oncology (ASCO) 
guidelines after documented nausea or vomiting has occurred without medications 
having been used. While antiemetic choice is at the discretion of the Investigator, high 
dose steroids should be avoided if possible as an antiemetic therapy. Dolasetron 
mesylate (Anzemet) is no longer indicated for chemotherapy indications due to QT 
prolongation per guidance of the Food and Drug Administration (FDA). Other serotonin 
5HT3 antagonists (which have been reported to prolong QT) may be used if required 
with caution and appropriate monitoring by the Investigator. If these agents are used 
 
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prophylactically on Cycle 1 Day 8 (when PK is performed) the time and dose must be 
noted on the eCRF. Antidiarrheals also may be used at the Investigator’s discretion. 
• Hematopoietic Growth Factors: The use of hematopoietic growth factors will not be 
permitted during screening in the Phase 1 or Phase 2 segments of the study or in Cycle 1 
of the Phase 1b segment of the study. Hematopoietic growth factors may be used 
beginning with Cycle 2 of the Phase1b segment and during all additional cycles. The 
use of myeloid and erythroid growth factors are to be utilized as per the 
recommendations of the ASCO guidelines. Treatment with myeloid growth factors is 
encouraged when the ANC is less than 1,000/μL. 
• Adequate hydration is recommended for the prevention of myeloma-related kidney 
disease. Generally, intravenous contrast is not used in CT scanning because of the risk 
to the kidney. Non-steroidal anti-inflammatory drugs should be avoided. 
• Bisphosphonate may be used in patients with osteolytic or osteopenic myelomatous bone 
disease. Commercially available bisphosphonates are to be used, preferably according to 
the manufacturer’s recommendations, as described in the prescribing information. 
• Patients with advanced stage disease and/or high tumor burden should be closely 
monitored, appropriate precautions should be taken, and treatment should be instituted as 
appropriate. 
• ASA (81 or 325 mg) is to be taken daily as prophylactic anticoagulation. Patients 
intolerant to ASA may use low molecular weight heparin. Lovenox is recommended. 
Coumadin will be allowed provided the patient is fully anticoagulate, with an INR of 2 
to 3. 
All patients will be monitored for signs and symptoms of VTE while on pomalidomide; 
diagnostic algorithms are provided in Appendix 9.1. 
5.6.2. 
Excluded Medication and Substances 
The following medications and supportive therapies and procedures are prohibited during the 
study: 
• Any anti-neoplastic treatment with activity against MM (with the exception of 
pomalidomide and dexamethasone). 
• Radiotherapy or standard systemic therapy within 2 weeks of Baseline (C1D1). 
Investigational therapies or biologics within 3 weeks of Baseline. Any AEs from 
previous therapies must be resolved to Baseline. 
• Because of the increased risk of VTE patients with MM taking pomalidomide and 
dexamethasone, combined oral contraceptive pills are not recommended. If a patient is 
currently using combined oral contraception the patient should switch to one of the 
effective methods described in Appendix 9.2. The risk of VTE continues for 4 to 
6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive 
steroids may be reduced during co-treatment with dexamethasone. 
• Hematopoietic growth factors during screening in the Phase 1 or Phase 2 segments of the 
study or in Cycle 1 of the Phase 1b segments of the study. 
The US pomalidomide package insert states that no formal drug interaction studies have been 
conducted; however pomalidomide is primarily metabolized by CYP1A2 and CYP3A and is 
also a substrate for P-glycoprotein (P-gp).[51]: 
 
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• Co-administration of pomalidomide with drugs that are strong inhibitors of CYP1A2, 
CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 
• Co-administration of pomalidomide with drugs that are strong inducers of CYP1A2, 
CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. 
• Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. 
Patients should be advised that smoking may reduce the efficacy of pomalidomide. 
The Canadian pomalidomide package insert states that no formal drug interaction studies have 
been conducted; however, pomalidomide is a substrate of P-glycoprotein (Pg-p) and is partly 
metabolized by CYP1A2 and CYP3A4.[58]: 
• The use of pomalidomide with concomitant strong CYP1A2 inhibitors and strong 
CYP3A4 inhibitors together should be avoided. 
• If strong inhibitors of CYP1A2 are coadministered with pomalidomide, patients should 
be closely monitored for the occurrence of AEs. 
• The risk of thromboembolic events may be increased with the simultaneous use of 
pomalidomide with erythropoietic agents, hormone replacement therapy or hormonal 
contraceptives. 
• Cigarette smoking may reduce the exposure to pomalidomide. 
• Pomalidomide may possibly impair mental and/or physical abilities required for the 
performance of hazardous tasks, such as driving a car or operating other complex or 
dangerous machinery. 
• Drugs that may interact with pomalidomide include: 
• fluvoxamine, Hormonal Replacement Therapy, and 
• Hormonal Contraception (estrogens and progestins). 
The EU pomalidomide package insert states that no formal drug interaction studies have been 
evaluated; however, pomalidomide is a substrate of Pg-p and is partly metabolized by CYP1A2 
and CYP3A4/5.[59] 
• Co-administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor 
ketoconazole, or the strong CYP3A4/5 inducer carbamazepine, had no clinically relevant 
effect on exposure to pomalidomide. 
• Co-administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide in 
the presence of ketoconazole increased exposure to pomalidomide by 104% with a 90% 
CI [88%, 122%] compared to pomalidomide plus ketoconazole. 
• If strong inhibitors of CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are 
co-administered with pomalidomide, patients should be closely monitored for the 
occurrence of adverse reactions. 
The dexamethasone prescribing information contains the following information regarding drug 
interactions [60]: 
• Aminoglutethimide: Aminoglutethimide may diminish adrenal suppression by 
corticosteroids. 
• Amphotericin B injection and potassium-depleting agents: When corticosteroids are 
administered concomitantly with potassium-depleting agents (e.g., amphotericin B, 
 
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diuretics), patients should be observed closely for development of hypokalemia. In 
addition, there have been cases reported in which concomitant use of amphotericin B 
and hydrocortisone was followed by cardiac enlargement and congestive heart failure. 
• Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in 
corticosteroid clearance. 
• Anticholinesterases: Concomitant use of anticholinesterase agents and corticosteroids 
may produce severe weakness in patients with myasthenia gravis. If possible, 
anticholinesterase agents should be withdrawn at least 24 hours before initiating 
corticosteroid therapy. 
• Anticoagulants, Oral: Co-administration of corticosteroids and warfarin usually results 
in inhibition of response to warfarin, although there have been some conflicting reports. 
Therefore, coagulation indices should be monitored frequently to maintain the desired 
anticoagulant effect. 
• Antidiabetics: Because corticosteroids may increase blood glucose concentrations, 
dosage adjustments of antidiabetic agents may be required. 
• Antitubercular Drugs: Serum concentrations of isoniazid may be decreased. 
• Cholestyramine: Cholestyramine may increase the clearance of corticosteroids. 
• Cyclosporine: Increased activity of both cyclosporine and corticosteroids may occur 
when the two are used concurrently. Convulsions have been reported with this 
concurrent use. 
• Dexamethasone Suppression Test (DST): False-negative results in the DST in patients 
being treated with indomethacin have been reported. Thus, results of the DST should be 
interpreted with caution in these patients. 
• Digitalis Glycosides: Patients on digitalis glycosides may be at increased risk of 
arrhythmias due to hypokalemia. 
• Ephedrine: Ephedrine may enhance the metabolic clearance of corticosteroids, resulting 
in decreased blood levels, and lessened physiologic activity, thus requiring an increase in 
corticosteroid dosage. 
• Estrogens, including Oral Contraceptives: Estrogens may decrease the hepatic 
metabolism of certain corticosteroids, thereby increasing their effect. 
• Hepatic Enzyme Inducers, Inhibitors and Substrates: Drugs which induce cytochrome 
P450 3A4 (CYP 3A4) enzyme activity (e.g., barbiturates, phenytoin, carbamazepine, 
rifampin) may enhance the metabolism of corticosteroids and require that the dosage of 
the corticosteroid be increased. Drugs which inhibit CYP 3A4 (e.g., ketoconazole, 
macrolide antibiotics such as erythromycin) have the potential to result in increased 
plasma concentrations of corticosteroids. 
• Dexamethasone is a moderate inducer of CYP 3A4. Co-administration with other drugs 
that are metabolized by CYP 3A4 (e.g., indinavir, erythromycin) may increase their 
clearance, resulting in decreased plasma concentration. 
• Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain 
corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. In 
addition, ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause 
adrenal insufficiency during corticosteroid withdrawal. 
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• Nonsteroidal Anti-Inflammatory Agents: Concomitant use of aspirin (or other 
nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of 
gastrointestinal side effects. Aspirin should be used cautiously in conjunction with 
corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased 
with concurrent use of corticosteroids. ASA (81 or 325 mg) QD is permitted for deep 
venous thrombosis (DVT) prophylaxis. 
• Phenytoin: In post-marketing experience, there have been reports of both increases and 
decreases in phenytoin levels with dexamethasone co-administration, leading to 
alterations in seizure control. 
• Skin Tests: Corticosteroids may suppress reactions to skin tests. 
• Thalidomide: Co-administration with thalidomide should be employed cautiously, as 
toxic epidermal necrolysis has been reported with concomitant use. 
• Vaccines: Patients on corticosteroid therapy may exhibit a diminished response to 
toxoids and live or inactivated vaccines due to inhibition of antibody response. 
Corticosteroids may also potentiate the replication of some organisms contained in live 
attenuated vaccines. Routine administration of vaccines or toxoids should be deferred 
until corticosteroid therapy is discontinued if possible. 
6. 
STUDY ASSESSMENTS 
6.1. 
Safety Measurements 
6.1.1. 
Demographics and Medical History 
A medical and surgical history will be obtained at screening for all patients. The medical 
history is to include demographic and background information, MM history, including date of 
and stage at diagnosis, and all previous treatment for MM, including radiation therapy, and 
response(s) to such treatment. 
6.1.2. 
Physical Examination 
A complete physical examination will be conducted for all patients at screening and at study 
treatment discontinuation. 
6.1.3. 
Vital Signs 
Vital signs, including weight, blood pressure (BP), heart rate, and temperature will be conducted 
for all patients at screening, on Day 1 of every treatment cycle, upon PD, and at study treatment 
discontinuation. Height will be collected at screening only. 
6.1.4. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
ECOG performance Status (Appendix 9.8) is to be documented for all patients at screening, on 
Day 1 of every treatment cycle, upon PD, and at study treatment discontinuation. 
6.1.5. 
12-Lead Electrocardiogram 
Twelve-lead ECGs monitoring is to be performed at screening, pre-dose on Day 1 of every 
treatment cycle, Day 8 (Cycle 1 only for Phase 1B), and at study treatment discontinuation. 
Additional ECGs may be taken at any time point at the Investigator’s discretion. 
 
 
 
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6.1.6. 
VTE Monitoring 
Monitoring for VTE will be performed at each visit during study treatment and at study 
discontinuation. 
6.1.7. 
Clinical Laboratory Tests 
All serum hematology, serum chemistries, serum function tests, and urinalysis will be analyzed 
by local laboratories. 
6.1.7.1. 
Hematology, Serum Chemistry and Urinalysis 
Blood samples for hematology are to be collected for all patients at screening, on Days 1, 2, 8, 
15, and 22 during Cycle 1, on Day 1 of every cycle beginning with Cycle 2, upon PD, and at 
study treatment discontinuation. In addition, complete blood count (CBC) will be conducted 
every 7 days for Cycle 1, every 14 days for Cycle 2, and on Day 1 of every cycle beginning with 
Cycle 3. 
Blood samples for serum chemistry are to be collected for all patients at screening, on Day 1 of 
every treatment cycle, and at study treatment discontinuation. Hematology and serum chemistry 
results must be available and reviewed by the Investigator prior to study drug administration. 
Urine for urinalysis is to be collected at screening, on Day 1of every treatment cycle, upon PD, 
and at study treatment discontinuation. 
The following clinical laboratory parameters are to be measured: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Hematology 
• 
Hematocrit 
• 
Platelet count 
• 
Hemoglobin 
• 
WBC with differential 
• 
Red blood cell count (RBC) 
• 
Reticulocyte count 
• 
INR 
(for patients on coumadin) 
• 
Mean corpuscular volume 
• 
ANC 
• 
Absolute lymphocyte count (ALC) 
Chemistry 
• 
Glucose 
• 
Creatinine 
• 
Calcium 
• 
Carbon dioxide 
• 
Albumin 
• 
Total bilirubin 
• 
Total protein 
• 
Lactate dehydrogenase (LDH) 
• 
Sodium 
• 
AST 
• 
Potassium 
• 
ALT 
• 
Magnesium 
• 
Gamma-glutamyl transpeptidase (GGT) 
• 
Phosphorus 
• 
Chloride 
• 
Blood urea nitrogen (BUN) 
• 
Uric acid 
• 
ALP 
Urinalysis 
• 
Specific gravity 
• 
Protein 
• 
pH 
• 
Ketones 
• 
Glucose 
• 
Microscopic examination [casts, RBCs, and 
WBCs] 
• 
Bilirubin 
 
INR will be measured at screening and on Day 1 of every treatment cycle for patients on 
coumadin. INR is to be between 2 to 3. If a patient’s INR is outside this range, then the 
anticoagulant dose should be adjusted (see Section 5.6.1). 
Clinical laboratory evaluations are to be repeated as necessary during treatment at a schedule 
determined by the Investigator, based on the patient’s clinical status. 
Laboratory abnormalities that are considered by the Investigator to be clinically significant for a 
particular patient at screening, and before study drug administration on C1D1 are to be reported 
as part of the patient’s medical history. 
 
 
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6.1.7.2. 
Screening Serology 
A blood sample for serology, including Hepatitis B surface antigen (HBsAg), HCV, and HIV, is 
to be collected from all patients at screening. 
6.1.7.3. 
Pregnancy Testing and Counseling 
POMALYST REMS™ Program (United States) 
A FCBP is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive months). 
Pregnancy tests (serum or urine test with a sensitivity of at least 25 mIU/mL) must occur 10 to 
14 days and again within 24 hours prior to initiation of study drug. FCBP with regular or no 
menstruation must have a pregnancy test weekly for the first 4 weeks and then every 28 days 
while on therapy (including breaks in therapy); at discontinuation of study drug and at Day 28 
following the last dose of study drug. Females with irregular menstruation must have a 
pregnancy test weekly for the first 4 weeks and then every 14 days while on therapy (including 
breaks in therapy), at discontinuation of study drug and at Day 14 and Day 28 following the last 
dose of study drug (see Appendix 9.3). FCBP must commit either to abstain continuously from 
heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously (one 
highly effective form of contraception – tubal ligation, intrauterine device [IUD], hormonal 
birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s 
vasectomy and one additional effective contraceptive method – male latex or synthetic condom, 
diaphragm or cervical cap. 
All patients must be counseled about pregnancy precautions, risks of fetal exposure and other 
risks. The counseling must be done on Day 1 of each cycle (or at a minimum of every 28 days) 
and at drug discontinuation. For additional requirements of the POMALYST REMS™ Program 
regarding pregnancy testing, counseling, and acceptable methods of birth control, see 
Appendix 9.4. 
RevAid® Program (Canada) 
A FCBP is any female patient who: 1) is still menstruating; or 2) who is amenorrheic from 
previous chemotherapy treatments; 3) who is perimenopausal. 
FCBP must have two medically supervised negative pregnancy tests prior to the first dispensed 
prescription of pomalidomide. Pregnancy tests must be performed in a licensed laboratory 
(serum test with a sensitivity of at least 25 mIU/mL) must occur 7 to 14 days and again within 
24 hours prior to initiation of study drug. The dates and results of pregnancy tests must be 
documented. FCBP with regular or no menstruation must have a pregnancy test weekly for the 
first month of treatment, monthly thereafter during treatment (or every 2 weeks if menses are 
irregular) and for 4 weeks after discontinuation of treatment. FCBP must use at least 2 effective 
methods of contraception at the same time for at least 4 weeks before starting treatment, during 
interruptions of treatment, for at least 4 weeks after stopping treatment. 
All patients must be counseled about pregnancy precautions, risks of fetal exposure and other 
risks. The counseling must be done on Day 1 of each cycle (or at a minimum of every 28 days) 
and at drug discontinuation. For additional requirements of the RevAid® Program regarding 
pregnancy testing, counseling, and acceptable methods of birth control, see Appendix 9.4. 
 
 
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European Pomalidomide Pregnancy Prevention 
For additional information on the European Pomalidomide Pregnancy Prevention Risk 
Management Plans, see Appendix 9.5. 
6.1.8. 
Adverse Events 
Monitoring of AEs will be conducted throughout the study. AEs, including SAEs, will be 
documented in the eCRFs from Baseline (i.e., C1D1) through 30 days after treatment 
discontinuation. Any SAE occurring more than 30 days after the last study drug dose that is 
considered by the Investigator to be study drug-related should also be reported. AEs that lead to 
study discontinuation should be followed until resolution or stabilization. SAEs will be 
assessed until 30 days after study treatment discontinuation. 
6.1.8.1. 
Definitions, Documentation, and Reporting 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product, 
which does not necessarily have a causal relationship with the treatment. An AE can be any 
unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the study drug, whether or not it is considered to 
be study drug related. This includes any newly occurring event or previous condition that has 
increased in severity or frequency since the administration of study drug. 
Disease progression is not to be reported as an AE. 
An SAE is any AE, occurring at any dose and regardless of causality that: 
• Results in death. 
• Is life-threatening. Life-threatening means that the patient was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry are not considered AEs if the illness or 
disease existed before the patient was enrolled in the study, provided that it did not 
deteriorate in an unexpected manner during the study (e.g., surgery performed earlier 
than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a persons’ ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event. An important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered an 
SAE when, based upon appropriate medical judgment, it may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalization, or the development of drug 
dependency or drug abuse. 
 
 
 
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Contact Information 
INC 24 Hour SAE Reporting 
E-mail: 
Fax: 
6.1.8.2. 
Pregnancy 
Female Patients 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female patient occurring while the patient is on Investigational Product (IP), 
or within at least 28 days of the patient’s last dose of study drug, are considered immediately 
reportable events. IP is to be discontinued immediately. The pregnancy, suspected pregnancy, 
or positive pregnancy test must be reported to the INC Safety Monitor immediately by 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form. 
The female patient should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling. 
The Investigator will follow the female patient until completion of the pregnancy, and must 
notify the INC Safety Monitor immediately about the outcome of the pregnancy (either normal 
or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent 
form. If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the abnormal 
outcome meets any of the serious criteria, it must be reported as an SAE to the INC Safety 
Monitor immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form, or approved equivalent form. 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to the INC Safety Monitor 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
 
Male Patients 
If a female partner of a male patient taking IP becomes pregnant, the male patient taking the IP 
should notify the Investigator immediately, and the pregnant female partner should be advised 
to call their healthcare provider immediately. 
6.1.8.3. 
Second Primary Malignancies 
Second primary malignancies will be monitored as events of interest and must be reported as 
SAEs. This includes any second primary malignancy, regardless of causal relationship to study 
drug (ACY-1215, pomalidomide, dexamethasone), occurring at any time for the duration of the 
study, from the time of signing the informed consent up to the time all patients have been 
followed for at least 1 year from discontinuation or have died. Events of second primary 
malignancy are to be reported using the SAE report form and must be considered an “Important 
Medical Event” even if no other serious criteria apply; these events must also be documented in 
the appropriate page(s) of the eCRF and patient’s source documents. Documentation on the 
diagnosis of the second primary malignancy must be provided at the time of reporting as an 
SAE (e.g., any confirmatory histology or cytology results, X-rays, CT scans, etc.). 
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6.1.8.4. 
Procedures for AE and SAE Reporting 
Each patient must be carefully monitored for the development of any AEs. 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 AEs (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 eCRF. Any clinically relevant deterioration in 
laboratory assessments or other clinical findings is considered an AE and must be recorded in 
the eCRF. When possible, signs and symptoms indicating a common underlying pathology 
should be noted as one comprehensive event. All pomalidomide and dexamethasone AEs must 
be reported in accordance to the safety guidelines presented in the prescribing 
information.[51,58,59,60] 
All SAEs that occur during the course of the study must be reported by the Investigator to the 
24-hour Safety Reporting line (see below) and entered into electronic data capture (EDC) 
within 1 working day from the point in time when the Investigator becomes aware of the SAE. 
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 
on an expedited basis. It is the responsibility of the Investigator to promptly notify the IRB/IEC 
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. 
For both serious and non-serious AEs, the Investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. 
Severity of AEs will be assessed by the Investigator according to the NCI CTCAE, Version 4.0 
(see http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 
14_QuickReference_8.5x11.pdf.). If the AE is not included in the CTCAE, Version 4.0, then 
the Investigator is to determine the intensity of the AE according to the following criteria: 
Mild (Grade 1): 
AE that disappears or is easily tolerated on continuation of 
study drug. 
Moderate (Grade 2): 
AE sufficiently discomforting to cause interference with 
usual work activities. 
Severe (Grade 3): 
AE that is incapacitating, with inability to work or perform 
daily activities. 
Life-Threatening (Grade 4): 
AE that is potentially life-threatening.2 
If the severity (Grade) changes within a day, the maximum intensity (Grade) should be 
recorded. If the intensity (Grade) changes over a longer period of time, the changes should be 
recorded as separate events (having separate onset and stop dates for each grade). 
 
 
 
 
2 
If a life-threatening (Grade 4) AE is immediately life-threatening, the event is, by definition, serious and is to 
be reported as described in Section 6.1.8.4. 
 
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Contact Information 
INC 24 Hour SAE Reporting 
E-mail: 
Fax: 
Relationship to study drug administration will be determined by the Investigator according to 
the following criteria: 
Unrelated: 
There is little or no chance that the study drug caused the 
AE; other conditions, including concurrent illnesses, 
progression, or expression of the disease state, or a 
reaction to a concomitant medication best explain the 
event. 
Possible: 
The association of the AE with the study drug is unknown; 
however, the AE is not clearly due to another condition. 
Probable: 
A reasonable temporal association exists between the AE 
and treatment administration and, based on the 
Investigator's clinical experience, the association of the AE 
with the study treatment seems likely. 
For the purpose of safety analyses, all AEs that are classified as possible or probable will be 
considered treatment-related events. 
Reporting to the Sponsor 
All SAEs must be reported to Acetylon whether or not considered causally related to the 
study drug. SAE event forms, created specifically by Acetylon, 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 Acetylon. 
 
 
6.1.8.5. 
Follow-Up of Adverse Events 
The Investigator must continue to follow all SAEs and non-serious AEs considered to be at least 
possibly related to study drug either until resolution or the Investigator assesses them as chronic 
or stable. This follow-up may extend after the end of the study. 
6.1.8.6. 
Reporting Safety Information 
The Investigator must promptly report to his or her IRB/IEC all unanticipated problems 
involving risks to patients. This includes death from any cause and all SAEs reasonably or 
possibly associated with the use of study drug. 
6.1.8.7. 
Protocol Deviations Due to an Emergency or Adverse Event 
Departures from the protocol will be determined as allowable on a case-by-case basis and only 
in the event of an emergency. The Investigator or other physician in attendance in such an 
emergency must contact the Medical Monitor as soon as possible to discuss the circumstances 
of the emergency. 
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The Medical Monitor, in conjunction with the Investigator, will decide whether the patient 
should continue to participate in the study. All protocol deviations and reasons for such 
deviations must be documented in the eCRF. 
6.2. 
Efficacy Measurements 
The following section describes the efficacy assessments that will be obtained during the study. 
All assessments collected on the same day as study drug administration must be collected before 
study drug is administered. In order to assess response to treatment, M-protein component is to 
be measured in serum and urine. FreeLite™ testing is to be performed and, as applicable, bone 
marrow aspirate and biopsies, and appropriate imaging studies (e.g., [CT], MRI) are to be 
performed. 
Clinical laboratory tests of efficacy assessments are to be performed locally. In addition, a 
central laboratory will analyze duplicate samples of serum immunoglobulin levels, SPEP and 
UPEP of M-protein levels, serum and urine IFE studies, and FreeLite™ Testing. A bone 
marrow aspirate sample will centrally analyzed for FISH/cytogenetics. Results from the central 
efficacy analysis will not be shared with sites. 
In the event of study treatment discontinuation for reasons other than PD, all patients will 
continue to be followed for efficacy assessments (assessment of response, extramedullary 
plasmacytoma assessment, quantitative serum immunoglobulin levels, SPEP and UPEP of 
M-protein levels, IFE, and SFLC) until the development of PD, or initiation of an alternate MM 
therapy. 
6.2.1. 
Myeloma Protein Measurements and Serum Immunoglobulins 
Serum-M protein levels (quantified from the SPEP test), urine M-protein levels (quantified from 
the UPEP test performed on 24-hour urine collection), and quantitative serum immunoglobulin 
levels will be obtained at screening, at Day 1 of each treatment cycle, PD, and at treatment 
discontinuation. Serum and urine IFE tests are to be performed at screening to identify the 
immunoglobulin subtype of MM and thereafter, will be performed by the central laboratory 
whenever M-protein is undetectable in both SPEP and UPEP studies to confirm CR. Response 
will be assessed using the IMWG criteria (see Appendix 9.5). 
6.2.2. 
FreeLite™ Testing 
Serum samples for FreeLite™ testing (serum FLCs) are to be collected from all patients at 
screening, on Day 1 of every treatment cycle, PD, and at treatment discontinuation. 
6.2.3. 
Bone Marrow Examination 
A bone marrow aspirate is to be performed at screening and when clinically indicated at the 
discretion of the treating physician. A biopsy is needed only if the marrow is unable to be 
aspirated. A bone marrow aspirate sample collected at screening will be sent for central 
cytogenetic and FISH analysis. 
6.2.4. 
Skeletal Survey and Other Imaging Studies 
Skeletal surveys (Appendix 9.9), are to be performed at screening (or within 60 days of Study 
Day 1), at treatment discontinuation, when clinically indicated, and to confirm CR. 
Other appropriate imaging studies (e.g., MRI, CT, X-ray) to document sites of myelomatous 
disease are to be performed at screening per standard of care, as determined by the Investigator. 
Appropriate imaging studies are to be repeated as necessary to confirm CR. 
 
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6.2.5. 
Extramedullary Plasmacytoma Assessments 
Assessment/measurement required only if present or if clinically indicated. Plasmacytomas that 
can be assessed clinically are to be assessed every cycle. Plasmacytomas that are assessed by 
radiography will be assessed at screening, every cycle, at study treatment discontinuation, and to 
assess best response. 
6.2.6. 
Assessment of Disease Response 
Assessment of response will include measurement of serum M-protein by SPEP and UPEP, 
SFLC analysis (see Section 6.2.2) and immunofixation studies. Objective response, as assessed 
by site Investigators using the recently revised IMWG criteria has been chosen as the primary 
endpoint for this study. The IMWG criteria were developed by the International Myeloma 
Working group in order to provide uniform reporting requirements for studies conducted in MM 
and to enable consistent comparison of results across studies. Based on the EBMT, IMWG 
criteria have been expanded, clarified, and updated to provide a new comprehensive evaluation 
system to assess not only response but also the magnitude of response, length of response, and 
OS, (Appendix 9.5). Use of the IMWG criteria, the international standard for the assessment of 
response for MM studies, will ensure that data across all centers is evaluated consistently. 
Response will be assessed every cycle throughout study drug treatment, and at treatment 
discontinuation in both the Phase 1b and Phase 2 segments of the study. In addition to the site 
Investigators, an Independent Central Adjudication Committee will review the myeloma 
response data (i.e., laboratory data and radiographic data) to determine response to treatment 
and dates of PD for each study patient. Determination of PD requires two consecutive 
assessments of disease progression. There is no specific requirement for the timing of these two 
assessments. 
Additional secondary endpoints of disease response will include TTR, DOR, TTP, and PFS. In 
addition, central laboratory data will be employed to maintain consistency in evaluation of 
efficacy endpoints. 
Overall response rates utilizing either or both criteria will be reported in the clinical study 
report. Response to treatment will also be blindly assessed by the Central Adjudication 
Committee using IMWG criteria and dates of PD. 
6.2.7. 
Survival 
All patients will be followed for survival for up to 1 year. Patients will be assessed 3 times per 
year (approximately every 4 months) to determine survival status. Cause of death is to be 
recorded in the CRF and the patient’s medical record 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.3. 
Pharmacokinetic Measurements 
Serial blood samples for PK assessments are to be collected from all patients during Cycle 1 of 
the Phase 1b and from patients at participating sites in the Phase 2 segment at the following time 
points: 
• Phase 1b, C1D1: pre-dose, 0.5, 1, 2, 4, and 6 hours post dose 
• Phase 1b, C1D2: 24 hours post dose 
• Phase 1b, C1D8: pre-dose, 0.5, 1, 2, 4, and 6 hours post dose 
• Phase 2, C1D1: pre-dose, 0.5 and 1 hour post dose 
• Phase 2, C1D22: 24 hours post morning dose of Day 21, 
• Phase 2, Day 1 of Cycles 2-6, at least 1 hour post dose 
The date and time of the patient’s most recent meal before the start of blood sample collection 
on each scheduled collection day and the date and time of each blood sample collection is to be 
documented in the eCRF on days that PK samples are drawn. 
PK samples should be collected as close to the scheduled time as possible: ≤ 1 hour before drug 
administration, ±5 minutes through 6 hours post dose and ±1 hour at the 24 hour post dose. If 
deviations in timing occur, the timing of the sample collection should be clearly marked. 
6.4. 
Pharmacodynamic Assessments 
Blood samples for pharmacodynamic assessments are to be collected from all patients during 
Cycle 1 of the Phase 1b segment at the following time points: 
• Phase 1b, C1D1: pre-dose, 0.5, 1, 2, 4, and 6 hours post dose 
• Phase 1b, C1D2: 24 hours post dose 
All details regarding handling and shipping of these samples will be provided in the Laboratory 
Procedures Manual. 
7. 
STATISTICAL PROCEDURES 
7.1. 
Sample Size Estimation 
Phase 1b (MTD): 
Using a 3+3 design, the total number of patients required for the MTD phase will range from 9 
to 30. 
Phase 2: 
The reference response rate is assumed to be 0.29. For a study with a sample size of 66, a 
one-sided 0.05 level test with power of 80% would be adequate to detect the response rate of 
0.29 against 0.44. Assuming a 10% drop out rate, a study of 75 patients would be sufficient. In 
order to have a robust study, a single interim analysis will be conducted when there are 30 
evaluable patients. The SRC will use the totality of information from the interim analysis to 
recommend whether the study should proceed as planned, be terminated for superiority or 
futility, or extended to allow for 86 evaluable patients. Assuming a 10% dropout rate, a study 
with n=95 would be sufficient. 
 
 
 
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7.2. 
Probability of Dose Escalation 
Table 11 displays the probabilities of dose escalation for any stage during the MTD 
determination, as a function of a given underlying DLT rate at the current dose level. 
Table 11 
Probabilities of Dose Escalation 
 
Underlying DLT Rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of Dose 
Escalation 
91% 
71% 
49% 
31% 
17% 
8% 
3% 
1% 
0.1% 
7.3. 
Populations for Analysis 
For both Phase 1 (MTD) and Phase 2 (Open-label Treatment): 
• Safety Population – all patients who receive at least 1 dose of study medication. 
• Intent-to-Treat (ITT) Population – all patients. 
• Efficacy Evaluable (EE) Population – all patients who meet eligibility criteria, receive at 
least 14 doses of study drug (i.e., ACY-1215, pomalidomide and low-dose 
dexamethasone) at the MTD, and have at least one post-baseline efficacy assessment. 
Safety analyses will be performed on the Safety Population, defined as all patients who 
receive at least 1 dose of study medication. 
7.4. 
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. 
7.5. 
Analysis Schedule 
7.5.1. 
Interim Analysis 
The interim analysis with the first 30 evaluable patients will be conducted using a one-sided 
95% CI estimate for the response rate. If the lower bound of the 95% CI estimate with the 
30 patients is ≥ 29%, the SRC may recommend either terminating the study at the interim based 
on treatment superiority, or continuing the study as planned. If the lower bound is < 29%, 
various predicted lower bounds of one-sided 95% CIs for the response rate will be constructed 
to further guide the SRC’s recommendation. For example, assuming a true response rate of 
44% for the remaining 36 patients, the expected lower bound of one-sided 95% CI with 66 
evaluable patients will be calculated. If the expected lower bound is ≥ 29%, the SRC may 
recommend continuing the study as planned. If the expected lower bound with 66 evaluable 
patients is < 29%, another simulation will be run with 86 evaluable patients. If the resulting 
lower bound is acceptable (e.g., close to or ≥ 29%), the SRC may recommend expanding the 
sample size by 20 patients. If the resulting lower bound is not acceptable (e.g., < 29%), the SRC 
may recommend terminating the study for futility. In addition, the expected lower bound of the 
one-sided 95% CI when the true response rate is equal to the observed value at the interim 
analysis will be calculated. The resulting scenario will be similar to the previous one: if the 
expected lower bound is ≥ 29%, the SRC may recommend continuing the study as planned, if 
the lower bound is < 29%, the SRC may recommend expanding the sample size by 20 patients. 
Additional simulations with other possible response rates (for example, assuming a 40% 
response rate), with or without adaptation, will also be conducted; the SRC will review all 
simulation results to make a recommendation at the interim. Furthermore, with the potential 
 
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adaptations at the interim, we find via an extensive simulation study the final CI estimate would 
have the accurate coverage level. Therefore, no statistical penalty or adjustment will be needed 
for the final inferential statistical procedure for the response rate. 
7.5.2. 
Final Analysis 
A final analysis is planned after all enrolled patients either complete 6 cycles of study treatment, 
at treatment discontinuation, or withdraw early from the study. 
7.5.3. 
Addendum 
An addendum to the final analysis will be prepared when all patients have withdrawn from the 
study. 
7.6. 
Statistical Methods 
7.6.1. 
General Methods 
Statistical analyses will be primarily descriptive in nature, since the goal of the study is to 
determine the DLT, MTD, and recommended dose of ACY-1215 in combination with 
pomalidomide and dexamethasone for further investigation. This goal will be achieved by the 
results of a deterministic algorithm; thus, statistical hypothesis testing is neither intended nor 
appropriate within this context. 
Continuous variables will be summarized using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum). Categorical variables will be summarized 
showing the number and percentage (n, %) of patients within each classification. Graphical 
displays will be provided where useful in the interpretation of results. 
7.6.2. 
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 by dose 
cohort. Reasons for discontinuation that are the basis for DLT will be categorized in distinction 
from other reasons for discontinuation. 
7.6.3. 
Demographics and Baseline Characteristics 
The baseline (C1D1) characteristics of patients enrolled in each dose cohort, the Phase 1b MTD 
segment and the Phase 2 segment, will be summarized. An accounting will be made of the 
study course for all patients who received study drug for each dose cohort and, in particular, the 
number of patients who died or withdrew during treatment will be specified and reasons for 
withdrawal categorized. Study drug administration will be summarized for each dose cohort. 
Information on dose reductions will be summarized. 
7.6.4. 
Extent of Exposure 
Descriptive statistics for patients treated in and completing every treatment cycle, including the 
number of doses missed or held and dose reductions required, will be presented for every 
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. 
 
 
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7.6.5. 
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 tabulated in a data listing. 
7.6.6. 
Safety Analysis 
Safety data for the Phase 1b MTD segment will be summarized when all patients have 
completed the first 28-day cycle (Cycle 1). Safety data for the Phase 2 segment, as well as for 
patients from the Phase 1b segment who continued treatment following the completion of the 
first cycle, will be analyzed when all patients have completed 48 weeks of the study or have 
discontinued from the study. 
Safety evaluations will be based on the incidence, intensity, and type of AEs, and changes in the 
patient’s physical examination findings, vital signs, ECG findings, and clinical laboratory 
results. All patients who received at least one dose of study drug will be included in the safety 
analysis. Summarization will focus on occurrence rates of: any SAEs; treatment-emergent AEs 
by system organ class (SOC) and preferred term; discontinuation rates of study therapy due to 
AE or toxicity based on clinical laboratory assessment and rates of hematologic toxicity. The 
frequency of DLT by dose cohort also will be summarized. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) for 
purposes of summarization. All AEs occurring on study will be listed in by-patient data listings. 
Treatment-emergent events will be tabulated, where treatment-emergent is defined as any AE 
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 AEs by maximum severity. 
Deaths, SAEs and AEs resulting in study discontinuation will be tabulated. AEs leading to dose 
reduction or interruption will also 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, ANC, ALC, 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 BP, heart 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. 
ECOG performance status will be summarized for changes from Baseline to treatment 
discontinuation; ECOG performance status on Day 1 of every treatment cycle will be presented 
in data listing format. 
 
 
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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. 
7.6.7. 
Efficacy Analysis 
Efficacy analysis will be performed on both the ITT Population and EE Population. The ITT 
Population will include all patients, and the EE Population will include all patients who meet 
eligibility criteria, receive at least 14 doses of study drug (i.e., ACY-1215, pomalidomide and 
low-dose dexamethasone), and have at least 1 post-baseline efficacy assessment. The primary 
analysis will be based on the EE population, and will use the Investigator-assessed response data 
evaluated according to consensus recommendations based on the IMWG criteria. Response rate 
will be percent of patients who achieve at least partial response (PR) at the recommended 
Phase 2 dose. Percent of patients achieving MR or better will also be collected as clinical 
benefit response. PFS will be defined as the time from first dose of study treatment to the first 
documentation of PD or death from any cause during study. Overall survival (OS) will be 
defined as the time from first dose of study treatment to death from any cause. For responders, 
TTR and response duration will be analyzed. TTR will be defined as the time from first dose of 
study treatment to the first documentation of response (either PR or CR). DOR will be defined 
as the time from the first PR or CR to the first documentation of PD or death, whichever occurs 
earlier. 
For data obtained from patients treated at doses of ACY-1215 not selected as the MTD, a case- 
by-case description of myeloma response (per IMWG criteria) will be provided. For the 
12 patients who initiate ACY-1215 at the recommended Phase 2 dose level, response rates 
together with confidence intervals will be provided. Kaplan-Meier curves will be used to 
characterize the time-to-event curves (PFS, OS, response duration) when there is censoring; 
univariate summary statistics will be provided for TTR. 
For the Phase 2 segment, a 0.95 confidence interval for the response rate will be constructed for 
evaluating the efficacy of ACY-1215. Kaplan-Meier curves will be constructed to characterize 
PFS, OS, and DOR. One sample standard inferences for PFS, OS and DOR will be made 
accordingly. 
7.6.8. 
Pharmacokinetic Analysis 
Study drug serum concentrations of ACY-1215 and pomalidomide will be determined at all pre- 
and post-dose time-points as specified in the Schedule of Assessments (Table 1). Parameters to 
be calculated based on a non-compartmental model approach will include Cmax, Tmax, AUC0-last, 
AUC from time zero to infinity (AUC0-∞), and t1/2. ACY-1215 and pomalidomide serum levels 
and non-compartmental PK parameters will be tabulated by dose cohort using descriptive 
statistics. Tabulated single- and multiple-PK dose results will be presented. 
7.6.9. 
Pharmacodynamic Analysis 
The fold change between pre- and post-dose time points in the levels of acetylated histones and 
acetylated tubulin will be determined in PBMCs. The resulting data may be used to generate a 
PK/pharmacodynamic model(s) of the relationship of changes in acetylated histones and/or 
tubulin with the plasma levels of ACY-1215 over time. A summary report will be generated of 
the pharmacodynamic analysis and results from PK/pharmacodynamic modeling. 
7.6.10. 
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 
 
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will be indicated in this plan; any further modifications will be noted in the final clinical study 
report. 
8. 
ADMINISTRATIVE REQUIREMENTS 
8.1. 
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. 
8.2. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki (Appendix 9.10). The IRB/IEC 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/IEC 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/IEC by the Investigator. 
8.3. 
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). 
8.4. 
Patient Confidentiality 
In order to maintain patient privacy, all eCRFs, study drug accountability records, study reports, 
and communications will identify the patient according to local or regulatory authority(ies). 
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 
documented in the eCRFs 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. 
8.5. 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by Acetylon, 
and given approval/favorable opinion by the IRB/IEC 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/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to patients. The IRB/IEC 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/IEC. 
Acetylon will submit all protocol modifications to the regulatory authority(ies) in accordance 
with the governing regulations. 
 
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When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact 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 eCRF and source documentation. 
8.6. 
Direct Access to Source Data 
Monitoring and auditing procedures developed by the Sponsor or designee will be followed, in 
order to comply with GCP guidelines. 
The study will be monitored by Acetylon or its designee. Monitoring will be done by personal 
visits from a representative of the Sponsor (site monitor) and will include on-site review of the 
eCRFs 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). 
All unused study drug and other study materials are to be returned to Acetylon after the clinical 
phase of the study has been completed (see Section 5.5). 
Regulatory authorities, the IRB/IEC, and/or Acetylon’s clinical quality assurance group may 
request access to all source documents, eCRFs, 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. 
8.7. 
Case Report Form Completion 
The Sponsor or designee will provide the study centers with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the eCRFs 
for the patients for whom they are responsible. 
eCRFs will be completed for each study patient dosed in the study. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, clarity, and timeliness of the data reported 
in the patient’s eCRF. 
The investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected. 
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for the 
patients for which he or she is responsible. The audit trail entry will show the user’s 
identification information and the date and time of the correction. 
The Sponsor or designee will retain the eCRF data and corresponding audit trails. A copy of the 
final archival eCRF in the form of a compact disk or other electronic media will be placed in the 
investigator’s study file. 
8.8. 
Record Retention 
The Investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(s). The Sponsor must be notified in writing if a custodial change occurs. 
 
 
 
 
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8.9. 
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. 
8.10. 
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 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 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9. 
APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.1. 
VTE Algorithms 
 
 
 
** if significant renal insufficiency, contrast allergy, or patient refusal of invasive 
procedures precludes performance of contrast venography, then a positive finding on 
serial compression ultrasound of the leg can be accepted as diagnostic of recurrent 
DVT and PE 
 
 
 
 
 
 
 
 
 
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9.2. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.3. 
POMALYST REMS™ Program (United States) 
The full prescribing information, Pregnancy Testing Guideline and Pregnancy Risk 
Minimization Plan for FCBP and male patients in the US taking pomalidomide can be accessed 
using the following web link: 
http://www.pomalystrems.com/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.4. 
RevAid® Complete Guide for Health Care Practitioners (Canada) 
The full prescribing information, Pregnancy Testing Guideline and Pregnancy Risk 
Minimization Plan for FCBP and male patients in Canada taking pomalidomide can be accessed 
using the following web link: 
https://www.revaid.ca/revaid/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.5. 
European Pomalidomide Pregnancy Prevention Risk Management 
Plans 
9.5.1. 
Pregnancy Prevention Risk Management Plans 
9.5.1.1. 
Pomalidomide (CC-4047) Pregnancy Prevention Risk Management Plan 
9.5.1.1.1. Pomalidomide Pregnancy Risk Minimization Plan for Celgene Clinical Trials 
Appendix 9.5 applies to all EU patients receiving pomalidomide therapy. The following 
Pregnancy Risk Minimization Plan documents are included in this Appendix: 
1. Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods (Section 9.5.1.1.2); 
2. Pomalidomide Education and Counselling Guidance Document (Section 9.5.1.1.3); 
3. Pomalidomide Information Sheet (Section 9.5.1.1.4). 
 
1. The Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods document (Section 9.5.1.1.2) provides the following 
information: 
• Potential risks to the fetus associated with pomalidomide exposure 
• Definition of Female of Childbearing Potential (FCBP) 
• Pregnancy testing requirements for patients receiving pomalidomide who are 
females of childbearing potential 
• Acceptable birth control methods for both female of childbearing potential and 
male patients receiving pomalidomide in the study 
• Requirements for counselling of all study patients receiving pomalidomide about 
pregnancy precautions and the potential risks of fetal exposure to pomalidomide 
2. The Pomalidomide Education and Counselling Guidance Document (Section 9.5.1.1.3) 
must be completed and signed by either a trained counselor or the Investigator at the 
participating clinical center prior to each dispensing of pomalidomide study treatment. 
A copy of this document must be maintained in the patient records. 
3. The Pomalidomide Information Sheet (Section 9.5.1.1.4) will be given to each patient 
receiving pomalidomide study therapy. The patient must read this document prior to 
starting pomalidomide study treatment and each time they receive a new supply of study 
drug. 
9.5.1.1.2. Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods 
Risks Associated with Pregnancy 
Pomalidomide was found to be teratogenic in a developmental study in rabbits. Pomalidomide 
is an analogue of thalidomide. Thalidomide is a known human teratogen that causes severe life- 
 
 
 
 
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threatening human birth defects. If Pomalidomide is taken during pregnancy, it may cause birth 
defects or death to an unborn baby. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who: 1) 
has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally 
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) 
for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 
consecutive months). 
Counselling 
For a female of childbearing potential, pomalidomide is contraindicated unless all of the 
following are met (ie, all females of childbearing potential must be counselled concerning the 
following risks and requirements prior to the start of pomalidomide study therapy): 
• She understands the potential teratogenic risk to the unborn child 
• She understands the need for effective contraception, without interruption, 28 days 
before starting study treatment, throughout the entire duration of study treatment, dose 
interruption and 28 days after the end of study treatment 
• She should be capable of complying with effective contraceptive measures 
• She is informed and understands the potential consequences of pregnancy and the need 
to notify her study doctor immediately if there is a risk of pregnancy 
• She understands the need to commence the study treatment as soon as study drug is 
dispensed following a negative pregnancy test 
• She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol (Section 9.5.1.1.2) 
• She acknowledges that she understands the hazards and necessary precautions associated 
with the use of pomalidomide 
The investigator must ensure that females of childbearing potential: 
• Comply with the conditions for pregnancy risk minimization, including confirmation 
that she has an adequate level of understanding 
• Acknowledge the aforementioned requirements 
For a female NOT of childbearing potential, pomalidomide is contraindicated unless all of the 
following are met (ie, all females NOT of childbearing potential must be counselled concerning 
the following risks and requirements prior to the start of pomalidomide study therapy): 
• She acknowledges that she understands the hazards and necessary precautions associated 
with the use of pomalidomide 
The effect of pomalidomide on spermatogenesis is not known and has not been studied. 
Therefore, male patients taking pomalidomide must meet the following conditions (ie, all males 
must be counselled concerning the following risks and requirements prior to the start of 
pomalidomide study therapy): 
• Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a female of childbearing potential 
 
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• Understand the need for the use of a condom even if he has had a vasectomy, if engaged 
in sexual activity with a pregnant female or a female of childbearing potential. 
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two 
reliable forms of contraception simultaneously or to practice complete abstinence from 
heterosexual contact during the following time periods related to this study: 1) for at least 28 
days before starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) 
for at least 28 days after study treatment discontinuation. 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception: 
• Highly effective methods: 
• Intrauterine device (IUD) 
• Hormonal (birth control pills, injections, implants) 
• Tubal ligation 
• Partner’s vasectomy 
• Additional effective methods: 
• Male condom 
• Diaphragm 
• Cervical Cap 
Because of the increased risk of venous thromboembolism in patients with multiple myeloma 
taking pomalidomide and dexamethasone, combined oral contraceptive pills are not 
recommended. If a patient is currently using combined oral contraception the patient should 
switch to another one of the effective methods listed above. The risk of venous 
thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception. 
The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone. 
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk 
of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in patients with neutropenia. 
Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential 
who commit to complete abstinence, as outlined below. 
Before starting study drug 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to 
starting study drug. The first pregnancy test must be performed within 10-14 days prior to the 
start of study drug and the second pregnancy test must be performed within 24 hours prior to the 
 
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start of study drug. The patient may not receive study drug until the study doctor has verified 
that the results of these pregnancy tests are negative. 
Male Patients: 
Must practice complete abstinence or agree to use a condom during sexual contact with a 
pregnant female or a female of childbearing potential while participating in the study, during 
dose interruptions and for at least 28 days following study drug discontinuation, even if he has 
undergone a successful vasectomy. 
During study participation and for 28 days following study drug discontinuation 
Female Patients: 
• FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for 
the first 28 days of study participation and then every 28 days while on study, at study 
discontinuation, and at day 28 following study drug discontinuation. If menstrual cycles 
are irregular, the pregnancy testing must occur weekly for the first 28 days and then 
every 14 days while on study, at study discontinuation, and at days 14 and 28 following 
study drug discontinuation. 
• At each visit, the Investigator must confirm with the FCBP that she is continuing to use 
two reliable methods of birth control. 
• Counselling about pregnancy precautions and the potential risks of fetal exposure must 
be conducted at a minimum of every 28 days. 
• If pregnancy or a positive pregnancy test does occur in a study patient, study drug must 
be immediately discontinued. 
• Pregnancy testing and counselling must be performed if a patient misses her period or if 
her pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be 
discontinued during this evaluation. 
• Females must agree to abstain from breastfeeding during study participation and for at 
least 28 days after study drug discontinuation. 
Male Patients: 
• Counselling about the requirement for complete abstinence or condom use during sexual 
contact with a pregnant female or a female of childbearing potential and the potential 
risks of fetal exposure to pomalidomide must be conducted at a minimum of every 28 
days. 
• If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
Additional precautions 
• Patients should be instructed never to give this medicinal product to another person and 
to return any unused capsules to the study doctor at the end of treatment. 
• Patients should not donate blood during therapy and for at least 28 days following 
discontinuation of study drug. 
• Male patients should not donate semen or sperm during therapy or for at least 28 days 
following discontinuation of study drug. 
 
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• Only enough study drug for one cycle of therapy may be dispensed with each cycle of 
therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.5.1.1.3. Pomalidomide Education and Counselling Guidance Document 
To be completed prior to each dispensing of study drug. 
Protocol Number:  
 
 
Patient Name (Print):  
DOB:     /    /    (mm/dd/yyyy) 
(Check the appropriate box to indicate risk category) 
Female: 
□⁯ 
If female, check one: 
⁯□ 
FCBP (Female of childbearing potential): sexually mature female who: 1) has not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the 
surgical removal of both ovaries) or 2) has not been naturally postmenopausal (amenorrhea 
following cancer therapy does not rule out childbearing potential) for at least 24 consecutive 
months (ie, has had menses at any time during the preceding 24 consecutive months) 
⁯□ 
NOT FCBP 
Male: ⁯□ 
 
Do Not Dispense study drug if: 
• The patient is pregnant. 
• No pregnancy tests were conducted for a FCBP. 
• The patient states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence of heterosexual contact) [at least 28 days prior to 
therapy, during therapy and during dose interruption]. 
FCBP: 
1. I verified that the required pregnancy tests performed are negative. 
2. I counselled FCBP regarding the following: 
• Potential risk of fetal exposure to pomalidomide: If pomalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby. Females are 
advised to avoid pregnancy while taking pomalidomide. The teratogenic potential of 
pomalidomide in humans cannot be ruled out. FCBP must agree not to become 
pregnant while taking pomalidomide. 
• Using TWO reliable methods of birth control at the same time or complete 
abstinence from heterosexual contact [at least 28 days prior to therapy, during 
therapy, during dose interruption and 28 days after discontinuation of study drug]. 
• That even if she has amenorrhea she must comply with advice on contraception 
• Use of one highly effective method and one additional method of birth control AT 
THE SAME TIME. The following are examples of highly effective and additional 
effective methods of contraception: 
 
 
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o Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (birth control pills, injections, implants) 
 Tubal ligation 
 Partner’s vasectomy 
o Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
• Pregnancy tests before and during treatment, even if the patient agrees not to 
have reproductive heterosexual contact. Two pregnancy tests will be performed 
prior to receiving study drug, one within 10-14 days and the second within 24 
hours of the start of study drug. 
• Frequency of pregnancy tests to be done: 
 Every week during the first 28 days of this study and a pregnancy test 
every 28 days during the patient’s participation in this study if menstrual 
cycles are regular or every 14 days if cycles are irregular. 
 If the patient missed a period or has unusual menstrual bleeding. 
 When the patient is discontinued from the study and at day 28 after study 
drug discontinuation if menstrual cycles are regular. If menstrual cycles 
are irregular, pregnancy tests will be done at discontinuation from the 
study and at days 14 and 28 after study drug discontinuation. 
• Stop taking study drug immediately in the event of becoming pregnant and to call 
their study doctor as soon as possible. 
• NEVER share study drug with anyone else. 
• Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
• Do not breastfeed a baby while participating in this study and for at least 28 days 
after study drug discontinuation. 
• Do not break, chew, or open study drug capsules. 
• Return unused study drug to the study doctor. 
3. Provide Pomalidomide Information Sheet to the patient. 
 
 
 
 
 
 
 
 
 
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FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR 
AT LEAST 24 CONSECUTIVE MONTHS, A HYSTERECTOMY, OR BILATERAL 
OOPHORECTOMY): 
1. I counselled the female NOT of childbearing potential regarding the following: 
• Potential risk of fetal exposure to pomalidomide (Refer to item #2 in FCBP) 
• NEVER share study drug with anyone else. 
• Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
• Do not break, chew, or open study drug capsules 
• Return unused study drug capsules to the study doctor. 
2. Provide Pomalidomide Information Sheet to the patient. 
MALE: 
1. I counselled the Male patient regarding the following: 
• Potential study drug fetal exposure to pomalidomide (Refer to item #2 in FCBP). 
• To engage in complete abstinence or use a condom when engaging in sexual contact 
(including those who have had a vasectomy) with a pregnant female or a female of 
childbearing potential, while taking study drug, during dose interruptions and for 28 
days after stopping study drug. 
• Males should notify their study doctor when their female partner becomes pregnant 
and female partners of males taking study drug should be advised to call their 
healthcare provider immediately if they get pregnant 
• NEVER share study drug with anyone else. 
• Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
• Do not donate semen or sperm while taking study drug and for 28 days after stopping 
study drug. 
• Do not break, chew, or open study drug capsules. 
• Return unused study drug capsules to the study doctor. 
2. Provide Pomalidomide Information Sheet to the patient. 
 
Investigator/Counselor Name (Print):  
 
(circle applicable) 
Investigator/Counselor Signature:  
 
Date:  
/ 
/ 
 
(circle applicable) 
 
**Maintain a copy of the Education and Counselling Guidance Document in the patient 
records.** 
 
 
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9.5.1.1.4. Pomalidomide Information Sheet 
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES 
Please read this Pomalidomide Information Sheet before you start taking study drug and each 
time you get a new supply. This Pomalidomide Information Sheet does not take the place of an 
informed consent to participate in clinical research or talking to your study doctor or healthcare 
provider about your medical condition or your treatment. 
What is the most important information I should know about pomalidomide? 
1. Pomalidomide may cause birth defects (deformed babies) or death of an unborn 
baby. Pomalidomide is similar to the medicine thalidomide. It is known that thalidomide 
causes life-threatening birth defects. Pomalidomide has not been tested in pregnant 
women but may also cause birth defects. Pomalidomide was found to cause birth defects 
when tested in pregnant rabbits. If you are a female who is able to become pregnant: 
• Do not take study drug if you are pregnant or plan to become pregnant 
• You must either not have any sexual relations with a man or use two 
reliable, separate forms of effective birth control at the same time: 
 for 28 days before starting study drug 
 while taking study drug 
 during dose interruptions of study drug 
 for 28 days after stopping study drug 
• You must have pregnancy testing done at the following times: 
 within 10 – 14 days and again 24 hours prior to the first dose of study 
drug 
 weekly for the first 28 days 
 every 28 days after the first month or every 14 days if you have irregular 
menstrual periods 
 if you miss your period or have unusual menstrual bleeding 
 28 days after the last dose of study drug (14 and 28 days after the last 
dose if menstrual periods are irregular) 
• Stop taking study drug if you become pregnant during treatment 
 If you suspect you are pregnant at any time during the study, you must 
stop study drug immediately and immediately inform your study doctor. 
The study doctor will report all cases of pregnancy to Celgene 
Corporation. 
• Do not breastfeed while taking study drug 
 The study doctor will be able to advise you where to get additional advice 
on contraception. 
 
 
 
 
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If you are a female not of childbearing potential: 
In order to ensure that an unborn baby is not exposed to pomalidomide, your study doctor will 
confirm that you are not able to become pregnant. 
If you are a male: 
The effect of pomalidomide on sperm development is not known and has not been studied. The 
risk to the fetus in females of child bearing potential whose male partner is receiving 
pomalidomide is unknown at this time. 
1. Male patients (including those who have had a vasectomy) must either not have 
any sexual relations with a pregnant female or a female who can become 
pregnant, or must use a condom during sexual contact with a pregnant female or 
a female that can become pregnant: 
 While you are taking study drug 
 During dose interruptions of study drug 
 For 28 days after you stop taking study drug 
2. Male patients should not donate sperm or semen while taking study drug and 
for 28 days after stopping study drug. 
3. If you suspect that your partner is pregnant any time during the study, you 
must immediately inform your study doctor. The study doctor will report all 
cases of pregnancy to Celgene Corporation. Your partner should call their 
healthcare provider immediately if they get pregnant. 
2. Restrictions in sharing study drug and donating blood: 
1. Do not share study drug with other people. It must be kept out of the reach 
of children and should never be given to any other person. 
2. Do not donate blood while you take study drug and for 28 days after stopping 
study drug. 
3. Do not break, chew, or open study drug capsules. 
4. You will be supplied with no more than one cycle of study drug 
5. Return unused study drug capsules to your study doctor. 
Additional information is provided in the informed consent form and you can ask your study 
doctor for more information. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.6. 
International Myeloma Working Group Response Criteria 
 
Response Category 
Response Criteria1 
SCR 
CR as defined below, plus 
1. Normal FLC ratio and 
2. Absence of clonal plasma cells in bone marrow by immunohistochemistry or 2 
to 4-color flow cytometry 
CR2 
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and ≤ 5% bone marrow plasma cellsb 
VGPR 
Serum and urine M-protein component detectable by immunofixation but not on 
electrophoresis or ≥ 90% reduction in serum M-protein plus urine M-protein level 
< 100 mg per 24 hours 
PR 
1. ≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary 
M-protein by ≥ 90% or to < 200 mg per 24 hours 
2. If the serum and urine M-protein are unmeasurable, a decrease ≥ 50% in the 
difference between involved and uninvolved FLC levels is required in place of 
the M-protein criteria 
3. If serum and urine M-protein are unmeasurable, and serum free light assay is 
also unmeasurable, ≥ 50% reduction in bone marrow plasma cells is required in 
place of M-protein provided baseline bone marrow plasma cell percentage was 
≥ 30% 
4. In addition to the above, if present at baseline, ≥ 50% reduction in the size of 
soft tissue plasmacytomas is also required 
SD 
Not meeting criteria for CR, VGPR, PR, or PD 
PD3 
Requires only one of the following: 
Increase of ≥ 25% from lowest response in: 
1. Serum M-component (the absolute increase must be ≥ 0.5 g/dl) and/or 
2. Urine M-component (the absolute increase must be ≥ 200 mg/24 hours) and/or 
3. In patients without measurable serum and urine M-protein levels, the difference 
between involved and uninvolved FLC levels (absolute increase must be 
> 10 mg/dl. 
4. In patients without measurable serum and urine M-protein levels and without 
measurable disease by FLC levels, bone marrow plasma cell percentage 
(absolute percentage must be ≥ 10%). 
5. Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas. 
6. Development of hypercalcemia (corrected serum calcium > 11.5 mg/dl) that can 
be attributed solely to the plasma cell proliferative disorder. 
Clinical relapse 
(Not used for TTP 
or PFS) 
Clinical relapse requires one or more of: 
1. Development of new soft tissue plasmacytomas or bone lesions on skeletal 
survey, magnetic resonance imaging, or other imaging 
2. Definite increase in the size of existing plasmacytomas or bone lesions. A 
definite increase is defined as a 50% (and at least 1 cm) increase as measured 
serially by the sum of the products of the cross-diameters of the measurable 
lesion 
3. Hypercalcemia (> 11.5 mg/dl [2.875 mmol/L]) 
4. Decrease in hemoglobin of ≥ 2 g/dl (1.25 mmol/L) 
5. Rise in serum creatinine by 2 mg/dl or more (≥ 177 mmol/L) 
6. Hyperviscosity 
1 
All response categories require 2 consecutive assessments made at any time before the institution of any new therapy; all 
categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. 
 
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VGPR and CR categories require serum and urine studies regardless of whether disease at baseline was measurable on 
serum, urine, both, or neither. Radiographic studies are not required to satisfy these response requirements. Bone marrow 
assessments need not be confirmed. For PD, serum M-protein component increases of more than or equal to 1 g/dL are 
sufficient to define relapse if starting M-component is ≥ 5 g/dL. 
2 
Clarifications to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by serum 
FLC levels: CR in such patients indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. 
VGPR in such patients requires a > 90% decrease in the difference between involved and uninvolved FLC levels 
3 
Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in patients without 
measurable disease by M protein and by FLC levels; “25% increase” refers to M protein, FLC, and bone marrow results, 
and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response value” does not 
need to be a confirmed value. 
Source: adapted from Rajkumar et al, 2011 [50] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.7. 
European Group for Blood and Bone Marrow Transplantation: 
Definition of Minimal Response 
 
Minimal Response (MR) requires all of the following: 
1. 25–49% reduction in the level of the serum monoclonal paraprotein maintained for a minimum of 
6 weeks. 
2. 50–89% reduction in 24 hour urinary light chain excretion, which still exceeds 200 mg/24 h, maintained 
for a minimum of 6 weeks. 
3. For patients with non-secretory myeloma only, 25–49% reduction in plasma cells in a bone marrow 
aspirate and on trephine biopsy, if biopsy is performed, maintained for a minimum of 6 weeks. 
4. 25–49% reduction in the size of soft tissue plasmacytomas (by radiography or clinical examination). 
5. No increase in the size or number of lytic bone lesions lesions (development of a compression fracture 
does not exclude response). 
MR also includes patients in whom some, but not all, the criteria for PR are fulfilled, provided the 
remaining criteria satisfy the requirements. 
No Change (NC) 
1. Not meeting the criteria of either MR or PD. 
Plateau 
1. Stable values (within 25% above or below value at the time response is assessed) maintained for at least 
3 months. 
Time point for assessing response 
1. Response to the transplant procedure will be assessed by comparison with results immediately prior to 
conditioning. 
2. If transplant is part of a treatment programme response to the whole treatment programme will be 
assessed by comparison with the results at the start of the programme. 
Source: adapted from Bladé et al, 1998 [61] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.8. 
Eastern Cooperative Oncology Group (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 
Source: adapted from Oken et al, 1982 [62] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.9. 
Skeletal (Bone) Survey Films 
The following are the minimum plain radiological films required for the skeletal (bone) survey: 
1. Lateral skull 
2. AP and lateral cervical spine 
3. AP and lateral thoracic spine 
4. AP and lateral lumbar spine 
5. PA chest 
6. AP pelvis 
7. AP upper extremities, shoulder to elbow 
8. AP lower extremities, hip to knee 
Other radiological films may be necessary to view symptomatic areas or known pre-existing 
lesions in skeletal regions not included in the films above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.10. 
Declaration of Helsinki 
The Declaration of Helsinki can be found at: 
http://www.wma.net/en/30publications/10policies/b3/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10. 
REFERENCES 
 
1 
Smith, ML, Newland AC. Treatment of myeloma. QJM 1999;92:11-14. 
2 
Morgan GJ. Advances in the biology and treatment of myeloma. Br J Haematology 
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3 
Kastrinakis N, Gorgoulis V, Foukas P, Dimopoulos M, Kittas C. Molecular aspects of multiple 
myeloma. Annals of Oncol 2000;11:1217-1228. 
4 
Mulligan, M. Myeloma and lymphoma. Semin Musculoskelet Radiol 2000;4:127-135. 
5 
Jemal A, Siegel R, Xu J, Ward E. CA Cancer J Clin 2010;60;277-300. 
6 
Musto P. The role of bisphosphonates for the treatment of bone disease in multiple myeloma. 
Leuk Lymphoma 1998;31:453-462. 
7 
Wang M, Dimopoulos MA, Chen C, Cibeira MT, Attal M, Spencer A, et al. Lenalidomide plus 
dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123-32. 
8 
Lecouvet F, Malghem J, Michaux L, Maldague B, Ferrant A, Michaux J-L, et al. Skeletal survey 
in advanced multiple myeloma: radiographic versus MR imaging survey. Br J Haem 
1999;106:35-39. 
9 
Van de Berg B, Lecouvet F, Michaux L, Ferrant A, Maldague B, Malghem J. Magnetic 
resonance imaging of the bone marrow in hematological malignancies. Eur Radiol 1998;8:1335- 
1344. 
10 
Berenson JR. New Advances in the biology and treatment of myeloma bone disease. Semin 
Hematol 2001;38(2, Suppl 3):15-20. 
11 
Kanis J, McCloskey E. Bisphosphonates in multiple myeloma. Cancer. 2000;88(12 
Suppl):3022-32. 
12 
Durie, B. Staging and kinetics of multiple myeloma. Semin Oncol 1986;13:300-9. 
13 
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response 
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ACY-1215 
12 July 2016 
page 111 
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Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Tassone P, et al. Aggresome induction 
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Ocio EM, Vilanova D, Atadja P, Maiso P, Crusoe E, Fernandez-Lazaro D, et al. In vitro and in 
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either bortezomib or lenalidomide in multiple myeloma. Haematologica 2010;95(5):794-803. 
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vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin 
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Duvic M, Olsen EA, Breneman D, Pacheco TR, Parker S, Vonderheid EC, et al. Evaluation of 
the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous 
T-cell lymphoma. Clin Lymphoma Myeloma 2009;9(6):412-416. 
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Zhang Y, Kwon S, Yamaguchi T, Cubizolles F, Rousseaux S, Kneissel M, et al. Mice lacking 
histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol 
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Raje N, Mahindra A, Vogl D, Voorhees P, Bensinger W, Hari P, et al. New Drug Partner for 
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Selective Histone Deacetylase (HDAC6) 6 Inhibitor Alone and in Combination with Bortezomib 
or Lenalidomide. Haematologica June 1 2013; 98 (supplement 1): 765/p.320. 
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Raje N, Hari P, Vogl DT, Jagannath S, Orlowski RZ, Supko JG, et al. Rocilinostat (ACY-1215), 
a Selective HDAC6 Inhibitor, Alone and in Combination with Bortezomib in Multiple Myeloma: 
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recommendations for the uniform reporting of clinical trials: report of the International Myeloma 
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Quayle SN, Tamang D, Yang M, Jones SS. ACY-1215, a selective inhibitor of HDAC6, 
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Quayle SN, Jones SS. ACY-1215, a first-in-class selective inhibitor of HDAC6, demonstrates 
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2009;101(10):708-720. 
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PrPOMALYST™ (pomalidomide) prescribing information (Canada). Celegne Corporation, 2014. 
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Imnovid (pomalidomide) summary of product characteristics (EU). Celgene Europe Limited, 
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Dexamethasone Prescribing Information. Roxane Laboratories, Inc., September 2007. 
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Bladé J1, Samson D, Reece D, Apperley J, Björkstrand B, Gahrton G, et al. Criteria for 
evaluating disease response and progression in patients with multiple myeloma treated by high- 
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Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982; 5(6):649-655. 
 
 
 
 
 
ACE-MM-102 Protocol 
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Clinical Study Protocol ACE-MM-102 
Summary of Changes 
Approved v 41.0 
 
 
 
SUMMARY OF PROTOCOL CHANGES 
CLINICAL STUDY PROTOCOL 
Protocol ACE-MM-102 
EudraCT Number: 2014-002338-29 
 
A phase 1b/2 multi-center, open label, dose- escalation study to determine the 
maximum tolerated dose, safety, and efficacy of ACY-1215 (ricolinostat) in 
combination with pomalidomide and low-dose dexamethasone in patients with 
relapsed-and-refractory multiple myeloma 
 
Prior Protocol Version: Amendment 3: 09 February 2015 
New Protocol Version: Amendment 4: 12 July 2016 
 
 
I. 
SUMMARY OF SIGNIFICANT CHANGES 
Changes included in Amendment 4, from Protocol Amendment 3 ACE-MM-102 (dated 09 
February 2016), are itemized below and detailed in Section II: 
 
• Protocol version. 
• Clerical change in Study Personnel. 
• Clarification for Duration of Survival Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 July 2016 
CONFIDENTIAL 
Acetylon Pharmaceuticals, Inc. 
1 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
12 July 2016 
CONFIDENTIAL 
Acetylon Pharmaceuticals, Inc. 
2 
Approved v41.0 
 
 
II. 
DETAILED TABLE OF CHANGES 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 4, 20 July 2016 
Rationale for Change 
Protocol Version 
• 
Cover Page 
• 
Page Header and Footer 
(additions are shown in bold): 
The protocol version was updated from Amendment 3 (09 February 
2015) to Amendment 4 (12 July 2016). 
Administrative Change. 
Length of follow-up to 
monitor survival, 
subsequent anti- 
myeloma therapies, 
and incidence of 
second primary 
malignancy (SPM) 
• 
Study Design (p.9) 
• 
3.1 Overall Design and Plan of the 
Study (p. 47) 
Upon discontinuation from study treatment for PD or any other 
reason, patients will be assessed 3 times per year (e.g., April, 
August, and December), for a period of 51 years, for survival, 
subsequent anti-myeloma therapies, and monitoring of second 
primary malignancies as outlined in Table 1: Schedule of 
Assessments. . 
Investigators are to report any second primary malignancies as 
SAEs regardless of causal relationship to study drugs, occurring at 
any time for the duration of the study, from the time of signing the 
informed consent up to the time all patients have been followed for 
at least 15 years from randomization or have died. 
An initial concern with the use of 
pomalidomide by Celgene was the 
possibility of secondary primary 
malignancies occurring in this 
population, mainly due to the 
structural similarities with 
lenalidomide. However, extensive 
research and tracking during 
commercial use of pomalidomide 
has shown no increased frequency 
of secondary primary malignancies 
with pomalidomide use over time. 
Therefore, we are reducing the 
follow-up period from 5 years to 
one year post-treatment 
discontinuation. 
• 
Table 1 . Schedule of Assessments 
(SOA) Footnote 3 (p.24) 
Patients will be followed 3 times per year, for up to a period of 5 1 
years, for survival, subsequent anti-myeloma therapies, and 
monitoring of second primary malignancy. Subsequent therapies 
should be collected until death or the end of the 15 years follow-up 
period. Survival follow-up may be done via phone. 
As above 
• 
Table 1 . Schedule of Assessments 
(SOA) Footnote 21 (p.25) 
• 
6.1.8.3 SPMs (p. 76) 
Second primary malignancies will be monitored as events of 
interest and must be reported as SAEs regardless of the dose cohort 
the patient is in. This includes any second primary malignancy, 
regardless of causal relationship to study drug (ACY-1215, 
pomalidomide, dexamethasone), occurring at any time for the 
duration of the study, from the time of signing the informed 
consent up to the time all patients have been followed for at 
least 15 years post the 30 day discontinuation visit from 
randomization or have died. Events of second primary 
malignancy are to be reported using the SAE report form and 
must be considered an “Important Medical Event” even if no 
As above 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
12 July 2016 
CONFIDENTIAL 
Acetylon Pharmaceuticals, Inc. 
3 
Approved v41.0 
 
 
 
 
 
other serious criteria apply; these events must also be 
documented in the appropriate page(s) of the case report form 
(CRF) and patient’s source documents. Documentation on the 
diagnosis of the second primary malignancy must be provided 
at the time of reporting as an SAE (e.g., any confirmatory 
histology or cytology results, X-rays, computed tomography 
[CT] scans, etc.). 
• 
6.2.7 Overall Survival (p. 80) 
All patients will be followed for survival for up to 5 1years. 
Patients will be assessed 3 times per year (approximately every 4 
months) to determine survival status. Cause of death is to be 
recorded in the CRF and the patient’s medical record. 
As above 


 
Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 3 
Summary of Changes 
 
 
Summary of Changes 
Clinical Study Protocol ACE-MM-102 
Amendment 3 (09 February 2015) 
A Phase 1b/2 Multicenter, Open Label, Dose-Escalation Study to Determine the 
Maximum Tolerated Dose, Safety, and Efficacy of ACY-1215 (Ricolinostat) in 
Combination with Pomalidomide and Low-dose Dexamethasone in Patients with 
Relapsed-and-Refractory Multiple Myeloma 
I. One substantive change was made to the protocol, as follows: 
• 
Identification of the ACY-1215 dose regimen to be utilized in the Phase 2 segment of the 
study (i.e., 160 mg by mouth [PO] once daily [QD] on Days 1 to 21 of a 28-day cycle). 
II. One key administrative change was made to the protocol, as follows: 
• 
The Medical Monitor was changed and applicable contact information provided. 
Additionally, administrative and editorial changes were made to update information and correct 
typographical errors; such changes are not itemized in the following table of changes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
09 February 2015 
CONFIDENTIAL 
Page 1 
 
Approved v 31.0 


Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 3 
Summary of Changes 
09 February 2015 
CONFIDENTIAL 
Approved v31.0 
Page 2 
 
 
TABLE OF CHANGES: 
Location(s) of Changes 
Description of Changes in Amendment 3, 09 February 2015 
(Deleted text are shown by strikethrough; additional text added in bold, as 
appropriate) 
Rationale for Change 
Study Personnel and 
Administrative Structure 
The Sponsor Medical Monitor was updated as follows: 
 Clinical Development 
Telephone:  
Mobile telephone:  
E-mail:  
Fax:  
Acetylon Pharmaceuticals, Inc. 
Administrative change. 
Telephone (office): 
office 
cell 
Telephone (mobile): 
E-mail: 
Synopsis, Study Design 
The following text was updated: 
ACY-1215 will be given QD or twice daily (BID) at the dose and schedule 
determined in the Phase 1b segment of the study. Based on findings from the 
Phase 1 segment of the study and as recommended by the SRC, the ACY-1215 
dose and schedule to be administered in the Phase 2 segment will be 160 mg 
PO QD on Days 1 to 21 of a 28-day cycle. 
As planned, based on the 
findings from the Phase 1 
segment of the study and as 
recommended by the Safety 
Review Committee (SRC), the 
ACY-1215 dose to be utilized 
in the Phase 2 segment has 
been selected. 
Synopsis, Test Products, 
Doses, and Mode of 
Administration 
The following text was updated: 
The ACY-1215 dose and schedule to be administered in the Phase 2 segment will 
be the dose160 mg PO QD on Days 1 to 21 of a 28-day cycle, as recommended by 
the SRC following review of the safety data from the Phase 1b segment of the 
study. 
As planned, based on the 
findings from the Phase 1 
segment of the study and as 
recommended by the SRC, the 
ACY-1215 dose to be utilized 
in the Phase 2 segment has 
been selected. 


Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 3 
Summary of Changes 
09 February 2015 
CONFIDENTIAL 
Approved v31.0 
Page 3 
 
 
Location(s) of Changes 
Description of Changes in Amendment 3, 09 February 2015 
(Deleted text are shown by strikethrough; additional text added in bold, as 
appropriate) 
Rationale for Change 
Table 1, Schedule of 
Assessments 
The following text was added to Footnote 22: 
In the Phase 2 segment, the ACY-1215 dose and schedule is 160 mg PO QD on 
Days 1 to 21 of a 28-day cycle. 
As planned, based on the 
findings from the Phase 1 
segment of the study and as 
recommended by the SRC, the 
ACY-1215 dose to be utilized 
in the Phase 2 segment has 
been selected. 
3.3, Rationale for the 
Dose and Schedule 
Selected 
The following text was added: 
Based on findings from the Phase 1 segment of the study and as recommended 
by the SRC, the ACY-1215 dose and schedule to be administered in the Phase 2 
segment will be 160 mg PO QD on Days 1 to 21 of a 28-day cycle. 
As planned, based on the 
findings from the Phase 1 
segment of the study and as 
recommended by the SRC, the 
ACY-1215 dose to be utilized 
in the Phase 2 segment has 
been selected. 
5.2.1, ACY-1215 
The following text was updated: 
Based on findings from the Phase 1 segment of the study and as recommended 
by the SRC, the ACY-1215 dose and schedule to be administered in Phase 2 will 
be the dose recommended by the SRC following review of the safety data from the 
Phase 1b segment of the study. Patients in the Phase 2 segment of the study will 
receive study drug ACY-1215 eitherwill be 160 mg PO QD or BID at the dose and 
schedule determined in the Phase 1b segment of the studyon Days 1 to 21 of a 28- 
day cycle. 
As planned, based on the 
findings from the Phase 1 
segment of the study and as 
recommended by the SRC, the 
ACY-1215 dose to be utilized 
in the Phase 2 segment has 
been selected. 


 
Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 2 
Summary of Changes 
 
Summary of Changes 
Clinical Study Protocol ACE-MM-102 
Amendment 2 (21 Aug 2014) 
A Phase 1b/2 Multicenter, Open Label, Dose-Escalation Study to Determine the 
Maximum Tolerated Dose, Safety, and Efficacy of ACY-1215 (Ricolinostat) in 
Combination with Pomalidomide and Low-dose Dexamethasone in Patients with 
Relapsed-and-Refractory Multiple Myeloma 
I. Substantive changes to the protocol include the following: 
• 
The addition of European Union (EU) study sites, requiring: 
o EU pomalidomide information, including The European Pomalidomide 
Pregnancy Prevention Risk Management Plans (new Appendix 9.5). 
o Updated patient privacy and record retention policies inclusive of US, Canadian, 
and EU regions. 
• 
Updates to study drug supply and accountability. 
• 
Updated timing and frequency of the following assessments: Immunofixation studies, 
assessment of response, skeletal surveys, and extramedullary plasmacytoma assessments. 
• 
Removal of serum thyroid function tests (TSH, T4, and T3). 
• 
Clarification to inclusion and exclusion criteria, including: 
o The exclusion of nonsecretory myeloma and serum free light chain-only 
myeloma. 
o Updates to the exclusion criteria of the following laboratory abnormalities: 
absolute neutrophil count (ANC), platelet count, and hemoglobin values. 
• 
Updates to dose modification instructions for pomalidomide for hematologic toxicities. 
• 
Updates to the use of hematopoietic growth factors. 
• 
Clarification to the definition of progressive disease. 
• 
Incorporation of the updated Investigator’s Brochure (IB) Version 5.0, including the 
following: 
o Information pertaining to pharmacokinetic (PK) data was updated. 
o Information pertaining to ongoing clinical studies was updated. 
o Additional nonclinical data and clinical data for ACY-1215 alone and in 
combination with immunomodulatory inhibitors (IMiDs). 
II. Key administrative changes to the protocol include the following: 
• 
Addition of EudraCT Number (2014-002338-29). 
• 
Incorporation of Independent Ethics Committees for regulatory approvals. 
• 
Updates to the list of abbreviations and references. 
Additionally, administrative and editorial changes were made to update information and correct 
typographical errors; most of these updates are not itemized in the following table of changes. 
 
 
 
21 Aug 2014 
CONFIDENTIAL 
Page 1 
 
Approved v 21.0 


Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 2 
Summary of Changes 
21 Aug 2014 
CONFIDENTIAL 
Approved v21.0 
Page 2 
 
 
TABLE OF CHANGES: 
Location(s) of Changes 
Description of Changes in Amendment 2, 21 Aug 2014 
(Deleted text are shown by strikethrough; additional text added in bold, as appropriate) 
Rationale for Change 
Title Page and Clinical 
Synopsis Cover Page 
EudraCT number was added (2014-002338-29) 
Administrative addition. 
Study Personnel and 
Administrative Structure 
Sponsor contact was updated to: 
Clinical Project Manager 
Telephone: 
Fax: 
Email: 
Administrative change. 
Clinical Study Synopsis, 
Number of Study Centers 
Approximately 15 19 
To increase the number of 
allowed study centers. 
Clinical Study Synopsis, 
Study Design, Phase 1b 
Segment, Identification of 
MTD and schedule 
Section 5.2.1, ACY-1215, 
Phase 1b segment 
Patients will be treated at Dose level 3 after the highest QD dose level has been determined. 
Updated to provide 
clarification. 
Clinical Study Synopsis, 
Study Design, Phase 1b 
Segment, Determination of 
MTD: Dose escalation rules 
Clinical Study Synopsis, 
Study Design, Phase 2 
Segment 
Section 5.2.5, Dose 
Escalation Procedure 
The use of hematopoietic growth factors will not be permitted during Cycle 1 screening in the 
Phase 1 or Phase 2 segments of the study or in Cycle 1 of the Phase 1b segment of the study; 
however... 
Updated to clarify use of 
hematopoietic growth 
factors. 
Clinical Study Synopsis, 
Study Design, Phase 1b 
Segment, Confirmation of the 
Safety of the MTD 
For all patients enrolled in the Phase 1b MTD segment, following the completion of Cycle 1, 
efficacy assessments will be conducted every cycle 2 cycles for the duration of the treatment 
period. 
Update to efficacy 
assessment frequency. 
Clinical Study Synopsis, 
Diagnosis and Main Criteria 
for Inclusion #7 
Section 4.2, Inclusion 
Criteria #8 
Must have measurable levels of myeloma paraprotein in serum (≥ 0.5 g/dL) or urine 
(≥ 0.2 g/24 hours). Patients who do not have myeloma paraprotein must have SFLC 
concentration of > 10 mg/dl provided SFLC ratio is abnormal. Nonsecretory myeloma and 
serum free light chain-only myeloma are is excluded. 
Update to acceptable levels 
of serum paraprotein. 


Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 2 
Summary of Changes 
21 Aug 2014 
CONFIDENTIAL 
Approved v21.0 
Page 3 
 
 
Location(s) of Changes 
Description of Changes in Amendment 2, 21 Aug 2014 
(Deleted text are shown by strikethrough; additional text added in bold, as appropriate) 
Rationale for Change 
Clinical Study Synopsis, 
Diagnosis and Main Criteria 
for Inclusion #9 
Section 4.2, Inclusion 
Criteria #10 
...The European Pomalidomide Pregnancy Prevention Risk Management Plans are 
described in Appendix 9.5. 
Addition of EU 
pomalidomide information. 
Clinical Study Synopsis, 
Exclusion Criteria #1 
Section 4.2, Exclusion 
Criteria #1 
Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent 
the patient from signing the ICF, including nonsecretory myeloma or SFLC-only myeloma. 
Addition of exclusion of 
nonsecretory or SFLC-only 
myeloma. 
Clinical Study Synopsis, 
Exclusion Criteria #5 
Section 4.3, Exclusion 
Criteria #5 
Any of the following laboratory abnormalities: 
• 
ANC < 1,000/µL (hematopoietic growth factors will not be permitted during 
screening in the Phase 1 or Phase 2 segments of the study or in Cycle 1 of the Phase 
1b segment of the study). 
• 
Platelet count < 50,000/µL < 75,000/µL for patients in whom < 50% of bone marrow 
nucleated cells are plasma cells. and < 50,000/µL for patients in whom ≥ 50% of bone 
marrow nucleated cells are plasma cells. 
• 
Hemoglobin < 8 g/dL (< 4.9 mmol/L; prior RBC transfusion or recombinant human 
erythropoietin use is permitted) 
Updated to clarify 
laboratory (ANC, platelet 
count, and hemoglobin) 
abnormalities. 
Clinical Study Synopsis, 
Exclusion Criteria #13 
Section 4.3, Exclusion 
Criteria #13 
...or to the European Pomalidomide Pregnancy Prevention Risk Management Plans, per 
Appendix 9.5. 
Addition of European (EU) 
pomalidomide information. 
Clinical Study Synopsis, 
Test Products, Doses, and 
Mode of Administration 
Acetylon will supply liquid ACY-1215 in appropriately sized vials for PO administration to 
investigational pharmacies. Celgene will supply pomalidomide Pomalidomide will be provided 
at 4, 3, 2, and 1 mg for PO administration. Sites in the US and Canada will utilize commercial 
supply of PO dexamethasone and. Acetylon will supply dexamethasone to sites in the 
European Union (EU). All sites will utilize commercial supply of aspirin or other anti- 
thrombotics or anti-coagulants. 
Removal of Celgene’s 
responsibility to provide 
pomalidomide. 
Dexamethasone will be 
considered as an 
investigational medicinal 
product (IMP) in EU and 
the sponsor is required to 
arrange cover for the cost 
and supply to the EU sites. 


Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 2 
Summary of Changes 
21 Aug 2014 
CONFIDENTIAL 
Approved v21.0 
Page 4 
 
 
Location(s) of Changes 
Description of Changes in Amendment 2, 21 Aug 2014 
(Deleted text are shown by strikethrough; additional text added in bold, as appropriate) 
Rationale for Change 
Clinical Study Synopsis, 
Statistical Methods 
Equivalently, the corresponding expected one-sided 95% confidence interval (CI) for the response 
rate will exclude 0.29 with 80% of chance. Assuming a 10% drop out rate, a study of 
75 patients would be sufficient. 
…The SRC will use the totality of information from the interim analysis to recommend whether 
the study should proceed as planned, be terminated for superiority or futility, or extended to allow 
for 9586 evaluable patients. 
Update to clarify sample 
size estimation. 
Schedule of Assessments, 
Immunofixation studies 
(serum and 24-hour urine) 
Assessments were added to the following timepoints: 
• 
Cycle 1 Day 1/Baseline 
• 
Cycles 2 and on, Day 1 
Update to immunofixation 
study assessment frequency. 
Schedule of Assessments, 
Footnote 11 
IFE studies will be performed at screening, Day 1 of each treatment cycle, and to confirm CR 
(undetectable M-protein by protein electrophoresis in urine and serum will trigger the central 
laboratory to perform IFE studies in urine and serum). 
Update to immunofixation 
study assessment frequency. 
Schedule of Assessments, 
Footnote 13 
For additional information, including acceptable forms of birth control, see Appendix 9.3 for the 
POMALYST REMS™ program, Appendix 9.4 for the RevAid® program, and Appendix 9.5 for 
the European Pomalidomide Pregnancy Prevention Risk Management Plans. 
Addition of European (EU) 
pomalidomide information. 
Schedule of Assessments, 
Footnote 14 
...See Appendix 9.5 for the European Pomalidomide Pregnancy Prevention Risk 
Management Plans. 
Addition of EU 
pomalidomide information. 
Schedule of Assessments, 
Footnote 15 
Skeletal survey to be performed at Screening (or within 60 days of Study Day 1), study treatment 
discontinuation and later, when clinically indicated, and to confirm CR. 
Update to skeletal survey 
assessment frequency. 
Schedule of Assessments, 
Footnote 16 
Plasmacytomas that can be assessed clinically are to be assessed every cycle 2 cycles. 
Update to plasmacytoma 
assessment frequency. 
Schedule of Assessments, 
Footnote 18 
Response will be assessed every cycle 2 cycles while on study drug treatment, and at study 
treatment discontinuation. Screening labs do not need to be repeated at C1D1 if they have 
been completed within 14 days. 
Update to assessment of 
response frequency. 
Schedule of Assessments, 
Footnote 25 
Serial blood samples for PK assessments are to be collected from all US and Canada patients 
during Cycle 1 of the Phase 1b segment and at participating sites in the Phase 2 segment at the 
following time points: 
Update to clarify regions for 
PK assessment collection. 
Section 1, Introduction 
A clear correlation between disease stage and survival duration has been demonstrated.[12] The 
criteria for diagnosis, staging, risk stratification, and response assessment of MM, as 
described by Kyle and Rajkumar, has been widely used as well.[13] 
Additional reference added 
regarding multiple myeloma 
assessment. 
Section 1.1, ACY-1215 
Clinical experience with pomalidomide was updated to include details of Phase 1b/2, Phase 2, and 
Phase 3 studies. 
New Phase 1b/2, Phase 2, 
and Phase 3 data available. 
Section 1.1.2, Nonclinical 
Pharmacokinetics 
Nonclinical pharmacokinetics text was updated to include the detection of ACY-1215 in urine and 
feces. 
New nonclinical 
pharmacokinetics data 
available. 


Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 2 
Summary of Changes 
21 Aug 2014 
CONFIDENTIAL 
Approved v21.0 
Page 5 
 
 
Location(s) of Changes 
Description of Changes in Amendment 2, 21 Aug 2014 
(Deleted text are shown by strikethrough; additional text added in bold, as appropriate) 
Rationale for Change 
Section 1.1.3, Toxicology 
The mutagenic potential for ACY 1215 appears to be low. ACY 1215 did not exhibit mutagenic 
ability in either in vitro assays including the Ames test or and the Chinese hamster ovary (CHO) 
micronucleus test...In addition, ACY-1215 did not exhibit mutagenic potential in the GLP in 
vivo micronucleus and comet assay in rats. 
New toxicology data 
available. 
Section 1.1.4, Clinical Data 
To date, clinical data are available from 33 61 patients with MM...and 18 46 were treated with 
ACY-1215 in combination with other anti-neoplastic agents... Of the 18 46 patients receiving 
combination therapy, 9 25 received ACY-1215 in combination with bortezomib and 
dexamethasone and 9 21 received ACY-1215 in combination.... 
Updates to the number of 
subjects for whom clinical 
data are available. 
Section 1.1.4.1, Safety 
Updated safety data available for ACY-1215. 
New safety data available. 
Section 1.1.4.2, Efficacy 
New section 
Section added to present 
available efficacy data for 
ACY-1215. 
Section 1.1.4.3, 
Pharmacokinetics 
Updated pharmacokinetics data available for ACY-1215. 
New pharmacokinetics data 
available. 
Section 3.1, Overall Design 
and Plan of the Study 
...All patients will be monitored for signs and symptoms of venous thromboembolism (VTE) 
while on pomalidomide; diagnostic algorithms are provided (Appendix Section 9.1). The study 
will conclude 30 days after the last enrolled patient discontinues from the study due to 
disease progression or treatment discontinuation. 
Clarification added to 
provide clear definition to 
the end of the study. 
Section 3.1, Overall Design 
and Plan of the Study 
Frequency of disease response was updated: 
• 
Patients are to be evaluated for disease response after every cycle and at study treatment 
discontinuation, starting with Cycle 1 
Update to frequency of 
disease response 
assessment. 
Section 3.2, Rationale for 
Study 
Text was added regarding the effects of combination treatment with ricolinostat and 
pomalidomide on MM cells. 
New data added to support 
study rationale. 
Section 3.2, Rationale for 
Study 
Safety data thus far in 33 15 patients treated with ACY-1215 monotherapy and 18 46 patients 
treated with ACY-1215 in combination with dexamethasone and either bortezomib or 
lenalidomide... 
Updates to the number of 
subjects treatment with 
ACY-1215 in mono- and 
combination therapy. 
Section 4.6, Withdrawal and 
Replacement of Patients, 
bullet #2 
PD Progressive Disease 
• 
Determination of PD requires two consecutive assessments of disease progression. 
There is no specific requirement for the timing of these two assessments. 
Updated to clarify definition 
of progressive disease. 
Section 4.9, Independent 
Response Assessment 
Committee 
New section 
Section add to describe role 
of the Independent 
Response Assessment 
Committee (IRAC). 


Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 2 
Summary of Changes 
21 Aug 2014 
CONFIDENTIAL 
Approved v21.0 
Page 6 
 
 
Location(s) of Changes 
Description of Changes in Amendment 2, 21 Aug 2014 
(Deleted text are shown by strikethrough; additional text added in bold, as appropriate) 
Rationale for Change 
Section 5.1.2, Pomalidomide 
and Dexamethasone 
Section 5.3.2, Packaging and 
labeling 
Celgene Pomalidomide will provide pomalidomide be provided at 4, 3, 2, and 1 mg for PO 
administration. 
Removal of Celgene’s 
responsibility to provide 
pomalidomide. 
Section 5.1.2, Pomalidomide 
and Dexamethasone 
For sites in the US and Canada, Ddexamethasone for PO administration will be supplied from 
commercially-available sources as 4 mg compressed tablets. (Dexamethasone tablets at strengths 
other than 4 mg may be used, as necessary.) Acetylon will supply dexamethasone to sites in the 
EU.... 
Dexamethasone is 
considered an IMP in EU 
and the sponsor is required 
to arrange cover for the cost 
and supply to the EU sites. 
Section 5.2.2, Pomalidomide, 
Paragraphs #1 and #2 
Drug will be shipped on a per patient basis by the contract to the patient’s home or to the clinic 
site pharmacy study site (in Canada only) for Investigational New Drug studies. 
Pomalidomide will be sent to the patients’ home or to the study site (in Canada only) via the 
POMALYST REMS™ and RevAid® programs (see Appendix 9.3 and Appendix 9.4, 
respectively). 
Pomalidomide can be 
shipped to the patient’s 
home or to the study site 
(Canada only). 
Section 5.2.2, Pomalidomide, 
Paragraph #2 
Pomalidomide (POMALYST®) will be administered based on the current approved dose and 
schedule: 4 mg PO QD on Days 1 to 21 of a 28-day cycle (see Table 2). 
Updated to provide 
clarification. 
Section 5.2.8.2, 
Pomalidomide, Table 6 
(Note, ANC must be ≥ 500/µL in the US and Canada and ≥ 1,000/μL in the EU to restart 
dosing) 
Updated to clarify ANC 
criteria in the US, Canada, 
and EU. 
Section 5.2.8.2, 
Pomalidomide, Instructions 
for Initiating a New 
Pomalidomide Cycle 
To initiate a new cycle of pomalidomide, ANC must be ≥ 500/µL in the US and Canada and 
≥ 1,000/μL in the EU, 
Clarified ANC criteria to 
initiate a new pomalidomide 
in the US, Canada, and EU. 
Section 5.3.2, Packaging and 
Labeling 
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: region-specific regulatory information. 
• 
Caution: New Drug--Limited by Federal (or US) law to investigational use. 
• 
Canada: Investigational Drug to be used by qualified investigators only. 
Label information updated 
to reflect regulatory 
information for all regions. 
Section 5.5, Study Drug 
Accountability 
Accountability for ACY-1215 (all centers), pomalidomide, and dexamethasone (EU only) at 
the study center is the responsibility of the Investigator...The Sponsor or its designee will 
review ACY-1215 study drug accountability at the study center on an ongoing basis during 
monitoring visits. 
All material containing ACY-1215 study drug will be treated and disposed of as hazardous waste 
in accordance with governing regulations. 
Updated as pomalidomide 
and dexamethasone are 
considered IMPs. 


Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 2 
Summary of Changes 
21 Aug 2014 
CONFIDENTIAL 
Approved v21.0 
Page 7 
 
 
Location(s) of Changes 
Description of Changes in Amendment 2, 21 Aug 2014 
(Deleted text are shown by strikethrough; additional text added in bold, as appropriate) 
Rationale for Change 
Section 5.6.1, Permitted 
Medication, Bullet #2 
Hematopoietic Growth Factors: The use of hematopoietic growth factors will not be permitted 
during Cycle 1 screening in the Phase 1 or Phase 2 segments of the study or in Cycle 1 of the 
Phase 1b segment of the study. 
Updated to clarify use of 
hematopoietic growth 
factors. 
Section 5.6.2, Excluded 
Medication and Substances, 
Bullet #4 
(New bullet added) 
• 
Hematopoietic growth factors during screening in the Phase 1 or Phase 2 segments 
of the study or in Cycle 1 of the Phase 1b segments of the study. 
Added bullet to clarify use 
of hematopoietic growth 
factors. 
Section 5.6.2, Excluded 
Medication and Substances 
New text added to provide EU pomalidomide package insert information 
Addition of European (EU) 
pomalidomide information. 
Section 6.1.7.1, Hematology, 
Serum Chemistry and 
Urinalysis, Clinical 
laboratory parameter table 
Removal of T4 (serum), TSH (serum), and T3 (serum). 
Newly enrolled patients will 
not have thyroid function 
testing. 
Section 6.1.7.3, Pregnancy 
Testing and Counseling, 
RevAid® Program (Canada) 
Criteria #3 
3) who is premenopausal perimenopausal. 
Update to clarify definition 
of female of child bearing 
potential (FCBP). 
Section 6.1.7.3, European 
Pomalidomide Pregnancy 
Prevention 
New subheading added 
Addition of European (EU) 
pomalidomide information. 
Section 6.1.8.4, Procedures 
for AE and SAE Reporting 
When possible, signs and symptoms indicating a common underlying pathology should be noted 
as one comprehensive event. All pomalidomide and dexamethasone AEs must be reported in 
accordance to the safety guidelines presented in the prescribing information.[51,58,59,60] 
Updated to provide safety 
reference document for 
pomalidomide and 
dexamethasone. 
Section 6.2.5, 
Extramedullary 
Plasmacytoma Assessments 
Plasmacytomas that can be assessed clinically are to be assessed every cycle 2 cycles. 
Plasmacytomas that are assessed by radiography will be assessed at screening, every cycle 2 
cycles, at study treatment discontinuation, and to assess best response. 
Updated to clarify 
assessment frequency. 
Section 6.2.6, Assessment of 
Disease Response 
Based on the EBMT, IMWG criteria have been expanded, clarified, and updated to provide a new 
comprehensive evaluation system to assess not only response but also the magnitude of response, 
length of response, and OS, and allow for the evaluation of patients with oligo-secretory disease 
(Appendix 9.5). 
… Response will be assessed every 2 cycles cycle throughout study drug treatment, and at 
treatment discontinuation in both the Phase 1b and Phase 2 segments of the study. 
...Determination of PD requires two consecutive assessments of disease progression. There 
is no specific requirement for the timing of these two assessments. 
Updated to clarify disease 
response assessment. 


Clinical Study Protocol 
ACE-MM-102 Protocol Amendment 2 
Summary of Changes 
21 Aug 2014 
CONFIDENTIAL 
Approved v21.0 
Page 8 
 
 
Location(s) of Changes 
Description of Changes in Amendment 2, 21 Aug 2014 
(Deleted text are shown by strikethrough; additional text added in bold, as appropriate) 
Rationale for Change 
Section 7.1, Sample Size 
Estimation, Phase 2 
For a study with a sample size of 66, a one sided 0.05 level test with power of 80% would be 
adequate to detect the response rate of 0.29 against 0.44. Assuming a 10% drop out rate, a 
study of 75 patients would be sufficient. 
…The SRC will use the totality of information from the interim analysis to recommend whether 
the study should proceed as planned, be terminated for superiority or futility, or extended to allow 
for 9586 evaluable patients. 
Update to clarify sample 
size estimation. 
Section 8.4, Patient 
Confidentiality 
In order to maintain patient privacy, all eCRFs, study drug accountability records, study reports, 
and communications will identify the patient according to local or regulatory authority(ies) by 
initials and the assigned patient number. 
Updated to allow for 
consideration of EU 
regulations. 
Section 8.8, 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 2 years after the last marketing application 
approval or 2 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. 
Updated to allow for 
consideration of region- 
specific regulations. 
Appendix 9.5, European 
Pomalidomide Pregnancy 
Prevention Risk Management 
Plans 
(New Appendix) 
New Appendix added to 
provide EU pomalidomide 
pregnancy prevention risk 
management plans. 


Clinical Study Protocol ACE-MM-102 
7 April 2014 
CONFIDENTIAL 
Page 1 of 27 
Approved v 1.0 
 
 
SUMMARY OF PROTOCOL CHANGES 
 
Protocol ACE-MM-102: A Phase 1b/2 Multi-center, Open Label, 
Dose- escalation Study to Determine the Maximum Tolerated Dose, Safety, 
and Efficacy of ACY-1215 in Combination with Pomalidomide and Low-dose 
Dexamethasone in Patients with Relapsed-and-Refractory Multiple Myeloma 
 
Prior Protocol Version: 
Original; 15 August 2013 
 
New Protocol Version: 
Amendment 1; 7 April 2014 
 
I. 
SUMMARY OF SIGNIFICANT CHANGES 
The primary changes made to the protocol by Amendment 1 include modification of eligibility criteria for 
increased patient safety and to be aligned with the current usage of pomalidomide, the addition of sparse 
blood sample collection time points for patients participating in Phase 2 of the study for pharmacokinetic 
(PK) assessment and the addition of text describing the pregnancy testing and counseling requirements of 
the RevAid® Program for study participants in Canada. 
Additionally, the text describing the statistical methods for the interim analysis that will be conducted on 
the first 30 evaluable patients was expanded to clarify how the analyses will be performed and how the 
Safety Review Committee (SRC) will use these data to issue recommendations regarding the future of the 
study. 
Other administrative and editorial changes incorporated into the Protocol by Amendment 1 are 
summarized in Section III. Minor editorial changes and abbreviation substitutions are not itemized. 


Clinical Study Protocol ACE-MM-102 
7 April 2014 
CONFIDENTIAL 
Page 2 of 27 
Approved v 1.0 
 
 
II. 
RATIONALE 
The protocol eligibility criteria were modified to better align the eligible patient population with the 
current standards for pomalidomide usage including the exclusion of patients with hemoglobin <8 g/dL, 
and creatinine clearance <45 mL/minute (per Cockcroft-Gault formula). An additional modification was 
made to the platelet count exclusion criterion in order to increase patient safety and in light of the 
definition of dose limiting toxicity (DLT) at platelet count < 25,000/μL. Eligibility was expanded to 
allow patients with non-secretory Multiple Myeloma. Eligibility criteria, study drug administration text, 
and labeling information were also updated to reflect the approval of pomalidomide in Canada and to 
incorporate the pregnancy testing, birth control, and pregnancy counseling requirements of the RevAid® 
Program. Additional PK blood sampling time points added during Phase 2 of the study. 
Finally, the statistical methods for the interim analysis were expanded to clarify how the totality of these 
data will be used by the SRC to make decisions regarding the future of the study (i.e. continue as planned, 
terminate for futility, or expand patient population). 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
Approved v1.0 
 
 
III. 
DETAILED TABLE OF CHANGES 
Deleted text is indicated by strikthrough while new text is indicated by bold font. 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Title 
Title Page, Synopsis 
The title was edited as follows: 
Old text: A Phase 1B/2, Open-label, Dose-Escalation 
Study to Determine the Maximum Tolerated Dose, Safety, 
and Efficacy of ACY-1215 in Combination with 
Pomalidomide and Low-dose Dexamethasone in Patients 
with Relapsed-and-Refractory Multiple Myeloma 
New text: A Phase 1B/2, Open-label, Dose-Escalation 
Study to Determine the Maximum Tolerated Dose, Safety, 
and Efficacy of ACY-1215 (ricolinostat) in Combination 
with Pomalidomide and Low-dose Dexamethasone in 
Patients with Relapsed-and-Refractory Multiple Myeloma 
Administrative change. 
Protocol Version 
Cover Page 
Version was updated from “Original (15 August 2013)” to 
“Amendment 1 (7 April 2014)” 
Administrative change. 
Sponsor Contact Information 
Study Personnel and 
Administrative Structure 
Changed the contact information for the Sponsor Contact: 
Old text: 
Clinical Operations 
Telephone: 
Mobile telephone: 
Fax: 
New text: 
linical Project Manager 
Telephone: 
Fax: 
Email: 
Administrative change. 
SAE Reporting 
Study Personnel and 
Administrative Structure, 
Section 6.1.7.2, 
Section 6.1.7.4 
Changed the contact information for SAE Reporting: 
Old text: 24-Hour SAE Reporting 
Telephone: 
Fax: 
New text: 24-Hour SAE Reporting 
Administrative change. 
 
7 April 2014 
CONFIDENTIAL 
Page 3 of 27 


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Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 7 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Study Design/Overall Design 
and Plan of the Study/Study 
Drug Dose and 
Administration 
Synopsis (Study Design), 
Section 5.2, Section 5.2.5 
Deleted the following text: 
Following completion of the first cycle, patients may 
continue the study at their assigned dose of ACY-1215. 
Redundant 
Study Design 
Synopsis (Study Design) 
Modified text as follows: 
For all patients enrolled in the Phase 1b MTD segment, 
following the completion of Cycle 1, efficacy assessments 
will be conducted every 56 days (± a 2-day window) 
2 cycles for the duration of the treatment period. 
To reduce the likelihood of 
protocol deviations if a response 
assessment occurs outside the 
56 day (± a 2-day) window. 
Number of Patients Planned 
Synopsis, (Number of 
Patients Planned), 
Section 4.1 
Modified text as follows: 
“… a total of up to 105 125 patients are planned to be 
enrolled, including up to 30 patients in the Phase 1b 
segment and up to 75 95 patients in the Phase 2 segment.” 
To reflect that the patient 
population may be expanded 
based on the outcome of the 
interim analysis (per revised 
statistical text). 
Inclusion Criteria 
Synopsis (Inclusion Criteria), 
Section 4.2 
Added text to Inclusion Criteria 7 as follows: 
7. Must have measurable levels of myeloma paraprotein in 
serum (≥ 0.5 g/dL) or urine (≥ 0.2 g/24 hours). Patients 
who do not have myeloma paraprotein must have 
SFLC concentration of > 10 mg/dl provided SFLC ratio 
is abnormal. Nonsecretory myeloma is excluded. 
To expand enrollment to patients 
with non-secretory Multiple 
Myeloma 
Inclusion Criteria 
Synopsis (Inclusion Criteria), 
Section 4.2 
Revised the following Inclusion Criteria 10: 
Old text: FCBP must have a negative serum or urine 
pregnancy test with a sensitivity of at least 25 mIU/mL 
within 10 – 14 days prior to, and again within 24 hours of 
starting pomalidomide and must either commit to 
continued abstinence from heterosexual intercourse or 
begin TWO acceptable methods of birth control, one 
highly effective method and one additional effective 
method AT THE SAME TIME, at least 28 days before she 
starts taking pomalidomide. FCBP must also agree to 
ongoing pregnancy testing (see Section 6.1.7.3). Men 
must agree to use a latex condom during sexual contact 
To update the pregnancy testing 
and birth control requirements 
based on the RevAid® program. 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 8 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
with a FCBP even if they have had a vasectomy. All 
patients must be counseled at a minimum of every 28 days 
about pregnancy precautions and risks of fetal exposure. 
See Appendix 9.3.1 Risks of Fetal Exposure, Pregnancy 
Testing Guidelines and Acceptable Birth Control Methods, 
AND also Appendix 9.3.2 Education and Counseling 
Guidance Document. 
New text: FCBP must have a negative serum (for study 
participants in Canada) or urine pregnancy test, as 
described in Appendix 9.3 for the POMALYST 
REMS™ program (study participants in the US) and 
Appendix 9.4 for the RevAid® program (study 
participants in Canada). FCBP and males must either 
commit to continued abstinence from heterosexual 
intercourse or must abide by birth control requirements 
as described in Appendix 9.3 for the POMALYST 
REMS™ program (study participants in the US) and 
Appendix 9.4 for the RevAid® program (study 
participants in Canada). 
Inclusion Criteria 
Synopsis (Inclusion Criteria), 
Section 4.2 
Added the following new Inclusion Criteria 13: 
13. Must be registered into the mandatory 
POMALYST REMS™ program, and be willing and 
able to comply with the requirements of the 
POMALYST REMS™ program (or RevAid® for study 
participants in Canada). 
To clarify that patients in the 
United States (US) must register 
with the POMALYST REMS™ 
program and patients in Canada 
must register with the RevAid® 
program. 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Added the following new text to Exclusion Criterion 2: 
2. Any serious concurrent medical conditions, laboratory 
abnormality, or psychiatric illness that might make the 
patient non-evaluable, or put the patient’s safety at risk, or 
prevent the patient from following the study 
requirements. 
To clarify the exclusion of 
potentially non-compliant 
patients. 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Added the following new text to Exclusion Criterion 4: 
4. Prior therapy with HDAC inhibitor or pomalidomide. 
To exclude patients with prior 
pomalidomide therapy. 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 9 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Revised Exclusion Criteria 5 as follows: 
5. Platelet count < 7550,000/ µL for patients in whom 
< 50% of bone marrow nucleated cells are plasma cells; or 
a platelet count < 30,000/ µL for patients in whom ≥ 50% 
of bone marrow nucleated cells are plasma cells. 
To increase patient safety, given 
the definition of DLT at 
25,000 platelets. 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Added the following new text to Exclusion Criterion 5: 
5. Hemoglobin < 8 g/dL (< 4.9 mmol/L; prior RBC 
transfusion or recombinant human erythropoietin 
use is permitted). 
To increase patient safety and 
exclude patients with low 
Hemoglobin. 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Deleted the following new text from Exclusion Criterion 5: 
5. Serum creatinine ≥ 3.0 mg/dL. 
To align with change below to 
Exclusion Criterion #4. 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Added the following new text to Exclusion Criterion 5: 
5. Creatinine clearance < 45 mL/min according to 
Cockcroft-Gault formula. If creatinine clearance 
calculated from the 24-hour urine sample is 
≥ 45 mL/min, patient will qualify for the trial. 
To align this criterion with 
current pomalidomide usage. 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Deleted the following new text from Exclusion Criterion 7: 
7. Corrected QT interval using Fridericia’s formula 
(QTcF) value > 480 msec at Screening and pre-dose on 
C1D1… 
To clarify this exclusion criterion. 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Revised Exclusion Criterion 8 as follows: 
8. Positive human immunodeficiency virus (HIV), 
hepatitis B virus (HBV) and/or known or suspected 
active hepatitis C virus (HCV) infection. 
To clarify this exclusion criterion. 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Added the following text to Exclusion Criterion 9: 
9. Hypersensitivity to thalidomide, lenalidomide, or 
dexamethasone (such as Steven Johnson Syndrome). 
Hypersensitivity, such as rash, that can be medically 
managed is allowable. 
To clarify this exclusion criterion. 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 10 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Added the following new text to Exclusion Criterion 10. 
10. Peripheral neuropathy ≥ Grade 2 despite supportive 
therapy. 
To clarify this exclusion criterion. 
Exclusion Criteria 
Synopsis (Exclusion 
Criteria), Section 4.3 
Added the following new text to Exclusion Criteria 13: 
13. Inability or unwillingness to comply with birth control 
requirements or any of the Pomalyst REMS or 
RevAid requirements (region-specific), per 
Appendix 9.3 and Appendix 9.4, respectively. 
To update this exclusion criterion 
based on the requirements of the 
RevAid® program. 
Test Products, Doses and 
Mode of Administration/ 
Study Drug Supply and 
Storage: Pomalidomide and 
Dexamethasone 
Synopsis (Study Design, Test 
Products, Doses and Mode of 
Administration), 
Section 5.1.2 
Added the following new text: 
Celgene will supply pomalidomide 4, 3, 2, and 1 mg for 
PO administration 
To specify that different 
concentrations of pomalidomide 
will be available. 
Test Products, Doses and 
Mode of Administration/ 
Study Drug Supply and 
Storage: ACY-1215 
Synopsis (Study Design, Test 
Products, Doses and Mode of 
Administration), 
Section 5.1.21 
Added the following new text: 
If Dose level 2 is well tolerated, Dose Level 3 of 160 mg 
BID will be explored. 
Deleted the following new text: 
If Dose level 1 is well tolerated, Dose Level 3 of 160 mg 
BID will be explored after completion of the highest daily 
dose cohort. 
To correct the language to better 
describe dose escalation during 
Phase 1b. 
Test Products, Doses and 
Mode of Administration/ 
Study Drug Supply and 
Storage: Pomalidomide 
Synopsis (Study Design, Test 
Products, Doses and Mode of 
Administration), Section 
5.2.2 
Added the following new text: 
Pomalidomide should be taken without food, at least 
2 hours before or 2 hours after a meal. 
To add instructions for 
Pomalidomide dosing 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 11 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Statistical 
Methods/Justification of 
Sample Size 
Synopsis (Statistical 
Methods), Section 7.1 
Revised the Justification of Sample Size text: 
Old text: 
The corresponding expected 95% confidence interval for 
the response rate is (0.3, 0.56) which would surpass the 
reference response rate of 0.29. Assuming a 10% dropout 
rate, a study with n=75 would be sufficient. 
New text: Equivalently, the corresponding expected one- 
sided 95% confidence interval (CI) for the response rate 
will exclude 0.29 with 80% of chance. In order to have 
a robust study, a single interim analysis will be 
conducted when there are 30 evaluable patients. The 
SRC will use the totality of information from the 
interim analysis to recommend whether the study 
should proceed as planned, be terminated for 
superiority or futility, or extended to allow for 86 
evaluable patients. Assuming a 10% dropout rate, a study 
with n=95 would be sufficient. 
To clarify how the interim 
analysis will be used by the SRC 
to make critical decisions 
regarding the future of the study. 
Statistical Methods/Interim 
Analysis 
Synopsis (Statistical 
Methods), Section 7.5.1 
Edited the text describing the Interim Analysis: 
Old text: An interim analysis of response will be 
conducted by an independent statistician after 30 patients 
have been treated for at least 4 months in the Phase 2 
segment. Accrual will continue during the interim 
analysis, and the sample size may be adjusted based on the 
95% confidence intervals around the observed response 
rate. Prediction analysis is planned for the final 95% 
confidence interval for the response rate with the planned 
sample size. If the lower bound of the interval includes 
0.29, a sample size adjustment will be considered. The 
size adjustment will depend upon the predicted 0.95 
To clarify the statistical methods 
that will be used for the interim 
analysis. 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 12 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
confidence interval estimates under various scenarios. 
New text: There will be a single, scheduled interim 
analysis of when there are 30 evaluable patients 
available in order to determine if the study should 
proceed as planned, be terminated, or extended to 
allow for 86 evaluable patients. Assuming a 10% 
dropout rate, a study with n=95 would be sufficient. 
(Section 7.5.1) 
The interim analysis with the first 30 evaluable patients 
will be conducted using a one-sided 95% CI estimate 
for the response rate. If the lower bound of the 95% CI 
estimate with the 30 patients is ≥ 29%, the SRC may 
recommend either terminating the study at the interim 
based on treatment superiority, or continuing the study 
as planned. If the lower bound is < 29%, various 
predicted lower bounds of one-sided 95% CIs for the 
response rate will be constructed to further guide the 
SRC’s recommendation. For example, assuming a true 
response rate of 44% for the remaining 36 patients, the 
expected lower bound of one-sided 95% CI with 66 
evaluable patients will be calculated. If the expected 
lower bound is ≥ 29%, the SRC may recommend 
continuing the study as planned. If the expected lower 
bound with 66 evaluable patients is < 29%, another 
simulation will be run with 86 evaluable patients. If the 
resulting lower bound is acceptable (e.g., close to or ≥ 
29%), the SRC may recommend expanding the sample 
size by 20 patients. If the resulting lower bound is not 
acceptable (e.g., < 29%), the SRC may recommend 
terminating the study for futility. In addition, the 
expected lower bound of the one-sided 95% CI when 
the true response rate is equal to the observed value at 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 13 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
the interim analysis will be calculated. The resulting 
scenario will be similar to the previous one: if the 
expected lower bound is ≥ 29%, the SRC may 
recommend continuing the study as planned, if the 
lower bound is < 29%, the SRC may recommend 
expanding the sample size by 20 patients. Additional 
simulations with other possible response rates (for 
example, assuming a 40% response rate), with or 
without adaptation, will also be conducted; the SRC 
will review all simulation results to make a 
recommendation at the interim. Furthermore, with the 
potential adaptations at the interim, we find via an 
extensive simulation study the final CI estimate would 
have the accurate coverage level. Therefore, no 
statistical penalty or adjustment will be needed for the 
final inferential statistical procedure for the response 
rate. 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Statistical Methods/Safety 
Analysis 
Synopsis (Statistical 
Methods) 
Revised text as follows: 
AEs SAEs, treatment-emergent AEs, frequency of 
DLTs, vital sign measurements, clinical laboratory 
information, and concomitant medications will be 
tabulated and summarized for each dose cohort when 
appropriate. 
To clarify the tabulation of safety 
data. 
Statistical Methods/Safety 
Analysis 
Synopsis (Statistical 
Methods), Section 7.6.6 
Added the following new text: 
AEs leading to dose reduction or interruption will also 
be tabulated. 
To clarify the tabulation of safety 
data. 
Statistical Methods/Efficacy 
Analysis 
Synopsis (Statistical 
Methods), Section 7.5.1, 
Section 7.6.7 
Revised text as follows: 
The ITT Population will include all treated patients, 
and the EE Population will include all patients who 
meet eligibility criteria, receive at least 14 doses of 
study drug (i.e., ACY-1215, pomalidomide and low- 
dose dexamethasone), and have at least 1 post-baseline 
efficacy assessment. The primary analysis will be based 
on the ITT principle EE population, and will use the 
Investigator-assessed response data evaluated according 
to consensus recommendations from the IMWG criteria. 
To clarify the statistical methods 
to be used for the efficacy 
analysis. 
Statistical Methods/Efficacy 
Analysis 
Synopsis (Statistical 
Methods), Section 7.6.7 
Added the following new text: 
Response rate will be percent of patients who achieve at 
least partial response (PR) at the recommended Phase 2 
dose. Percent of patients achieving MR or better will 
also be collected as clinical benefit response. 
To clarify the methods used for 
evaluation of the primary efficacy 
endpoint of objective response. 
Statistical Methods/Efficacy 
Analysis 
Synopsis (Statistical 
Methods), Section 7.6.7 
Added the following new text: 
Duration of Response (DOR) will be defined as the time 
from the first PR or CR to the first documentation of 
disease progression PD or death, whichever occurs 
earlier. 
To clarify the methods used for 
evaluation of DOR. 
 
 
 
 
 
7 April 2014 
CONFIDENTIAL 
Page 14 of 27 


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Clinical Study Protocol ACE-MM-102 
Summary of Changes 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Study Design 
SOA and Footnote 18, 
Section 6.2.6 
Modified text as follows: 
Response will be assessed every 56 days (± a 2-day 
window) 2 cycles while on study drug treatment, and at 
study treatment discontinuation. Assessment of response 
will include measurement of serum M-protein by 
electrophoresis, SFLC analysis, and IFE studies (see 
footnotes 10-12). 
To reduce the likelihood of 
protocol deviations if a response 
assessment occurs outside the 
56 day (± a 2-day) window. 
Protocol now allows patients with 
free light chain myeloma. 
SOA 
SOA, Footnote 2 
Added new Footnote 2: 
Pregnancy tests may be conducted locally for patients 
who are unable to attend the 30 day follow-up visit at 
the study center; all other assessments may be 
conducted via phone. 
To clarify how the 30-day follow- 
up visits may be conducted. 
SOA 
SOA, Footnote 3, Section 
6.1.1 
Added new text to existing Footnote 3: 
Subsequent therapies should be collected until death or 
the end of the 5 year follow-up period. Survival follow- 
up may be done via phone. 
To clarify extent and methods of 
follow-up assessments. 
SOA, Demographics and 
Medical History 
SOA, (former) Footnote 3 
Deleted the following text: 
As part of the patient’s MM treatment history, study 
centers are to submit a local cytogenetics report and 
fluorescence in situ hybridization (FISH) analysis report 
obtained prior to enrollment, if available; ideally, the FISH 
report collected should include assessment of t(4;14); 
t(11;14); t(6;14); t(14;16); t(14;20); and del 17p. These 
data will be submitted for centralized review. 
Deleted instruction as it is no 
longer applicable for this study. 
SOA 
SOA, Footnote 5 
Revised as follows: 
A bone marrow aspirate and/or at least a unilateral biopsy 
is to be performed at Screening and a sample sent for 
central cytogenetic and fluorescence in situ 
hybridization (FISH) analysis (a bone marrow biopsy is 
needed only if the marrow is unable to be aspirated). A 
bone marrow biopsy/aspirate may be done as clinically 
indicated, at the discretion of the treating physician for 
and when assessment of disease. 
To clarify that FISH analysis will 
be performed centrally. 
 
7 April 2014 
CONFIDENTIAL 
Page 16 of 27 


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Clinical Study Protocol ACE-MM-102 
Summary of Changes 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Pharmacokinetic 
Measurements 
Schedule of Assessments 
(Footnote 25), Section 6.3 
Modified text as follows: 
PK samples are to should be collected as close to the 
scheduled time as possible: ≤ 1 hour before drug 
administration, ±5 minutes through 6 hours post dose and 
±1 hour at the 24 hour post dose. If deviations in 
timing occur, the timing of the sample collection should 
be clearly marked. 
To clarify timing of PK blood 
collection sampling. 
Overall Design and Plan of 
the Study 
Section 3.1 
Deleted the following text: 
“…and 12-lead electrocardiograms (ECGs) taken in 
triplicate, with the average of the 3 ECGs used to calculate 
the corrected QT interval (QTc). 
Clarification of text describing 
12-lead ECG recordings. 
Overall Design and Plan of 
the Study 
Section 3.1 
Revised text as follows: 
All safety and efficacy laboratory tests will be analyzed 
by local laboratories. A central laboratory will analyze 
duplicate samples of serum immunoglobulin levels, SPEP 
and UPEP of M-protein levels, serum and urine 
immunofixation (IFE) studies, and SFLC analysis. bone 
marrow biopsy/aspirate, and fluorescence in situ 
hybridization (FISH)/cytogenetic. A bone marrow 
aspirate sample will be centrally analyzed for 
fluorescence in situ hybridization (FISH)/cytogenetics. 
Results from the central efficacy analysis will not be 
shared with sites 
Clarification of how the safety 
and efficacy analyses will be 
conducted. 
Justification of the Study 
Design 
Section 3.4 
Added the following new text: 
Sparse PK sampling in Phase 2 will be analyzed to 
determine relationship of drug exposure to response 
and potential adverse events. 
Time points for PK blood 
sampling were added to the 
Phase 2 study segment. 
 
 
 
 
 
 
 
 
7 April 2014 
CONFIDENTIAL 
Page 18 of 27 


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Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 20 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Patient Management 
Section 4.7 
Added new text as follows: 
Upon discontinuation from the study for PD or any 
other reason, patients will be assessed 3 times per year 
(e.g., April, August, and December), for up to 5 years 
for survival, subsequent anti-myeloma therapies, and 
monitoring of second primary malignancies as outlined 
in Table 1. SAEs will be followed until 30 days after 
study treatment discontinuation. Subsequent therapies 
should be collected until death or end of the 5 year 
follow-up period. Survival follow up may be done via 
phone, when relevant. Patients who discontinue study 
treatment due to reasons other than PD will also be 
followed for efficacy assessments (see Section 6.2) until 
PD, death, or initiation of an alternate MM therapy, 
whichever occurs first. 
Patients who have been contacted at least 3 times 
without success (at least 1 month apart) should be sent 
a certified letter. If no contact is established, the 
patient will be deemed lost to follow up. A similar 
process will be followed for patients being followed up 
by phone. All attempted contact should be documented 
in the patient’s medical chart. 
To clarify methods of patient 
follow-up after patients following 
study discontinuation as well as 
define parameters for Loss to 
Follow Up. 
Study Drug Supply and 
Storage/Pomalidomide and 
Dexamethasone 
Section 5.1.2 
Pomalidomide will be dispensed by pharmacists to patients 
for the duration of their participation in this study at no 
charge to them or their insurance provider, through the 
region-specific POMALYST REMS™ or RevAid® 
program. Patients will have to be registered in such a 
program and follow the required procedures to receive 
pomalidomide supply. Only enough pomalidomide for 
one cycle of therapy will be supplied to the patient every 
cycle. Pomalidomide capsules are to be stored at room 
temperature (20 -25° C or 68-77° F), per the package 
insert away from direct sunlight and protected from 
excessive heat and cold. Additional storage conditions 
and dose dispensing instructions will be provided in detail 
within the Pharmacy Manual. 
To update registration methods of 
for receipt of pomalidomide and 
storage conditions for 
pomalidomide. 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 21 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Study Drug Dose and 
Administration/ACY-1215 
Section 5.2.1 
Modified text as follows: 
On study center visit days requiring 
PK/pharmacodynamic blood draws, ACY-1215 must 
be taken in the study center. On other study drug 
administration days that coincide with scheduled study 
center visits, ACY-1215 willmay be administered at the 
study center or at home. If ACY-1215 is being given 
BID, pomalidomide and dexamethasone are to be given 
with the first dose of ACY-1215. When taking The ACY- 
1215 BID, doses should be taken approximately every 
twelve hours. A plus or minus 2 hour window is 
acceptable for BID dosing. 
To clarify how ACY-1215 will be 
administered. 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 22 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Study Drug Dose and 
Administration/Pomalidomide 
Synopsis (Test Products, 
Doses and Mode of 
Administration), 
Section 5.2.2 
Added new text: 
Pomalidomide (POMALYST®) will be provided to 
research patients for the duration of their participation 
in this trial at no charge to them or their insurance 
providers. Pomalidomide will be provided in 
accordance with the Celgene Corporation’s 
POMALYST REMS™ or RevAid® program. Per the 
standard POMALYST REMS™ and RevAid® program 
requirements, all physicians who prescribe 
pomalidomide for research patients enrolled into this 
trial, and all research patients enrolled into this trial, 
must be registered in and must comply with all 
requirements of the POMALYST REMS™ and 
RevAid® program. Drug will be shipped on a per 
patient basis by the contract pharmacy to the clinic site 
for Investigational New Drug studies. Only enough 
pomalidomide for one cycle of therapy will be supplied 
to the patient each cycle. This is in accordance with the 
POMALYST REMS™ and RevAid® programs. 
If it is missed for the entire day, it should not be made up, 
rather it should be taken at the next scheduled time 
point. 
Pomalidomide will be sent to the patients’ home via the 
POMALYST REMS™ and RevAid® programs (see 
Appendix 9.3 and Appendix 9.4, respectively). 
To update how pomalidomide 
will be provided to patients in the 
POMALYST REMS and RevAid 
Programs and how the dose will 
be administered. 
Dose Modifications/ 
ACY-1215 
Section 5.2.8.1 
Added new text: 
Patients should receive 80% of planned doses for to be 
evaluable for SRC review. 
To clarify evaluation of DLT. 
Dose Modifications/ 
Pomalidomide 
Section 5.2.8.2 
Added new text: 
Hold the pomalidomide dose for remainder of cycle. If the 
patient was not receiving GCSF therapy, initiate GCSF 
therapy at the discretion of the treating physician. 
(Note, ANC must be ≥1000/ μL to restart dosing). 
To clarify text describing 
initiation of GCSF therapy for 
patients with neutropenia and 
resumption of pomalidomide 
dosing. 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Dose Modifications/ 
Pomalidomide 
Section 5.2.8.2 
Added new text: 
(Note, platelet count must recover to ≥ 50,000/ μL to 
restart dosing). 
To clarify text describing 
resumption of pomalidomide 
dosing in patients with Grade 4 
thrombocytopenia. 
Packaging and Labeling 
Section 5.3.2 
Added new text: 
• Canada: Investigational Drug to be used by qualified 
investigators only. 
To update packaging and labeling 
to reflect approval of 
pomalidomide in Canada. 
Packaging and Labeling 
Section 5.3.2 
Revised text as follows: 
Celgene will provide pomalidomide 4, 3, 2, and 1 mg 
for PO administration. Pomalidomide will be 
dispensed to patients for the duration of their 
participation in this study at no charge to them or their 
insurance providers, through the region-specific 
POMALYST REMS™ or RevAid® program (see 
Appendix 9.3 and Appendix 9.4). Pomalidomide will be 
distributed to patients at the same time they receive ACY- 
1215. Bottles will contain a sufficient number of capsules 
for one cycle of dosing, respectively). 
Pomalidomide capsules are to be stored, per the 
package insert (47, 52). 
To update packaging and labeling 
to reflect approval of 
pomalidomide in Canada. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 April 2014 
CONFIDENTIAL 
Page 23 of 27 


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Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 25 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
effective form of contraception – tubal ligation, IUD, 
hormonal (birth control pills, injections, hormonal 
patches, vaginal rings or implants) or partner’s 
vasectomy and one additional effective contraceptive 
method – male latex or synthetic condom, diaphragm 
or cervical cap. 
All patients must be counseled about pregnancy 
precautions, risks of fetal exposure and other risks. 
The counseling must be done on Day 1 of each cycle (or 
at a minimum of every 28 days) and at drug 
discontinuation. For additional requirements of the 
POMALYST REMS™ Program regarding pregnancy 
testing, counseling, and acceptable methods of birth 
control, see Appendix 9.3. 
RevAid® Program (Canada) 
A FCBP is any female patient who: 1) is still 
menstruating; or 2) who is amenorrheic from previous 
chemotherapy treatments; 3) who is premenopausal. 
FCBP must have two medically supervised negative 
pregnancy tests prior to the first dispensed prescription 
of pomalidomide. Pregnancy tests must be performed 
in a licensed laboratory (serum test with a sensitivity of 
at least 25 mIU/mL) must occur 7 to 14 days and again 
within 24 hours prior to initiation of study drug. The 
dates and results of pregnancy tests must be 
documented. FCBP with regular or no menstruation 
must have a pregnancy test weekly for the first month 
of treatment, monthly thereafter during treatment (or 
every 2 weeks if menses are irregular) and for 4 weeks 
after discontinuation of treatment. FCBP must use at 
least 2 effective methods of contraception at the same 
time for at least 4 weeks before starting treatment, 
during interruptions of treatment, for at least 4 weeks 
after stopping treatment. 
All patients must be counseled about pregnancy 
precautions, risks of fetal exposure and other risks. 
RevAid® programs. 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 26 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
The counseling must be done on Day 1 of each cycle (or 
at a minimum of every 28 days) and at drug 
discontinuation. For additional requirements of the 
RevAid® Program regarding pregnancy testing, 
counseling, and acceptable methods of birth control, 
see Appendix 9.4. 
Efficacy Measurements/ 
Bone Marrow Examination 
Section 6.2.3 
Revised text as follows: 
A bone marrow aspirate is to be performed at Screening 
and when clinically indicated at the discretion of the 
treating physician. A biopsy is needed only if the 
marrow is unable to be aspirated. A bone marrow 
aspirate sample collected at Screening will be sent for 
central cytogenetic and FISH analysis and when 
clinically indicated at the discretion of the treating 
physician. A biopsy is needed only if the marrow is 
unable to be aspirated. 
Additionally, all bone marrow samples collected will be 
used for pharmacodynamic assessments (see Section 6.4). 
To clarify that bone marrow 
aspirate samples will be centrally 
analyzed for FISH/cytogenetics. 
Appendix 
Appendix 9.3 
Replaced former Appendix 9.3 “Pomalidomide Pregnancy 
Risk Minimization Plan with the following: 
9.3. 
POMALYST REMS™ Program (United 
States) 
The full prescribing information, Pregnancy Testing 
Guideline and Pregnancy Risk Minimization Plan for 
FCBP and male patients in the US taking 
pomalidomide can be accessed using the following web 
link: 
http://www.pomalystrems.com/ 
To reference the weblink 
containing all the relevant 
resources for the POMALYST 
REMS program. 


Clinical Study Protocol ACE-MM-102 
Summary of Changes 
7 April 2014 
CONFIDENTIAL 
Page 27 of 27 
Approved v1.0 
 
 
 
Protocol Item 
Location of Changes 
Description of Changes in Amendment 1, 7 April 2014 
Rationale for Change 
Appendix 
Appendix 9.4 
Added the following new Appendix 9.4: 
9.4. 
RevAid® Complete Guide for Health Care 
Practitioners (Canada) 
The full prescribing information, Pregnancy Testing 
Guideline and Pregnancy Risk Minimization Plan for 
FCBP and male patients in Canada taking 
pomalidomide can be accessed using the following web 
link: 
https://www.revaid.ca/revaid/ 
To reference the weblink 
containing all the relevant 
resources for the RevAid 
program.