Conditions: Brain Stem Neoplasm Pineal Region Neoplasm Recurrent Lymphoma Recurrent Malignant Solid Neoplasm Recurrent Primary Central Nervous System Neoplasm Recurrent Visual Pathway Glioma Refractory Lymphoma Refractory Malignant Solid Neoplasm Refractory Primary Central Nervous System Neoplasm Refractory Visual Pathway Glioma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of entinostat in treating pediatric patients with solid tumors that have come back or have not responded to treatment. Entinostat may block some of the enzymes needed for cell division and it may help to kill tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of entinostat administered as a single-agent, once weekly to children with recurrent or refractory solid tumors.

II. To define and describe the toxicities of entinostat administered as a single agent, once weekly to children with recurrent or refractory solid tumors.

III. To characterize the pharmacokinetics of entinostat in children with recurrent or refractory cancer.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of entinostat within the confines of a phase 1 study.

II. To assess change in histone H3 and H4 acetylation in peripheral blood mononuclear cells (PBMCs) as a marker of the biologic activity of entinostat.

OUTLINE: This is a dose escalation study.

Patients receive entinostat orally (PO) on days 1, 8, 15, and 22. Cycles repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Arms:
arm 1: Patients receive entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Entinostat intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
Pediatric Early Phase Clinical Trial 
Network (PEP-CTN) and  
Developmental Therapeutics (DVL) 
Chair 
Brenda J. Weigel, M.D. 
weige007@umn.edu 
 
PEP-CTN and  
Developmental Therapeutics (DVL) 
Vice Chair  
Elizabeth Fox, M.D. 
foxe@email.chop.edu 
 
PEP-CTN Operations  
Data & Statistics Center Director 
Thalia Beeles, MPH 
tbeeles@childrensoncologygroup.org 
 
PEP-CTN Statistician  
Charles G. Minard, Ph.D. 
minard@bcm.edu 
 
 
PEP-CTN and  
DVL Chair’s Office 
University of Minnesota/ 
Masonic Cancer Center 
Masonic Children’s Hospital 
420 Delaware Street, SE 
MMC 366 
Minneapolis, MN  55455 
 
P 612 626 5501 
F 612 624 3913 
 
 
Children’s Oncology Group 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
PEP-CTN Operations Data & 
Statistics Center 
222 E. Huntington Drive 
Suite 100  
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
 
A National Cancer Institute  
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
         Page i 
 
 
 
January 31, 2019 
 
Martha Kruhm, M.S., RAC 
Head, Protocol and Information Office (PIO)  
National Institutes of Health/NCI/DCTD/CTEP/OIB/PIO 
9609 Medical Center Drive, OIB MSC 9742, Room #5W246 
Bethesda, MD 20892-9742 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #4 to ADVL1513, A Phase 1 Study of 
Entinostat, an Oral Histone Deacetylase Inhibitor, in Pediatric Patients with 
Recurrent or Refractory Solid Tumors, Including CNS Tumors and Lymphoma.  
 
The protocol has been amended in response to the Request for Amendment from 
Dr. Malcolm Smith, dated December 20, 2018, in which COGC transitions to PEP-
CTN.  
 
Please contact us if you have any further questions. 
 
 
Sincerely, 
 
Alina Stout, Protocol Coordinator for 
Andrew Bukowinski, M.D., ADVL1513 Study Chair, and 
Brenda Weigel, M.D., PI, PEP-CTN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 














                         
 
 
 
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STUDY COMMITTEE 
 
 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Andrew Bukowinski, MD 
Brenda J. Weigel, MD 
Children’s Hospital of Pittsburgh of UPMC 
Chair, Developmental Therapeutics  
Hematology/Oncology 
Hematology/Oncology 
4401 Penn Ave.  
University of Minnesota Medical Center - Fairview 
Pittsburgh, PA 15224 
Department of Pediatrics 
420 Delaware Street, SE  MMC 366 
Minneapolis, MN 55455 
 
STUDY VICE CHAIR  
Bill Hoon Chang, MD, PhD 
Pediatric Hematology/Oncology 
Elizabeth Fox, MD 
3181 SW Sam Jackson Park Rd., CDRC-P 
Vice Chair, Developmental Therapeutics 
Portland, OR 97239 
Children’s Hospital of Philadelphia 
Pediatrics/Division of Oncology 
3501 Civic Center Blvd. 
CTRB-4016 
 
Philadelphia, PA 19104 
SENIOR STATISTICIAN 
Charles Minard, PhD 
Baylor College of Medicine  
One Baylor Plaza, BCM 122 
 
Houston, TX 77030 
Charles Keller, MD 
Hematology/Oncology 
12655 SW Beaverdam Rd.-West 
Beaverton, OR 97005 
 
 
 
 
 
STUDY PHARMACOLOGIST 
 
Joel M. Reid, PhD  
 
Mayo Clinic 
 
Guggenheim 17-42C 
 
200 First Street SW 
 
Rochester, MN 55905 
 
 
 
 
 
 
 
 
 
 
 
 
 


                         
 
 
 
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STUDY COMMITTEE, CONT. 
 
 
PROTOCOL COORDINATOR 
STUDY PHARMACIST 
Alina Stout, BS 
Olga Militano, PharmD 
Children’s Oncology Group – Operations Center 
Children’s Oncology Group – Operations Center 
222 E. Huntington Drive, Suite 100 
222 E. Huntington Drive, Suite 100 
Monrovia  CA  91016 
Monrovia, CA  91016 
 
STUDY NURSE 
 
Elizabeth Ann Gilger, RN 
 
Cincinnati Children's Hospital Medical Center 
 
Oncology Program, MLC 11013 
 
3333 Burnet Avenue 
 
Cincinnati, OH 45229 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For PEP-CTN Operations and Data/Statistics 
Contacts see: 
http:members.childrensoncologygroup.org 
 
 
AGENT NSC# AND IND#’s 
 
 
 
NCI-Supplied Agent: 
Entinostat (SNDX-275, MS-275, NSC#706995, 
 
 
IND Sponsor: CTEP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTION 8.3.6 AND 8.4.6 FOR SPECIMEN SHIPPING ADDRESSES 




                         
 
 
 
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continue receiving protocol therapy provided that the patient meets the criteria for starting subsequent cycles (Section 
5.2) and does not meet any of the criteria for removal from protocol therapy or off study criteria (Section 10.0). 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
 
1.1.1 
To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose of entinostat administered as a single-agent, once weekly to children with 
recurrent or refractory solid tumors. 
 
1.1.2 
To define and describe the toxicities of entinostat administered as a single agent, 
once weekly to children with recurrent or refractory solid tumors. 
 
1.1.3 
To characterize the pharmacokinetics of entinostat in children with recurrent or 
refractory cancer. 
 
1.2 
Secondary Aims 
 
1.2.1 
To preliminarily define the antitumor activity of entinostat within the confines of 
a Phase 1 study. 
 
1.2.2 
To assess change in histone H3 and H4 acetylation in peripheral blood 
mononuclear cells (PBMCs) as a marker of the biologic activity of entinostat. 
 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction/Rationale for Development 
 
HDAC inhibitors as anti-cancer agents 
Epigenetic processes provide a mechanism for controlling gene expression by impacting 
chromatin configuration. Along with methylation, acetylation of histones plays a key role 
in regulating gene expression by controlling the interaction between histones and DNA.1 
Histone acetylation relaxes the chromatin conformation and allows access of transcription 
factors to DNA promoter regions, thus leading to gene expression. Histone acetyl 
transferases (HAT) and histone deacetylase (HDAC) enzymes modulate acetylation, which 
determines whether the nucleosome complex is in a more compact or open state.2 
 
Processes that control cell fate, such as cell cycle progression, differentiation, and apoptosis 
are strongly influenced by acetylation status of histones and the resultant impact on gene 
transcription. There are four classes of HDACs, which are grouped by their homology to 
yeast proteins.3 The Class I family consists of HDACs 1, 2, 3, and 8. The Class II family 
contains HDACs 4, 5, 7, and 9 (class IIa) as well as HDACs 6 and 10 (class IIb). Class III 
HDACs are also known as SIRTs and include seven family members. The class IV family 


                         
 
 
 
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only includes HDAC 11. The relative role of each of the HDACs in biologic processes 
continue to be elucidated. 
 
Considerable evidence now implicates histone modification in oncogenesis. HDACs play 
an important role in cell differentiation and also modulate the balance between pro- and 
anti-apoptotic processes in cells. Deacetylation by HDACs alters the activity of many 
transcription factors that play a role in cancer, including c-Myc, E2F, p53, and nuclear 
factor kB.2 Dysregulation of histone acetylation may lead to aberrant repression of tumor 
suppressor genes, resulting in maintenance of malignant phenotype. Many cancer cells 
show high levels of HDAC expression and hypoacetylation of histones.4 
 
HDAC inhibition is thought to reactivate abnormally repressed expression of pro-apoptotic 
genes in tumor cells.  HDAC inhibitors lead to cell cycle arrest and differentiation in many 
cancer cell lines. Several HDAC inhibitors are in various stages of development. 
  
Entinostat (SNDX-275) 
Entinostat (SNDX-275) is an oral small molecule inhibitor of class I and IV HDACs 
(HDACs 1, 2, 3, and 11).3 Entinostat has demonstrated significant growth inhibitory 
activity against cancer cells in vitro.5,6 Entinostat has also shown in vivo anti-tumor activity 
in a variety xenograft models.3,7 The potency and selectivity for specific HDAC isoforms 
may separate entinostat from other HDAC inhibitors in clinical development. In contrast 
to other HDAC inhibitors in clinical development, entinostat inhibits class I HDACs more 
potently than class II HDACs. As there is some in vitro data that inhibition of class I 
HDACs is sufficient to induce apoptosis in cancer cell lines, entinostat may demonstrate 
anti-tumor activity with limited clinical toxicity against a variety of cancers.7 
 
Entinostat strongly inhibits the class I HDACs, HDACs 1, 2, and 3 with IC50 values of 
0.119 M, 0.123 M, and 0.181 M, respectively.8 The agent also inhibits HDAC 11 with 
an IC50 of 0.427 M, but is considerably less effective at inhibiting other HDACs.  Growth 
of several human cancer cell lines was inhibited by entinostat with IC50 values ranging 
from 0.041 to 4.71 M. Entinostat was most potent against ovarian cancer (IC50 = 0.0415 
M), lung cancer (IC50 = 0.0195 M), leukemia (IC50 = 0.0212-0.589 M), and gastric 
cancer (IC50 = 0.820 M) cell lines.7 Along with in vitro cell growth inhibition, increased 
levels of the cell cycle inhibitor p21 and cell cycle arrest were observed. In addition, 
hyperacetylation of histones was seen in tumor cell lines at concentrations of 0.3  and 
1 M. Entinostat also demonstrated significant in vivo antitumor activity against xenograft 
models of melanoma, prostate, breast, and non-small cell lung cancer.9 
 
Rationale for use of HDAC inhibitors in combination with other anti-cancer agents 
includes, the increased expression of pro-apoptotic genes with these agents. Many HDAC 
inhibitors have been tested in combination with cytotoxic chemotherapy and radiation 
therapy. In estrogen receptor positive breast cancer models, combination of entinostat 
overcomes resistance to aromatase inhibitors.10 Entinostat also shows synergy with EGFR 
inhibition in lung cancer cell lines.11 
 
 


                         
 
 
 
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2.2 
Preclinical Studies 
 
2.2.1 
Antitumor Activity 
Pediatric solid tumors commonly exhibit alterations in transcription factors whose 
target genes regulate cell proliferation, differentiation, and survival. HDAC 
inhibitors have the potential to allow expression of genes repressed through 
epigenetic mechanisms. For this reason, HDAC inhibitors have been tested in vitro 
against a variety of pediatric cancer cell lines. Cell lines from neuroblastoma, 
Ewing sarcoma, retinoblastoma, osteosarcoma, and medulloblastoma were 
inhibited at entinostat sub-micromolar concentrations.6 Entinostat demonstrated 
more potent in vitro inhibition than vorinostat against several pediatric solid tumor 
cell lines, including the Rh30 rhabdomyosarcoma cell line (entinostat IC50 = 0.062 
M versus vorinostat IC50: 1.72 M) and TC-71 Ewing sarcoma cell line 
(entinostat IC50 = 0.10 M versus vorinostat IC50 = 1.28 M).6,12 Similar to the 
HDAC inhibitors vorinostat and sodium butyrate, treatment of Ewing sarcoma 
cells with entinostat leads to histone acetylation, growth inhibition, and 
apoptosis.13 
 
In cell lines derived from osteosarcoma lung metastases, entinostat induces Fas 
ligand mediated cell death through downregulation of the apoptosis inhibitor, c-
FLIP. In vivo treatment with entinostat resulted in decreased c-FLIP expression 
and induced tumor regression in nu/nu-mice with osteosarcoma lung metastases.14 
Growth of established tumors in neuroblastoma and Ewing sarcoma models were 
also significantly suppressed with entinostat doses of 24.5 mg/kg given every 5-7 
days.6 
 
In alveolar rhabdomyosarcoma, Pax3:Foxo1 fusion oncogene mediates resistance 
to cytotoxic chemotherapy and radiation. There is some evidence that Pax3:Foxo1 
expression may be epigenetically regulated. Treatment with entinostat silences 
protein and mRNA expression of Pax3:Foxo1 in both mouse and human alveolar 
rhabdomyosarcoma (ARMS) cells.15 In contrast, treatment with vorinostat appears 
to have no effect on Pax3:Foxo1 expression in human ARMS cells. Moreover, 
through apparent downregulation of Pax3:Foxo1 expression, entinostat separately 
shows synergy with each vincristine, actinomycin-D, and radiation therapy in an 
orthotopic mouse model of alveolar rhabdomyosarcoma. Entinostat appears to 
enhance the effects of vincristine in embryonal rhabdomyosarcoma as well, 
although the mechanism for this effect is unclear.16 
 
Data suggests that aberrant regulation of histone acetylation also plays in the 
progression and maintenance of pediatric central nervous system (CNS) tumors. 
As a single-agent, vorinostat has shown activity against glioma, medulloblastoma, 
and supratentorial primitive neuroectodermal tumor cells.17-19 Several studies have 
shown synergy with vorinostat and radiation in pediatric brain tumor cells.20 The 
Children’s Oncology Group ACNS0927 study evaluated vorinostat in combination 
with radiation therapy for children with diffuse intrinsic pontine glioma, and 
efficacy data from this study is pending. Similar to vorinostat, entinostat enhances 
the effect of radiation in human glioma cells.21 In addition, entinostat enhances 
chemotherapy-induced apoptosis in primary human medulloblastoma cells by 


                         
 
 
 
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promoting p53-dependent activation of Bax.22 In combination with doxorubicin 
and other chemotherapeutic agents, entinostat induces apoptosis in glioblastoma 
cells and suppresses growth of medulloblastoma tumors in vivo.22,23 
 
HDAC inhibitors and entinostat, in particular, may also be relevant in hematologic 
malignancies. In Hodgkin lymphoma cell lines, entinostat inhibits proliferation 
and induces cell death. The anti-cancer activity of entinostat correlates with 
increased H3 acetylation and upregulation of p21 expression.24  
 
 
2.2.2 
Animal Toxicology 
 
Single-dose toxicology studies were conducted in mice and rats. Maximum non-
lethal doses were 380 mg/kg in mice and 150 mg/kg in rats. Repeated doses 
administered to rats, beagle dogs, and cynomolgus monkeys demonstrated toxic 
effects on tissues with high cellular turnover. Adverse effects included fur 
thinning, scabbing of skin, atrophy of lymphatic organs, and bone marrow toxicity 
(leukopenia, anemia, and thrombocytopenia). Gastrointestinal toxicity was noted 
in monkeys (diarrhea, vomiting) and rats (diarrhea, reduced food consumption). 
Toxic effects on reproductive organs and fertility were noted, and embryo-fetal 
toxicity was noted in rats and rabbits at doses below 2 mg/kg daily. 
 
2.2.3 
Preclinical Pharmacokinetic Studies 
 
Preclinical pharmacokinetics of entinostat have been evaluated in mice, rats, dogs, 
and monkeys using a liquid chromatography-mass spectroscopy method to 
measure concentrations. Peak plasma concentrations were achieved between 5 and 
30 minutes after oral administration to mice, rats, and dogs and 2 hours after dosing 
in monkeys. Oral bioavailability after a single dose ranged from 30% in dogs to 
80% in monkeys. In dogs, lower gastric pH increased absorption of entinostat from 
30% to 55%, and feeding decreased absorption compared to fasting. 
 
Entinostat was moderately metabolically stable in liver microsomes of humans and 
all animal species evaluated as well as in human cytochrome P-450 preparations. 
Reversible inhibition by entinostat was noted for CYP2C8 and CYP3A4. Moderate 
reversible inhibition was also demonstrated for CYP1A2, CYP2B6, CYP2C9, 
CYP2C19, CYP2D6, and CYP2E1, but only by > 50% at the highest 
concentrations. Entinostat did not inhibit any UGT enzymes. It was found to 
induce CYP1A2, CYP2C6, and CYP2B8 as well as UGT1A4. No formal drug 
interaction studies have been performed. 
 
Entinostat was excreted to a similar extent in urine and feces of albino and 
pigmented rats, with 68% to 85% excreted in the first 24 hours.  
 
2.3 
Adult Studies 
 
2.3.1 
Phase 1 Studies 
 


                         
 
 
 
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Several clinical studies of entinostat have been completed in adults. Six trials (NCI 
or industry-sponsored) using entinostat as monotherapy have been completed. In a 
phase 1 study in adults with refractory solid tumors and lymphoma, daily oral 
administration was not tolerable as the first two patients experienced DLT at the 
first dose level of 2 mg/m2.25 
 
Pharmacokinetic analysis showed the half-life to be 39 to 80 hours. Twenty-eight 
patients were treated on a once every 14-day schedule. The MTD was 10 mg/m2 
and dose-limiting toxicities were grade 3 fatigue, anorexia, nausea, and vomiting. 
 
In another phase 1 trial in adults with refractory solid tumors and lymphoid 
malignancies, entinostat was administered orally once weekly for 4 weeks of a 6-
week cycle.26 Among 19 evaluable patients, no grade 4 toxicities were observed. 
DLTs were grade 3 hypophosphatemia, hyponatremia, and hypoalbuminemia. The 
MTD was 6 mg/m2 on this schedule. An additional phase 1 trial or entinostat 
evaluated multiple schedules.27 Toxicities were similar to other phase 1 trials and 
DLTs were hypophosphatemia and asthenia. A twice-weekly schedule was found 
to not be tolerable, and the recommended phase 2 dose (RP2D) was 4 mg/m2 when 
entinostat is given weekly for 3 weeks every 28 days. 
 
Several adult phase 1 combination trials with entinostat and other agents (including 
azacytidine, 13-cis-retinoic acid, imatinib, sorafenib, clofarabine, and lapatanib) 
have been completed or are ongoing. 
 
2.3.2 
Phase 2 Studies 
 
Two phase 2 single-agent trials of entinostat in adults have been completed. Single-
agent entinostat (15 mg weekly or 10-15mg every other week) was well tolerated 
and demonstrated tumor reduction in 63% of evaluable patients in a phase 2 trial 
for patients with refractory Hodgkin’s lymphoma.28 A phase 2 study using 2 
different dosing scheduled of single-agent entinostat for patients with metastatic 
melanoma showed no objective responses, but stable disease in 25% of patients.29 
Several phase 2 combination studies for adult patients with non-small cell lung 
cancer, breast cancer, hematologic malignancies, colorectal cancer, and renal cell 
carcinoma are ongoing or have been completed. Entinostat with exemestane was 
compared to exemestane plus placebo in a randomized phase 2 trial for patients 
with recurrent or metastatic estrogen receptor-positive breast cancer.30 Treatment 
with the entinostat combination improved PFS to 4.3 months versus 2.3 months 
(one-sided p = 0.055) and improved overall survival from 19.8 months to 28.1 
months (one-sided p = 0.018). Based on these data, entinostat has received 
Breakthrough Therapy designation from the U.S. Food and Drug Administration 
(FDA). The combination of entinostat and exemestane is being evaluated in a 
Phase 3 trial for postmenopausal women with metastatic ER-positive breast cancer 
whose disease has progressed on hormonal therapy. 
 
Based on the compiled results of clinical trials thus far, the recommended dose 
regimens for further development of entinostat in adults are 5 mg once weekly, 10 
mg once every 2 weeks, and 7 to 15 mg weekly for 3 weeks of a 4-week cycle. 


                         
 
 
 
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2.3.3 
Pharmacology/Pharmacokinetics/Correlative and Biological Studies 
 
Pharmacokinetics of entinostat were characterized in three separate phase 1 
trials.25,27,31 Variability in pharmacokinetic parameters across the studies was seen, 
possibly due to different sampling schemes and different assays used in each study. 
In general, pharmacokinetics for entinostat were linear with proportional AUC and 
peak concentrations across dose levels up to 12 mg/m2, and toxicity appears to be 
dose-dependent. Entinostat is not metabolized by CYP enzymes, and the primary 
elimination pathway is unknown. The elimination half-life of entinostat ranged 
from 54 to 161 hours in one single-agent Phase 1 study, and ranged from 39 to 80 
hours in another study. Pharmacokinetic parameters are not affected by 
combination treatment with exemestane or erlotinib. Lastly, food appears to impact 
entinostat PK, and therefore, the agent should be taken on an empty stomach at 
least 1 hour before and 2 hours after a meal. 
 
In a phase 1 trial, hyperacetylation of histone H3 was seen in peripheral blood 
mononuclear cells from several patients with solid tumors after administration of 
entinostat at doses of 2 mg/m2 and 10 mg/m2.25,27 
 
 
2.4 
Pediatric Studies 
 
2.4.1 
Prior Experience in Children 
There have been no prior pediatric studies with entinostat. 
 
 
2.5 
Overview of Proposed Pediatric Study 
 
This will be a phase 1 dose-escalation trial of entinostat in pediatric patients with recurrent 
or refractory solid tumors including CNS tumors and lymphoma. The primary study 
objectives are to identify the maximum tolerated dose (MTD) or recommended phase 2 
dose (RP2D), characterize the toxicity profile, evaluate the change in histone acetylation, 
and describe the pharmacokinetics of entinostat in pediatric patients with solid tumors. 
 
Patients age 1 to 21 years with recurrent or refractory solid tumors, including CNS tumors 
and lymphoma will be eligible. Entinostat will be administered orally at a starting dose of 
3 mg/m2 once weekly, which is equivalent to the RP2D of 5 mg in adults when entinostat 
is administered on a weekly schedule. Entinostat will be administered continuously once 
weekly in 28-day cycles. Cohorts will be enrolled and doses escalated using the rolling six 
design.32 Doses will be escalated by approximately 30% in each subsequent cohort. 
 
The MTD will be determined from toxicities observed during the first cycle of treatment. 
The MTD will be the dose level below which ≥ 2 out a cohort of up to 6 patients 
experience DLTs. Disease evaluations will be performed at the end of Cycle 1, then every 
other cycle for 2 cycles, then every 3 cycles. Pharmacokinetic and pharmacodynamic 
sampling will be performed during the 1st cycle of treatment. 


                         
 
 
 
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3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in 
conjunction with the Oncology Patient Enrollment Network (OPEN), a web-based registration 
system available on a 24/7 basis. It is integrated with the NCI Cancer Trials Support Unit (CTSU) 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in the 
RAVE database. 
 
Access requirements for OPEN:  
Investigators and site staff will need to be registered with CTEP and have a valid and active Cancer 
Therapy Evaluation Program-Identity and Access Management (CTEP-IAM) account (check at < 
https://ctepcore.nci.gov/iam/index.jsp >). This is the same account (user id and password) used for 
credentialing in the CTSU members' web site. To perform registrations in OPEN, the site user must 
have been assigned the 'Registrar' role on the relevant Group or CTSU roster. OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. 
 
3.1 
Current Study Status  
Investigators should refer to the COG website to determine if the study is currently open 
for accrual.  If the study is listed as active, investigators should then access the Studies 
Requiring Reservations page to ensure that a reservation for the study is available. To 
access the Studies Requiring Reservations page:  
1. Log in to https://open.ctsu.org/open/ 
2.  Click the Slot Reservation Tab. The Site Patient page opens.  
3.  Click the Report Tab. The Slot Reservation Report opens. Available Slots are 
detailed per study strata. 
 
3.2 
IRB Approval 
NCI Pediatric CIRB approval or local IRB approval of this study must be obtained by a 
site prior to enrolling patients. Sites must submit CIRB/IRB approvals to the NCI’s Cancer 
Trials Support Unit (CTSU) Regulatory Office and allow 3 business days for processing. 
The CTSU IRB Certification Form may be submitted in lieu of the signed IRB approval 
letter. All CTSU forms can be located on the CTSU web page (www.ctsu.org). Any other 
regulatory documents needed for access to the study enrollment screens will be listed for 
the study on the CTSU Member’s Website under the Regulatory Tab. 
 
Sites participating on the NCI CIRB initiative and accepting CIRB approval for the study 
are not required to submit separate IRB approval documentation to the CTSU Regulatory 
Office for initial, continuing or amendment review. This information will be provided to 
the CTSU Regulatory Office from the CIRB at the time the site’s Signatory Institution 
accepts the CIRB approval. The Signatory site may be contacted by the CTSU Regulatory 
Office or asked to complete information verifying the participating institutions on the 
study. 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 


                         
 
 
 
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Regulatory Submission Portal: www.ctsu.org (members’ area) → Regulatory Tab 
→ Regulatory Submission 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
For general (non-regulatory) questions, call the CTSU General Helpdesk at 1-888-823-
5923 or contact CTSU by email at ctsucontact@westat.com. 
 
Study centers can check the status of their registration packets by accessing the Site 
Registration Status page on the CTSU Member’s Website under the Regulatory Tab. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory 
Office.) 
 
3.3 
Patient Registration 
Prior to enrollment on study, patients must be assigned a COG patient ID number. This 
number is obtained via the COG Registry in the OPEN system once authorization for the 
release of protected health information (PHI) has been obtained. 
 
3.4 
Reservation and Contact Requirements 
Before enrolling a patient on study, a reservation must be made through the OPEN website 
and the Study Chair or Vice Chair should be notified. (The patient will need a COG patient 
ID number in order to obtain a reservation). Patients must be enrolled within 7 calendar 
days of making a reservation.  
 
Reservations may be obtained 24-hours a day through the OPEN website.  
 
3.5 
Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the patient or the patient’s parents or guardian if the patient is a 
child, and a signed informed consent and assent will be obtained according to institutional 
guidelines. 
 
3.6 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent. This can be accomplished 
through one of the following mechanisms: a) the COG screening protocol, b) an IRB-
approved institutional screening protocol or c) the study-specific protocol. Documentation 
of the informed consent for screening will be maintained in the patient’s research chart. 
Studies or procedures that were performed for clinical indications (not exclusively to 
determine eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 


                         
 
 
 
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3.7 
Eligibility Checklist 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist. A signed copy of the checklist will be uploaded 
into RAVE immediately following enrollment. 
 
3.8 
Institutional Pathology Report 
Immediately following enrollment, the institutional pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into RAVE. The report must 
include the associated study number and COG patient registration and accession numbers. 
Personal identifiers, including the patient’s name and initials must be removed from the 
institutional pathology report prior to submission. 
 
3.9 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have 
been met. Patients who give informed consent for the protocol in order to undergo 
screening for eligibility are not considered enrolled and should not be enrolled until the 
screening is completed and they are determined to meet all eligibility criteria. Study 
enrollment is accomplished by going to the CTSU OPEN (Oncology Patient Enrollment 
Network) https://open.ctsu.org/open/. For questions, please contact the COG Study 
Research 
Coordinator, 
or 
the 
CTSU 
OPEN 
helpdesk 
at 
https://www.ctsu.org/CTSUContact.aspx. Patients must be enrolled before treatment 
begins. The date protocol therapy is started must be no later than five (5) calendar days 
after the date of study enrollment. Patients must not receive any protocol therapy prior 
to enrollment. 
 
 
3.10 
Dose Assignment 
The dose level will be assigned via OPEN at the time of study enrollment. 
 
 
4.0 
PATIENT ELIGIBILITY 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy. Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility. If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are older than 7 days, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, 
bilirubin, ALT (SGPT) and serum  creatinine. If the recheck is outside the limits of eligibility, the 
patient may not receive protocol therapy and will be considered off protocol therapy. Imaging 
studies must be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging 
if necessary).  
 
 
Clarification in timing when counting days: As an example, please note that if the patient’s last day 
of prior therapy is September 1st, and the protocol requires waiting at least 7 days for that type of 
prior therapy, then that patient cannot be enrolled until September 8th. 


                         
 
 
 
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Important note: The eligibility criteria listed below are interpreted literally and cannot be 
waived (per COG policy posted 5/11/01). All clinical and laboratory data required for 
determining eligibility of a patient enrolled on this trial must be available in the patient’s 
medical or research record which will serve as the source document for verification at the 
time of audit. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age:  Patients must be ≥ than 12 months and  21 years of age at the time of study 
enrollment. 
 
4.1.2 
Patients must have a BSA of ≥ 1.17 m2 at time of study enrollment. 
 
4.1.3 
Patients must be able to swallow intact tablets. 
 
4.1.4 
Diagnosis: Patients with recurrent or refractory solid tumors, including CNS 
tumors or lymphoma, are eligible. Patients must have had histologic verification 
of malignancy at original diagnosis or relapse except in patients with intrinsic brain 
stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations 
of CSF or serum tumor markers including alpha-fetoprotein or beta-HCG.  
 
4.1.5 
Disease Status:  
Patients must have either measurable or evaluable disease (see Sections 12.2 and 
12.3 for definitions).  
 
4.1.6 
Therapeutic Options: Patient’s current disease state must be one for which there is 
no known curative therapy or therapy proven to prolong survival with an 
acceptable quality of life. 
  
4.1.7 
Performance Level:  Karnofsky  50% for patients > 16 years of age and Lansky 
 50 for patients  16 years of age (See Appendix I). Note:  Neurologic deficits in 
patients with CNS tumors must have been relatively stable for at least 7 days prior 
to study enrollment. Patients who are unable to walk because of paralysis, but who 
are up in a wheelchair, will be considered ambulatory for the purpose of assessing 
the performance score. 
 
 
4.1.8 
Prior Therapy 
Patients must have fully recovered from the acute toxic effects of all prior anti-
cancer therapy and must meet the following minimum duration from prior anti-
cancer directed therapy prior to enrollment. If after the required timeframe, the 
defined eligibility criteria are met, e.g. blood count criteria, the patient is 
considered to have recovered adequately. 
 
a. Cytotoxic chemotherapy or other anti-cancer agents known to be 
myelosuppressive. See DVL homepage for commercial and Phase 1 
investigational agent classifications. For agents not listed, the duration 


                         
 
 
 
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of this interval must be discussed with the study chair and the study-
assigned Research Coordinator prior to enrollment. 
i. 
Solid Tumor Patients: ≥ 21 days after the last dose of cytotoxic or 
myelosuppressive chemotherapy (42 days if prior nitrosourea).  
 
ii. Lymphoma Patients:  
• 
A waiting period prior to enrollment is not required for 
patients 
receiving 
standard 
cytotoxic 
maintenance 
chemotherapy (i.e. corticosteroid, vincristine, 6MP, and/or 
methotrexate). 
 
• 
≥ 14 days must have elapsed after the completion of other 
cytotoxic therapy, with the exception of hydroxyurea, for 
patients not receiving standard maintenance therapy. 
Additionally, patients must have fully recovered from all 
acute toxic effects of prior therapy. 
 
Note: Cytoreduction with hydroxyurea must be discontinued 
≥ 24 hours prior to the start of protocol therapy. 
  
 
b. Anti-cancer agents not known to be myelosuppressive (e.g. not 
associated with reduced platelet or ANC counts): ≥ 7 days must have 
elapsed from the last dose of agent. See DVL homepage for 
commercial and Phase 1 investigational agent classifications. For 
agents not listed, the duration of this interval must be discussed with 
the study chair and the study-assigned Research Coordinator prior to 
enrollment.  
 
c. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of 
antibody, and toxicity related to prior antibody therapy must be 
recovered to Grade ≤ 1. 
 
d. Hematopoietic Growth Factors: ≥ 14 days must have elapsed from the 
last dose of a long-acting growth factor (e.g. Pegfilgrastim) or 7 days 
for short-acting growth factor. For agents that have known adverse 
events occurring beyond 7 days after administration, this period must 
be extended beyond the time during which adverse events are known 
to occur.  The duration of this interval must be discussed with the study 
chair and the study-assigned Research Coordinator. 
 
e. Interleukins, Interferons and Cytokines (other than Hematopoietic 
Growth Factors): ≥ 21 days must have elapsed from the last dose of 
interleukins, interferon or cytokines (other than Hematopoietic 
Growth Factors). 
 
f. Stem cell Infusions (with or without TBI): 
• 
Allogeneic (non-autologous) bone marrow or stem cell transplant, 
or any stem cell infusion including DLI or boost infusion: ≥ 84 


                         
 
 
 
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days must have elapsed from infusion and no evidence of GVHD. 
 
• 
Autologous stem cell infusion including boost infusion: ≥ 42 days 
must have elapsed from infusion. 
 
g. Cellular Therapy: ≥ 42 days must have elapsed from last dose of any 
type of cellular therapy (e.g. modified T cells, NK cells, dendritic 
cells, etc.) 
 
h. XRT/External Beam Irradiation including Protons: ≥ 14 days must 
have elapsed after local XRT; ≥ 150 days after TBI, craniospinal XRT 
or if radiation to  50% of the pelvis; ≥ 42 days if other substantial 
BM radiation. 
 
i. 
Radiopharmaceutical Therapy (e.g., radiolabeled antibody, 131I-
MIBG): ≥ 42 days must have elapsed from the last dose of 
systemically administered radiopharmaceutical therapy. 
 
j. 
HDAC Inhibitors: Patients must not have received prior therapy with 
entinostat. Patients who have received therapy with other HDAC 
inhibitors are eligible. 
 
 
4.1.9 
Organ Function Requirements 
 
4.1.9.1 Adequate Bone Marrow Function Defined as: 
 
a. For patients with solid tumors, including lymphoma, without known 
bone marrow involvement: 
- 
Peripheral absolute neutrophil count (ANC)  1000/mm3 
- 
Platelet count  100,000/mm3 (transfusion independent, defined 
as not receiving platelet transfusions for at least 7 days prior to 
enrollment) 
- 
Hemoglobin ≥ 8.0 g/dl, with or without transfusion 
 
b. 
Patients with known bone marrow metastatic disease will not be 
eligible. 
 
 
4.1.9.2 Adequate Renal Function Defined as: 
- 
Creatinine clearance or radioisotope GFR  70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 


                         
 
 
 
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2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from 
the Schwartz formula for estimating GFR33 utilizing child length 
and stature data published by the CDC. 
 
4.1.9.3 Adequate Liver Function Defined as: 
- 
Bilirubin (sum of conjugated + unconjugated)  1.5 x upper limit of 
normal (ULN) for age  
- 
SGPT (ALT)  3 × ULN = 135 U/l. For the purpose of this study, the 
ULN for SGPT is 45 U/l.  
- 
Serum albumin  2 g/dl. 
 
 
4.1.10 Informed Consent: All patients and/or their parents or legally authorized 
representatives must sign a written informed consent. Assent, when appropriate, 
will be obtained according to institutional guidelines. 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Pregnancy or Breast-Feeding: 
Pregnant or breast-feeding women will not be entered on this study due to risks of 
fetal and teratogenic adverse events as seen in animal studies. Pregnancy tests must 
be obtained in girls who are post-menarchal. Males or females of reproductive 
potential may not participate unless they have agreed to use an effective 
contraceptive method both during and for 3 months after participation in this study. 
Abstinence is an acceptable method of contraception. Those who become pregnant 
while on treatment with entinostat must discontinue immediately and consult their 
treating physician. 
 
 
 
 
4.2.2 
Concomitant Medications 
 
4.2.2.1 Corticosteroids: 
Patients receiving corticosteroids who have not been on a stable or 
decreasing dose of corticosteroid for at least 7 days prior to enrollment are 
not eligible. If used to modify immune adverse events related to prior 
therapy, ≥ 14 days must have elapsed since last dose of corticosteroid. 
 
4.2.2.2 Investigational Drugs: 
Patients who are currently receiving another investigational drug are not 


                         
 
 
 
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eligible. 
 
4.2.2.3 Anti-cancer Agents: 
Patients who are currently receiving other anti-cancer agents are not 
eligible. 
 
4.2.2.4 Patients requiring concurrent administration of valproic acid are not 
eligible for this trial. 
 
4.2.2.5 Anti-GVHD agents post-transplant:  
Patients who are receiving cyclosporine, tacrolimus or other agents to 
prevent graft-versus-host disease post bone marrow transplant are not 
eligible for this trial. 
 
4.2.3 
Study Specific: 
• 
Patients with a BSA ˂ 1.17 m2 at time of study enrollment are not eligible. 
• 
Patients who are not able to swallow intact tablets are not eligible. 
 
4.2.4 
Cardiac: 
Patients with a known history of QTc prolongation (> 480 msec), or known history 
of ventricular tachycardia, ventricular fibrillation or Torsades de pointes are not 
eligible. 
 
4.2.5 
Infection: 
Patients who have an uncontrolled infection are not eligible. 
 
4.2.6 
Transplantation: 
Patients who have received a prior solid organ transplantation are not eligible. 
 
4.2.7 
Patients who in the opinion of the investigator may not be able to comply with the 
safety monitoring requirements of the study are not eligible. 
 
4.2.8 
Patients with a history of allergy to medications that have a benzamide structure 
(e.g., metoclopramide, procarbazine, domperidone, cisapride etc.) are not eligible. 
 
 
 




                         
 
 
 
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If the MTD has been exceeded at the first dose level, then the subsequent cohort 
of patients will be treated at a dose of 2.3 mg/m2 (dose level -1). If dose level -1 is 
not well tolerated, further de-escalation will not occur. The study will be closed to 
accrual. 
 
Entinostat doses will be rounded to the nearest 1 mg (see dosing tables in Appendix 
IV). 
 
5.3.2 
Intra-Patient Escalation 
Intra-patient dose escalation is not allowed.  
 
5.4 
Grading of Adverse Events 
Adverse events (toxicities) will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded 
from 
the 
CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Any 
suspected or confirmed dose-limiting toxicity should be reported immediately (within 24 
hours) to the Study Chair. 
 
5.5 
Definition of Dose-Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are possibly, probably or definitely 
attributable to protocol therapy. The DLT observation period for the purposes of dose-
escalation will be the first cycle of therapy. 
 
Dose limiting hematological and non-hematological toxicities are defined differently. 
 
5.5.1 
Non-Hematological Dose-Limiting Toxicity 
5.5.1.1 Any Grade 3 or greater non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
- 
Grade 3 nausea and vomiting of less < 3 days duration 
- 
Grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to 
levels that meet initial eligibility criteria or baseline within 7 days. See 
Appendix III for values that represent thresholds between CTCAE grades.  
Note: For the purposes of this study the ULN for ALT is defined as 45 U/L. 
- 
Grade 3 or 4 fever < 5 days duration. 
- 
Grade 3 infection < 5 days duration. 
- 
Grade 
3 
hypophosphatemia, 
hypokalemia, 
hypocalcemia 
or 
hypomagnesemia responsive to supplementation. 
• 
Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable by 
patients that it requires treatment interruption. 
• 
Note: Allergic reactions that necessitate discontinuation of study drug will not 
be considered a dose-limiting toxicity. 
 
5.5.2 
Hematological dose limiting toxicity 
5.5.2.1 Hematological dose limiting toxicity is defined as: 
 


                         
 
 
 
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• 
Grade 4 thrombocytopenia (platelet count < 25,000/mm3) or Grade 4 
neutropenia (see Section 6.1), not due to malignant infiltration. 
• 
Grade 3 thrombocytopenia with clinically significant bleeding, 
petechiae, or purpura or that persists for ≥ 7 days or that requires platelet 
transfusion on ≥ 2 separate days within a 7-day period. 
 
5.5.2.2 Note: Grade 3 or 4 febrile neutropenia will not be considered a dose-
limiting toxicity. 
 
 
 
6.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
 
The Study Chair must be notified of any dosage modification or use of myeloid growth factor. 
 
6.1 
Dose Modifications for Hematological Toxicity 
 
6.1.1 
If a patient experiences Grade 4 neutropenia or thrombocytopenia, the treatment 
will be held. Counts should be checked every 3-4 days for thrombocytopenia or 
neutropenia during this time. If the toxicity resolves to meet eligibility parameters 
within 14 days of drug discontinuation, the patient may resume treatment at the 
next lower dose level. For patients enrolled at Dose Level -1 (see Section 5.3.1), 
the dose should be reduced to 1.6 mg/m2. Doses reduced for toxicity will not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.  
 
6.1.2 
If toxicity does not resolve to meet eligibility parameters within 14 days of drug 
discontinuation, the patient must be removed from protocol therapy. 
 
6.1.3 
If hematological dose-limiting toxicity recurs in a patient who has resumed 
treatment at the reduced dose, the patient must be removed from protocol therapy. 
 
6.2 
Dose Modifications for Non-Hematological Toxicity 
 
6.2.1 
If a patient experiences non-hematological dose-limiting toxicity as defined in 
Section 5.5.1, the treatment will be held. When the toxicity resolves to meet 
eligibility parameters or baseline within 14 days of drug discontinuation, the 
patient may resume treatment at the next lower dose level. For patients enrolled at 
Dose Level -1 (see Section 5.3.1), the dose should be reduced to 1.6 mg/m2. Doses 
reduced for toxicity will not be re-escalated, even if there is minimal or no toxicity 
with the reduced dose. 
 
6.2.2 
If toxicity does not resolve to meet eligibility or baseline parameters within 14 
days of drug discontinuation, the patient must be removed from protocol therapy. 
 
6.2.3 
If the same dose-limiting toxicity recurs in a patient who has resumed treatment at 
the reduced dose level, the patient must be removed from protocol therapy. 
 
 


                         
 
 
 
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7.0 
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
7.1 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, immunotherapy, or 
biologic therapy may NOT be administered to patients receiving study drug. If these 
treatments are administered, the patient will be removed from protocol therapy. 
 
7.2 
Investigational Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 
Supportive Care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. Careful monitoring of electrolytes for 
hypophosphatemia and other electrolyte imbalances during treatment with entinostat is 
recommended and electrolyte supplementation may be warranted. See COG Supportive Care 
Guidelines at https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. 
See Section 4.2.2 for drugs that should not be used concomitantly with entinostat. 
 
7.4 
Growth Factors 
Growth factors that support platelet or white cell number or function are not allowed. 
 
7.5 
Concomitant Medications 
Concurrent therapy with valproic acid is not allowed for patients receiving study drug. 
 
 
 
8.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
8.1 
Required Clinical, Laboratory and Disease Evaluation 
All clinical and laboratory studies to determine eligibility must be performed within 7 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
(see Section 4.0) must be no older than seven (7) days at the start of therapy.  Laboratory 
tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess 
eligibility.  If a post-enrollment lab value is outside the limits of eligibility, or laboratory 
values are older than 7 days, then the following laboratory evaluations must be re-checked 
within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) 
and serum  creatinine.  If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies must 
be obtained within 14 days prior to start of protocol therapy (repeat the tumor imaging if 
necessary). 
 
 


                         
 
 
 
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STUDIES TO BE OBTAINED 
Pre-
Study 
During Cycle 1 
Prior to Subsequent 
Cycles^ 
History 
X 
Weekly 
X 
Physical Exam with vital signs 
X 
Weekly 
X 
Height, weight, BSA 
X 
X 
Performance Status 
X 
 
CBC, differential, platelets 
X 
Twice Weekly 
Weekly3 
Pharmacokinetics1 
X 
X 
X 
Urinalysis 
X 
 
Electrolytes including Ca2+, PO43-, Mg2+; 
glucose 
X 
Weekly 
X 
Creatinine, ALT, bilirubin 
X 
Weekly 
X 
Albumin 
X 
X 
Tumor Disease Evaluation 
X 
End of Cycle 1 
Every other cycle x 2 
then q 3 cycles4 
Pharmacodynamics Studies (H3 and H4 
Histone Acetylation in PBMCs)6 
X 
X7 
 
Pregnancy Test2 
X 
 
Patient Diary5 
 
Weekly 
X 
^  
Studies may be obtained within 72 hours prior to the start of the subsequent cycle. 
1 
See Section 8.3 for timing of PK studies. 
2 
Women of childbearing potential require a negative pregnancy test prior to starting treatment; sexually 
active patients must use an acceptable method of birth control. Abstinence is an acceptable method of 
birth control. Patients of reproductive potential must use secure methods of contraception during 
treatment and for 3 additional months after the end of treatment. Those who become pregnant while on 
treatment with entinostat must discontinue immediately and consult their treating physician. 
3 
If patients develop Grade 4 neutropenia or Grade 4 thrombocytopenia then CBCs should be checked 
every 3 to 4 days until recovery to Grade 3. 
4 
Tumor Disease Evaluation should be obtained on the next consecutive cycle after initial documentation 
of either a PR or CR. Subsequent scans may restart 2 cycles after the confirmatory scan. Please note that 
for solid tumor patients, if the institutional investigator determines that the patient has progressed based 
on clinical or laboratory evidence, he/she may opt not to confirm this finding radiographically. 
5 
Patient diary (see Appendix V) should be reviewed after completion of each treatment cycle and 
uploaded into RAVE. During Cycle 1, patient diary should be reviewed weekly and uploaded into 
RAVE. 
6 
These blood draws will only occur in patients who consent to this optional component of the study. 
7 
See Section 8.4 for timing of the pharmacodynamics studies. 
 
8.2 
Radiology Studies 
 
8.2.1 
Central Radiology Review for Response:Patients who respond (CR, PR) to 
therapy or have long term stable disease (SD) (≥ 6 cycles) on protocol therapy 
will be centrally reviewed. COG Operations Center will notify the Imaging 
Center of any patient requiring central review. The Imaging Center will then 
request that the treating institution forward the requested images for central 
review. The central image evaluation results will be entered into RAVE for 
review by the COG Operations Center and for data analysis.  
 


                         
 
 
 
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The images are to be forwarded electronically to the Imaging Research Center at 
Children’s Hospital Los Angeles via the ImageInBox. 
COG institutions that are not connected via the ImageInBox can send the images 
on CD ROM or USB flash drive. Submitted imaging studies should be clearly 
marked with the COG patient ID, study number (STUDY #ADVL1513) and date 
and shipped to Syed Aamer at the address below: 
 
Syed Aamer, MBBS, CRP 
Administrator, Imaging Research Center 
Children’s Hospital Los Angeles  
4650 Sunset Boulevard, MS # 81 
Los Angeles, CA 90027 
 
 
8.3 
Pharmacology (required) 
8.3.1 
Description of Studies and Assay 
Pharmacokinetics (PK) will be performed to determine the PK of entinostat in 
children. Pharmacokinetic analysis will be conducted at a centralized laboratory 
using validated assays. 
 
8.3.2 
Sampling Schedule (See Appendix VI) 
Blood samples will be obtained prior to drug administration and at the following 
time points: 
• 
Day 1 of Cycle 1: pre-dose, and at 0.5, 1, 3, 6, 24 (Day 2), and 48 
to 96 hours post-dose. 
• 
Day 8 of Cycle 1: pre-dose. 
• 
Day 22 of Cycle 1: pre-dose, 1 hour post-dose. 
• 
Day 28 of Cycle 1: prior to Day 1, Cycle 2 dose. 
 
8.3.3 
Sample Collection and Handling Instructions 
Blood samples (3 ml) will be collected in specified collection tubes according to 
the lab manual. Sample kits with pre-printed labels will be provided by Covance. 
 
8.3.4 
Sample Processing 
Samples will be processed according to the lab manual. 
 
8.3.5 
Sample Labeling 
Each tube must be labeled with the patient’s COG patient ID number. If not using 
pre-printed labels, they must also be labeled with the date and time the sample was 
drawn. Data should be recorded on the Pharmacokinetic Study Form, which must 
accompany the samples. Sample kits with pre-printed labels will be provided by 
Covance. 
 
8.3.6 
Sample Shipping Instructions 


                         
 
 
 
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Samples should be batched per patient and shipped frozen on dry ice in opaque 
containers at the end of Cycle 1 according to the lab manual. 
 
 
8.4 
Pharmacodynamic Studies (optional) 
 
8.4.1 
Description of Studies 
In consenting patients, exploratory pharmacodynamic assessment of histone H3 
and H4 acetylation will be performed in PBMCs to evaluate the change in 
acetylation after administration of entinostat as a potential biomarker of HDAC 
inhibition. 
 
8.4.2 
Sampling Schedule (See Appendix VII) 
Whole blood specimens (3 ml) will be collected from all consenting patients at: 
• 
Day 1 of Cycle 1: pre-dose, and at 6 and 24 (Day 2) hours post-
dose. 
• 
Day 8 of Cycle 1: pre-dose. 
 
8.4.3 
Sample Collection and Handling Instructions 
Blood samples (3 ml) will be collected in CPT tubes for pharmacodynamic 
evaluation according to the lab manual. Record the exact time that the sample is 
drawn along with the exact time that the drug is administered. Sample kits with 
pre-printed labels will be provided by Covance. 
 
8.4.4 
Sample Processing 
• 
Samples will be processed according to the lab manual. 
• 
During blood draw, fill tube with blood as completely as possible. Mix the 
blood in the vacutainer tube by gently inverting the tube 6 to 8 times. 
• 
Keep all samples refrigerated from the moment of drawing until shipment. 
 
8.4.5 
Sample Labeling 
Each tube must be labeled with the patient’s study registration number, the study 
I.D., and the date and time the sample was drawn. Data should be recorded on the 
Pharmacodynamics Study Form, which must accompany the sample(s). Sample 
kits with pre-printed labels will be provided by Covance. 
 
8.4.6 
Sample Shipping Instructions 
• 
Keep all samples refrigerated from the moment of drawing until shipment. 
• 
Samples must be shipped THE SAME DAY as blood is taken using 
overnight shipping. If possible, schedule of treatment should be planned 
to avoid sending samples on Fridays and Saturdays. 
• 
Sample tubes should be placed in a plastic bag and preferably be packed 
with a cold pack (like U-tek -1ºC/+30ºF Tegrant Corporation cold pack) 
rather than a frozen ice pack. To minimize any movement during transit 
and prevent damage of blood cells, the plastic bag with tubes must be 
properly insulated from the cold pack with packing material (bubble wrap, 
paper towels, crumpled paper, etc.) and placed on the cold pack (not 


                         
 
 
 
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between bottom of the box and pack or between 2 cold packs) so that tubes 
do not touch the pack. Please avoid using wet ice, as accidental contact 
with water will break down blood cells. Please also fill any empty space 
in the package with packing material. 
• 
Refer to instructions in the lab manual. 
• 
Include Appendix VII, Pharmacodynamic Study Form, with the shipment 
• 
Ship samples to the following address: 
 
Trepel Laboratory 
CCR, NCI, NIH 
10 Center Drive 
Building 10, Clinical Center, Room 12C208 
Bethesda, MD 20892 
 
 
 
9.0 
AGENT INFORMATION 
 
9.1 
Entinostat 
(SNDX-275, MS-275, NSC#706995, 
), NCI-supplied agent 
9.1.1 
Structure and molecular weight  
Chemical name:  
3-Pyridylmethyl N-{4-[(2-
aminophenyl)carbamoyl]benzyl}carbamate 
 
Molecular formula:  
C21H20N4O3 
 
Structural formula: 
 
 
 
Molecular weight:  
376.41 
 
Mechanism of action: Entinostat inhibits to a family of enzymes called histone 
deacetylases (HDACs) that regulate chromatin remodeling and gene transcription via 
the dynamic process of acetylation and deacetylation of core histones. Entinostat 
inhibits histone deacetylases, changes chromatin configuration, and induces 
differentiation and apoptosis of cancer cells through an epigenetic mechanism. 
 
9.1.2 
Supplied by: 


                         
 
 
 
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Entinostat is supplied by Syndax Pharmaceuticals, Inc. and distributed by DCTD, 
NCI. 
 
9.1.3 
Formulation 
The agent is supplied as a 1 mg (pink to light red, in bottles of 40), or 5 mg (yellow, 
in bottles of 40) film-coated tablets (round-biconvex). Each tablet also contains 
mannitol, carboxymethyl starch sodium, hydroxypropyl cellulose, potassium 
bicarbonate, and magnesium stearate. The film coating consists of hydroxypropyl 
methylcellulose, talc, titanium dioxide, and ferric oxide pigments (red and yellow). 
 
9.1.4 
Storage 
Store the bottles at room temperature (15-30oC), and protect from light. Tablets 
may be dispensed in pharmacy amber dispensing bottles with storage at a 
temperature equal or below 15-30C (59-86F; do not freeze) with an expiration 
period of 30 days from the date of repackaging. 
 
9.1.5 
Stability 
Shelf life stability studies of the intact bottles are on-going. Tablets dispensed in 
pharmacy amber dispensing bottles should have an expiration date of 30 days from 
the date of repackaging. 
 
 
9.1.6 
Administration 
Administer orally, on an empty stomach, at least 1 hour before or 2 hours after a 
meal. Tablets should be swallowed whole and not split, crushed or chewed. If a 
patient vomits within 30 minutes after the dose of entinostat is administered, that 
dose may be repeated. If the patient vomits more than 30 minutes after 
administration of entinostat, the dose will be considered as having been taken, and 
administration should resume with the subsequent regularly scheduled dose.  
 
9.1.7 
Drug interactions 
No formal drug interaction studies have been performed in humans. 
Data from in vitro experiments showed that, while entinostat inhibited cytochrome 
P-450 enzymes 2B6 and 3A4, the degree of the inhibition make it unlikely that any 
in vivo systemic interactions would occur. Intestinal CYP 3A4 may be inhibited 
by entinostat. However, entinostat did not inhibit any UGT enzymes tested. In 
addition, entinostat was found to induce CYP 1A2, CYP 2C6, and CYP 2B8 as 
well as UGT 1A4. Finally, entinostat is a substrate for P-glycoprotein (P-gp) and 
breast cancer resistance protein (BCRP) transporters. 
 
9.1.8 
Entinostat Toxicities 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 






                         
 
 
 
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Esophagitis; Flatulence; Gastrointestinal disorders - Other (hyperdefecation); Gastrointestinal 
hemorrhage3; Hemorrhoids; Mucositis oral; Pancreatitis; Periodontal disease; Rectal mucositis; Rectal 
pain; Small intestinal mucositis; Typhlitis; Visceral arterial ischemia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Generalized 
edema; Injection site reaction; Multi-organ failure; Non-cardiac chest pain; Pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase 
increased; Aspartate aminotransferase increased; Blood bilirubin increased; CPK increased; Creatinine 
increased; GGT increased; INR increased; Investigations - Other (coagulopathy); Investigations - Other 
(vitamin D deficiency); Lipase increased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoglycemia; 
Hypomagnesemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Bone pain; 
Chest wall pain; Generalized muscle weakness; Muscle cramp; Musculoskeletal and connective tissue 
disorder - Other (thorax pain); Myositis; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Depressed level of consciousness; Dizziness; Dysphasia; 
Intracranial hemorrhage; Neuralgia; Olfactory nerve disorder; Peripheral motor neuropathy; Peripheral 
sensory neuropathy; Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; Libido decreased 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; Renal and urinary disorders - 
Other (bladder distension); Renal calculi; Renal hemorrhage; Urinary frequency; Urinary retention 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Atelectasis; Epistaxis; 
Hypoxia; Laryngeal mucositis; Pharyngeal mucositis; Pleural effusion; Pleuritic pain; Pulmonary edema; 
Respiratory failure; Tracheal mucositis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; 
Photosensitivity; Pruritus; Purpura; Rash maculo-papular; Skin and subcutaneous tissue disorders - Other 
(hyperkeratotic lesions/squamous cell carcinoma); Urticaria 
SURGICAL AND MEDICAL PROCEDURES - Surgical and medical procedures - Other (packed RBC 
transfusion) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Thromboembolic event 
 
 
 
Note: MS-275 (SNDX-275, entinostat) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
 
9.2 
Agent Ordering and Agent Accountability 
NCI supplied agent may be requested by the eligible participating investigator (or their 
authorized designee) at each participating institution. The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The responsible 
investigator at each participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA form 1572 (Statement of Investigator), NCI Biosketch, 
Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several 
participating investigators at one institution, CTEP supplied investigational agents for the 
study should be ordered under the name of one lead participating investigator at that 
institution. 
 


                         
 
 
 
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Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status, and a “current” password, 
and active person registration status.  For questions about drug orders, transfers, returns, or 
accountability, call or email PMB any time.  Refer to the PMB’s website for specific policies 
and guidelines related to agent management. 
 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
9.3 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
the PMB using the appropriate NCI Investigational Oral Agent (Drug) Accountability 
Record (DARF) available on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
9.4 
Investigator Brochure Availability 
The current versions of the IB for the agent will be accessible to site investigators 
and research staff through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password and active person registration status. Questions about 
IB access may be directed to the PMB IB coordinator via email. 
 
9.5 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents: 
http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration: 
RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent management.htm 
• 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP  
• 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• 
CTEP IAM account help: 
ctepreghelp@ctep.nci.nih.gov  
• 
PMB email: 
PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: 
IBCoordinator@mail.nih.gov 
• 
PMB phone and hours of service: 
(240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) 


                         
 
 
 
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10.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
10.1 
Criteria for Removal from Protocol Therapy  
 
a) 
Clinical (including physical examination or serum tumor markers) or radiographic 
evidence of progressive disease (See Section 12.0). 
b) 
Adverse Events requiring removal from protocol therapy (See Section5_2Section 
6.0). 
c) 
Refusal of protocol therapy by patient/parent/guardian 
d) 
Non-compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
e) 
Physician determines it is not in the patient’s best interest. 
f) 
Repeated eligibility laboratory studies (CBC with differential, bilirubin, ALT (SGPT) 
or serum creatinine) are outside the parameters required for eligibility prior to the start 
of entinostat (See Section 8.1). 
g) 
Study is terminated by Sponsor. 
h) 
Pregnancy. 
 
Patients who are removed from protocol therapy during cycle 1 should continue to 
have the required observations in Section 8.1 until the originally planned end of the 
cycle or until all adverse events have resolved per Section 13.4.4, whichever happens 
LATER. The only exception is with documentation of the patient’s withdrawal of 
consent. Patients who are removed from protocol therapy in subsequent cycles should 
have the necessary observations to ensure adequate clinical care.  
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Ongoing adverse events, or adverse events that emerge after the patient 
is removed from protocol therapy, but within 30 days of the last dose of investigational 
agent, must be followed and reported via RAVE and CTEP-AERS (if applicable).  Follow-
up data will be required unless consent is withdrawn. 
 
10.2 
Off Study Criteria 
 
a) 
Thirty days after the last dose of the investigational agent. 
b) 
Death 
c) 
Lost to follow-up 
d) 
Withdrawal of consent for any required observations or data submission. 
e) 
Enrollment onto another COG therapeutic (anti-cancer) study  
f) 
The fifth anniversary of the date the patient was enrolled on this study. 
g) 
The patient does not receive protocol treatment after study enrollment.  
 
 
11.0 
STATISTICAL AND ETHICAL CONSIDERATIONS 
 
11.1 
Sample Size and Study Duration 


                         
 
 
 
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A minimum of 4 patients will be enrolled in this study. The expected maximum number of 
evaluable patients required to estimate the MTD/RP2D is 12. Once the MTD or 
recommended Phase 2 dose has been defined, up to 6 additional patients with recurrent or 
refractory solid tumors may be enrolled to acquire PK data in a representative number of 
young patients (i.e. patients < 12 years old). Therefore, a maximum of 22 patients are 
expected to be enrolled which allows for 6 patients at each of 2 dose levels, 6 additional 
patients enrolled at the MTD/RP2D for PK analysis, and a 20% inevaluable rate. Review 
of the enrollment rate into previous COG new agent studies indicates that 1-2 patients per 
month are available, which will permit completion of the study within 11-22 months. An 
absolute maximum of 36 patients is anticipated in the unlikely scenario that each of 2 dose 
levels is expanded to 12 patients due to different classes of AEs, 6 additional patients are 
enrolled at the MTD for PK analysis, and a 20% inevaluable rate. The absolute maximum 
would require about 18-36 months for completion. 
 
 
11.2 
Definitions 
 
11.2.1 Evaluable For Adverse Events 
Any patient who receives at least one dose of the study drug(s) and who 
experiences a dose-limiting toxicity is considered evaluable for Adverse Events. 
In addition, for the dose-escalation portion during Cycle 1, patients must receive 
at least 85% of the prescribed dose per protocol guidelines and must have the 
appropriate toxicity monitoring studies performed to be considered evaluable for 
dose limiting toxicity. Patients who do not have DLT and are not considered 
evaluable for toxicity will be replaced. 
 
11.2.2 Maximum Tolerated Dose 
• 
The MTD will be the maximum dose at which fewer than one-third of patients 
experience DLT (See Section 5.5) during Cycle 1 of therapy.  
 
• 
In the unlikely event that two DLTs observed out of 6 evaluable patients are 
different 
classes 
of 
Adverse 
Effects 
(e.g. 
hepatotoxicity 
and 
myelosuppression), AND all of the following conditions are met, expansion 
of the cohort to 12 patients will be considered:  
 
•  One of the DLTs does not appear to be dose-related 
•  The Adverse Effects are readily reversible 
•  The study chair, DVL statistician, DVL committee chair or vice chair, and 
IND sponsor all agree that expansion of the cohort is acceptable 
 
If fewer than 1/3 of patients in the expanded cohort experience dose-limiting 
toxicities, the dose escalation can proceed. 
 
• 
The DLTs observed in the pharmacokinetic (PK) expansion cohort will be 
counted towards the total number of DLTs observed at the MTD during the 


                         
 
 
 
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dose escalation portion of the study. If ≥ 1/3 of the cohort of patients at the 
MTD (during the dose escalation plus the PK expansion) experience DLT then 
the MTD will be exceeded.  
 
 
11.3 
Dose Escalation and Determination of MTD 
 
The rolling six phase 1 trial design will be used for the conduct of this study.32 Two to six 
patients can be concurrently enrolled onto a dose level, dependent upon (1) the number of 
patients enrolled at the current dose level, (2) the number of patients who have experienced 
DLT at the current dose level, and (3) the number of patients entered but with tolerability 
data pending at the current dose level. Accrual is suspended when a cohort of six has 
enrolled or when the study endpoints have been met.  
 
Dose level assignment is based on the number of participants currently enrolled in the 
cohort, the number of DLTs observed, and the number of participants at risk for developing 
a DLT (i.e., participants enrolled but who are not yet assessable for toxicity). For example, 
when three participants are enrolled onto a dose cohort, if toxicity data is available for all 
three when the fourth participant entered and there are no DLTs, the dose is escalated and 
the fourth participant is enrolled to the subsequent dose level. If data is not yet available 
for one or more of the first three participants and no DLT has been observed, or if one DLT 
has been observed, the new participant is entered at the same dose level. Lastly, if two or 
more DLTs have been observed, the dose level is de-escalated. This process is repeated for 
participants five and six. In place of suspending accrual after every three participants, 
accrual is only suspended when a cohort of six is filled. When participants are inevaluable 
for toxicity, they are replaced with the next available participant if escalation or de-
escalation rules have not been fulfilled at the time the next available participant is enrolled 
onto the study. 
 
The following table provides the decision rules for enrolling a patient at (i) the current dose 
level (ii) at an escalated dose level, (iii) at a de-escalated dose level, or whether the study 
is suspended to accrual: 
 
 
# Pts 
Enrolled 
# Pts with 
DLT 
# Pts without 
DLT 
# Pts with 
Data Pending 
Decision 
 
2 
0 or 1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
2 
2 
0 
0 
De-escalate* 
 
 
 
 
 
 
 
3 
0 
0, 1 or 2 
1, 2 or 3 
Same dose level 
 
3 
1 
0, 1 or 2 
0, 1 or 2 
Same dose level 
 
3 
0 
3 
0 
Escalate** 
 
3 
≥ 2 
0 or 1 
0 or 1 
De-escalate* 
 
 
 
 
 
 
 
4 
0 
0, 1, 2 or 3 
1, 2, 3 or 4 
Same dose level 
 
4 
1 
0, 1, 2 or 3 
0, 1, 2 or 3 
Same dose level 
 
4 
0 
4 
0 
Escalate** 
 
4 
≥ 2 
0, 1 or 2 
0, 1 or 2 
De-escalate* 
 
 
 
 
 
 
 
5 
0 
0, 1, 2, 3 or 4 
1, 2, 3, 4 or 5 
Same dose level 






                         
 
 
 
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Response and progression will be evaluated in this study using the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).34 Key points are 
that 5 target lesions are identified and that changes in the largest diameter (unidimensional 
measurement) of the tumor lesions but the shortest diameter of malignant lymph nodes are 
used in the RECIST v 1.1 criteria. 
 
12.2.1 Definitions 
 
12.2.1.1 Evaluable for objective response: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will be considered evaluable for 
response. For all other patients, only those patients 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 
response.  
 
12.2.1.2 Evaluable Non-Target Disease Response: Patients 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.  
 
12.2.2 Disease Parameters 
 
12.2.2.1 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, as ≥ 10 mm with CT scan, or ≥ 10 
mm with 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 
must show definitive evidence of progression to be considered 
measurable. 
 
12.2.2.2 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 no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and followed. 
 
12.2.2.3 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes 
with ≥ 10 mm to < 15 mm short axis), are considered non-measurable 
disease. 
Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 


                         
 
 
 
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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 patient, these are 
preferred for selection as target lesions. 
 
12.2.2.4 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 that 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. 
 
12.2.2.5 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.  
 
12.2.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  
 
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. 
 
12.2.3.1 Clinical lesions:  Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and  10 mm 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.  


                         
 
 
 
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12.2.3.2 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.  
 
12.2.3.3 Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body 
scans). Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  
 
12.2.3.4 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.   
 
12.2.3.5 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 patient to be considered in complete clinical response.  
 
12.2.3.6 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). 
 
 
Cytology should be obtained if an effusion appears or worsens during 
treatment when the measurable tumor has met criteria for response or 
stable disease. 
 
12.2.3.7 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 


                         
 
 
 
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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. 
 
 Note:  A ‘positive’ FDG-PET scan lesion means one that is FDG avid 
with an uptake greater than twice that of the surrounding tissue 
on the attenuation corrected image. 
 
 
12.2.4 Response Criteria for Patients with Solid Tumor and Measurable Disease 
 
12.2.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short 
axis to <10 mm. If immunocytology is available, 
no disease must be detected by that methodology.  
Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment (for 
patients with neuroblastoma).  
 
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). Note: in 
presence of SD or PR in target disease but 
unequivocal progression in non-target or non-
measurable disease, the patient has PD if there is 
an overall level of substantial worsening in non-
target disease such that the overall tumor burden 
has 
increased 
sufficiently 
to 
merit 
discontinuation of therapy 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 


                         
 
 
 
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reference the smallest sum diameters while on 
study 
 
 
12.2.4.2 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. 
 
12.2.5 Overall Response Assessment 
 
Table 1: For Patients 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 
≥ 28 days Confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
≥ 28 days 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 ≥ 
28 days from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


                         
 
 
 
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*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients 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. 
 
Table 2: For Patients 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 
 
Table 4: Overall Response for Patients with Neuroblastoma and Measurable Disease 
 
CT/MRI 
MIBG 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
CR/PR/SD 
Non-PD 
Non-PD 
Any 
SD 
PR 
CR/PR 
Non-PD 
Non-PD 
Any 
PR 
CR/PR 
PR 
Non-PD 
Non-PD 
Any 
PR 
CR 
CR 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
CR 
CR 
CR 
Normal 
CR 
 
12.2.6 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect. Best response is determined as outlined in Section 
12.6 from a sequence of overall response assessments. 
 
12.3 
Response Criteria for Patients with Solid Tumors and Evaluable Disease 
 
12.3.1 Evaluable Disease 
The presence of at least one lesion, with no lesion that can be accurately measured 
in at least one dimension.  Such lesions may be evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers or other reliable 
measures.  
 
12.3.2 Complete Response 
Disappearance of all evaluable disease. 


                         
 
 
 
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12.3.3 Partial response 
Partial responses cannot be determined in patients with evaluable disease 
 
12.3.4 Stable Disease (SD) 
That which does not qualify as Complete Response (CR), Partial Response (PR), 
or Progressive Disease. 
 
12.3.5 Progressive Disease 
The appearance of one or more new lesions or evidence of laboratory, clinical, or 
radiographic progression. 
 
12.3.6 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.6 from a sequence of overall response assessments. 
 
12.4 
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions 
 
12.4.1 MIBG Positive Lesions 
Patients who have a positive MIBG scan at the start of therapy will be evaluable 
for MIBG response. The use of 123I for MIBG imaging is recommended for all 
scans. If the patient has only one MIBG positive lesion and that lesion was 
radiated, a biopsy must be done at least 28 days after radiation was completed and 
must show viable neuroblastoma. 
 
12.4.2 The following criteria will be used to report MIBG response by the treating 
institution: 
 
Complete response:  Complete resolution of all MIBG positive lesions 
Partial Response:  Resolution of at least one MIBG positive lesion, with 
persistence of other MIBG positive lesions 
Stable disease:  
No change in MIBG scan in number of positive lesions 
Progressive disease: Development of new MIBG positive lesions 
 
12.4.3 The response of MIBG lesions will be assessed on central review using the Curie 
scale14 as outlined below. Central review responses will be used to assess efficacy 
for study endpoint. See Section 8.2 for details on transferring images to the 
Imaging Research Center. 
 
NOTE: This scoring should also be done by the treating institution for end of 
course response assessments. 
 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded 
as:  
0 = no site per segment,  


                         
 
 
 
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1 = 1 site per segment,  
2 = more than one site per segment,  
3 = massive involvement (>50% of the segment).  
 
The absolute score is obtained by adding the score of all the segments. See 
diagram of sectors below: 
 
 
The relative score is calculated by dividing the absolute score at each time point 
by the corresponding pre-treatment absolute score. The relative score of each 
patient is calculated at each response assessment compared to baseline and 
classified as below: 
1. Complete response: all areas of uptake on MIBG scan completely resolved. 
If morphological evidence of tumor cells in bone marrow biopsy or aspiration 
is present at enrollment, no tumor cells can be detected by routine morphology 
on two subsequent bilateral bone marrow aspirates and biopsies done at least 21 
days apart to be considered a Complete Response. 
2. Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 
(lesions strongly reduced). 
3. Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) 
to 1.0 (lesions not reduced). 
4. Progressive disease: New lesions on MIBG scan. 
 
 
12.4.4 Overall Response Assessment 
 
Table 5: Overall Response Evaluation for Neuroblastoma Patients and MIBG Positive Disease 
Only 
If patients are enrolled without disease measurable by CT/MRI, any new or newly 
identified lesion by CT/MRI that occurs during therapy would be considered 
progressive disease. 
 
MIBG 
CT/MRI 
Bone Scan 
Bone Marrow 
Catechol 
Overall 
PD 
Any 
Any 
Any 
Any 
PD 


                         
 
 
 
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Any 
New Lesion 
Any 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
SD 
No New Lesion 
Non-PD 
Non-PD 
Any 
SD 
PR 
No New Lesion 
Non-PD 
Non-PD 
Any 
PR 
CR 
No New Lesion 
Non-PD 
Non-PD 
Elevated 
PR 
CR 
No New Lesion 
CR 
CR 
Normal 
CR 
 
 
12.4.5 Overall Best Response Assessment 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect. Best response is determined from the sequence of the 
overall response assessments as described in Table 3 in Section 12.6. 
 
 
12.5 
Response Criteria for Patients with CNS Tumors 
 
12.5.1 Measurable Disease 
Any lesion that is at minimum 10 mm in one dimension on standard MRI or CT, 
for CNS tumors. 
 
12.5.2 Evaluable Disease  
Evaluable disease is defined as at least one lesion, with no lesion that can be 
accurately measured in at least one dimension. Such lesions may be evaluable by 
nuclear medicine techniques, immunocytochemistry techniques, tumor markers, 
CSF cytology, or other reliable measures. 
 
12.5.3 Selection of Target and Non-Target Lesions 
For most CNS tumors, only one lesion/mass is present and therefore is considered 
a “target” for measurement/follow up to assess for tumor progression/response. If 
multiple measurable lesions are present, up to 5 should be selected as “target” 
lesions. Target lesions should be selected on the basis of size and suitability for 
accurate repeated measurements. All other lesions will be followed as non-target 
lesions. The lower size limit of the target lesion(s) should be at least twice the 
thickness of the slices showing the tumor to decrease the partial volume effect 
(e.g., 8 mm lesion for a 4 mm slice). 
 
Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
12.5.4 Response Criteria for Target Lesions 
Response criteria are assessed based on the product of the longest diameter and its 
longest perpendicular diameter. Development of new disease or progression in any 
established lesions is considered progressive disease, regardless of response in 
other lesions – e.g., when multiple lesions show opposite responses, the 
progressive disease takes precedence. Response Criteria for target lesions: 
 


                         
 
 
 
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• 
Complete Response (CR): Disappearance of all target lesions. 
 
• 
Partial response (PR): ≥ 50% decrease in the sum of the products of the two 
perpendicular diameters of all target lesions (up to 5), taking as reference the 
initial baseline measurements. 
 
• 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of 
the two perpendicular diameters of all target lesions to qualify for PR, nor 
sufficient increase in a single target lesion to qualify for PD. 
 
• 
Progressive Disease (PD): 25% or more increase in the sum of the products 
of the perpendicular diameters of the target lesions, taking as reference the 
smallest sum of the products observed since the start of treatment, or the 
appearance of one or more new lesions. 
 
12.5.5 Response Criteria for Non-Target Lesions: 
 
• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Incomplete Response/Stable Disease (IR/SD): The persistence of one or 
more non-target lesions. 
 
• 
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. 
 
12.5.6 Response criteria for tumor markers (if available): 
Tumor markers will be classified simply as being at normal levels or at abnormally 
high levels. 
 
12.5.7 Overall Response Assessment 
The overall response assessment takes into account response in both target and 
non-target lesions, the appearance of new lesions and normalization of markers 
(where applicable), according to the criteria described in the table below. The 
overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, marker and new lesions in the preceding 
columns. 
 
 
 
 
 
 
 
 
 
 
 


                         
 
 
 
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Target Lesions 
 
Non-target Lesions 
 
Markers 
 
New Lesions 
 
Overall 
Response 
CR 
CR 
Normal 
No 
CR 
CR 
IR/SD 
Normal 
No 
PR 
CR  
CR, IR/SD 
Abnormal 
No 
PR 
PR 
CR, IR/SD 
Any 
No 
PR 
SD 
CR, IR/SD 
Any 
No 
SD 
PD 
Any 
Any 
Yes or No 
PD 
Any 
PD 
Any 
Yes or No 
PD 
Any 
Any 
Any 
Yes 
PD 
 
Each patient will be classified according to his “best response” for the purposes of 
analysis of treatment effect.  Best response is determined as outlined in Section 
12.6 from a sequence of overall response assessments. 
 
 
12.6 
Best Response 
 
12.6.1 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. 
 
Table 3.  Sequences of overall response assessments with corresponding best 
response. 
1st Assessment 
2nd Assessment 
Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
12.6.2 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). 
 


                         
 
 
 
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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. 
 
 
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.  
 
 
13.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event data collection and reporting which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  Adverse events are reported in a routine manner at scheduled times 
during a trial.  (Please follow directions for routine reporting provided in the Case Report Forms 
for this protocol).  Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  The following sections provide information 
about expedited reporting. 
 
 
Reporting requirements may include the following considerations: 1) whether the patient has 
received an investigational or commercial agent; 2) whether the adverse event is considered serious; 
3) the grade (severity); and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event. 
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND).  In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
 
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source.  The NCI, rather than a commercial distributor, may on some occasions 
distribute commercial agents for a trial. 
 
13.1 
Steps to Determine If an Adverse Event Is To Be Reported In an Expedited Manner 
 
Step 1: Identify the type of adverse event using the NCI CTCAE version 5.0. All 
appropriate treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
Step 2:  Grade the adverse event using the NCI CTCAE. 
 
Step 3:  Review Table A in this section to determine if: 
• 
the adverse event is considered serious; 
• 
there are any protocol-specific requirements for expedited reporting of specific 
adverse events that require special monitoring; and/or 






                         
 
 
 
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Weight loss 
METABOLISM AND NUTRITION DISORDERS 
Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
Arthralgia 
 
Back pain 
 
Generalized muscle weakness 
 
Pain in extremity 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
Epistaxis 
 
• See also the Specific Protocol Exceptions to Expedited Reporting (SPEER) in Section 9.1.8 of the 
protocol. Additional protocol-specific exceptions to expedited reporting of serious adverse events 
are the toxicities in bold font listed under the drug information section of the protocol (Section 9.1). 
 
As referenced in the CTEP Adverse Events Reporting Requirements, an AE that resolves and then recurs 
during a subsequent cycle does not require CTEP-AERS reporting unless (1) the Grade increases; or (2) 
hospitalization is associated with the recurring AE. 
 
13.2 
When to Report an Event in an Expedited Manner  
 
• 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via 
the web at http://ctep.cancer.gov (telephone CTEP at: 301-897-7497 within 24 hours of 
becoming aware of the event if the CTEP-AERS 24-Hour Notification web-based 
application is unavailable) and by telephone call to the Study Chair. Once internet 
connectivity is restored, a 24-hour notification phoned in must be entered electronically 
into CTEP-AERS by the original submitter at the site. 
 
• 
When the adverse event requires expedited reporting, submit the report within 5 or 7 
calendar days of learning of the event (refer to Table A). 
 
• 
Expedited AE reporting for this study must only use CTEP-AERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page at https://eapps-
ctep.nci.nih.gov/ctepaers. 
 
13.3 
Expedited Reporting Methods  
 
13.3.1 CTEP-AERS Reporting 
To report adverse events in an expedited fashion use the NCI’s Adverse Event 
Expedited 
Reporting 
System 
(CTEP-AERS) 
that 
can 
be 
found 
at 
http://ctep.cancer.gov. 
 
A CTEP-AERS report must be submitted electronically via the CTEP-AERS Web-
based application located at https://eapps-ctep.nci.nih.gov/ctepaers. If prompted to 
enter 
a 
sponsor 
email 
address, 
please 
type 
in: 
PEPCTNAERS@childrensoncologygroup.org. 
 


                         
 
 
 
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Send supporting documentation to the NCI by fax (fax# 301-230-0159) and by 
email to the ADVL1513 COG Study Assigned Research Coordinator. ALWAYS 
include the ticket number on all faxed and emailed documents. 
 
13.4 
Definition of Onset and Resolution of Adverse Events 
 
 
Note: These guidelines below are for reporting adverse events on the COG case report 
forms and do not alter the guidelines for CTEP-AERS reporting. 
 
13.4.1 If an adverse event occurs more than once in a course (cycle) of therapy only the 
most severe grade of the event should be reported. 
 
13.4.2 If an adverse event progresses through several grades during one course of therapy, 
only the most severe grade should be reported. 
 
13.4.3 The duration of the AE is defined as the duration of the highest (most severe) grade 
of the Adverse Effects.  
 
13.4.4 The resolution date of the AE is defined as the date at which the AE returns to 
baseline or less than or equal to Grade 1, whichever level is higher (note that the 
resolution date may therefore be different from the date at which the grade of the 
AE decreased from its highest grade).  If the AE does not return to baseline the 
resolution date should be recorded as "ongoing."   
 
13.4.5 An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course. An adverse 
event which resolves and then recurs during a different course, must be reported 
each course it recurs.  
 
13.5 
Other Recipients of Adverse Event Reports 
 
13.5.1 Events that do not meet the criteria for CTEP-AERS reporting (Section 13.2) 
should be reported at the end of each cycle using the forms provided in the CRF 
packet (See Section 14.1). 
 
13.5.2 COG will forward reports and supporting documentation to the Study Chair. 
 
13.5.3 Adverse events determined to be reportable must also be reported according to the 
local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
13.6 
Reporting Secondary AML/MDS 
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that 
occur in patients following their chemotherapy for cancer must be reported to the 
Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation Program 
(CTEP) via CTEP-AERS and included as part of the second malignant neoplasm reporting 
requirements for this protocol (see data submission packet).  Submit the completed CTEP-
AERS report within 14 days of an AML/MDS diagnosis occurring after protocol treatment 


                         
 
 
 
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for cancer. 
 
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event:  
1) Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
2) Myelodysplastic syndrome (MDS)  
3) Treatment-related secondary malignancy. 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol. 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
13.7 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and emailed to the 
ADVL1513 COG Study Assigned Research Coordinator along with any additional medical 
information. The potential risk of exposure of the fetus to the investigational agent should 
be documented in the “Description of Event” section of the CTEP-AERS report. 
 
13.7.1 Pregnancy 
• 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
occurring on study or within 6 months following the last dose of study 
therapy should be reported in an expedited manner via CTEP-AERS as 
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other 
(Pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” System Organ Class (SOC). 
 
• 
Pregnancy should be followed until the outcome is known. If the baby is 
born with a birth defect or anomaly, then a second CTEP-AERS report is 
required.  
 
13.7.2 Pregnancy Loss (Fetal Death) 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
 
• 
 Any pregnancy loss should be reported expeditiously, as Grade 4 


                         
 
 
 
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“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death.   
 
13.7.3 Death Neonatal 
• 
Neonatal death, defined in CTCAE as “Newborn deaths occurring during 
the first 28 days after birth” that is felt by the investigator to be at least 
possibly due to the investigational agent/intervention, should be reported 
expeditiously. 
 
• 
A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the “General disorders and administration” SOC when 
the death is the result of a patient pregnancy or pregnancy in partners 
of men on study. 
 
• 
Do NOT report a neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
Pregnancy should be followed up until the outcome of the pregnancy is known at intervals 
deemed 
appropriate 
by 
her 
physicians. 
This 
form 
is 
available 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/PregnancyRepo
rtForm.pdf.  
 
 
14.0 
RECORDS, REPORTING, AND DATA AND SAFETY MONITORING PLAN 
 
14.1 
Categories of Research Records  
Research records for this study can be divided into three categories 
 
1. 
Non-computerized Information:  Roadmaps, Pathology Reports, Surgical Reports. 
These forms are uploaded into RAVE. 
 
2. 
Reference Labs, Biopathology Reviews, and Imaging Center data: These data 
accompany submissions to these centers, which forward their data electronically 
to the COG Statistics & Data Center. 
 
3. 
Computerized Information Electronically Submitted: All other data will be entered 
in RAVE with the aid of schedules and worksheets (essentially paper copies of the 
OPEN and RAVE screens) provided in the case report form (CRF) packet. 
 
See separate CRF Packet, which includes submission schedule. 
 
14.2 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are 


                         
 
 
 
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due January 31, April 30, July 31 and October 31. Note: If this study has been assigned to 
CDUS-Complete reporting, all adverse events (both routine and expedited) that have occurred 
on the study and meet the mandatory CDUS reporting guidelines must be reported via the 
monitoring method identified above. If this study has been assigned to CDUS-Abbreviated 
reporting, no adverse event reporting (routine or expedited) is required to be reported via 
CDUS. 
This is not a responsibility of institutions participating in this trial. 
 
14.3 
CRADA/CTA/CSA 
Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by 
a Clinical Trials Agreement (CTA) or a Cooperative Research and Development 
Agreement. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study. Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators. The protocol 
documents for studies utilizing investigational Agents contain confidential 
information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. 
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other investigational Agent(s), each the subject of different collaborative 
agreements , the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as “Multi-
Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
 


                         
 
 
 
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c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the 
FDA, as appropriate and unless additional disclosure is required by law or court 
order 
as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected , used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP for immediate delivery to Collaborator(s) for advisory review and comment 
prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible 
and preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and 
other media presentations must also be forwarded to CTEP prior to release. Copies 
of any manuscript, abstract and/or press release/ media presentation should be sent 
to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
14.4 
Data and Safety Monitoring Plan 
Data and safety is ensured by several integrated components including the COG Data and 
Safety Monitoring Committee. 


                         
 
 
 
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14.4.1 Data and Safety Monitoring Committee 
This study will be monitored in accordance with the Children’s Oncology Group 
policy for data and safety monitoring of Phase 1 and 2 studies. In brief, the role of 
the COG Data and Safety Monitoring Committee is to protect the interests of 
patients and the scientific integrity for all Phase 1 and 2 studies. The DSMC 
consists of a chair; a statistician external to COG; one external member; one 
consumer representative; the lead statistician of the PEP-CTN scientific 
committee; and a member from the NCI. The DSMC meets at least every 6 months 
to review current study results, as well as data available to the DSMC from other 
related studies. Approximately 6 weeks before each meeting of the Phase 1 and 2 
DSMC, study chairs will be responsible for working with the study statistician to 
prepare study reports for review by the DSMC. The DSMC will provide 
recommendations to the COG PEP-CTN Chair and the Group Chair for each study 
reviewed to change the study or to continue the study unchanged. Data and Safety 
Committee reports for institutional review boards can be prepared using the public 
data monitoring report as posted on the COG Web site. 
 
14.4.2 Monitoring by the Study Chair and Developmental Therapeutics Leadership  
The study chair will monitor the study regularly and enter evaluations of patients’ 
eligibility, evaluability, and dose limiting toxicities into the study database. In 
addition, study data and the study chair’s evaluations will be reviewed by the COG 
PEP-CTN Chair, Vice Chair and Statistician on a weekly conference call. 


                         
 
 
 
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REFERENCES 
 
1. 
Esteller M: Epigenetics in cancer. The New England journal of medicine 358:1148-59, 2008 
2. 
Lane AA, Chabner BA: Histone deacetylase inhibitors in cancer therapy. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 27:5459-68, 2009 
3. 
Hess-Stumpp H, Bracker TU, Henderson D, et al: MS-275, a potent orally available inhibitor of histone 
deacetylases--the development of an anticancer agent. The international journal of biochemistry & cell 
biology 39:1388-405, 2007 
4. 
Nakagawa M, Oda Y, Eguchi T, et al: Expression profile of class I histone deacetylases in human cancer 
tissues. Oncology reports 18:769-74, 2007 
5. 
Suzuki T, Ando T, Tsuchiya K, et al: Synthesis and histone deacetylase inhibitory activity of new benzamide 
derivatives. Journal of medicinal chemistry 42:3001-3, 1999 
6. 
Jaboin J, Wild J, Hamidi H, et al: MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in 
vivo antitumor activity against pediatric solid tumors. Cancer research 62:6108-15, 2002 
7. 
Saito A, Yamashita T, Mariko Y, et al: A synthetic inhibitor of histone deacetylase, MS-27-275, with marked 
in vivo antitumor activity against human tumors. Proceedings of the National Academy of Sciences of the 
United States of America 96:4592-7, 1999 
8. 
Syndax: Entinostat (SNDX-275) Investigator's Brochure, Version 13, Syndax Pharmaceuticals Inc, 2014 
9. 
Hess-Stumpp H, Apetri E, Hoffman J: MS-275, a potent orally active inhibitor of histone deactylases, is 
efficacious in a wide range of experimental tumors: In vivo efficacy data. . Proceedings of the American 
Association of Cancer Research 46:607, 2005 
10. 
Sabnis GJ, Goloubeva O, Chumsri S, et al: Functional activation of the estrogen receptor-alpha and aromatase 
by the HDAC inhibitor entinostat sensitizes ER-negative tumors to letrozole. Cancer research 71:1893-903, 
2011 
11. 
Witta S, Gemmill R, HIrsch F: Restoring E-cadherin expression increases sensitivity to epidermal growth 
factor receptor inhibitors in lung cancer cell lines. Cancer research 66:944-950, 2006 
12. 
Keshelava N, Houghton PJ, Morton CL, et al: Initial testing (stage 1) of vorinostat (SAHA) by the pediatric 
preclinical testing program. Pediatr Blood Cancer 53:505-8, 2009 
13. 
Sonnemann J, Dreyer L, Hartwig M, et al: Histone deacetylase inhibitors induce cell death and enhance the 
apoptosis-inducing activity of TRAIL in Ewing's sarcoma cells. Journal of cancer research and clinical 
oncology 133:847-58, 2007 
14. 
Rao-Bindal K, Koshkina NV, Stewart J, et al: The histone deacetylase inhibitor, MS-275 (entinostat), 
downregulates c-FLIP, sensitizes osteosarcoma cells to FasL, and induces the regression of osteosarcoma 
lung metastases. Current cancer drug targets 13:411-22, 2013 
15. 
Abraham J, Nunez-Alvarez Y, Hettmer S, et al: Lineage of origin in rhabdomyosarcoma informs 
pharmacological response. Genes & development 28:1578-91, 2014 
16. 
Keller C: Personal Communication.  
17. 
Spiller SE, Ravanpay AC, Hahn AW, et al: Suberoylanilide hydroxamic acid is effective in preclinical studies 
of medulloblastoma. Journal of neuro-oncology 79:259-70, 2006 
18. 
Kumar KS, Sonnemann J, Beck JF: Histone deacetylase inhibitors induce cell death in supratentorial 
primitive neuroectodermal tumor cells. Oncology reports 16:1047-52, 2006 
19. 
Yin D, Ong JM, Hu J, et al: Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor: effects on gene 
expression and growth of glioma cells in vitro and in vivo. Clinical cancer research : an official journal of 
the American Association for Cancer Research 13:1045-52, 2007 
20. 
Sonnemann J, Kumar KS, Heesch S, et al: Histone deacetylase inhibitors induce cell death and enhance the 
susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells. International journal of 
oncology 28:755-66, 2006 
21. 
Camphausen K, Burgan W, Cerra M, et al: Enhanced radiation-induced cell killing and prolongation of 
gammaH2AX foci expression by the histone deacetylase inhibitor MS-275. Cancer research 64:316-21, 2004 
22. 
Hacker S, Karl S, Mader I, et al: Histone deacetylase inhibitors prime medulloblastoma cells for 
chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation. Oncogene 30:2275-81, 2011 


                         
 
 
 
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23. 
Bangert A, Hacker S, Cristofanon S, et al: Chemosensitization of glioblastoma cells by the histone 
deacetylase inhibitor MS275. Anti-cancer drugs 22:494-9, 2011 
24. 
Jona A, Khaskhely N, Buglio D, et al: The histone deacetylase inhibitor entinostat (SNDX-275) induces 
apoptosis in Hodgkin lymphoma cells and synergizes with Bcl-2 family inhibitors. Experimental hematology 
39:1007-1017 e1, 2011 
25. 
Ryan QC, Headlee D, Acharya M, et al: Phase I and pharmacokinetic study of MS-275, a histone deacetylase 
inhibitor, in patients with advanced and refractory solid tumors or lymphoma. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 23:3912-22, 2005 
26. 
Kummar S, Gutierrez M, Gardner ER, et al: Phase I trial of MS-275, a histone deacetylase inhibitor, 
administered weekly in refractory solid tumors and lymphoid malignancies. Clinical cancer research : an 
official journal of the American Association for Cancer Research 13:5411-7, 2007 
27. 
Gore L, Rothenberg ML, O'Bryant CL, et al: A phase I and pharmacokinetic study of the oral histone 
deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas. Clinical cancer 
research : an official journal of the American Association for Cancer Research 14:4517-25, 2008 
28. 
Younes A: Abstract 3952. Blood 116, 2010 
29. 
Hauschild A, Trefzer U, Garbe C, et al: Multicenter phase II trial of the histone deacetylase inhibitor 
pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma. 
Melanoma Res 18:274-8, 2008 
30. 
Yardley DA, Ismail-Khan RR, Melichar B, et al: Randomized phase II, double-blind, placebo-controlled 
study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic 
estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31:2128-35, 
2013 
31. 
Gojo I, Jiemjit A, Trepel JB, et al: Phase 1 and pharmacologic study of MS-275, a histone deacetylase 
inhibitor, in adults with refractory and relapsed acute leukemias. Blood 109:2781-90, 2007 
32. 
Skolnik JM, Barrett JS, Jayaraman B, et al: Shortening the timeline of pediatric phase I trials: the rolling six 
design. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26:190-
5, 2008 
33. 
Schwartz GJ, Gauthier B: A simple estimate of glomerular filtration rate in adolescent boys. J Pediatr 
106:522-6, 1985 
34. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 
 
 


                         
 
 
 
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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
 
Karnofsky 
Lansky 
Score 
Description 
Score Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time spent 
in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the day; 
no active play, able to participate in all quiet 
play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to very 
passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 
 
 




                         
 
 
 
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APPENDIX III: TOXICITY-SPECIFIC GRADING 
 
Bilirubin 
 
Grade 1: 
≤ 1.5 x ULN 
Grade 2: 
> 1.5- 3.0 x ULN 
Grade 3: 
> 3.0-10.0 x ULN 
Grade 4: 
> 10.0 x ULN 
 
ALT: For the purpose of this study, the ULN for SGPT is 45 U/L regardless of baseline.  
 
 
Grade 1: 
≤ 135 
Grade 2: 
136- 225 
Grade 3: 
226- 900 
Grade 4: 
> 900 
 
AST: For the purpose of this study, the ULN for SGPT is 50 U/L regardless of baseline. 
 
Grade 1: 
≤ 150 
Grade 2: 
151-250 
Grade 3: 
251-1000 
Grade 4: 
> 1000 
 
GGT: 
 
Grade 1: 
> ULN- 2.5 x ULN 
Grade 2: 
> 2.5- 5.0 x ULN 
Grade 3: 
> 5.0-20.0 x ULN 
Grade 4: 
> 20.0 x ULN 
 
 






                         
 
 
 
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Day 22 
 
 
AM / PM 
 
 
 
 
 
 
 






                         
 
 
 
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APPENDIX VIII: ISOLATION OF PBMCS AND PLASMA FOR CORRELATIVE STUDIES 
 
 
 
Isolation and Storage of Peripheral Blood Mononuclear Cells (PBMCs) 
 
a) Purpose 
 
To isolate Peripheral Blood Mononuclear Cells (PBMCs) for long term storage. 
 
 
b) Equipment and Material Required 
 
• 
Whole blood samples to be processed (freshly collected into 
CPT) 
• 
Cell preparation tubes (CPT) 
• 
Centrifuge (capable of centrifugation at 1,600 × rcf) 
• 
Pipette and tips 
• 
0.5 and 2.0 ml cryo tubes (capable of being stored at -80˚C 
or -150˚C) 
• 
Extra 
collection 
tubes 
(to 
counterbalance 
during 
centrifugation) 
• 
1 x PBS (room temperature) 
 
 
c) Procedure 
 
1. Gently invert CPT tubes 5 times before placing in the centrifuge 
2. Counter balance extra collection tubes for centrifugation 
3. Centrifuge the samples for 20 minutes at 1,600 × rcf at room temperature 
***Ensure that tubes will not hit inside of centrifuge rotor once centrifugation 
begins 
4. Remove tubes from centrifuge, ensuring that tubes are kept in the upright position so as 
not to disturb layers. 
5. Aliquot plasma into labeled 2 ml aliquots, as appropriate (see SOP Processing Blood 
Samples Step 4 - 5) 
***Be careful not to disrupt the cell layer while aspirating plasma (see image 
above) 
6. Transfer small amount of remaining plasma and cells from CPT tubes into a 15 ml conical 
tube 


                         
 
 
 
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7. Rinse CPT tubes using 5 ml of 1 × PBS (gently pipette up and down) 
***Be careful not to disturb the gel matrix. Rinsing should remove most of the 
cells from the gel matrix. The wash may be reddish in color. 
8. Transfer the rinse mixture into the same 15 ml conical tube (one tube per patient sample) 
9. Discard the rinsed CPT tubes in the biohazard waste 
10. Bring the total volume, in the 15 ml conical tube, to 15 ml using 1 × PBS  
11. Mix the cells by gently inverting the tube 5 times 
12. Centrifuge at 300 × rcf for 15 minutes at room temperature 
13. Aspirate and discard the supernatant, being careful not to disturb the cell pellet 
14. Add 200-500 µl of PBS to the cell pellet and pipette gently to resuspend pellet (use smallest 
volume of PBS to fully resuspend pellet) 
15. Aliquot resuspended cells into 0.5 ml labeled cryo tubes and place in -80˚C freezer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




                         
 
 
 
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CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol 
and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can 
be approved to enroll patients.  Assignment of site registration status in the CTSU Regulatory Support 
System (RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory 
criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not 
required to submit IRB approval documentation to the CTSU Regulatory Office. For sites using the 
CIRB, IRB approval information is received from the CIRB and applied to the RSS in an automated 
process. Signatory Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the 
CIRB via IRBManager to indicate their intent to open the study locally.  The CIRB’s approval of the 
SSW is then communicated to the CTSU Regulatory Office.  In order for the SSW approval to be 
processed, the Signatory Institution must inform the CTSU which CIRB-approved institutions aligned 
with the Signatory Institution are participating in the study. 
 
Requirements For ADVL1513 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-signed 
CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
For applicable studies with a radiation and/or imaging (RTI) component, the enrolling site must be 
aligned to a RTI provider.  To manage provider associations access the Provider Association tab on 
the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove 
associated providers.  Sites must be linked to at least one IROC credentialed provider to participate on 
trials with an RT component. Enrolling sites are responsible for ensuring that the appropriate 
agreements are in place with their RTI provider, and that appropriate IRB approvals are in place.   
 


                         
 
 
 
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Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and 
tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab →Regulatory 
Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
      1818 Market Street, Suite 3000 
      Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support.