Clinical trial NCT02661815
Conditions: Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Carcinoma
Sponsor: Dana-Farber Cancer Institute
Start date: 2016-06-15; Completion date: 2017-07-28
Enrollment: 6 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Participants with Ovarian, Fallopian Tube, or Peritoneal Cancer that has recurred within 12 months of prior treatment that includes Platinum Chemotherapy are invited to take part in this study. This research study is studying a combination of a new chemotherapy drug called Ricolinostat together with the chemotherapy Paclitaxel and a drug called Bevacizumab as a possible treatment for this diagnosis.

Detailed description:
This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies.

The FDA (the U.S. Food and Drug Administration) has not approved Ricolinostat as a treatment for any disease. The FDA has approved Paclitaxel as a treatment option for Ovarian, Fallopian Tube, or Peritoneal Cancer . The FDA has approved Bevacizumab in combination with chemotherapy as a treatment option for Ovarian, Fallopian Tube, or Peritoneal Cancer .

In this study, we are hoping to learn what is the highest dose of Ricolinostat that can be given safely together with Paclitaxel on a weekly basis or with Paclitaxel on a weekly basis and Bevacizumab every other week. Ricolinostat is a drug that stops cancer from growing by blocking the action of a protein called HDAC.

Arms: arm 1: Paclitaxel 80mg/m2 weekly days 1, 8, and 15 of a 28-day cycle Ricolinostat dosing as identified as the RP2D combination dose arm 2: Paclitaxel 70mg/m2 weekly days 1, 8, and 15 of a 28-day cycle Ricolinostat dosing as identified as the RP2D combination dose arm 3: Paclitaxel 80mg/m2 weekly days 1, 8, and 15 of a 28-day cycle Bevacizumab 10mg/kg days 1 and 15 of a 28-day cycle Ricolinostat dosing as identified as the RP2D combination dose arm 4: Ricolinostat with weekly paclitaxel dosed at 80 mg/m2 per week (3 out of 4 weeks).
Interventions: intervention 1: Paclitaxel intervention 2: Ricolinostat intervention 3: Bevacizumab
Intervention descriptions: intervention 1: Please see arm/group description. intervention 2: Please see arm/group description. intervention 3: Please see arm/group description.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 
 
DF/HCC Protocol #: 15-483 
 
TITLE:  A Phase 1b Study of weekly paclitaxel and oral ricolinostat for the treatment of 
recurrent platinum resistant ovarian, primary peritoneal, or fallopian tube cancer 
 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute  
450 Brookline Ave.  
Boston MA 02215 
 
*Principal Investigator (PI): 
Joyce Liu, M.D. 
 
Dana-Farber Cancer Institute  
 
450 Brookline Ave.   
 
                                                      Boston, MA 02215 
 
Telephone: 617 632-5269  
 
Fax: 617 632-3479 
                                                      email:  joyce_liu@dfci.harvard.edu 
 
Statistician: 
 
  
Willam Barry, Ph.D                                          
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
Telephone:  617 632-5134 
Fax:  617 632-2444 
email:  bbarry@jimmy.harvard.edu 
 
 
Responsible Research Nurse: 
  
Christin Whalen, RN  
 
Dana-Farber Cancer Institute 
 
450 Brookline Ave.  
Boston, MA 02215 
Telephone:  617-582-7738 
 
Fax:  617 632-7921 
 
email:  christin_whalen@dfci.harvard.edu  
 
Study agents:   
Ricolinostat:  NSC#, supplied by Acetylon 
Paclitaxel:  Commercial 
Bevacizumab:  Commercial 
 
IND #:  127956    
IND Sponsor: Joyce Liu, M.D.  
 
Protocol Type / Version # / Version Date: Amendment 4/Version 5.0/October 20, 2016  


DF/HCC Protocol #: 15-483 
Protocol Version Date: October 20, 2016 
 
2 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Participants with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 participants at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional participants will be 
entered at the next lowest dose level if only 3 
participants were treated previously at that dose. 
1 out of 3 
Enter at least 3 more participants at this dose level. 
• If 0 of these 3 participants experience DLT, proceed 
to the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
participants will be entered at the next lowest dose 
level if only 3 participants were treated previously at 
that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At 
least 6 participants must be entered at the recommended 
phase 2 dose. 
 
 
 
Patients with recurrent or persistent epithelial ovarian, fallopian 
tube, or primary peritoneal carcinoma 
Ricolinostat per assigned dose level 
Paclitaxel 80 mg/m2 days 1, 8, and 15 


DF/HCC Protocol #: 15-483 
Protocol Version Date: October 20, 2016 
 
3 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objectives...................................................................................................5 
1.3 
Secondary Objectives...............................................................................................5 
2. 
BACKGROUND .................................................................................................................5 
2.1 
Ovarian Cancer ........................................................................................................5 
2.2 
Ricolinostat ..............................................................................................................6 
2.3 
Paclitaxel ................................................................................................................11 
2.4 
Rationale ................................................................................................................12 
3. 
PARTICIPANT SELECTION ...........................................................................................12 
3.1 
Eligibility Criteria ..................................................................................................12 
3.2 
Exclusion Criteria ..................................................................................................14 
3.3 
Inclusion of Women and Minorities ......................................................................16 
4. 
REGISTRATION PROCEDURES ...................................................................................16 
4.1 
General Guidelines for DF/HCC Institutions ........................................................16 
4.2 
Registration Process for DF/HCC Institutions .......................................................17 
4.3 
General Guidelines for Other Investigative Sites ..................................................17 
4.4 
Registration Process for Other Investigative Sites.................................................17 
5. 
TREATMENT PLAN ........................................................................................................17 
5.1 
Treatment Regimen ................................................................................................17 
5.2 
Pre-Treatment Criteria ...........................................................................................18 
5.3 
Agent Administration.............................................................................................19 
5.4 
Definition of Dose-Limiting Toxicity (DLT) ........................................................20 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................22 
5.6 
Criteria for Taking a Participant Off Protocol Therapy .........................................22 
5.7 
Duration of Follow Up ...........................................................................................23 
5.8 
Criteria for Taking a Participant Off Study ...........................................................23 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................24 
6.1 
Dose Modification Tables ......................................................................................24 
6.2 
General Management of Adverse Events ..............................................................24 
6.3 
Hematologic Toxicities ..........................................................................................25 
6.4 
Non-Hematologic Toxicities ..................................................................................26 
6.5 
Dose Modifications for Bevacizumab ...................................................................27 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................28 
7.1 
Expected Toxicities ................................................................................................28 
7.2 
Adverse Event Characteristics ...............................................................................29 
7.3 
Expedited Adverse Event Reporting ......................................................................29 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) ......................30 


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4 
7.5 
Expedited Reporting to Hospital Risk Management .............................................30 
7.6 
Routine Adverse Event Reporting .........................................................................30 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................30 
8.1 
Ricolinostat ............................................................................................................30 
8.2 
Paclitaxel ................................................................................................................32 
8.3 
Bevacizumab ..........................................................................................................33 
9. 
SPECIAL STUDIES:  NEUROLOGICAL ASSESSMENT .............................................35 
9.1 
Total Neuropathy Score-Nurse (TNSn©) ..............................................................35 
10. 
STUDY CALENDAR .......................................................................................................36 
11. 
MEASUREMENT OF EFFECT........................................................................................38 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................38 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................44 
12.1 
Data Reporting .......................................................................................................44 
12.2 
Data Safety Monitoring..........................................................................................45 
12.3 
Collaborative Agreements Language .....................................................................45 
13. 
STATISTICAL CONSIDERATIONS...............................................................................45 
13.1 
Study Design/Endpoints.........................................................................................45 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................46 
13.3 
Stratification Factors ..............................................................................................46 
13.4 
Interim Monitoring Plan ........................................................................................46 
13.5 
Analysis of Primary Endpoints ..............................................................................46 
13.6 
Analysis of Secondary Endpoints ..........................................................................47 
13.7 
Reporting and Exclusions ......................................................................................48 
14. 
PUBLICATION PLAN .....................................................................................................48 
REFERENCES ..............................................................................................................................49 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................52 
APPENDIX B 
TOTAL NEUROPATHY SCORE-nurse (TNSn©) ..................................53 
 
APPENDIX C 
PATIENT DRUG DIARY DOSES 1 THROUGH 4.................................62 
 
APPENDIX D 
PATIENT DRUG DIARY DOSE 1 ONLY..............................................63 
 
 


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5 
 
1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a phase Ib study of the combination of weekly paclitaxel and oral ricolinostat given to 
patients who have recurrent ovarian, peritoneal or fallopian tube cancer in order to establish a 
maximally tolerated dose (MTD).  Once the MTD has been established, expansion cohorts will 
be performed testing (1) this combination in women with recurrent ovarian cancer and no 
significant neuropathy (CTCAE v4.0 grade 1 or less), (2) this combination in women with 
recurrent ovarian cancer and CTCAE v4.0 grade 2 neuropathy, or (3) this combination together 
with bevacizumab in women with recurrent ovarian cancer and no significant neuropathy.   
 
1.2 
Primary Objectives 
 
1.2.1 To determine the MTD of oral daily ricolinostat combined with weekly paclitaxel given 
on a 3 out of 4 week schedule.    
 
1.3 
Secondary Objectives 
 
1.3.1 To gain an estimate of toxicities especially peripheral neurotoxicity for combined weekly 
paclitaxel and ricolinostat for the treatment of recurrent ovarian, fallopian tube or 
peritoneal cancer. 
 
1.3.2 To gain an estimate of preliminary response rate for these agents combined. 
 
1.3.3 To gain an estimate of duration of response (DOR) and progression-free survival (PFS) 
of the combination of weekly paclitaxel and oral ricolinostat in women with recurrent 
ovarian cancer. 
 
2. BACKGROUND 
 
2.1 
Ovarian Cancer 
 
Ovarian cancer is a deadly disease that affects women globally, is diagnosed at an advanced 
stage in most patients and has no effective screening tests for early detection (1).  The worldwide 
incidence of this cancer is 225,500 diagnoses per year; in the United States in 2014, 21,980 
women will be diagnosed with ovarian cancer (1, 2).  Global mortality of this cancer remains 
high with 140,200 deaths per year, and minimal improvement in mortality has been observed for 
women diagnosed with ovarian cancer over the past decade (1).  Treatment strategies that have 
led to an overall survival (OS) improvement for newly diagnosed patients have included the 
addition of paclitaxel to platinum, the use of intraperitoneal cisplatin in patients with optimally 
cytoreduced cancer (<1 cm of residual cancer after upfront cytoreductive surgery), and 
incorporation of weekly paclitaxel versus every 3 week paclitaxel as part of upfront treatment for 
ovarian cancer (3-5).  Neoadjuvant chemotherapy has emerged as a treatment alternative 
especially in patients who are unable to undergo upfront cytoreductive surgery because of the 
extent of cancer or those patients who are too ill or frail to undergo upfront cytoreductive surgery 
(6).    Anti-angiogenics, specifically bevacizumab, were the first biologic to be tested in ovarian 


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6 
cancer but to date addition of bevacizumab in randomized trials has demonstrated progression 
free survival (PFS) benefit, but no OS benefit (7-9).  
 
In 2014, 2 agents were FDA approved for the treatment of recurrent ovarian cancer:  
bevacizumab in combination with chemotherapy in patients with platinum resistant ovarian 
cancer and the oral PARP inhibitor olaparib for women with a gBRCA mutation, recurrent 
ovarian cancer and who have received at least 3 lines of prior chemotherapy (FDA package 
insert for avastin and FDA package insert for olaparib).   
 
Most patients will recur after being diagnosed with advanced ovarian cancer; for patients with 
platinum-sensitive recurrence (defined as cancer recurring ≥6 months after the last platinum), 
additional platinum-based therapy is given (10).   For patients with recurrent platinum resistant 
cancer (defined as cancer recurring <6 months after last platinum), single agent chemotherapy is 
administered.   New agents and rational combinations of biologics and chemotherapy are needed 
to improve outcomes in women with recurrent ovarian cancer.  
 
Long-term complications of chemotherapy specifically paclitaxel include neuropathy; the most 
commonly used agents for ovarian cancer treatment (platinum and taxanes) lead to neuropathic 
complications that alter quality of life and also may lead to premature treatment discontinuation 
 
2.2 
Ricolinostat 
 
Ricolinostat (alternative designations ACY-1215, ACY-63, ACY-161-63) is an orally active, 
small-molecule histone deacetylase (HDAC) inhibitor with potential for enhanced target 
selectivity. The chemical name of ricolinostat is 2-(Diphenylamino)-N-(7-(hydroxyamino)-7-
oxoheptyl)-pyrimidine-5-carboxamide. Ricolinostat targets the Class IIb HDAC6 enzyme, which 
is one of 18 known histone deacetylase enzymes present in human cells. Selective inhibition of 
HDAC6, while retaining reduced inhibitory activity of HDAC1, 2, and 3, may uniquely enable 
the preservation of normal gene expression in cells while severely disrupting the ability of cells 
to dispose of damaged, misfolded proteins in lysosomes via the aggresome pathway, an 
alternative and complementary pathway to protein degradation by the proteasome complex. 
Because metabolically active cancer cells produce large amounts of misfolded proteins, 
inhibition of HDAC6 in combination other agents could result in rapid accumulation of 
misfolded protein, thus increasing cellular stress and potentially triggering self-destruction of 
diseased cells via programmed cell death that would be expected to lead to regression of disease. 
 
Preclinical rationale exists for using histone deacetylase (HDAC) inhibition as a therapeutic 
strategy against ovarian cancer (12, 13). Ovarian cancer cell lines treated with HDAC inhibitors 
demonstrated an accumulation of cells in G1 and G2, induced apoptosis, and increased levels of 
acetylated histones 3 and 4.  As single agents, non-selective HDAC inhibitors have little activity 
in recurrent ovarian cancer, however HDAC inhibitors combined with chemotherapy such as 
platinum agents and paclitaxel resulted in synergy (12, 13).  Specifically, the combination of 
ricolinostat with paclitaxel enhanced tumor growth suppression in ovarian cancer xenotransplant 
models (Figure 1).  While the precise mechanism of this synergy remains under investigation, 
HDAC6 controls the acetylation (and therefore activation) state of key cellular proteins with 
important functions in cancer, such as the chaperone HSP90 and TP53, the “safe keeper of the 
genome”. Additionally, HDAC6 regulates acetylation of the key microtubule protein α-tubulin, 
whose stability is also directly impacted and implicated in the mechanism of action of paclitaxel.  


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7 
Ricolinostat, via selective HDAC6 inhibition while retaining reduced and more tolerable levels 
of HDAC1, 2 and 3 inhibition, has the potential for a substantially reduced side-effect profile 
versus current HDAC inhibitor drugs and drug candidates while retaining potential for anticancer 
effectiveness.  Ricolinostat is being studied in ongoing clinical phase 1 and 2 studies of multiple 
myeloma.   
 
A 
 
 
 
    B 
D ays
T u m o r V o lu m e  (m m
3)
0
5
1 0
1 5
2 0
2 5
0
1 0 0 0
2 0 0 0
3 0 0 0
4 0 0 0
5 0 0 0
6 0 0 0
V e h ic le
P a c lita x e l (1 0  m g /k g   IV  Q O D  x 5 )
P a c lita x e l (1 0  m g /k g   IV  Q O D  x 5 ) +
A C Y -1 2 1 5  (5 0  m g /k g  IP  Q D  5 /2  x 3 w k )
D ays
T u m o r V o lu m e  (m m
3)
0
5
1 0
1 5
2 0
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
6 0 0
7 0 0
V e h ic le
A C Y -1 2 1 5  (5 0  m g /k g   IP  Q D  5 /2  x 3 w k )
P a c lita x e l (1 0  m g /k g  IP  Q D  5 /2  x 2 w k )
P a c lita x e l (1 0  m g /k g  IP  Q D  5 /2  x 2 w k ) +
A C Y -1 2 1 5  (5 0  m g /k g   IP  Q D  5 /2  x 3 w k )
 
Figure 1 – Combination treatment of (A) A2780 and (B) TOV-21G ovarian cancer xenograft models with ACY-
1215/ricolinostat plus paclitaxel resulted in greater suppression of tumor growth relative to control and single agent 
treatments. 
 
HDAC6 inhibition is also expected to result in reversal of axonal transport defect which is 
observed in such diseases as Alzheimer’s Disease, Huntington’s Disease, ALS as well as 
chemotherapy-induced peripheral neuropathy caused by taxanes (paclitaxel), vinca alkaloids, and 
proteasome inhibitors as well as possibly platinum.  In fact, treatment with ricolinostat was 
shown to reduce peripheral hypersensitivity in a rat model of paclitaxel-induced peripheral 
neuropathy (Figure 2).  Thus, the rationale for combining weekly paclitaxel and ricolinostat in 
this study for recurrent ovarian cancer is to enhance anti-cancer activity based on the observed 
synergy with paclitaxel and ricolinostat in ovarian cancer cell lines and xenograft models, and to 
possibly mitigate the peripheral neuropathy observed with weekly paclitaxel administration.    
 
 
Figure 2 – ACY-1215/ricolinostat treatment reverses paclitaxel induced neuropathy in rats. Rats were treated daily 
with paclitaxel for 13 days (6 mg/kg on days 0-6 and 12 mg/kg on days 7-12). Confirmation of increased paw 
sensitivity associated with neuropathic pain was measured using the Von Frey filament test for tactile allodynia. 
Treatment with the analgesic Gabapentin (150 mg/kg, IP, given one hour before Von Frey test) and ACY-
1215/ricolinostat (30 mg/kg, oral, twice per day) was started on day 13, and both agents led to reductions in paw 
sensitivity. 
 


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8 
2.2.1 Pharmacokinetics of Ricolinostat 
 
2.2.1.1 
Nonclinical Pharmacokinetics 
 
The absorption of ricolinostat has been extensively studied in 3 species: mouse, rat, and dog. 
Preclinical PK studies have been conducted predominantly under fasted conditions where 
ricolinostat was delivered by the oral route. In dog, fasted and fed conditions were compared for 
impact on exposure.  Ricolinostat was rapidly absorbed (Tmax < 1 hr) following oral 
administration to mouse, rat and dog, with oral bioavailability of 11-19% in rodents and ~45% in 
dogs. Clearance following intravenous administration is less than (in mouse and dog), or equal to 
(in rat) hepatic blood flow.   The elimination half-life (t1/2) following oral dosing is similar 
across all species examined (mouse, rat and dog) and generally ranges from 1 – 4 hours, with a 
longer t1/2 in rat at higher dose levels. 
 
The PK of different liquid strength formulations have been compared in dogs at a dose level of 
160 mg.  The current liquid formulation (CLF), 20 mg/mL, attained a Cmax of 1424 ± 324 ng/mL 
with an area under the plasma concentration time curve (AUC) extrapolated to infinity (AUC0-∞) 
of 4450 ± 862 ng·hr/mL compared to a Cmax of 2070 ± 550 ng/mL and AUC0-∞ of 
6217 ± 1236 ng·hr/mL of a diluted version of the CLF (12 mg/mL).  In a separate study, the 
diluted version of the CLF (12 mg/mL) attained a Cmax of 2100 ± 920 ng/mL with an AUC0-∞ of 
8035 ± 1702 ng·h/mL compared to a Cmax of 3440 ± 750 ng/mL and AUC0-∞ of 
7655 ± 1893 ng·h/mL of the ALF (10 mg/mL).  Subsequently, a population PK model was 
developed for the combined human data from the monotherapy Phase 1a trial described below 
with the dog data.  The model adequately characterized the combined data and was used to 
assess the relative bioavailability of the ALF (120 mg) to the CLF.  The simulation suggested a 
120-mg dose of the ALF may yield a similar Cmax and exposure to 160 mg of the CLF. 
 
2.2.1.2 
Clinical Pharmacokinetics 
 
Clinical data are available from 123 patients with MM, of whom 15 were treated with 
ricolinostat monotherapy at doses up to 360 mg and 108 were treated with ricolinostat in 
combination with other anti-neoplastic agents in 2 clinical studies (Ricolinostat investigator’s 
brochure). Of the 108 patients receiving combination therapy, 44 received ricolinostat in 
combination with bortezomib / dexamethasone, 31 received ricolinostat in combination with 
lenalidomide / dexamethasone, and 33 received ricolinostat in combination with pomalidomide / 
dexamethasone.  The plasma PK of ricolinostat monotherapy in a total of 15 patients treated with 
ricolinostat Oral Solution, 20 mg/mL was determined in Study ACY-100 and area under the 
concentration curve from time 0 to 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. Maximal plasma (Cmax) and 
exposure (AUC) levels observed in patients treated at 160 mg (mean Cmax 626±150 ng/mL, and 
mean AUC0-4 1074±439 ng•h/mL) and 240 mg (mean Cmax 719±329 ng/mL, and mean AUC0-
4 1231±430 ng•h/mL) were similar, suggesting an exposure plateau was reached at dose levels 
≥160 mg. 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. The drug was rapidly absorbed (Tmax ~1 hour) from the gastrointestinal tract. 
Preliminary analysis of PK parameters revealed measurable levels of ricolinostat in all patients, 
with mean Cmax levels ranging from 85±39 to 503±195 ng/mL (0.2 to 1.2 μM). 
 


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9 
PK results from patients treated with ricolinostat monotherapy suggest an exposure plateau was 
reached at dose levels ≥160 mg because PK data from 160 mg and 240 mg were similar; 
therefore, QD doses of ricolinostat >240 mg will not be investigated. PK data also show 
ricolinostat to be rapidly absorbed (Tmax ~1 hour) from the gastrointestinal tract. The apparent 
elimination half-life was ~3 hours, with drug levels ranging from ~1 ng/mL to below the lower 
limit of quantification (0.5 ng/mL) by 24 hours post-dose. 
 
2.2.2 Pharmacodynamics 
 
Pharmacodynamic analyses in PBMCs collected from patients receiving ricolinostat 
monotherapy confirm the mechanism of action of ricolinostat, with demonstration of acetylation 
of tubulin (an HDAC6 effect), preferentially to histone acetylation (a Class 1 HDAC effect), at 
clinically achievable exposures of ricolinostat (see Section 4.3.1.1). 
 
2.2.3 Safety and Toxicities of ricolinostat in animals 
 
Ricolinostat is a selective (10-fold) and potent inhibitor (biochemical IC50 5.7 nM) of HDAC6 
over Class I HDACs 1, 2 and 3. The principal side effects associated with Class 1 HDAC 
inhibition in the clinic, including thrombocytopenia, neutropenia, significant gastrointestinal 
effects, and fatigue, have not been observed with ricolinostat in preclinical studies, most notably 
in the GLP 28-Day repeat-dose study in dog where the highest maximal plasma levels of 
ricolinostat at ≥10 μM were attained. 
 
Cardiovascular Findings  
The cardiovascular effects of ricolinostat in the dog included increased heart rate (by 19 – 24 
bpm) and decreased systolic pressure (by 5 – 15 mmHg), were moderate and transient and 
occurred in all dose groups, including the low dose group (10 mg/kg), where maximal plasma 
levels were similar to the upper range of the efficacious concentration observed in preclinical 
studies.   One dog in the high dose group (60 mg/kg) in the cardiovascular safety study exhibited 
QTc prolongation several hours after maximal plasma levels were observed. These effects were 
not observed in the low and mid dose groups (10 and 30 mg/kg). Based on the Cmax level in this 
one dog versus other unaffected dogs, QTc prolongation is unlikely if the substantially lower 
efficacious concentration range observed in cellular and animal studies is similar in humans.   
Serial ECGs were performed in patients treated with ricolinostat monotherapy, with no clinically 
important effect of ricolinostat on ECG parameters in the course of the study.  
 
Hematology: Red Blood Cells  
Minimal to mild decrease in RBC mass was observed at all 3 ricolinostat dose levels in dog, 
including the low dose group (30 mg/kg/day) in the pivotal 28-day repeat dose study, with 
exposure and Cmax levels (Day 28) ranging from 16,800 to 26,800 ng∙h/mL and 4,080 to 9,490 
(9.4 to 22 μM). These levels of ricolinostat range from 2 to 4-fold higher than the upper range of 
the efficacious concentration observed in preclinical studies. These changes were accompanied 
by marginal and non-adverse increases in total protein and albumin levels. In the rat (males 
only), a slight reduction that was within normal limits of variability was observed in RBC 
parameters at ≥60 mg/kg/day.  
 
In clinical studies of ricolinostat, hematological and clinical chemistry parameters are monitored 
frequently throughout each treatment cycle, as described in the protocol. Anemia has been 


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10 
reported in patients treated with ricolinostat alone or in combination, and has been considered 
study drug-related in some cases.  
 
Body Weight  
Slight body weight decrease was observed at all 3 dose levels in the dog, including the low dose 
group (30 mg/kg/day) in the pivotal 28-day repeat dose study with exposure and Cmax levels 
(Day 28) ranging from 16,800 to 26,800 ng·h/mL and 4,080 to 9,490 (9.4 to 22 μM). These 
levels of ricolinostat range from 2 to 4-fold higher than the upper range of the efficacious 
concentration observed in preclinical studies. Body weight is measured once per treatment cycle 
as described in the clinical protocol. No clinically significant effect on body weight has been 
seen in clinical studies of ricolinostat alone or in combination. 
 
2.2.4 Human studies of ricolinostat 
 
Safety  
Review of safety data from patients treated with ricolinostat monotherapy or in combination with 
bortezomib / dexamethasone or lenalidomide /dexamethasone has shown ricolinostat to be 
generally well tolerated and to have a manageable safety profile.  
 
Ricolinostat Monotherapy  
Among patients treated with ricolinostat monotherapy, no deaths or other SAEs were considered 
by the Investigator to be related to ricolinostat, and no AEs reported were considered to represent 
DLTs (IB). As no DLTs occurred with ricolinostat monotherapy, an MTD was not identified.  
 
A total of 15 patients were treated with ricolinostat monotherapy at doses ranging from 40 to 360 
mg. Across dose cohorts, the median duration of therapy ranged from 1.7 weeks to 12.3 weeks, 
with a maximum duration of therapy of 29.5 weeks.   Most (14 of 15 patients; 93%) patients 
treated with ricolinostat monotherapy experienced at least 1 AE. Most AEs reported were 
considered by the Investigator to be mild or moderate (Grade 1 or 2) in intensity and unrelated to 
study drug.   Among all 15 patients treated with ricolinostat monotherapy, the most common 
AEs, regardless of dose, were blood creatinine increased (5 patients; 33%), fatigue, 
hypercalcemia, and upper respiratory tract infection (4 patients each; 27%), and anemia, cough, 
diarrhea, and dizziness (3 patients each; 20%). Diarrhea occurred only at ricolinostat doses ≥160 
mg.  AEs that were assessed by the Investigator as Grade 3 or 4 intensity and possibly related to 
study drug were seen at ricolinostat doses ≥160 mg and were all hematologic abnormalities, 
including anemia (160 mg) and neutropenia and leukopenia (360 mg). None of these events was 
a dose-limiting toxicity (DLT), based on the protocol definitions. 
 
2.2.5 Rationale for the dose and schedule of ricolinostat 
 
Clinical data show that the plasma exposure of ACY-1215 CLF plateaus at levels ≥ a 160-mg 
dose.  For this study, a 120-mg dose of the alternative liquid formulation (ALF) of 10 mg/mL 
ACY-1215 is predicted to yield exposure similar to that obtained with a 160-mg dose of ACY-
1215 CLF based on population PK modeling of human and dog PK data (see Section 2.2.1.1).  
Doses will be escalated to determine if an MTD exists for ACY-1215 when administered in an 
ALF in combination with paclitaxel. 
 


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11 
2.3 
Paclitaxel 
 
Weekly paclitaxel is an established standard of care therapy for recurrent ovarian cancer and 
several studies have demonstrated activity of weekly paclitaxel for the treatment of recurrent 
ovarian cancer.   
 
In addition, peripheral neuropathy that persists post-initial platinum and taxane-based 
chemotherapy makes re-treatment with additional taxanes and platinum more challenging.   
Table 1 summarizes the results of weekly paclitaxel in recurrent ovarian cancer. 
 
Table 1: Summary of Response Rates to Weekly Paclitaxel Based on Published  
 
Literature 
 
Study- 
Reference 
N 
Population 
Regimen 
Response 
Survival 
14    
53 
Taxane- and 
platinum-
resistant 
80 mg/m2 
weekly  
25% total 
(3% CR, 
22% PR) 
24 wk PFS 
58 wk OS 
15 
57 
Platinum-
resistant 
80mg/m2 
weekly  
56% total 
(12% CR, 
44% PR) 
5.0 mo PFS 
13.7 mo OS 
16 
208 
(randomized 
– 105 pts 
with weekly 
paclitaxel) 
≤ 1 prior 
platinum-
containing 
regimen 
67 mg/m2 
weekly 
35% total 
(12% CR, 
23% PR) 
6.1 mo PFS 
13.6 mo OS 
17 
22 
Retrospective 
Taxane- and 
platinum-
resistant 
60-80 
mg/m2 
weekly 
50% (27% 
CR, 23% 
PR) 
27 wk PFS 
(in 
responders) 
18 
28 
Mostly taxane 
and platinum 
resistant 
80mg/m2 for 
6-8 weeks 
50% total 
(50% PR) 
6 mo PFS 
(in SD or 
responders) 
19 
39 
1-3 prior 
platinum-
containing 
regimens 
80m/gm2 3 
wk on/1 wk 
off 
45.9% 
(13.5% 
CR, 32.4% 
PR) 
 
20 
32 
Taxane and 
platinum-
resistant 
80mg/m2  
6 wks on / 2 
wks off 
31.2% 
(3.1% CR, 
28.1% PR) 
 
21 
48 
Platinum-
resistant (6 
mo)  
80mg/m2 
weekly 
- cont x 12 
weeks 
- optional 3 
wk on/1 wk 
off p 12 wks 
20.9% 
total (4.2% 
CR, 16.7% 
PR) 
3.6 mo 
“response 
duration” 
Survival 
data not 
reported 
22 
34 
Platinum-
80 mg/m2 
53% total 
6.10 mo 


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12 
resistant 
weekly  
(9% CR, 
44% PR) 
PFS 
10.43 mo 
OS 
23 
49 
Retrospective  
Different 
doses 
28% total 
149 d PFS 
359 d OS 
24 
53 
Retrospective  
No taxane in 
prior 6 months 
80-90 
mg/m2 
weekly 
48% total 
(4% CR, 
43% PR) 
4.8 mo PFS 
13.5 mo OS 
25 
70 
(29 weekly 
paclitaxel vs. 
41 paclitaxel/ 
bevacizumab) 
Retrospective  
60-70mg/m2 
weekly 
48% total 
(17% CR, 
31% PR) 
6.2 mo PFS 
18.8 mo OS 
 
 
2.4 
Rationale 
 
The rationale for this study is as follows: 
1)  Weekly paclitaxel is a standard of care treatment for women with recurrent ovarian, 
peritoneal or fallopian tube cancer.  Despite evidence of activity in recurrent ovarian cancer, 
resistance eventually develops to paclitaxel.  Additionally, the development of peripheral 
neurotoxicity may limit paclitaxel administration even when it remains an active agent. 
 
2)  Ricolinostat is an HDAC6 inhibitor that shows pre-clinical synergy when combined with 
weekly paclitaxel in ovarian cancer PDX models. 
 
3)  In addition, ricolinostat, because it is an HDAC6 inhibitor, may have additional benefits in an 
ovarian cancer population because of its ability to restore impaired axonal transport and may 
lessen observed neurotoxicity with weekly paclitaxel.    
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Participants must have recurrent or persistent epithelial ovarian, fallopian tube or primary 
peritoneal carcinoma. Histologic documentation of the original primary tumor is required 
via the pathology report. 
 
3.1.2 Participants must have measurable disease by RECIST 1.1 criteria.  See Section 11 for 
the evaluation of measurable disease. 
 


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13 
3.1.3 Participants must have had at least one prior platinum-based chemotherapeutic regimen 
for management of primary disease (e.g., a regimen containing carboplatin, cisplatin, or 
another organoplatinum compound).  This initial treatment may have included 
intraperitoneal therapy, consolidation, biologic/targeted (non-cytotoxic) agents (e.g., 
bevacizumab) or extended therapy administered after surgical or non-surgical assessment.   
 
Participants are allowed to receive, but are not required to receive, biologic/targeted (non-
cytotoxic) therapy as part of their primary treatment regimen. 
 
3.1.4 Participants must have recurrence within 12 months of their last platinum-containing 
regimen. 
 
3.1.5 Age 18 years or older     
 
3.1.6 ECOG performance status 0 or 1   
 
3.1.7 Life expectancy of greater than 16 weeks 
 
3.1.8 Participants must have normal organ and marrow function as defined below: 
 
− 
leukocytes  
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
 
≥100,000/mcL 
− 
total bilirubin 
≤ the institutional upper limit of normal 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
creatinine  
within normal institutional limits 
OR 
− 
creatinine clearance 
≥60 mL/min/1.73 m2 for participants with creatinine 
levels above institutional normal. 
 
3.1.9 Previous toxicities from previous treatment must have resolved to grade 1 or less 
3.1.9.1 For patients in expansion cohort B, stable Grade 2 neuropathy will be allowed. 
 
3.1.10 The effects of both paclitaxel and oral ricolinostat on the developing human fetus are 
unknown.  For this reason, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry and for the duration of study participation.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately.    
 
3.1.11 Participants must be able and willing to swallow pills and to absorb oral medications. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent document 
 
3.1.13 Participants must be able and willing to follow protocol instructions and schedules. 
 
 


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14 
3.2 
Exclusion Criteria 
 
3.2.1 Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 4 weeks earlier.  In addition, 
no small molecule kinase inhibitors or any other type of investigational agent may have 
been administered within 4 weeks before first dose of study treatment. 
 
3.2.2 Participants may not be receiving any other investigational agents for treatment of their 
cancer. 
 
3.2.3 No hormonal therapy is allowed within 1 week of initiating study treatment. 
 
3.2.4 Participants may not have had radiation to >25% of the bone marrow. 
 
3.2.5 Prior treatment with a histone deacetylase inhibitor. 
 
3.2.6 Participants may have received prior treatment with weekly paclitaxel; however, 
participants who have had progression on or within 8 weeks of their last dose of weekly 
paclitaxel will not be eligible.    
 
3.2.7 Participants with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
 
3.2.8 History of severe allergic reactions attributed to compounds of similar chemical or 
biologic composition to either paclitaxel or ricolinostat.  Patients who require 
administration of paclitaxel through a desensitization procedure are not eligible for this 
study.    
 
3.2.9 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.10 Patients with chronic viral illnesses such as HIV-positivity and active hepatitis B or C are 
ineligible because they are at increased risk of lethal infections when treated with 
marrow-suppressive therapy. 
 
3.2.11 Any signs, symptoms, and/or radiographic evidence of a complete or partial bowel 
obstruction 
 
3.2.12 Patients with a history of other invasive malignancies, with the exception of non-
melanoma skin cancer and other specific malignancies as noted below, are excluded if 
there is any evidence of other malignancy being present within the last three years.  
Patients are also excluded if their previous cancer treatment contraindicates this protocol 
therapy. 
• Carcinoma in situ of the breast or cervix 
• Primary endometrial cancer meeting the following conditions:  Stage not greater than 


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15 
IA, grade 1 or 2, no more than superficial myometrial invasion, without vascular or 
lymphatic invasion; no poorly differentiated subtypes, including papillary serous, 
clear cell, or other FIGO grade 3 lesions. 
 
3.2.13 Patients who have received prior chemotherapy for any abdominal or pelvic tumor 
OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer 
within the last three years are excluded. Patients may have received prior adjuvant 
chemotherapy for localized breast cancer, provided that it was completed more than three 
years prior to registration, and the patient remains free of recurrent or metastatic disease. 
 
3.2.14 Patients with clinically significant cardiovascular disease. This includes: 
• Myocardial infarction or unstable angina within 6 months prior to registration. 
• New York Heart Association (NYHA) Class II or greater congestive heart failure. 
(see Appendix III ) 
• History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular 
fibrillation) or serious cardiac arrhythmia requiring medication. This does not include 
asymptomatic atrial fibrillation with controlled ventricular rate. 
• Any history of congenital long QT syndrome 
• The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) 
>500 ms within 28 days before randomization.  Note: if initial QTcF is found to be > 
500 ms, two additional EKGs separated by at least 3 minutes should be performed.  If 
the average of these three consecutive results for QTcF is ≤500 ms, the subject meets 
eligibility in this regard. 
3.2.15 Patients with serious non-healing wound, ulcer, or bone fracture within 28 days before 
registration.  Patients should not have had any major surgical procedures within 28 days 
of registration. 
 
3.2.16 Patients with history of organ transplant. 
 
3.2.17 Patients with active bleeding or pathologic conditions that carry high risk of bleeding, 
such as known bleeding disorder, coagulopathy, or tumor involving (in contact with, 
invading or encasing) major vessels. 
 
3.2.18 Gastrointestinal disorders that may interfere with absorption of oral agents, such as 
malabsorption syndromes.  Additionally, patients requiring drainage gastrostomy (e.g. 
PEG tube) and/or parenteral hydration and/or nutrition support are not eligible 
 
3.2.19 Patients with history or evidence upon physical examination of CNS disease, including 
primary brain tumor, seizures which are not controlled with non-enzyme inducing 
anticonvulsants, any brain metastases and/or epidural disease, or history of 
cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid 
hemorrhage within six months prior to the first date of study treatment.  
 


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16 
3.2.20 The following are additional exclusion criteria for patients enrolling in Expansion Cohort 
C: 
3.2.20.1 
Uncontrolled blood pressure (>140/90).  Patients should have a blood 
pressure of ≤140/90 taken by a medical professional within one week of 
starting on study 
3.2.20.2 
Proteinuria >2+ on urinalysis 
3.2.20.3 
Serosal involvement of the bowel that would render the patient at 
increased risk of gastrointestinal perforation 
3.2.20.4 
Other gastrointestinal orders that could increase the potential risk of 
perforation or fistula formation, including but not limited to the following: 
• Intra-abdominal metastases/tumor invading the GI mucosa 
• Active peptic ulcer disease within 28 days of registration 
• Inflammatory bowel disease (including ulcerative colitis and 
Crohn’s disease), diverticulitis, cholecystitis, symptomatic 
cholangitis, or appendicitis. 
3.2.20.5 
Any of the following within 6 months of registration: 
• abdominal fistula 
• gastrointestinal perforation 
• bowel obstruction or gastric outlet obstruction 
Note:  patients requiring drainage gastrostomy (e.g., PEG tube) 
and/or parenteral hydration and/or nutrition are not eligible 
• intraabdominal abscess 
Note:  complete resolution of an intraabdominal abscess must be 
confirmed prior to registration even if the abscess occurred more 
than 6 months prior to registration. 
3.2.20.6 
Major  surgery within 3 months of the first dose of study drugs if there 
were no wound healing complications or within 6 months of the first dose 
of study drugs if there were wound complications. 
 
3.2.21 Any serious and/or unstable pre-existing medical disorder (aside from malignancy 
exception above), psychiatric disorder, or other conditions that could interfere with 
subject’s safety, obtaining informed consent or compliance to the study procedures, in the 
opinion of the Investigator. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 


DF/HCC Protocol #: 15-483 
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17 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
N/A 
 
4.4 
Registration Process for Other Investigative Sites 
 
N/A 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
All patients will receive ricolinostat administered in the 10mg/mL ALF daily on days 1-21 of 
each treatment cycle, with the exception of dose level -1, where ricolinostat is given on days 1-5, 
8-12 and 15-19 of a 28-day cycle. On paclitaxel administration days, paclitaxel is to be given 
immediately after ricolinostat. Study Day 1 is defined as the first day the patient receives study 
drug.  Following completion of the first cycle, patients may continue the study at their assigned 
dose of ricolinostat.   
 
Weekly paclitaxel will be administered weekly on days 1, 8, and 15 of a 28 day cycle, with 28 
consecutive days defined as a treatment cycle. Treatment will be administered on an outpatient 
basis.  Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant's 
malignancy. 
 
Dose Level 
Ricolinostat (mg) 
(oral administration in a 28-
day cycle) 
Paclitaxel (mg/m2) (days 1, 8, 
and 15 of a 28-day cycle) 
(IV administration) 
                Level -1 
80 mg daily 5 days per week 
out of 7 
80  
Level 1 (starting dose) 
80 mg daily days 1-21 
80 
Level 2 
120 mg daily days 1-21 
80 


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18 
Level 3 
180 mg daily days 1-21 
80 
Level 4 
240 mg daily days 1-21 
80 
 
Additional dose levels may be added based upon toxicities observed within dose levels.  In 
addition, 3 additional patients may be placed on a dose level once the MTD has been established 
in order to obtain additional information about the toxicities of that dose level. 
 
After a recommended Phase 2 dosing (RP2D) has been determined, three 10-patient expansion 
cohorts will be enrolled at this dosing level to gain greater experience with this drug 
combination,  to explore the potential effects of combining ricolinostat with paclitaxel on the 
development of chemotherapy-induced peripheral neuropathy (cohort A: PN grades 0 and 1, 
cohort B: PN grade 2), and to explore the safety of the RP2D dosing in combination with 
bevacizumab given FDA approval of paclitaxel and bevacizumab for recurrent platinum-resistant 
ovarian cancer .  Dosing within these three expansion cohorts would be as follows: 
• Expansion cohort A:   
o Paclitaxel 80mg/m2 weekly days 1, 8, and 15 of a 28-day cycle 
o Ricolinostat dosing as identified as the RP2D combination dose 
• Expansion cohort B: 
o Paclitaxel 70mg/m2 weekly days 1, 8, and 15 of a 28-day cycle 
o Ricolinostat dosing as identified as the RP2D combination dose 
• Expansion cohort C:   
o Paclitaxel 80mg/m2 weekly days 1, 8, and 15 of a 28-day cycle 
o Bevacizumab 10mg/kg days 1 and 15 of a 28-day cycle 
o Ricolinostat dosing as identified as the RP2D combination dose 
 
5.2 
Pre-Treatment Criteria 
 
5.2.1 Screening Visit 
 
Participants must meet criteria at screening as outlined in section 3.0. All screening tests 
must be done within 4 weeks of study entry with exception of tumor measurements which 
must be done within 2 weeks of starting treatment. 
 
5.2.2 Hematologic Criteria 
 
Cycle 1, Day 1: 
• Absolute neutrophil count ≥ 1500/mcL 
• Platelets ≥ 100,000/mcL 
Cycles 2 and beyond, Day 1 
• Absolute neutrophil count ≥ 1000/mcL 
• Platelets ≥ 100,000/mcL 
 
5.2.3 All Cycles, Day 1 
 
Participants must have the following: 


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19 
• Serum creatinine < 1.5x institutional upper limit of normal (ULN) or calculated 
creatinine clearance of ≥ 50 mL/min.  
• AST/ALT ≤ 3 times ULN or ≤ 5 times ULN if liver metastases are present. 
• ECOG performance status of 0 or 1. 
• No evidence of life-threatening medical problems. 
• No evidence of a bowel obstruction or an impending bowel obstruction. 
• Continued willingness and ability to swallow pills and absorb oral medications. 
• For Expansion Cohort C patients:   
o Blood pressure ≤140/90 on days receiving bevacizumab. 
o Urine protein of 2+ or less by urinalysis 
 
5.2.4 For Cycles 2 and Beyond 
 
All treatment-related toxicities experienced during the preceding cycle (excepting alopecia) must 
have returned to grade 1 or less 
 
5.3 
Agent Administration 
 
5.3.1 Ricolinostat/ACY-1215 
 
ACY-1215 Oral Solution 10 mg/mL will be supplied by Acetylon Pharmaceuticals, Inc. as a 
liquid for oral administration in amber glass bottles and will be stored in the pharmacy at -20ºC.  
Additional storage conditions and dose preparation instructions will be provided in detail within 
the Pharmacy Manual. Study center pharmacy personnel will prepare individual patient doses of 
ACY-1215 Oral Solution 10 mg/mL to be administered either during scheduled study-center 
visits or by the patient at home.   
 
Administration:  Ricolinostat will be administered PO QD at least 1 hour after ingestion of food 
and followed by 4oz of water.  Patients will be instructed not to ingest food or other PO 
medication for at least 2 hours after each ricolinostat dose.  On other study drug administration 
days that coincide with scheduled study-center visits, ricolinostat may be administered at the 
study center or at home. Dosing weight will be per institutional standard. 
 
Dosing:  Ricolinostat dosing will be escalated as per the dosing level table in Section 5.1  Dosing 
for individual participants will be determined by their enrollment cohort.   
 
Hydration: No prehydration is required.  Prehydration may be administered per clinical practice 
based on clinical factors individual to the participant. 
 
Order of Administration:  Participants should take ricolinostat orally immediately (within 30 
minutes) of initiating paclitaxel infusion on paclitaxel administration days. 
 
Adverse Effects:  Observed side effects with ricolinostat are described in Section 7.1.1.  
Investigators should also refer to the Investigator’s Brochure for additional details and 
information. 
 
 


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20 
5.3.2 Paclitaxel 
 
Administration: Administration of paclitaxel should be prepared and administered per 
institutional standards, and as per the FDA package insert.   
 
Dosing:  The starting dose of paclitaxel will be 80mg/m2 weekly on days 1, 8, and 15 of a 28-
day cycle.  Dose modifications should be as described in Section 6. 
 
Paclitaxel must be diluted prior to infusion.  Paclitaxel will be diluted in 0.9% Sodium Chloride 
for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride 
Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 
1.2mg/mL.  The solutions are physically and chemically stable for up to 27 hours at ambient 
temperature (approximately 25°C / 77°F) and room lighting conditions. 
 
Drug, Tubing and Filtration:   Paclitaxel should be administered through an inline filter with a 
microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2® or 
IVEX-HP®, which incorporate short inlet and outlet PVC-coated tubing has not resulted in 
significant leaching of DEHP.   
 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which may be leached 
from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, 
polypropylene) or plastic (polypropylene, polyolefin) bags and administered through 
polyethylene-lined administration sets. 
 
Hydration: No prehydration is required.  Prehydration may be administered per clinical practice 
based on clinical factors individual to the participant. 
 
Premedications:  All patients should be premedicated with corticosteroids, diphenhydramine, and 
H2 antagonists prior to paclitaxel administration in order to prevent severe hypersensitivity 
reactions. 
 
Order of Administration:  Participants should take ricolinostat orally immediately (within 30 
minutes) of initiating paclitaxel infusion on paclitaxel administration days. 
 
Adverse Effects:  Consult the package insert for the most current and complete information. 
 
 
5.4 
Definition of Dose-Limiting Toxicity (DLT)  
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
The definition of a DLT-evaluable patient includes the following:  
1)  The patient is not removed from the study during cycle 1 because of disease progression 
or withdrawal of consent 
2)  The patient received weekly paclitaxel as per the protocol 
3)  The patient demonstrated proof via the pill diary that all doses of ricolinostat were taken 
or attempted to be taken, and  


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21 
4)  The patient was compliant with all study procedures and laboratory measurements.   
 
The definition of a DLT is defined by the following criteria and will be assessed during cycle 1 
only:   
1) Any treatment-related CTCAE v4.0 grade 3 or 4 non-hematologic event with the 
following exceptions: 
a. Grade 3/4 nausea, vomiting or diarrhea, unless grade 3/4 symptoms persist 
without resolution despite optimal symptomatic treatment 
b. Grade 3 transaminitis present for ≤ 7 days 
c. Easily correctable asymptomatic Grade 3 laboratory abnormalities 
2) Any of the following treatment-related hematologic events: 
a. Febrile neutropenia defined as Grade 3/4 neutropenia with fever ≥ 38.5°C 
and/or demonstrated infection  
b. Any Grade 4 neutropenia last 5 days or more 
c. Any incident of Grade 4 thrombocytopenia (platelet count < 25,000/µL) 
d. Failure of the absolute neutrophil count (ANC) to recover to ≥ 1000/µL or 
platelets to recover to ≥ 50,000/µL within 14 days of therapy, and 
e. Any incident of Grade 4 anemia 
3) Any clinically significant treatment-related abnormal laboratory value resulting in a 
dose delay of >14 days and/or 
4) <75% of ricolinostat dosing taken by the patient during the first cycle due to any study-
related toxicity 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.  Patients who are not evaluable for DLT will be 
replaced.   
 
Number of Participants with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 participants at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional participants will be 
entered at the next lowest dose level if only 3 participants 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more participants at this dose level. 
• If 0 of these 3 participants experience DLT, proceed to the 
next dose level. 
• If 1 or more of this group suffer DLT, then dose escalation 
is stopped, and this dose is declared the maximally 
administered dose.  Three (3) additional participants will 
be entered at the next lowest dose level if only 3 
participants were treated previously at that dose. 
≤1 out of 6 at highest dose level below 
the maximally administered dose 
This is generally the recommended phase 2 dose. At least 6 
participants must be entered at the recommended phase 2 
dose. 


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22 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
The Overall PI should be alerted if the participant is taking any agent known to be a strong 
inhibitor or inducer of CYP3A4 or CYP2C8.  A reference to interactors with CYP450 enzymes 
may be found at http://medicine.iupui.edu/clinpharm/ddis/.  
 
Participants on chronic medications that can be given concomitantly with protocol drugs  
should be maintained on the same dose and dose schedule throughout the study period, as 
medically feasible. The investigator should instruct the participant to notify the study site about 
any new medications he/she takes after the start of the study drug. 
 
All supportive measures consistent with optimal patient care will be given throughout the 
study. Bisphosphonates, vitamin D and calcium supplementation, topical medications, 
antiemetics, anti-diarrheal medications, anticoagulants and anti-infective agents may be used at 
the discretion of the treating physician.  
 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient is permitted with the following exceptions: 
 
•  Other investigational therapies must not be used while the participant is on the study. 
 
•  Myeloid growth factors are not permitted during the first cycle of therapy but may be used 
during the subsequent cycles as determined by the treating physican in order to maintain 
the patient on study and following standard of care guidelines.  
 
•  Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) other than 
the study treatments must not be given to participants while he/she is on the study. If such 
agents are required for a participant then the participant must be removed from this study. 
 
•  Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to: St. John’s Wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 
Patients should stop using these herbal medications 7 days prior to first dose of study drug. 
Fruits include the CYP3A inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus 
fruits.   
 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
indefinitely or until one of the following criteria applies: 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 


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23 
 
• 
Participant demonstrates an inability or unwillingness to comply with the treatment  
regimen and/or documentation requirements 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI: 
 
Joyce Liu, M.D. 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
Phone:  (617) 632-5269 or pager:  (617) 632-3352  
 
5.7 
Duration of Follow Up 
 
Participants will be followed for 30 days after removal from protocol therapy or until death, 
whichever occurs first.  Participants removed from protocol therapy for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 
5.8 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
A ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the ODQ website or obtained from the ODQ registration staff.  
 
 


DF/HCC Protocol #: 15-483 
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24 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Modification Tables 
 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  No dose 
modifications are allowed in cycle 1 (except in the setting of a DLT being declared; in this 
setting, dose modification may be considered after discussion with the PI for the patient 
developing the DLT if continued study treatment is being considered). No dose increases will be 
allowed after a dose reduction. 
  
Paclitaxel dose reductions will be per the following table: 
 
Drug 
Starting Dose 
Dose Reduction 
Level A 
Dose Reduction 
Level B 
Paclitaxel  
80 mg/m2/week  
70 mg/m2/week 
60 mg/m2/week 
 
Ricolinostat dose reductions should be made per the dose levels outlined below.  Patients must 
start dose reductions from the dose level assigned at study entry.  Intrapatient dose escalations 
are not allowed.  Patients on dose levels that are higher than the MTD (once an MTD has been 
identified) may have their dosing decreased to the MTD at the discretion of the treating 
investigator, in discussion with the overall PI. 
 
Dose Level 
Ricolinostat (mg) 
(oral administration in 
a 28-day cycle) 
1st dose reduction 
2nd dose reduction 
Level -1 
80 mg daily 5 days per 
week out of 7 
Off therapy  
N/A 
Level 1  
(starting dose) 
80 mg daily days 1-21 
80 mg daily 5 days per 
week out of 7 
Off therapy 
Level 2 
120 mg daily days 1-21 
80 mg daily days 1-21 
80 mg daily 5 days per 
week out of 7 
Level 3 
180 mg daily days 1-21 
120 mg daily days 1-21 80 mg daily days 1-21 
Level 4 
240 mg daily days 1-21 
180 mg daily days 1-21 120 mg daily days 1-21 
 
Any dose modifications should be carried through to future cycles of therapy once performed. 
 
6.2 
General Management of Adverse Events 
 
Patients should be assessed clinically for toxicity at each clinic visit through use of the NCI 
CTCAE version 4 grading scale.  Dosing should occur only if a patient’s clinical assessment and 
laboratory test values are acceptable. 
 
Dose modifications for specific toxicities are outlined in the sections below.  In general, patients 


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who experience any treatment-related grade 3 or higher non-hematologic toxicities or grade 2 
non-hematologic toxicities that persist despite maximal support (excluding those outlined below 
and any easily correctable asymptomatic grade 3 laboratory abnormalities) should have study 
treatment held until these symptoms resolved to grade 1 or less.  Treatment may then be resumed 
with dose reductions as per Section 6.1.  The investigator may choose to reduce the dose of 
paclitaxel, ricolinostat, or both, depending on which drugs are felt to be contributory to the 
development of the specific adverse event.  Patients whose toxicities do not recover to grade 1 or 
less within 14 days should be removed from protocol-directed therapy.  No dose modifications 
are allowed for alopecia. 
 
Patients who require treatment delays for non-treatment-related toxicities should be discussed 
with the PI. 
 
6.3 
Hematologic Toxicities 
 
Study treatment should not be administered unless the patient meets hematologic 
parameters of ANC ≥ 1000/mm3 and platelet count ≥ 100,000/mm3 on day 1 of the cycle or 
ANC ≥ 1000/mm3 and platelet count ≥ 75,000/mm3 on days 8 and 15 of the cycle (Of note, on 
Cycle 1 Day 1, patients must have an ANC ≥ 1500/mm3, as per Section 5.1.2.  Treatment may be 
delayed for a maximum of 14 days until these parameters are met.  If patient counts fail to 
recover adequately within 14 days, protocol-directed therapy should be discontinued. 
 
Dose modifications should occur for neutropenic or thrombocytopenic events, as detailed in the 
following tables, once the patient’s ANC and/or platelet counts have recovered to meet the 
hematologic parameters for dosing outlined above.  Dose modifications should be carried 
through to future cycles of therapy once performed. 
 
Table 6.3.A:  Dose modifications for neutropenia 
 
Hematologic Event 
Dose Modification 
Initial Occurrence 
Febrile neutropenia† 
Grade 4 neutropenia lasting ≥ 7 
days 
ANC < 1000/mcL on Day 1, 8, or 
15 
Treatment delay > 7 days for 
neutropenia 
Reduce paclitaxel by one dose 
level 
Initiate G-CSF if not already 
receiving 
Second Occurrence 
If any of the above toxicities occur 
after initial dose reduction 
Reduce paclitaxel by one dose 
level† 
Reduce ricolinostat by one dose 
level 
Third occurrence 
If any of the above toxicities occur 
after two dose reductions 
Discontinue patient from protocol-
directed therapy 
†Paclitaxel may not be reduced below 60mg/m2 weekly.  If neutropenic event occurs at 
paclitaxel dose of 60mg/m2, paclitaxel dosing should be maintained at 60mg/m2 and 
ricolinostat reduced to the next lower dose level. 
 
 
 


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Table 6.3.B:  Dose modifications for thrombocytopenia 
 
Hematologic Event 
Dose Modification 
Initial Occurrence 
Grade 4 thrombocytopenia 
(platelets < 25,000/mcL) 
Grade 3 thrombocytopenia with 
bleeding event (platelets 25,000 
to  <50,000/mcL) 
Platelets < 100,000/mcL on Day 1 
or <75,000/mcL on Day 8 or 15 
Treatment delay > 7 days for 
thrombocytopenia 
Reduce paclitaxel by one dose 
level 
 
Second Occurrence 
If any of the above toxicities occur 
after initial dose reduction 
Reduce paclitaxel by one dose 
level 
Reduce ricolinostat by one dose 
level 
Third occurrence 
If any of the above toxicities occur 
after two dose reductions 
Discontinue patient from protocol-
directed therapy 
 
6.4 
Non-Hematologic Toxicities 
 
6.4.1 Neuropathy 
 
Neuropathy is a commonly observed toxicity with paclitaxel administration, and patients should 
be carefully monitored for development of neuropathy symptoms.  Patients who develop grade 2 
or higher neuropathy should be held until the neuropathy resolved to grade 1 or better.  Study 
treatment may then be resumed with paclitaxel reduced by one dose level.  Patients who are 
already on a dose of paclitaxel 60mg/m2 weekly should be removed from protocol-directed 
therapy.  Patients who do not have recovery of their neuropathy symptoms to grade 1 or better 
within 14 days should be removed from protocol-directed therapy. 
 
For patients in the expansion cohort who have stable baseline grade 2 neuropathy, study 
treatment should be held for neuropathy that worsens to grade 3 or higher.  Study treatment may 
be resumed at one dose level reduction of paclitaxel for patients whose neuropathy recovers to 
grade 2 within 14 days.  If grade 3 or higher neuropathy recurs in these patients, protocol-
directed therapy should be discontinued. 
 
6.4.2 Hepatic Toxicity 
 
Hepatic toxicity can be observed with paclitaxel administration.  Liver function studies should be 
monitored during therapy as per protocol.  Dose modifications for paclitaxel-related hepatic 
toxicity should be made as per the table below: 
 
AST, ALT, and Alk Phos  
Bilirubin 
Paclitaxel Dosing 
CTCAE grade 1 
AND ≤ ULN 
Continue current dose level 
CTCAE grade 2 
OR 
CTCAE Grade 1 
Reduce by one dose level†. 
≥ CTCAE grade 3 
Or 
≥ CTCAE Grade 2 
Hold until recovered to AST, 
ALT, and alkaline phosphatase ≤ 
Grade 1 and bilirubin recovered to 


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≤ ULN.  Reduce by one dose level 
at time of treatment resumption 
Second recurrence of any of the above after one dose 
reduction  
Reduce paclitaxel by one dose 
level†† 
Recurrence of toxicity which would require a 3rd dose 
reduction 
Discontinue protocol-directed 
therapy 
†At the discretion of the investigator, treatment may be held until recovery of liver function 
tests to AST, ALT, and alkaline phosphatase ≤ Grade 1 and bilirubin ≤ ULN. 
††Paclitaxel dose may not be reduced below 60mg/m2.  If patient is at the lowest paclitaxel 
dose, protocol-directed therapy should be discontinued. 
 
6.4.3 Nausea 
 
Nausea may be observed with both paclitaxel and ricolinostat.  Nausea should be managed per 
institutional standards with supportive medications as needed.  Dosing delays and reductions 
may be considered for patients with persistent grade 3 or higher nausea that is unresponsive to 
anti-emetic therapy.  Dose reduction levels should be as outlined in Section 6.1.  The investigator 
may choose to reduce the dose of paclitaxel, ricolinostat, or both, depending on which drugs are 
felt to be contributory to the development of nausea. 
 
6.4.4 Diarrhea 
 
Diarrhea may also be observed with both paclitaxel and ricolinostat and should be managed per 
institutional standards with supportive medications as needed.  Dosing delays and reductions 
may be considered for patients with persistent grade 2 or higher diarrhea that remains 
uncontrolled despite maximal medical management.  Dose reduction levels should be as outlined 
in Section 6.1.  The investigator may choose to reduce the dose of paclitaxel, ricolinostat, or 
both, depending on which drugs are felt to be contributory to the development of diarrhea. 
 
Recommended management for diarrhea is loperamide antidiarrheal therapy, with a dosage 
schedule of 4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-free for 
12 hours.  The maximum dosage of loperamide should not exceed 16mg in a 24 hour period.   
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
6.4.5 Fatigue 
 
Fatigue may be seen with paclitaxel and ricolinostat.  Patients experiencing persistent grade 2 
fatigue despite maximal support or grade 3 or higher fatigue may be dose-reduced as per the dose 
reduction levels outlined in Section 6.1 per investigator discretion.  The investigator may choose 
to reduce the dose of paclitaxel, ricolinostat, or both. 
 
6.5 
Dose Modifications for Bevacizumab 
 
In general, adverse events noted with bevacizumab should be managed by optimizing medical 
management, including with anti-hypertensives as required.  Dose modifications for 
bevacizumab are not generally indicated for bevacizumab-related toxicities.  Patients in the 
expansion cohort who experience a bevacizumab-related toxicity where it is felt that 
bevacizumab should be discontinued for safety considerations should be discussed with the study 


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PI. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1 
Expected Toxicities 
 
7.1.1 Adverse Event List for Ricolinostat 
 
Ricolinostat has been studied as monotherapy in a limited number of patients with multiple 
myeloma.  Among patients treated with ricolinostat monotherapy, most AEs were reported to be 
Grade 1 or 2 in intensity and unrelated to study drug.  Grade 3 AEs that were considered to be at 
least possibly related to ricolinostat were hematologic in nature, and included anemia, 
leucopenia, and neutropenia. 
 
Additional non-hematologic AEs that have been observed in patients receiving ricolinostat 
monotherapy included blood creatinine increased (33%); fatigue (27%); hypercalcemia (27%); 
upper respiratory tract infection (27%); cough (20%); diarrhea (20%); and dizziness (20%).  Of 
these events, diarrhea occurred at ricolinostat doses ≥ 160mg; no dose relationship was apparent 
with regard to the occurrence of any of the other AEs. 
 
For additional information, please refer to the ricolinostat Investigator’s Brochure. 
 
7.1.2 Adverse Event List for Paclitaxel 
 
Paclitaxel is FDA-approved for the treatment of ovarian cancer, and is associated with a number 
of toxicities, including nausea, vomiting, diarrhea, alopecia, constipation, peripheral neuropathy, 
myelosuppression, allergic/hypersensitivity reaction, bradycardia, nail changes, and elevation of 
liver function tests.  
 
Please refer to the FDA package insert for a comprehensive list of adverse events. 
7.1.3 Adverse Event List for Bevacizumab 
 
Bevacizumab is FDA-approved in conjunction with paclitaxel, topotecan, or pegylated liposomal 
doxorubicin for the treatment of platinum-resistant ovarian cancer, and is associated with a  
number of toxicities, including hypertension, headache, epistaxis, hoarseness, proteinuria, 
thromboembolic events (venous and arterial), arthralgia, myalgia, infection, impaired healing, 
bleeding events, gastrointestinal perforation, fistula formation, myelosuppression, and allergic or 
infusion reactions. 
 
Please refer to the FDA package insert for a comprehensive list of adverse events. 
 


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7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting  
 
7.3.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form. 
  
7.3.2 Cross-Reporting 
 
All SAEs that occur during the course of the study must be reported to the Sponsor Investigator –
Joyce Liu, MD, MPH at the contact information below. The Sponsor Investigator will notify INC 
Drug Safety (on behalf of Acetylon) within 1 business day, of all serious adverse events and 
expedited safety reports submitted to relevant regulatory authorities, as per the contact 
information below. All SAEs must be reported whether or not considered causally related to the 
study drug. SAE forms will be provided to each clinical study site. The information collected 
will include patient number, a narrative description of the event and an assessment by the 
Investigator as to the severity of the event and relatedness to study drug. Follow-up information 
on the SAE may be requested by Dana-Farber Cancer Institute and Acetylon. 
 
 
 
 
 
 
INC Drug Safety on behalf of Acetylon - Drug Safety Reporting Contact Information  
Joyce Liu, M.D., MPH 
joyce_liu@dfci.harvard.edu 


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INC 1 business day SAE Reporting 
E-mail: incdrugsafety@incresearch.com 
Fax: 1 (877) 464-7787 
 
If there are serious, unexpected adverse drug reactions associated with the use of the study drug, 
the Sponsor will notify the appropriate regulatory agency(ies) and all participating Investigators 
on an expedited basis. It is the responsibility of the Investigator to promptly notify the 
Institutional Review Board (IRB) of all unexpected serious adverse drug reactions involving risk 
to human patients. An unexpected event is one that is not reported in the Investigator’s Brochure. 
 
7.3.3 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.5 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.6 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1. 
 
8.1 
Ricolinostat 
 
8.1.1 Description 
The International Nonproprietary Name (INN) and United States Adopted Name (USAN) of the 
active pharmaceutical ingredient (API) of ricolinostat Oral Solution is ricolinostat. Other codes 
used to identify the same compound during its development are ricolinostat, ACY-161-63 and 
ACY-63.  
 
The International Union of Pure and Applied Chemistry (IUPAC) name of ricolinostat is 2-


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31 
(Diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)-pyrimidine-5-carboxamide.   
 
Molecular Formula and Weight:   
Molecular Formula:  C24H27N5O3 
Molecular Weight:  433.5 
 
8.1.2 Study Drug 
 
ACY-1215 Oral Solution, 10 mg/mL will be supplied by the Sponsor as a liquid for PO 
administration in amber glass bottles with a white child-resistant, tamper-evident cap. A total of 
12 mL of the 10 mg/mL formulation is contained in each bottle of ACY-1215. 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.   
 
Bottles will be supplied with a label attached to each bottle detailing product name and amount, 
lot number, 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.  
 
Dispensing of the amount needed for individual patients should be performed by appropriately 
trained personnel according to the pharmacy instructions. 
 
8.1.3 Storage and Stability 
ACY-1215 Oral Solution 10 mg/mL should be stored at -20°C at the clinical site. Patients should 
store ACY-1215 Oral Solution according to the instructions for use. 
 
8.1.4 Compatibility 
There are no known compatibility issues with oral ricolinostat and intravenous paclitaxel.  
During this phase Ib study, possible interactions will be monitored.   
 
8.1.5 Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
8.1.6 Availability 
Ricolinostat will be distributed by Acetylon Pharmaceuticals, Boston, MA. 
 
8.1.7 Preparation 
Dispensing of the amount needed for individual patients should be performed by appropriately 
trained personnel according to the pharmacy instructions in the pharmacy manual.   Ricolinostat 
will come already prepared and no reconstitution will be necessary.    
 
8.1.8 Administration 
Patients should take ricolinostat every day at the same time (+/- 2 hours) at least 1 hour after 
ingestion of food and followed by 4 ounces of water.  Patients should not ingest food or other PO 


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medication for at least 2 hours after each dose of ricolinostat.  
 
8.1.9 Ordering 
ACY-1215 Oral Solution, 10 mg/mL will be ordered by the research pharmacy through Acetylon 
Pharmaceuticals, Boston, MA, using the process described in the Pharmacy Manual. 
 
8.1.10 Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.) 
 
8.1.11 Destruction and Return 
Destruction of unused ACY-1215 Oral Solution, 10 mg/mL will be as per institutional research 
pharmacy policies.   
 
8.2 
Paclitaxel 
 
8.2.1 Description 
Paclitaxel is a chemotherapy agent that disrupts microtubule formation and is commonly used in 
many cancers for treatment.    
   
8.2.2 Form 
Paclitaxel is supplied as a 6mg/mL non-aqueous solution in multi dose vials containing 
30mg/5mL, 100mg/16.7mL, or 300mg/50mL of paclitaxel.  In addition to 6mg of paclitaxel, 
each mL of sterile non-pyrogenic solution contains 527mg of purified Cremophor® EL 
(polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. 
  
8.2.3 Storage and Stability 
Unopened vials of paclitaxel are stable to the date indicated on the package when stored between 
20 to 25°C (68 to 77°F).  Protect from light.   
 
Commercially available paclitaxel will be labeled with an expiration date. All solutions of 
paclitaxel exhibit a slight haziness directly proportional to the concentration of drug and the time 
elapsed after preparation, although when prepared as described below, solutions of paclitaxel 
(0.3-1.2mg/ml) are physically and chemically stable for 27 hours.   
 
8.2.4 Compatibility 
There are no known compatibility issues with oral ricolinostat and intravenous paclitaxel.   
 
8.2.5 Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
8.2.6 Availability 
Paclitaxel is commercially available both from Bristol-Myers Squibb Oncology as well as 
generic manufacturers.  Consult the American Hospital Formulary Service Drug Information 


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guide, Facts and Comparisons, or the package insert for additional information. 
 
8.2.7 Preparation 
Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium 
Chloride for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium 
Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 
1.2mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient 
temperature (approximately 25°C / 77°F) and room lighting conditions. 
 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which may be leached 
from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, 
polypropylene) or plastic (polypropylene, polyolefin) bags and administered through 
polyethylene-lined administration sets. 
 
8.2.8 Administration 
Paclitaxel should be administered through an inline filter with a microporous membrane not 
greater than 0.22 microns. Use of filter devices such as IVEX-2® or IVEX-HP®, which 
incorporate short inlet and outlet PVC-coated tubing, has not resulted in significant leaching of 
DEHP. 
 
Weekly dosing of paclitaxel should be given via intravenous infusion over a period of 
approximately 60 minutes. 
 
All patients should be premedicated with corticosteroids, diphenhydramine, and H2 antagonists 
prior to paclitaxel administration in order to prevent severe hypersensitivity reactions as dictated 
by national treatment guidelines, FDA package insert recommendations, and individual hospital 
policies and procedures.  Patients who experience severe hypersensitivity reactions to drug may 
need to repeat the premedication and to be re-challenged with a dilute solution and slow infusion. 
Severe life-threatening hypersensitivity reactions to paclitaxel should not proceed with a re-
challenge, and consultation of an allergy specialist should be obtained if any type of allergic 
reaction occurs with paclitaxel for future guidance on management.     
 
8.2.9 Ordering 
Paclitaxel is commercially available and will be ordered by the institution’s pharmacy.   
 
8.2.10 Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.   
 
8.2.11 Destruction and Return 
Unused paclitaxel will be destroyed as per individual institutional pharmacy policies and 
procedures.   
 
8.3 
Bevacizumab 
 
8.3.1 Description 
Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody.  Bevacizumab 


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blocks the binding of vascular endothelial growth factor (VEGF) to its receptors resulting in 
inhibition of angiogenesis. 
   
8.3.2 Form 
Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid ready for parenteral 
administration.  Each 400mg or 100mg glass vial contains bevacizumab with phosphate, 
trehalose, polysorbate 20, and Sterile Water for Injection, USP. 
  
8.3.3 Storage and Stability 
Bevacizumab should be stored in the refrigerator (2° to 8°C) and should remain refrigerated until 
just prior to use.  Do not freeze.  Do not shake.  Commercially available bevacizumab will be 
labeled with an expiration date.  
 
8.3.4 Compatibility 
There are no known compatibility issues with oral ricolinostat and intravenous bevacizumab. 
 
8.3.5 Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
8.3.6 Availability 
Bevacizumab is commercially available from Genentech, Inc.  Consult the American Hospital 
Formulary Service Drug Information guide, Facts and Comparisons, or the package insert for 
additional information. 
 
8.3.7 Preparation 
Vials contain no preservative and are intended for single use only.  Place the calculated dose in 
100mL of 0.9% sodium chloride for injection.   
 
8.3.8 Administration 
Bevacizumab is administered intravenously as a continuous infusion.  The initial dose should be 
administered over a minimum of 90 minutes (+/- 10 min).  If no adverse reactions occur after the 
initial dose, the second dose should be administered over a minimum of 60 minutes (+/0 10 min).  
If no adverse reactions occur after the second dose, all subsequent doses should be administered 
over a minimum of 30 minutes (+/- 10 min).  If infusion-related adverse reactions occur, all 
subsequent infusions should be administered over the shortest period that was well-tolerated.     
 
8.3.9 Ordering 
Bevacizumab is commercially available and will be ordered by the institution’s pharmacy.   
 
8.3.10 Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.   
 


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8.3.11 Destruction and Return 
Unused bevacizumab will be destroyed as per individual institutional pharmacy policies and 
procedures.   
 
 
9. SPECIAL STUDIES:  NEUROLOGICAL ASSESSMENT 
 
Paclitaxel is associated with the development of chemotherapy-induced neuropathy.  Based upon 
pre-clinical data, it is hypothesized that ricolinostat may prevent development or worsening of 
chemotherapy-induced neuropathy in patients receiving weekly paclitaxel therapy.  Patients in 
the dose expansion cohorts will therefore undergo additional neurologic evaluation as detailed 
below to assess on-treatment changes in neuropathy signs and/or symptoms. 
 
9.1 
Total Neuropathy Score-Nurse (TNSn©) 
 
9.1.1 Background 
 
Paclitaxel is an active agent in a variety of solid tumors through its inhibition of microtubule 
dynamics leading to aberrant mitosis and cell death. Its activity on microtubules is also thought 
to be associated with one of the most debilitating side effects of this class of drugs, 
chemotherapy-induced peripheral neuropathy (CIPN). In animal models paclitaxel has been 
found in the dorsal root ganglia of the peripheral nervous system (26) and leads to demyelination 
and disrupted axoplasmic transport (27). This results in pain and decreased sensitivity, 
particularly in body parts with long nerve tracts, such as the extremities. In patients paclitaxel-
induced peripheral neuropathy varies with dose and schedule from 46 to 79% for any CIPN and 
2 to 28% of patients have > grade 3 CIPN (paclitaxel label). CIPN frequently leads to paclitaxel 
dose reductions and at times to treatment discontinuation. Currently there is no FDA-approved 
drug available for treatment of CIPN. 
 
This study will implement the TNS© to assess baseline peripheral neuropathy and intermittently 
during the course of treatment in the expansion phase of the trial. The TNSn© will be used to 
evaluate peripheral nerve function and changes in it that might occur during the clinical trial. 
TNSn© was designed specifically to be implemented by trained health professionals who are not 
necessarily neurologists.  TNSn© is based on the Total Neuropathy Score© (TNS©) which was 
validated in diabetic neuropathy (28).  TNS© and its spin-offs such as TNSc©(clinical) and 
TNSn© have been widely used in single center academic studies, multi-center academic studies 
and multi-center clinical trials. 
 
The TNSn© focuses on the detection of and change in the onset and progression of peripheral 
neuropathy by measuring five categories: sensory, motor, and autonomic symptoms, sensibility 
to “pin” (small fiber sensory function) and sensibility to vibration (large fiber function).  Key 
features include bilateral assessment of function, measurements along a distal-to-proximal 
gradient and the use of established and quantitative measures of sensation.  The output of the 
TNSn© is a total score on a 0-20 scale, with five distinct sub-scores each on a 0-4 scale. 
 
 Further details are in Appendix B. 
 


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9.1.2 Method of Assessment 
 
The TNSn© will be assessed by the research nursing team.  The full TNSn© assessment is 
included in Appendix B.  Research nurses will be trained on use of the TNSn© prior to 
administration to any patients. 
 
9.1.3 Timing of Assessments 
 
The TNSn© will be administered only to patients in the expansion cohort at baseline, on day 1 of 
cycles 1, 2, and 3, and on day 1 of every other cycle thereafter.  The TNSn© will also be 
administered at the end of treatment visit.  If the TNSn© cannot be administered on day 1 of a 
given cycle, it may be “made up” at the next subsequent visit. 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the participant’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
 
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted. 
 
All study assessments and agents during the DLT assessment period must be administered on the 
protocol-specified date; no treatment windows are allowed during the DLT assessment period 
with the exception of those mandated by holidays, in discussion with the overall PI. 
 
 
Pre-
Therapy 
Each 
Cycle 
Day 
1,8,15 
Each 
Cycle 
Day 1 
only 
Every 
other 
cycle 
Off of all 
study 
therapy 
Informed Consent 
1 
 
 
 
 
Medical History 
1 
 
 
 
 
Physical Examination 
1 
X 
 
 
X 
Vital signs (Blood 
Pressure, Heart Rate and 
Temperature) 
1 
X 
 
 
X 
Performance Status 
(ECOG) 
1 
X 
 
 
X 
Adverse Event  
Assessment  
2 
X 
 
 
3 
CBC/Differential/Platelets 
2 
X 
 
 
X 


DF/HCC Protocol #: 15-483 
Protocol Version Date: October 20, 2016 
 
37 
PT/INR and PTT 
2 
 
 
 
X 
Serum chemistry4 
2 
X 
 
 
X 
Urinalysis 
2 
X5 
 
 
 
Pregnancy Test (if 
childbearing potential 
exists) 
2 
 
 
 
 
Radiographic tumor 
measurement 
1 
 
 
6 
 
CA-125 
2 
 
X 
 
 
Electrocardiogram (ECG) 
1 
 
X 
 
 
Neurological testing 
7 
 
 
8 
X 
Patient Medication 
Calendar for ricolinostat 
recording 
 
9 
 
 
 
 
One cycle = 28 days 
 
Notes: 
1. Must be obtained within 28 days prior to initiating protocol therapy. 
2. Must be obtained within 14 days prior to initiating protocol therapy. 
3. Report all adverse events that occur within 30 days of last protocol treatment. 
4. Serum chemistry includes the following:  sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, gluocose, calcium, magnesium, AST (SGOT), ALT (SGPT), alkaline 
phosphatase, total bilirubin, total protein, albumin, globulin 
5. Required at baseline for all patients.  Required at days 1 and 15 of each cycle only for 
patients in Expansion Cohort C. 
6. Tumor measurements by CT scan or MRI should be performed every 2 cycles (+/- 7 days) 
and include imaging of the chest, abdomen, and pelvis.  The same modality should be used 
throughout the study unless contraindicated for medical reasons. 
7. As detailed in Section 9.1 
8. Should be performed on Day 1 of Cycle 1, 2, 3, and then every other cycle, as detailed in 
Section 9.1.  If performed as baseline testing within 7 days of Cycle 1 Day 1, the TSRn does 
not need to be repeated for Cycle 1 Day 1. 
9. Patients should record ricolinostat dosing in the medication diary as per Appendix C. 


DF/HCC Protocol #: 15-483 
Protocol Version Date: October 20, 2016 
 
38 
 
11. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, participants with measurable disease 
will be assessed by standard criteria.  For the purposes of this study, participants should be re-
evaluated every 2 cycles.  In addition to a baseline scan, confirmatory scans will also be obtained 
at least 4 weeks following initial documentation of an objective response; the next planned 
restaging imaging study may be used as the confirmatory scan. 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 2 cycles.   
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area should not be 
considered measurable unless they have demonstrated progression following radiation.  
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 


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39 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  


DF/HCC Protocol #: 15-483 
Protocol Version Date: October 20, 2016 
 
40 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 


DF/HCC Protocol #: 15-483 
Protocol Version Date: October 20, 2016 
 
41 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is necessary to document progression. If there is 
concern about radiation exposure from CT, MRI may be used instead of CT in selected 
instances.  
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 


DF/HCC Protocol #: 15-483 
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42 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 


DF/HCC Protocol #: 15-483 
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43 
11.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 


DF/HCC Protocol #: 15-483 
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44 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
11.1.7 Response Review 
 
Scans will be evaluated by the Dana Farber/Harvard Cancer Center Tumor Imaging 
Metrics Core (DF/HCC TIMC). 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this study. 


DF/HCC Protocol #: 15-483 
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45 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
12.3 
Collaborative Agreements Language 
 
N/A.  Ricolinostat (ACY-1215) will be provided as an investigational product by Acetylon 
Pharmaceuticals, Inc. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a phase Ib study, and the primary objective is to determine the MTD dose of ricolinostat 
with weekly paclitaxel dosed at 80 mg/m2 per week (3 out of 4 weeks).   The study design is a 
3+3 design, escalating if 0/3 or 1/6 participants have a DLT during the first cycle of therapy (i.e. 
the first 28 days), at the discretion of the Principal Investigator.  If additional experience is 
necessary with a dose level that has passed the DLT period, 3 additional patients may be entered 
at the discretion of the principal investigator and also at the suggestion of Acetylon.  
 
The planned dose escalation and dose levels of ricolinostat for this study are outlined in Section 
5.1.  If treatment-related toxicities emerge during the course of this study, additional interim dose 
levels may be added based upon the observed toxicities. 
 
Probabilities of dose escalation (based on a binomial distribution) are tabulated below for a series 
of assumed true toxicity rates: 
 
True 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.65 
0.7 
0.8 
0.9 


DF/HCC Protocol #: 15-483 
Protocol Version Date: October 20, 2016 
 
46 
Toxicity 
Rate 
Probability 
of 
Escalation 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.053 
0.032 
0.009 
0.001 
    
At least 6 patients will be treated at MTD, and no more than 1 patient should experience a DLT 
at the MTD level.  Based on the exact binomial distribution, we would be unlikely to escalate the 
dose (the probability is 0.053) if the true toxicity was 65% or greater. 
 
Once the MTD/RP2D of ricolinostat with paclitaxel has been established, an additional 10 
patients will be added who have no significant peripheral neuropathy (grade 1 or less) at the 
MTD (Expansion cohort A) as well as 10 patients who have grade 2 peripheral neuropathy at the 
MTD dose of ricolinostat together with paclitaxel at 70mg/m2 per week (3 out of 4 weeks) 
(Expansion cohort B).  
 
An additional cohort at the MTD (Expansion cohort C) will also be enrolled to evaluate the 
addition of bevacizumab to the RP2D of ricolinostat with paclitaxel.  To ensure patient safety, 
this cohort will enroll 3 patients; if no DLT events are observed, an additional 3 patients will be 
enrolled, and if no or 1 DLT are observed in the 6 patients, an additional 4 patients will be 
enrolled. 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
Depending on the number of dose levels, it is anticipated that between 15 and 24 patients will be 
enrolled to the dose escalation portion of this study and up to 30 patients will be enrolled to the 
three expansion cohorts with 10 patients each.  With 10 patients in each cohort, the probability of 
observing at least one serious toxicity event is 80% if the true toxicity rate is 15%. With 10 
participants, the maximum width to a binomial exact 90% confidence interval is 0.56. 
 
Accrual rate will be up to 3 patients per month because of the phase I dose escalation design.  
Once the MTD has been reached, and the dose expansion cohorts are opened, accrual will be 2 to 
4 patients per month.  Therefore, the anticipated total accrual duration will be between 13 to 23 
months. 
 
13.3 
Stratification Factors 
 
Once the MTD of the phase Ib has been determined, expansion cohorts will be enrolled with 
patients with no clinically significant neuropathy at the start of treatment (CTCAE grade 0 or 1; 
Cohorts A and C) and patients with grade 2 neuropathy (Cohort B).  Up to 10 patients will be 
treated in both cohorts.    
 
13.4 
Interim Monitoring Plan 
 
There is no interim monitoring plan in this study.   
 
13.5 
Analysis of Primary Endpoints 
 


DF/HCC Protocol #: 15-483 
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47 
The initial analysis will report on the MTD in the dose escalation portion of the study, including 
toxicity profile. All participants will be evaluable for toxicity if they received any protocol 
therapy. All assessments will be performed by dose level. All participants will be analyzed in 
their dose assigned group, even with intra-patient dose escalation. 
 
13.6 
Analysis of Secondary Endpoints 
 
The following secondary endpoints will be explored in the expansion cohorts: 
 
(1) Toxicities especially peripheral neurotoxicity assessed using TNS© by measuring five 
categories: sensory, motor, and autonomic symptoms, sensibility to “pin” (small fiber 
sensory function) and sensibility to vibration (large fiber function). The output of the 
TNSn© is a total score on a 0-20 scale, with five distinct sub-scores each on a 0-4 scale   
(Section 9). 
 
(2) Best Overall Response, defined as the best response recorded from the start of the 
treatment until disease progression/recurrence (Section 10.1.3.4). 
 
(3) Duration of overall response (DOR), measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented. Participants without events reported are 
censored at the last disease evaluation (Section 10.1.4),  
 
(4) Progression-free survival (PFS), defined as the duration of time from registration to 
progression, or death due to any cause, whichever occurs first. Participants alive without 
disease progression are censored at date of last disease evaluation (Section 10.1.5).  
 
The limited number of subjects will provide insufficient statistical power for a formal cohort 
analysis and statistical inferences. However, we will explore trends across groups as a 
descriptive analysis plan that is estimation-only.   
 
The TNSn© is a straightforward tool to evaluate baseline peripheral neuropathy and its 
development throughout the treatment course. The TNSn© focuses on the detection of and 
change in the onset and progression of peripheral neuropathy by measuring five categories: 
sensory, motor, and autonomic symptoms, sensibility to “pin” (small fiber sensory function) and 
sensibility to vibration (large fiber function).  Key features include bilateral assessment of 
function, measurements along a distal-to-proximal gradient and the use of established and 
quantitative measures of sensation.  The output of the TNSn© is a total score on a 0-20 scale, 
with five distinct sub-scores each on a 0-4 scale. Further details are in Appendix B or the Manual 
of Operations. Descriptive statistics for the semi-quantitative neurotoxicity scale (e.g., quantiles, 
ranges, means, SD) will be computed for baseline assessments and for absolute change from 
baseline at each specified follow-up visit (e.g, completion of the 4th week cycle) within each 
cohort. Graphic methods (e.g., box plots and histograms) will also be employed to closely 
examine distributions of the longitudinal measures. The same descriptive analysis will be 
performed for each sub-component of the TNSn.  
 
All participants will be evaluable for toxicity if they received any protocol therapy.  All 
participants who have received at least one dose of protocol therapy will be included in the 


DF/HCC Protocol #: 15-483 
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48 
efficacy analysis. All assessments will be performed by dose level. All participants will be 
analyzed in their dose assigned group, even with intra-patient dose escalation. 
 
The frequency of all binary and categorical endpoints of safety and efficacy will be reported 
using 95% binomial exact confidence intervals. Time-to-event analysis of DOR and PFS will be 
based on the Kaplan-Meier product-limit estimator, using 95% confidence interval. 
 
SAS computer software 9.4 will be used for this analysis. 
 
13.7 
Reporting and Exclusions 
 
13.7.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
13.7.2 Evaluation of the Primary Efficacy Endpoint 
 
Analyses will be performed employing intent-to-treat.  Specifically, all participants 
included in the study must be assessed for response/outcome to therapy, even if there are 
major protocol therapy deviations or if they are ineligible. Each participant should be 
assigned one of the following categories: 1) complete response, 2) partial response, 3) 
stable disease, 4)  progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). By arbitrary convention, category 9 usually designates the "unknown" 
status of any type of data in a clinical database.  
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  


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REFERENCES 
 
1)  Siegel R, Ma J, Zou Z, Jemal A.  Cancer Statistics 2014.  CA Cancer J Clin. 2014;64:9-29.  
 
2)  Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA 
Cancer J Clin 2011;61:69–90.  
 
3) Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, et al.  Evaluation of new 
platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the 
Gynecologic Cancer Intergroup.J Clin Oncol. 2009; 27:1419-25. 
 
4)  McGuire WP, Hoskins WJ, Brady MF et al.  Cyclophosphamide and cisplatin compared with 
paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer.  New Engl Journal 
of Medicine 1996;334:1-6. 
 
5)  Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E, et al. Long-term 
results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin 
for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 
3016): a randomised, controlled, open-label trial. Lancet Oncol 2013;14:1020–6. 
 
6)  Vergote I, Trop_e CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant 
chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 
2010;363:943–53. 
 
7)   Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG et al.    OCEANS:  A 
randomized, double-blind, placebo-controlled phase III study of chemotherapy with or without 
bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, 
or fallopian tube cancer.   Journal of Clinical Oncology 2012;30:2039-2045. 
 
8)  Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation 
of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473–83. 
 
9)   Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A 
phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;365:2484–96. 
 
10)  Liu J and Matulonis UA.  New strategies in ovarian cancer:  Translating the Molecular 
Complexity of Ovarian Cancer into Treatment Advances.  Clinical Cancer Research, 2014 Oct 
15;20(20):5150-6. 
 
11)  Ricolinostat Investigator’s Brochure 
 
12)  Kim MS, Blake M, Baek JH et al.  Inhibition of histone deacetylase increases cytotoxicity to 
anticancer drugs targeting DNA.  Cancer Research 2003;63:7291-300. 
 
13)  Nolan L, Johnson PWM, Ganesan A. et al.  Will histone deacetylase inhibitors require 
combination with other agents to fulfill their therapeutic potential?  British J of Cancer 
2008;99:689-694. 


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14)   Markman M, Hall J, Spitz D, et al.  Phase II trial of weekly single-agent paclitaxel in 
platinum/paclitaxel-refractory ovarian cancer.  JCO 2002;20:2365-2369. 
 
15)   Kaern J, Baekelandt M, Trope CG.  A phase II study of weekly paclitaxel in platinum and 
paclitaxel-resistant ovarian cancer patients.  Eur J Gyn Oncol. 2002;23:383-389. 
 
16)  Rosenberg P, Andersson H, Boman K, et al.  Randomized trial of single agent paclitaxel 
given weekly versus every three weeks and with peroral versus intravenous steroid 
premedication to patients with ovarian cancer previously treated with platinum.  Acta 
Oncologica.  2002;41:418-424. 
 
17)   Boruta D, Fowler WC Jr, Gehrig PA, et al.  Weekly paclitaxel infusion as salvage therapy 
in ovarian cancer.  Cancer Investigation.  2003;21:675-681. 
 
18)  Ghamande S, Lele S, Marchetti D, et al.  Weekly paclitaxel in patients with recurrent or 
persistent advanced ovarian cancer.  Int J Gyn Cancer.  2003;13:142-147. 
 
19)  Kita T, Kikuchi Y, Takano M, et al.  The effect of single agent weekly paclitaxel in heavily 
pretreated patients with recurrent or persistent advanced ovarian cancer.  Gyn Oncol.  
2004;92:813-818. 
 
20)  Dunder I, Berker B, Atabekoglu C, et al.  Preliminary experience with salvage weekly 
paclitaxel in women with advanced  recurrent ovarian carcinoma.  Eur J Gyn Oncol.  
2005;26:79-82. 
 
21)  Markman M, Blessing J, Rubin SC, et al.  Phase II weekly paclitaxel (80 mg/m2) in 
platinum and paclitaxel-resistant ovarian and  primary peritoneal cancers:  A Gynecologic 
Oncology Group study.  Gyn Oncol.  2006;101:436-440. 
 
22)  Le T, Hopkins L, Baines KA, et al.  Prospective evaluations of continuous weekly paclitaxel 
regimen in recurrent platinum resistant epithelial ovarian cancer.  Gyn Oncol.  2006;102:49-53. 
 
23) Byrd L, Thisthlewaite FC, Clamp A, et al.  Weekly paclitaxel in the treatment of recurrent 
ovarian carcinoma.  Eur J Gyn Oncol.  2007; 28:174-178. 
 
24)  Linch M, Stavridi F, Hook J, et al.  Experience in a UK cancer centre of weekly paclitaxel in 
the treatment of relapsed ovary and peritoneal cancer.  Gyn Oncol.  2008;109:27-32. 
 
25)  O’Malley DM, Richardson DL, Rheaume PS, et al.  Addition of  bevacizumab to weekly 
paclitaxel significantly improves progression free survival in heavily pretreated recurrent 
epithelial ovarian cancer.  Gyn Oncol.  2011;121:269-272.   
 
26)  Cavaletti G, Cavalletti E, Oggioni N, et al.  Distribution of paclitaxel within the nervous 
system of the rat after repeated intravenous administration.  Neurotoxicology.  2000:21(3):389-
93. 
 


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27)  Lipton RB, Apfel SC, Dutcher JP, et al.  Taxol produces a predominantly sensory 
neuropathy.  Neurology.  1989;39(3):368-73. 
 
28)  Cornblath DR, Chaudhry V, Carter K, et al.  Total neuropathy score: validation and 
reliability study.  Neurology.  1999; 53(8):1660-4.


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
TOTAL NEUROPATHY SCORE-NURSE (TNSn©) 
 
Total Neuropathy Score-Nurse (TNSn) 
Copyright Johns Hopkins University 2008, all rights reserved. 
 
 


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APPENDIX C: PATIENT DRUG DIARY (DOSE LEVELS 1 THROUGH 4) 
Today’s Date ______________________________ 
Cycle # ______ 
Patient Name ______________________________ 
Patient Study ID _________________ 
1. Complete one form for each cycle (28 days). 
2. Record the date, the dose you took, and when you took it. 
3. Take dose 1 hour after eating followed by a half glass of water; do not eat for 2 hours after taking dose. 
4. If you miss a dose, you have up to 2 hours to make this dose up. Otherwise, write “missed” where you 
would normally write the time of your dose. Do not make up vomited doses. 
5. Refrain from taking herbal medications, eating citrus fruits and drinking citrus juices. 
6. Blacked out rows are days where you would not be expected to take ricolinostat. 
7. The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
RICOLINOSTAT 
Take _____ (number) ______ mg once daily at least 1 hour after and 2 hours before any food or other medications.  
Day 
Date 
Milligrams taken 
Time 
Please note if dose not taken here 
1 
1/1/15 
80 
8:00 AM 
-- 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
Patient’s Signature: ___________________________________        Date: ___________________ 
Physician/Nurse/Data Manager’s Signature _________________________  Date______________ 
 


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APPENDIX D:  PATIENT DRUG DIARY (DOSE LEVEL -1 ONLY) 
Today’s Date ______________________________ 
Cycle # ______ 
Patient Name ______________________________ 
Patient Study ID _________________ 
1. Complete one form for each cycle (28 days). 
2. Record the date, the dose you took, and when you took it. 
3. Take dose 1 hour after eating followed by a half glass of water; do not eat for 2 hours after taking dose. 
4. If you miss a dose, you have up to 2 hours to make this dose up. Otherwise, write “missed” where you 
would normally write the time of your dose. Do not make up vomited doses. 
8. Refrain from taking herbal medications, eating citrus fruits and drinking citrus juices. 
5. Blacked out rows are days where you would not be expected to take ricolinostat. 
6. The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
RICOLINOSTAT 
Take _____ (number) ______ mg once daily at least 1 hour after and 2 hours before any food or other medications.  
Day 
Date 
Milligrams taken 
Time 
Please note if dose not taken here 
1 
1/1/15 
80 
8:00 AM 
-- 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
Patient’s Signature: ___________________________________        Date: ___________________ 
Physician/Nurse/Data Manager’s Signature _________________________  Date______________