A Phase 2, Multi-center, Open-label Study of Oral ENMD-2076 for the Treatment of Patients With Advanced Fibrolamellar Carcinoma (FLC)
Phase: PHASE2
Conditions: Advanced Adult Hepatocellular Carcinoma, Advanced Fibrolamellar Carcinoma
Sponsor: CASI Pharmaceuticals, Inc.

Protocol Number 2076-CL-006 
 
CASI Pharmaceuticals, Inc. 
Version 8.1 
 
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CLINICAL STUDY PROTOCOL 
 
Protocol Title:  A Phase 2 Multi-center, Open-label Study of Oral ENMD-2076 for 
the Treatment of Patients with Advanced Fibrolamellar Carcinoma (FLC) 
 
Protocol Number 2076-CL-006 
IND # 123,973 
Study Product: 
ENMD-2076 
Indication: 
Fibrolamellar Carcinoma 
Phase: 
II 
Name and Affiliation of 
Principal Investigator: 
Ghassan K. Abou-Alfa, MD. 
Memorial Sloan Kettering Cancer Center 
 
 
Name and Address of Sponsor: 
Rong Chen, MD, PhD 
Chief Medical Officer 
CASI Pharmaceuticals, Inc. 
9620 Medical Center Drive, Suite 300 
Rockville, MD 20850 
 
 
GCP Statement: 
This study will be performed in compliance with GCP, 
including the archiving of essential documents. 
The information in this document is confidential and is proprietary to CASI Pharmaceuticals. It is 
understood that information in this document shall not be disclosed to any third party, in any 
form, without prior written consent of CASI Pharmaceuticals. 
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1. 
SYNOPSIS 
TITLE:  A Phase 2 Multi-center, Open-label Study of Oral ENMD-2076 for the Treatment of Patients with 
Advanced Fibrolamellar Carcinoma (FLC) 
INVESTIGATIONAL PRODUCT:  ENMD-2076 
INDICATION:  Fibrolamellar Carcinoma 
PHASE OF DEVELOPMENT:  II 
INVESTIGATIONAL SITES/LOCATIONS:  Multi-centers, a list of investigators and affiliated investigational 
sites/locations is maintained in the trial master file 
OBJECTIVES:   
Primary Objective:  
• 
To determine the Overall Response Rate (ORR) using RECIST v 1.1 criteria when patients with advanced 
fibrolamellar carcinoma (FLC) are treated with daily oral ENMD-2076 
Secondary Objectives:  
• 
To evaluate the 6-month Progression Free Survival (PFS6) rate when patients with FLC are treated with daily 
oral ENMD-2076. 
• 
To evaluate the median Progression Free Survival (PFS), Time to Progression (TTP), and Overall Survival 
(OS). 
• 
To determine the safety of ENMD-2076 as defined by the frequency and severity of adverse events when 
patients with FLC are treated with daily oral ENMD-2076. 
• 
To explore biomarkers predictive of tumor response to ENMD-2076 in FLC patients. 
 
STUDY DESIGN:  This is a Phase 2 study in 29 patients with advanced FLC. Primary efficacy analysis will be 
based on overall response rate using RECIST v 1.1 criteria. Secondary endpoints will include 6-month 
progression free survival rate, median PFS, TTP, and OS and the evaluation of safety.  
Patients will be given an oral, daily dose of ENMD-2076 based on body surface area. In case of adverse events, 
two dose reductions at the discretion of the investigator will be allowed for each patient.  If adverse events 
resolve, the dose can be increased in 50 mg increments as tolerated.  Dosing interruptions/delays will be allowed 
at the discretion of the investigator for recovery from adverse events or inter-current illness, particularly if the 
patient is benefiting from therapy with ENMD-2076. After a treatment interruption for adverse events, treatment 
can be resumed at a lower dose and increased in 50 mg increments as tolerated. 
Tumor measurements will occur every two months (± 1 week) after initial study drug administration. The overall 
response rate will be determined based on RECIST v 1.1 criteria. Survival and time to progression will be 
determined as the time from first study drug administration until death from any cause or documented 
progression. Patients who discontinue therapy for any reason other than progression will continue to receive 
imaging until progression or death.  
An interim analysis will be conducted after 16 patients will have reached study endpoints of responses 
per RECIST 1.1 criteria after two cycles of treatment..  The purpose of the interim analysis is to determine 
whether it is futile to continue the study. 
NUMBER OF SUBJECTS (PLANNED):  29 
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DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:   
Eligible patients must fulfil the following inclusion criteria: 
 
1. 
Histologically or cytologically confirmed advanced not amenable to curative resection fibrolamellar 
carcinoma (FLC). 
a) This review will be conducted by a pathologist at the participating site to confirm the diagnosis. If there 
is a discrepancy, a review of a different archived specimen if available (heterogeneity is common) 
and/or identify a liver pathologist at another site who can provide independent review. 
b) Archived specimens will be collected for subsequent immunohistochemistry, genomic analysis and 
possibly other research. 
 
2. 
All forms of prior local therapy are allowed as long as patients have either a target lesion, which has not 
been treated with local therapy and/or the target lesion(s) within the field of the local-regional therapy that 
has shown an increase of ≥ 20% in size. Local-regional therapy must be completed at least 4 weeks prior to 
the baseline CT scan. 
3. 
Patients with prior systemic regimens are allowed. There is no limitation to the number of previous 
systemic regimens but must have recovered from any toxicity attributable to prioir therapy.  
4. 
Are at least 4 weeks from major surgery or systemic therapy and recovered. 
5. 
At least one measureable lesion by RECIST 1.1. 
6. 
Male or non-pregnant, non-breastfeeding female at least 18 years of age. Patients aged at 12~18 years may 
be recruited  but only at the site principle investigator's request and subject to IRB approval. 
7. 
Have clinically acceptable laboratory screening results within certain limits specified below: 
• AST and ALT ≤ 5 times upper limit of normal (ULN)  
• Total bilirubin ≤ 3.0 x ULN 
• Creatinine ≤ 1.5 x ULN or Cr Cl > 60 cc/min 
• Absolute neutrophil count ≥ 1500 cells/mm3 
• Platelets ≥ 50,000/mm3 
8. 
Have an ECOG performance status of 0-2 for ≥ 16 years of age and a Lansky performance status of 70-100 
for < 16 years of age.  
9. 
Women and men of child producing potential must agree to use effective contraceptive methods prior to 
study entry, during study participation, and for at least 30 days after the last administration of study 
medication.  A serum pregnancy test within 72 hours prior to the initiation of therapy will be required for 
women of childbearing potential. 
10. 
Have the ability to understand the requirements of the study, provide written informed consent or assent, 
which includes authorization for release of protected health information, abide by the study restrictions, and 
agree to return for the required assessments. 
 
 
Eligible patients must not have any of the following exclusion criteria: 
 
1. 
Have active, acute, or chronic clinically significant infections, chronic hepatitis or HIV, thromboembolic or 
hemorrhagic event with concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin 
or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (eg, 
clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low 
molecular weight heparin (LMWH) are permitted. 
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2. 
Have uncontrolled hypertension (systolic blood pressure greater than 150 or diastolic blood pressure greater 
than 100) or history of congestive heart failure (AHA Grade 2 or higher).  
3. 
Have active cardiovascular disease. 
4. 
QTc interval corrected for heart rate of greater than 470 msec in adults and 450 msec in pediatrics (< 18 
years). 
5. 
Have additional uncontrolled serious medical or psychiatric illness that in the point of view of the 
investigator can render the patient unable to receive therapy or make it unsafe to receive therapy. 
6. 
Require treatment with any of the exclusionary medications listed in Appendix D. 
7. 
Known untreated or unstable CNS metastatic disease. 
8. 
Have persistent 2+ protein by urinalysis (patients with 2+ proteinuria that have a spot protein:creatinine 
ratio of less than 0.3 may be enrolled) or a history of nephrotic syndrome. 
9. 
Subjects with history of another primary cancer, with the exception of: a) curatively resected non-
melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with 
no known active disease present in the opinion of the investigator will not affect patient outcome in the 
setting of current FLC diagnosis. 
 
TEST PRODUCT(S), DOSE AND MODE OF ADMINISTRATION:  ENMD-2076 is provided as hard 
gelatin capsules containing 50 mg of drug. 
Patients will receive a daily oral dose (fasting) of ENMD-2076 of 150, 200 or 250 mg/day based on body surface 
area.  
DURATION OF TREATMENT:  Following the Screening and Baseline Period (Day -28 to 1) each treatment 
cycle will consist of a 4-week Treatment Period (Cycle 1 to Cycle 6+). Patients will be treated until disease 
progression, unacceptable toxicity or death. 
DISCONTINUATION FROM TREATMENT:   
The Investigator or the Sponsor may discontinue individual patients from the study at any time.  Patients will be 
encouraged to complete the study; however, they may voluntarily withdraw at any time.  The Investigator or 
designee will document the reason for discontinuation. Patients who went off therapy without evidence of disease 
progression will have CT scans every two months until disease progression or death. 
 
A patient will be withdrawn from treatment for the following reasons: 
• 
Significant adverse event 
• 
Pregnancy 
• 
Disease progression 
• 
Consent withdrawn 
• 
Noncompliance 
 
PRIMARY EFFICACY ENDPOINT: 
Overall response rate based on RECIST v 1.1 criteria will be used to evaluate response every two months after 
first study drug administration. Patients who go off therapy without evidence of disease progression will have CT 
scans every two months until progression.  
SECONDARY EFFICACY ENDPOINTS: 
• 
Progression-free survival rate at 6 months (PFS6).  
• 
The median PFS or TTP as based on RECIST 1.1 and measured by time from first study drug administration 
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until progression or death. 
• 
The median overall survival as measured by time from first study drug administration to death or study 
completion.  
• 
Safety data will be collected from time of informed consent through study completion /withdrawal up to 30 
days after the last dose of study medication by each subject. 
 
SAFETY ENDPOINTS: 
Safety will be evaluated by collecting information on adverse events and by routine assessments.  All adverse 
events will be graded using the NCI CTCAE version 4.0 and recorded in the CRF.  Specific safety assessments 
include the following: 
 
• 
Treatment-emergent AEs graded according to NCI CTCAE v4. The frequency and severity of AEs will be 
evaluated following administration of oral ENMD-2076 
• 
Change from Baseline in vital signs (blood pressure, heart rate, respiratory rate, and body temperature) 
• 
Change from Baseline in clinical laboratory tests from values obtained prior to treatment 
• 
Change from Baseline in electrocardiograms (ECGs)  
 
Serious adverse events require expedited reporting to the medical monitor as described in the protocol. 
 
STATISTICAL ANALYSIS:   
We have designed this study using a Simon’s Optimal two-stage design to allow for an early interim analysis to 
determine potential futility and an overall final analysis with criteria established to allow for sufficient power and 
type 1 error rate to provide results to support this Phase 2 trial.  The null hypothesis that the true response rate is 
2% will be tested against a one-sided alternative that the true response rate is 15%. In the first stage, 16 patients 
will have reached study endpoints of response s per RECIST 1.1 criteria after two cycles of treatment. If there are 
zero responses in these 16 patients, the study will be stopped. Otherwise, 13 additional patients will be accrued 
for a total of 29. The null hypothesis will be rejected if 2 or more responses are observed in 29 patients. This 
design yields a type I error rate of 9.4% and power of 90% when the true response rate is 15%. The probability of 
early termination due to drug inefficacy is 72%.   
 
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DOCUMENT APPROVAL 
PRINCIPAL INVESTIGATOR: 
I have read and reviewed this Protocol 2076-CL-006, and I agree to conduct this trial according 
to this Protocol, to comply with its requirements subject to ethical and safety considerations, and 
to conduct the trial in accordance with all applicable regulations, Good Clinical Practice (GCP), 
Title 21 of the Code of Federal Regulations (CFR) sections 50, 56 and 312 and International 
Conference on Harmonization Guidelines on Good Clinical Practice (ICH E6). I further agree to 
comply with all other applicable federal, state, and local laws and regulations in connection with 
my conduct of this trial, including, without limitation, all applicable medical information privacy 
rule requirements. 
I understand that the Sponsor may decide to suspend or terminate the study at any time for 
whatever reason; such a decision will be communicated to me in writing. Conversely, should I 
decide to withdraw from execution of the study I will communicate my intention immediately in 
writing to the Sponsor. 
CASI Pharmaceuticals, Inc. approves this protocol. 
SPONSOR REPRESENTATIVE 
 
___________________________________________ 
 
_______________________ 
Signature 
 
 
 
 
 
 
 
Date 
Print Name:  Rong Chen, MD, PhD,     
         Chief Medical Officer 
 
  
PRINCIPAL INVESTIGATOR 
 
___________________________________________ 
 
_______________________ 
Signature 
 
 
 
 
 
 
 
Date 
 
Print Name:  _________________________________ 
 
16 Sept 2015
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TABLE OF CONTENTS 
1.!
SYNOPSIS ............................................................................................................................................................. 2!
2.!
LIST OF ABBREVIATIONS ................................................................................................................................ 9!
3.!
ETHICAL CONDUCT OF THE STUDY AND REGULATORY REQUIREMENTS ...................................... 10!
3.1!
Institutional Review Board (IRB) ................................................................................................................... 10!
3.2!
Ethical Conduct of the Study .......................................................................................................................... 10!
3.3!
Subject Information and Consent .................................................................................................................... 10!
3.4!
Approval of the Study Protocol and Amendments ......................................................................................... 10!
3.5!
Ongoing Information for Institutional Review Board .................................................................................... 11!
3.6!
Premature Closure of the Study ...................................................................................................................... 11!
4.!
INTRODUCTION ................................................................................................................................................ 12!
4.1!
Background ..................................................................................................................................................... 12!
4.2!
Rationale ......................................................................................................................................................... 12!
4.3!
Potential Risks and Benefits ........................................................................................................................... 14!
4.3.1!
Risks of ENMD-2076 ............................................................................................................................... 14!
4.3.2!
Potential Benefits ...................................................................................................................................... 14!
5.!
STUDY OBJECTIVES ........................................................................................................................................ 14!
5.1!
Primary Objective ........................................................................................................................................... 14!
5.2!
Secondary Objectives ...................................................................................................................................... 14!
5.3!
Endpoints ........................................................................................................................................................ 15!
6.!
INVESTIGATIONAL PLAN .............................................................................................................................. 15!
6.1!
Overall Study Design and Plan – Description ................................................................................................ 15!
6.2!
Discussion of Study Design and Choice of Control Group(s) ........................................................................ 16!
6.3!
Selection of Study Population ......................................................................................................................... 16!
6.3.1!
Inclusion Criteria ...................................................................................................................................... 16!
6.3.2!
Exclusion Criteria ..................................................................................................................................... 17!
6.3.3!
Removal of Subjects from Therapy or Assessment ................................................................................. 18!
6.3.4!
Replacement Policy .................................................................................................................................. 19!
7.!
STUDY PRODUCT ............................................................................................................................................. 19!
7.1!
Study Medication Supply ................................................................................................................................ 19!
7.2!
Description of Study Product .......................................................................................................................... 19!
7.3!
Description of Comparator Product ................................................................................................................ 20!
7.4!
Dosing ............................................................................................................................................................. 20!
7.5!
Packaging and Labelling ................................................................................................................................. 21!
7.6!
Conditions for Storage and Use ...................................................................................................................... 22!
7.7!
Method of Assigning Subjects to Treatment Groups ...................................................................................... 22!
7.8!
Dispensing and Accountability ....................................................................................................................... 22!
7.9!
Patient Compliance ......................................................................................................................................... 22!
7.10!
Prior and Concomitant Therapy ..................................................................................................................... 23!
8.!
EFFICACY AND SAFETY ASSESSMENTS .................................................................................................... 24!
8.1!
Primary Efficacy Variable(s) .......................................................................................................................... 24!
8.2!
Secondary Efficacy Variables ......................................................................................................................... 24!
8.2.1!
Objective Tumor Responses/Benefit Assessments .................................................................................. 24!
8.2.2!
Guidelines for Evaluation of Measurable Disease and Response ............................................................ 24!
8.3!
Safety Variables .............................................................................................................................................. 24!
8.3.1!
Clinical Laboratory ................................................................................................................................... 25!
8.3.2!
Medical History and Physical Examination ............................................................................................. 26!
8.3.3!
Standard 12-lead Electrocardiograms (ECGs) ......................................................................................... 26!
8.3.4!
Vital Signs ................................................................................................................................................ 26!
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8.3.5!
ECOG Performance Status ....................................................................................................................... 26!
8.3.6!
Adverse Events ......................................................................................................................................... 26!
8.3.7!
Pregnancy Information ............................................................................................................................. 32!
9.!
STUDY PROCEDURES AND FLOW CHART ................................................................................................. 33!
9.1!
Study Periods .................................................................................................................................................. 37!
9.1.1!
Screening Period (Days –28 to –1) ........................................................................................................... 37!
9.1.2!
Treatment Period ...................................................................................................................................... 37!
9.1.3!
End of Cycle 6 Assessment Time point ................................................................................................... 37!
9.1.4!
End of Study Drug Administration Visit .................................................................................................. 37!
9.2!
Study Procedures ............................................................................................................................................ 37!
9.2.1!
Pharmacokinetic analysis ......................................................................................................................... 37!
9.2.2!
Tissue biomarker analysis: ....................................................................................................................... 38!
9.2.3!
Genomic testing ........................................................................................................................................ 38!
9.2.4!
Tumor biopsy: .......................................................................................................................................... 39!
10.! STATISTICAL METHODS PLANNED AND SAMPLE SIZE ........................................................................ 41!
10.1!
Subject Populations ........................................................................................................................................ 41!
10.2!
Subject Disposition ........................................................................................................................................ 41!
10.3!
Demographics and Baseline Characteristics .................................................................................................. 41!
10.4!
Efficacy Analysis ........................................................................................................................................... 41!
10.5!
Safety Analysis ............................................................................................................................................... 42!
10.5.1!
Adverse Events ...................................................................................................................................... 42!
10.5.2!
Clinical Laboratory ................................................................................................................................ 42!
11. QUALITY CONTROL AND QUALITY ASSURANCE ..................................................................................... 43!
10.6!
Source Data and Records ............................................................................................................................... 43!
10.7!
Reporting of Results ....................................................................................................................................... 43!
10.8!
Confidentiality of Subject Data ...................................................................................................................... 44!
11.! REPORTING AND PUBLICATION .................................................................................................................. 45!
11.1!
Confidentiality of Study Data ........................................................................................................................ 45!
11.2!
Publication Policy .......................................................................................................................................... 45!
12.! REFERENCES ..................................................................................................................................................... 45!
13.! APPENDIX A ...................................................................................................................................................... 47!
14.! APPENDIX B ...................................................................................................................................................... 48!
15.! APPENDIX C ...................................................................................................................................................... 49!
16.! APPENDIX D ...................................................................................................................................................... 50!
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2. 
LIST OF ABBREVIATIONS  
AE 
Adverse event 
CR 
Complete Response 
CRF 
Case report form 
CT 
Computed tomography 
CTM 
Clinical trial material 
FLC 
Fibrolamellar carcinoma 
GCP 
 
Good Clinical Practice 
HCC 
Hepatocellular carcinoma 
IRB 
Institutional Review Board 
MRI 
Magnetic resonance imaging 
MUGA 
Multi-gated acquisition scan 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS6 
Progression Free Survival at 6 months 
PR 
Partial Response 
SAE 
Serious adverse event 
SD 
Stable Disease 
TTP 
Time to Progression 
ULN 
Upper limit of normal 
 
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3. 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY 
REQUIREMENTS 
3.1 
Institutional Review Board (IRB) 
The study protocol and any amendments will be reviewed by an Institutional Review Board 
(IRB). The IRB will review the informed consent form, their updates (if any), and any written 
materials given to the subjects. A list of all IRBs and contact information will be included in the 
study report. 
3.2 
Ethical Conduct of the Study 
The study will be conducted in accordance the ethical principles that have their origins in the 
Declaration of Helsinki and in compliance with the Protocol, U.S. 21 CFR Part 312, current 
International Conference on Harmonization (ICH) guidelines on Good Clinical Practice (GCP), 
and applicable regulatory requirements. 
3.3 
Subject Information and Consent 
The investigator will obtain a freely given written consent from each subject after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards, and any other aspects 
of the study that are relevant to the subject's decision to participate. The consent form must be 
signed and dated by the subject before he/she is exposed to any protocol-specific procedure. 
The investigator will explain that the subjects are completely free to refuse to enter the study or 
to withdraw from it at any time, without any consequences for their further care and without the 
need to justify. 
The patient will receive a copy of the patient information and the signed informed consent.  
The patient will be informed if information becomes available that may be relevant to his/her 
willingness to continue participation in the study. 
Each subject will be informed that a monitor or a health authority inspector, in accordance with 
applicable regulatory requirements, may review the portions of their source records and source 
data related to the study. Data protection and confidentiality will be handled in compliance with 
local laws. 
3.4 
Approval of the Study Protocol and Amendments 
Substantive changes in the protocol include changes that affect the safety of patients or changes 
that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosages, assessment variable(s), the number of patients treated, or the patient selection 
criteria.  Such changes must be prepared as a protocol amendment by the Study Monitor and 
implemented only upon joint approval of the Sponsor, Investigator, and the Study Monitor.  A 
protocol amendment must receive IRB approval prior to implementation.  In parallel with the 
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IRB approval process, the protocol amendment will be submitted to the appropriate regulatory 
authority as an amendment to the regulatory submission under which the study is being 
conducted.  If a protocol amendment requires changes in the informed consent document, the 
revised informed consent document prepared by the Investigator must be approved by the 
Sponsor, Study Monitor, and the IRB. 
 
Emergency departures from the protocol that eliminate an apparent immediate hazard to a 
particular patient and that are deemed crucial for the safety and well-being of that patient may be 
instituted for that patient only.  The Investigator or other attending physician also will contact the 
Medical Monitor as soon as possible in the case of such a departure.  These departures do not 
require pre-approval by the IRB; however, the IRB and Medical Monitor must be notified in 
writing as soon as possible after the departure has been made.  In addition, the Investigator will 
document in the patient’s CRF the reasons for the protocol deviation and the ensuing events. 
 
3.5 
Ongoing Information for Institutional Review Board 
While the study is ongoing and at study completion/discontinuation, the Investigator must submit 
to the IRB the following information in accordance with US Federal regulatory requirements: 
 
• 
Information on serious or unexpected AEs showing due diligence in providing this 
information as soon as possible 
• 
Periodic reports on the progress of the study  
• 
Final Study Summary upon study completion or premature closure of study 
3.6 
Premature Closure of the Study 
The Sponsor reserves the right to temporarily suspend or prematurely discontinue this study 
either at a single site or at all sites at any time and for any reason.  If such action is taken, CASI 
Pharmaceuticals will discuss this with the Investigators (including the reasons for taking such 
action) at that time.  CASI Pharmaceuticals will promptly inform all Investigators and/or 
institutions conducting the study if the study is suspended or terminated for safety reasons, and 
will also inform the regulatory authorities of the suspension or termination of the study and the 
reason(s) for the action.  If required by applicable regulations, the Investigators must inform the 
IRB promptly and provide the reason for the suspension or termination. 
 
If the study is prematurely discontinued, all study data must be returned to CASI 
Pharmaceuticals.  In addition, the site must conduct final disposition of all unused study 
medication in accordance with CASI Pharmaceuticals procedures for the study. 
 
Financial compensation to Investigators and/or institutions will be in accordance with the 
agreement established between the investigator and CASI Pharmaceuticals or designee. 
 
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The Investigators will submit a Final Study Summary to the institutional review board upon 
study completion or premature closure of the study. 
4. 
INTRODUCTION 
4.1 
Background 
Fibrolamellar carcinoma (FLC) is a rare malignant neoplasm of the liver. It has distinct clinical, 
histological and prognostic features from conventional hepatocellular carcinoma (HCC). It 
generally occurs in young individuals and is typically not associated with such underlying liver 
diseases as hepatitis and cirrhosis or other risks commonly present in HCC.  FLC represents 
0.6% to 8.6% of all hepatocellular carcinomas, according to 1986 to 1999 SEER data and various 
international series (El Serag et al., 2004; Sooklim et al., 2003; Moreno-Luna et al., 2005). 
 
FLC is often advanced when diagnosed due to lack of symptoms (Yen and Chang 2009). 
Surgical resections are the optimal treatment for localized tumors, FLC has a very high 
recurrence rate. In cases of postoperative recurrence, resection is not often possible. As the tumor 
is quite rare, there is no standard first line systemic treatment option available. The survival rate 
for FLC largely depends on whether (and to what degree) the cancer has metastasized, i.e. spread 
to the lymph nodes or other organs (Ang et al., 2006). Overall prognosis remains poor, because 
of its primary chemo resistance and early recurrence of metastasis. The absence of treatment 
options highlights the need for new compounds with activity in this patient population. Tumor 
growth relies on angiogenesis, the formation of new blood vessels from pre-existing vascular 
beds, in order to receive an adequate supply of oxygen and nutrients (Semela and Dufour, 2004). 
Inhibition of angiogenesis may represent a therapeutic option in the treatment of FLC. 
 
Recent clinical genomic research published in Science (Honeyman et al., 2014) reported the 
identification of a recurrent DNAJB1-PRKACA chimeric transcript that is expressed in 100% of 
FLC tumor tissue examined but not in adjacent normal liver, suggesting that this genetic 
alteration contributes to tumor pathogenesis of FLC. The chimeric RNA is predicted to code for 
a protein that is the catalytic domain of protein kinase A, which results in Aurora A kinase being 
overly expressed in FLC patients. Aurora kinases A, an important regulator in the cell 
proliferation process and often over-expressed in human cancers, is therefore believed to be a 
promising therapeutic target for FLC.   
 
VEGF is one of the main inducers of liver tumor angiogenesis. Increased levels of VEGF have 
been observed in HCC. Hepatoma cells are believed to possess a proliferation mechanism 
regulated by an autocrine mechanism, a paracrine mechanism, or both, which are mediated by 
FGF-1/FGFR or FGF-2/FGFR (or both). In addition, a gain of FGF-R2 (IIIb), -R2 (IIIc), and -R3 
(IIIb) may be associated with malignant transformation of liver tumor and may eventually serve 
as useful diagnostic and prognostic indicators (Asada et al., 2003).  
4.2 
Rationale 
ENMD-2076 is an orally active, small molecule, multi-targeted kinase inhibitor with a 
mechanism of action against angiogenesis, proliferation and the cell cycle. ENMD-2076 has 
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selective activity against the mitotic kinase Aurora A, as well as kinases involved in 
angiogenesis (VEGFRs, fibroblast growth factor receptors-FGFRs) and cell growth (Src).  
 
In pre-clinical in vivo animal model studies, ENMD-2076 exhibited anti-angiogenic activity by 
preventing the formation of new blood vessels and inducing regression of formed vessels at well-
tolerated doses. ENMD-2076 induced strong tumor regression when administered orally in 
animal models of human tumors derived from leukemia, colon, and breast cancer cell lines with 
minimal toxicity.  
 
In a pre-clinical study using three different human HCC cell lines, (SMMC-7721, QGY-7703 
and HepG 2) were used to establish the tumor xenograft models in nude mice. After the 
inoculated tumors grew to more than 100 mm3, mice were randomly assigned into one of the 
groups receiving vehicle, sorafenib, ENMD-2076 alone or in combination with chemotherapy 
agents, including doxorubicin or 5-FU, respectively, for 20 days. After commencing 
administration, dynamic measurement was performed every 3 days to determine the tumor sizes 
and body weights of the tumor-bearing mouse to assess tumor growth inhibition and adverse 
effects. In the SMMC-7721, QGY-7703 and HepG 2 xenograft models, ENMD-2076 induced 
tumor growth inhibition significantly greater (P<0.01 in all three models) than that of sorafenib.  
The tumor growth inhibition rates in the ENMD-2076 treated groups were also significantly 
higher (P<0.01 in all three models) than those seen in the groups treated with doxorubicin and 5 
FU. These results show that ENMD-2076 demonstrated robust antitumor activity against three 
cell line-derived xenograft models of HCC, which is superior to that of sorafenib, doxorubicin, 
and 5FU, supporting clinical investigation of this agent in HCC patients who do not tolerate, or 
have failed or relapsed from other systemic treatment such as sorafenib, doxorubicin or 5 FU.  
In clinical studies, clinical benefit has been observed with partial responses in one FLC patient, 
who relapsed from multiple treatments including TACE/doxorubicin, TACE/cisplatin, liver 
transplantation, and sorafenib. The patient was on ENMD-2076 for 18 4-week cycles while 
maintaining stable disease for 17 months.  
 
There are, however, no first line systemic options available and few clinical trials currently under 
going to explore treatment of anti-angiogenic agents in FLC (NCT01642186). 
 
The absence of current first line treatment options and the current anti-angiogenic clinical trial 
landscape make ENMD-2076 a viable candidate to potentially fill a currently unmet medical 
need in the treatment of FLC. 
 
In order to address the urgency of the needs, FDA encourage studies of drugs or biological 
products for diseases that are life-threatening or severely debilitating in pediatric patients and 
that lack adequate therapy could begin earlier than studies of other products, despite the relative 
lack of safety and effectiveness information. (FDA Guidance for Industry: How to Comply with 
the Pediatric Research Equity Act. September 2005) 
 
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CASI Pharmaceuticals has submitted the study protocol to FDA and had a discussion about the 
study plan. FDA agreed the study dose regimen for the proposed age groups (12 years and 
above) with the current available pharmacokinetic and clinical data. FDA has 
granted orphan drug designation to ENMD-2076 for the FLC indication. 
 
This protocol will evaluate efficacy and safety of ENMD-2076 in patients with FLC. 
4.3 
Potential Risks and Benefits 
4.3.1 
Risks of ENMD-2076 
As of April 2014, 210 cancer patients have been enrolled in clinical studies of ENMD-2076. The 
most frequent treatment-related AEs in the clinical studies in advanced cancer patients include 
hypertension, fatigue, nausea, diarrhea, dizziness/light-headedness, mucositis, and pruritis/rash. 
Serious adverse events included fatigue, hypertension, gallbladder pain, cholecystitis, elevated 
liver function tests, hyponatremia, dehydration, mucositis, gastrointestinal bleed, neutropenia, 
dyspnea, exacerbation of congestive heart failure, speech impairment/aphasia, and acute 
asymptomatic pancreatitis. Other events reported in Phase 2 include decreased platelets, 
hand/foot syndrome, ischemic colitis, and thyroiditis.  
 
Refer to the Investigator’s Brochure for detailed safety information on the clinical and 
non-clinical studies. 
4.3.2 
Potential Benefits 
It is unknown whether there will be an improvement of disease symptoms or survival in patients 
undergoing therapy with ENMD-2076. Patients who participate in this trial of ENMD-2076 will 
provide useful information that will guide its use in future patients with FLC. 
5. 
STUDY OBJECTIVES 
5.1 
Primary Objective 
The primary objective of this trial is to determine the overall response rate using RECIST v 1.1 
criteria when patients with advanced fibrolamellar carcinoma (FLC) are treated with daily oral 
ENMD-2076. 
5.2 
Secondary Objectives 
The secondary objectives are: 
• To evaluate the 6-month progression free survival (PS6) rate using RECIST v 1.1 criteria 
when patients with FLC are treated with daily oral ENMD-2076. 
• To evaluate the median Progression Free Survival (PFS), Time to Progression (TTP), and 
Overall Survival (OS). 
• To determine the safety of ENMD-2076 as defined by the frequency and severity of adverse 
events when patients with FLC are treated with daily oral ENMD-2076. 
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• To explore biomarkers predictive of tumor response to ENMD-2076 in FLC patients 
 
5.3 
Endpoints 
Revised RECIST criteria (version 1.1) as defined in Appendix C will be used to evaluate 
response. Response will be evaluated after every two cycles of treatment. Complete response 
(CR), partial response (PR), stable disease (SD), and progressive disease (PD) will be defined as 
outlined in the revised RECIST criteria, Appendix C and Section 6.3. SD is defined if the disease 
is stable on two measurements or longer, i.e. 4 treatment cycles or longer. Progression free 
survival (PFS) is defined as the time from the first day of treatment to the first observation of 
disease progression or death due to any cause or last follow-up. PFS will be censored for patients 
who are alive and free of progression at the time of last follow-up. Duration of overall response 
is measured from the time measurement criteria are first met for CR/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 on study). 
Patients who are removed from the study for reasons other than documented PD will be followed 
at 2 month intervals until study endpoint. 
6. 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan – Description 
This is a Phase 2 multi-center, open label study in 29 FLC patients.  Patients will receive a daily 
oral dose (fasting) of ENMD-2076 as a single treatment agent. The starting dose will be based on 
body surface area.  If adverse events, two dose reductions at the discretion of the investigator 
will be allowed for each patient. If adverse events resolve, the dose can be increased in 50 mg 
increments as tolerated.  Dosing interruptions/delays will be allowed at the discretion of the 
investigator for recovery from adverse events or inter-current illness, particularly if the patient is 
benefiting from ENMD-2076 treatment. After a treatment interruption for adverse events, 
treatment can be resumed at a lower dose and increased in 50 mg increments as tolerated.  
Patients may be treated until disease progression or unacceptable toxicity. 
Once a potential patient has been identified and signed the informed consent form, the screening 
and baseline visit procedures will be completed.  Following the baseline visits, patients meeting 
all study entry criteria will start Cycle 1 and get their first dose of ENMD-2076. Each cycle of 
treatment consists of a 4-week treatment period. Patients who complete the initial cycle of 
therapy (4 weeks of treatment) without evidence of significant toxicity or clinical evidence of 
progressive disease may receive additional 4-week cycles of treatment.  
 
Patients who discontinue therapy for any reason other than progression will continue to receive 
imaging until progression or death.  All recruited subjects will be followed for safety and overall 
survival. 
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6.2 
Discussion of Study Design and Choice of Control 
Group(s) 
The primary objective of this trial is to determine the overall response rate using RECIST v 1.1 
criteria when patients with advanced fibrolamellar carcinoma (FLC) are treated with daily oral 
ENMD-2076. Since there is no standard therapy approved to treat patients with FLC, it is 
appropriate for this evaluation to be conducted as a single arm, open label, non-controlled study.   
 
The interim analysis with the initial 16 patients is to establish proof of concept before expanding 
the treatment to the full planned population of patients. 
6.3 
Selection of Study Population 
6.3.1 
Inclusion Criteria 
The subjects must meet the following inclusion criteria: 
1. Histologically or cytologically confirmed advanced not amenable to curative resection 
fibrolamellar carcinoma.  
a) This review will be conducted by a pathologist at the participating site to confirm the 
diagnosis. If there is a discrepancy, a review of a different archived specimen if 
available (heterogeneity is common) and/or identify a liver pathologist at another site 
who can provide independent review. 
b) Archived specimens will be collected for subsequent immunohistochemistry, genomic 
analysis, and possibly other research. 
2. All forms of prior local therapy are allowed as long as patients have either a target lesion 
which has not been treated with local therapy and/or the target lesion(s) within the field of 
the local-regional therapy that has shown an increase of ≥ 20% in size. Local-regional 
therapy must be completed at least 4 weeks prior to the baseline CT scan.  
3. Patients with prior systemic regimens are allowed,.  There is no limitation to the number of 
previous systemic regimens but must have recovered from any toxicity attributable to prioir 
therapy. 
4. Are at least 4 weeks from major surgery or systemic therapy and recovered. 
5. At least one measureable lesion by RECIST 1.1. 
6. Male or non-pregnant, non-breastfeeding female at least 18 years of age. Patients aged at 
12~18 years may be recruited  but only at the site principle investigator's request and subject 
to IRB approval 
7. Have clinically acceptable laboratory screening results within certain limits specified below: 
• 
AST and ALT ≤ 5 times upper limit of normal (ULN)  
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• 
Total bilirubin ≤ 3.0 x ULN 
• 
Creatinine ≤ 1.5 x ULN or Cr Cl > 60 cc/min 
• 
Absolute neutrophil count ≥ 1500 cells/mm3 
• 
Platelets ≥ 50,000/mm3 
8. Have an ECOG performance status of 0-2 for ≥ 16 years of age and a Lansky performance 
status of 70-100 for < 16 years of age. 
9. Women and men of child producing potential must agree to use effective contraceptive 
methods prior to study entry, during study participation, and for at least 30 days after the last 
administration of study medication. A serum pregnancy test within 72 hours prior to the 
initiation of therapy will be required for women of childbearing potential. 
10. Have the ability to understand the requirements of the study, provide written informed 
consent or assent which includes authorization for release of protected health information, 
abide by the study restrictions, and agree to return for the required assessments. 
6.3.2 
Exclusion Criteria 
The presence of any of the following excludes a subject from study enrolment: 
1. Have active, acute, or chronic clinically significant infections, chronic hepatitis or HIV, 
thromboembolic or hemorrhagic event with concomitant treatment, in therapeutic doses, with 
anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa 
inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose 
warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are 
permitted. 
2. Have uncontrolled hypertension (systolic blood pressure greater than 150 or diastolic blood 
pressure greater than 100) or history of congestive heart failure (AHA Grade 2 or higher). 
3. Have active cardiovascular disease. 
4. QTc interval corrected for heart rate of greater than 470 msec in adults and 450 msec in 
pediatrics (<18 years). 
5. Have additional uncontrolled serious medical or psychiatric illness that in the point of view 
of the investigator can render the patient unable to receive therapy or make it unsafe to 
receive therapy. 
6. Require treatment with any of the exclusionary medications listed in Appendix D. 
7. Known untreated or unstable CNS metastatic disease. 
8. Have persistent 2+ protein by urinalysis (patients with 2+ proteinuria that have a spot 
protein:creatinine ratio of less than 0.3 may be enrolled) or a history of nephrotic syndrome. 
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9. Subjects with history of another primary cancer, with the exception of: a) curatively resected 
non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other 
primary solid tumor with no known active disease present in the opinion of the investigator 
will not affect patient outcome in the setting of current FLC diagnosis. 
6.3.3 
Removal of Subjects from Therapy or Assessment 
The Investigator or the Sponsor may discontinue individual patients from the study at any time.  
Patients will be encouraged to complete the study; however, they may voluntarily withdraw at 
any time.  The Investigator or designee will document the reason for discontinuation. Patients 
who went off therapy without evidence of disease progression will have CT scans every two 
months until disease progression or death. 
A patient will be withdrawn from treatment for the following reasons: 
• 
Significant adverse event: 
If a patient suffers an AE that, in the judgment of the Investigator, the Sponsor, or the 
Medical Monitor, presents an unacceptable consequence or risk to the patient, whether or 
not the AE is considered related to study medication, the patient will be withdrawn from 
treatment. 
• 
Pregnancy 
If a female patient becomes pregnant at any time during the study, she will be 
discontinued from further participation and treatment.  See Section 8.3.7 for further 
information on recording and follow-up of pregnancies. 
• 
Disease progression: 
Progression by RECIST v. 1.1 criteria, unless in the judgement of the investigator the 
patient has derived benefit from the treatment. 
• 
Consent withdrawn: 
The patient chooses to terminate participation in the study. 
• 
Noncompliance 
Failure to receive or refusal of study medication. 
Failure to comply with protocol requirements.  The patient has a serious deviation from the 
protocol that would compromise the integrity of the study data.  All occurrences of 
noncompliance must be documented on the appropriate CRF pages. 
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6.3.4 
Replacement Policy 
Withdrawn patients will not be replaced. 
7. 
STUDY PRODUCT 
7.1 
Study Medication Supply 
CASI Pharmaceuticals will supply all ENMD-2076 clinical trial material (CTM), including study 
medication and supplies, to the study site.  CTM will be shipped to the study site only after 
receipt of required documents in accordance with applicable regulatory requirements and 
standard operating procedures.  The Principal Investigator, or authorized study personnel, upon 
receipt of the study medication supplies, will conduct an inventory and acknowledge receipt to 
CASI Pharmaceuticals, or designee. 
7.2 
Description of Study Product  
ENMD-2076 is an off-white to yellow, odorless, crystalline solid manufactured by DSM Pharma 
Chemicals (DSM).  The structural formula is illustrated in Figure 1.   
Figure 1 
Structural Formula of ENMD-2076 
 
ENMD-2076 is provided as hard gelatin capsules and is intended for oral administration.  The 
active 
pharmaceutical 
ingredient 
is 
chemically 
synthesized 
2-(2-phenylvinyl)-4-[4-
methylpiperazin-1-yl)]-6-(5-methyl-2H-pyrazol-3-yl-amino)-pyrimidine L(+) tartrate salt with an 
empirical formula of C25H31O6N7•(2.5 H2O) and molecular weight of 570.59. 
 
ENMD-2076 will also be supplied as 50 mg formulated pharmaceutical product filled into hard 
gelatin capsules, size 1 white body capsule. The composition of this formulated product is a 
granulated mixture comprised as noted in the Table 1 below. All components of the formulation 
are common excipients used in formulating a wide range of oral drug products. 
 
Table 1: Composition of the Formulation for ENMD-2076 Capsules 
Component 
% in Final Mixture 
Intragranular Component 
 
ENMD-2076 
50% 
MCC Avicel PH 101 
30% 
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Methocel E5LV  
3% 
Sodium croscarmelose  
3% 
Cab-o-Sil (colloidal silicon dioxide) 
0.5% 
Mg Stearate (non-bovine #5712)  
0.5% 
Extragranular Component 
 
MCC Avicel PH 101 
10% 
Sodium croscarmelose  
2% 
Cab-o-Sil (colloidal silicon dioxide) 
0.5% 
Mg Stearate (non-bovine #5712)  
0.5% 
Total 
100% 
 
7.3 
Description of Comparator Product  
Not applicable. 
7.4 
Dosing 
The planned starting dose for this study is approximately 160 mg/(m2) of body surface area and 
is dosed in 50 mg increments per the following chart.  
 
Body Surface Area (m2) 
Daily Dose 
< 1.00 
150 mg 
1.00 - < 1.40 
200 mg 
≥ 1.40 
250 mg 
 
The Investigator will provide specific instructions to the patient regarding self-administration of 
each dose.  All patients will be instructed to refrain from eating for one hour before and one hour 
following all doses. 
 
If adverse events occur from treatment, two dose reductions at the discretion of the investigator 
will be allowed for each patient.  If adverse events resolve, the dose can be increased in 50 mg 
increments as tolerated.  Dosing interruptions/delays will be allowed at the discretion of the 
investigator for recovery from adverse events or inter-current illness, particularly if the patient is 
benefiting from therapy with ENMD-2076. After a treatment interruption for adverse events, 
treatment can be resumed at a lower dose and increased in 50 mg increments as tolerated. 
 
Dose Adjustment Guideline for 
ENMD2076-related Toxicity  
Recommended Action 
Persistent (i.e. lasting more than 2 weeks 
despite optimal medical intervention) 
OR 
Grade 2 toxicity that is deemed intolerable 
OR 
Grade ≥3 toxicity 
• Hold dose until toxicity resolves to Grade 
≤1 or baseline (maximum 14 days). 
• If the patient is benefiting from treatment 
but toxicity does not resolve to Grade ≤1 or 
baseline within 14 days of discontinuation 
of study drug, then study drug treatment 
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may be delayed for an additional week. If 
toxicity persists despite the additional week 
off drug, then study drug will be 
discontinued permanently. 
• If the toxicity resolves to Grade ≤1 or 
baseline within 14-21 days, restart drug 
administration as shown below. 
First Reduction 
• Allow toxicity to resolve to Grade ≤1 or 
baseline, then restart dosing at dose 
level -1, 200 mg/day 
Second Occurrence 
• Hold dose until toxicity resolves to ≤ Grade 
1 or baseline (maximum 14 days). 
• If the patient is benefiting from treatment 
but toxicity does not resolve to ≤ Grade 1 
or baseline within 14 days of 
discontinuation of study drug, then study 
drug treatment may be delayed for an 
additional week. If toxicity persists despite 
additional week off drug, then study drug 
will be discontinued permanently. 
• If the toxicity resolves to ≤ Grade 1 or 
baseline within 14-21 days then restart 
dosing at a dose level -2 (150mg/day) 
Third Occurrence 
• Discontinue study medication. 
• If patient is benefiting from therapy, 
discuss with PI. 
 
Each cycle of treatment consists of a 4-week treatment period. Patients who complete the initial 
cycle of therapy (4 weeks of treatment) without evidence of significant toxicity or clinical 
evidence of progressive disease may receive additional 4-week cycles of treatment. 
 
If any individual patient develops ≥ 2+ proteinuria on qualitative assessment of protein on 
urinalysis, then a spot urine protein:creatinine ratio will be obtained, and a 24-hour urine 
collection will be obtained for quantification.  If the spot protein:creatinine ratio remains equal to 
or below 1, then patients may continue to receive study drug until the 24-hour urine collection is 
complete (no longer than one week is allowed).  If 24-hour urine shows greater than 3.5 g 
protein/24 hours then study drug will be held until the a repeat study shows a 24-hour urine 
below 3.5g. 
7.5 
Packaging and Labelling  
ENMD-2076 will be packaged and labelled by AAI Pharma Services (Wilmington, NC) and 
stored by Fisher Clinical Services (Allentown, PA).  Each bottle of bulk study drug will contain a 
label with the following information: 
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• 
ENMD-2076 50 mg   
• 
CASI Pharmaceuticals Lot Number (example): 4392-001 
• 
Contents: Number of capsules (100 capsules) 
• 
Instructions: Take orally as directed 
• 
Store at Ambient Temperature (15-25°C) 
• 
Caution: New Drug – Limited by Federal Law to Investigational Use 
• 
Sponsor: CASI Pharmaceuticals, Inc., Rockville MD, USA 
7.6 
Conditions for Storage and Use 
ENMD-2076 will be stored under secure (with limited access), humidity-, and 
temperature-controlled conditions for the duration of the study until the material is returned to 
CASI Pharmaceuticals or destroyed by authorization from CASI Pharmaceuticals.  The Study 
Monitor will inspect the drug storage area and review the drug accountability procedures 
discussed with the Investigator and personnel authorized to handle and/or dispense study drug.  
ENMD-2076 bottles will be stored at ambient temperature (15-25°C) in an area accessible only 
to authorized staff.  Patients will be asked to store their one-month supply of drug at ambient 
temperature.  Study drug inventory forms will be kept by the Investigator, or designee, and 
examined and reconciled by the Study Monitor throughout the study. 
7.7 
Method of Assigning Subjects to Treatment Groups 
This is a non-randomized study with all eligible patients assigned to active treatment with 
ENMD-2076. 
7.8 
Dispensing and Accountability 
Study medication should only be dispensed once a patient has (1) signed an informed consent 
form, (2) met all eligibility criteria for entry into the study, (3) completed all screening and 
continuing eligibility requirements, and (4) been assigned a patient identification number. 
 
Only patients enrolled in the study may receive study medication.  Only authorized study 
personnel (the Investigator and his/her designees) may administer study medication, in 
accordance with all applicable regulatory requirements. 
 
The investigator is responsible for maintaining accountability for the receipt, dispensing, and 
return of all study medication. 
7.9 
Patient Compliance 
Authorized site personnel will administer the Day 1 dose of ENMD-2076.  A one-month 
(+7 days) supply of study drug will be dispensed to each patient following the Day 1 study visit 
of each cycle.  Patients will be instructed to return all empty study medication containers, any 
partially used or unused study medication, and daily diary pages at each visit to ensure 
compliance and record study drug accountability.  If a patient realizes they miss a dose within 4 
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hours of the scheduled time, the dose should be taken.  Otherwise, they should delay until the 
next day and consider the dose missed.  Doses should not be repeated for any vomited doses.  
Any missed or vomited doses should be noted in their dosing diary. 
 
Information regarding study medication administration and compliance will be recorded in the 
CRF. 
 
A patient may refuse to take study drug or withdraw consent from further participation in the 
study at any time.  Study site personnel will establish patient compliance with the study 
procedures and dosing at each visit. 
7.10 Prior and Concomitant Therapy 
All prescription and non prescription concomitant medications should be recorded on the 
appropriate page of the electronic case report form (eCRF).  
 
The in vitro studies implicate the involvement of cytochrome P450 enzymes CYP3A4 in the 
pathways involved in the metabolism of ENMD-2076.  No formal drug-drug interaction studies 
have been completed with ENMD-2076 and drugs that are substrates, inhibitors, or inducers of 
cytochrome P450 CYP3A4.  Patients who require agents on the provided list in Appendix D will 
be excluded from enrolling in the study.  Patients who require such an agent during participation 
in the study may be allowed to continue if the following apply: they have stable or responding 
disease (as confirmed by the Investigator); no alternative treatment is available; and they have 
close clinical monitoring while they are enrolled in the clinical trial. 
 
Grapefruit juice is also a well-known inhibitor of CYP3A4 and should not be consumed during 
participation in the trial. 
 
Concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-
related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel) 
are not allowed. Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and 
prophylactic low molecular weight heparin (LMWH) are permitted. 
 
Radioembolization is not allowed but will allow palliative radiation. 
 
Any other medication which is considered necessary for the patient’s welfare, and which is not 
expected to interfere with the evaluation of the study drug, may be given at the discretion of the 
Investigator.   
 
No other investigational agents are permitted during the entire duration of treatment with study 
drug. 
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8. 
EFFICACY AND SAFETY ASSESSMENTS 
8.1 
Primary Efficacy Variable(s) 
Overall response rate using RECIST v 1.1 criteria.  Response will be measured every two 
months after first study drug administration. Patients who went off therapy without evidence of 
disease progression will have CT scans every two months until progression. 
8.2 
Secondary Efficacy Variables 
• 6-month progression free survival (PSF6) rate 
• The median PFS and TTP as based on RECIST 1.1 and measured by time from first study 
drug administration until progression or death. 
• The median Overall survival as measured by time from first study drug administration to 
death or study completion.  
• Safety data will be collected from time of informed consent through study completion 
/withdrawal up to 30 days after the last dose of study medication by each subject. 
8.2.1 
Objective Tumor Responses/Benefit Assessments 
Tumor responses in patients will be determined by the RECIST guidelines (version 1.1) defined 
in Appendix C.  In the absence of significant treatment-related toxicity or clinical evidence of 
progressive disease, patients will be allowed to continue on 4-week cycles of ENMD-2076.  The 
frequency and timing of the assessment of tumor burden/clinical benefit are described in Table 4.  
Unscheduled benefit assessments may be conducted when clinically indicated during the study. 
•  
8.2.2 
Guidelines for Evaluation of Measurable Disease and Response 
Guidelines for evaluation of measurable disease and response are outlined in Section 4 of 
Appendix C. 
 
The same modality 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 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
 
Details regarding method of assessment (i.e., CT scan) are outlined in Section 3.2.2 of Appendix 
C. 
8.3 
Safety Variables 
Safety will be evaluated by collecting information on adverse events and by routine assessments.  
All adverse events will be graded using the NCI CTCAE version 4.0 and recorded in the CRF.   
Specific safety assessments include the following: 
• Treatment emergent AEs graded according to NCI CTCAE v4. The frequency and 
severity of AEs will be evaluated following administration of oral ENMD-2076 
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• Change from Baseline in vital signs (blood pressure, heart rate, respiratory rate, and body 
temperature) 
• Change from Baseline in clinical laboratory tests from baseline values obtained prior to 
treatment 
• Change from Baseline in electrocardiograms (ECGs)  
 
Serious adverse events require expedited reporting to the medical monitor as described in the 
protocol   
8.3.1 
Clinical Laboratory 
Non-fasting blood and urine specimens for the measurement and evaluation of clinical 
chemistry, hematology/coagulation, urinalysis, and pregnancy hormones (female patients with 
childbearing potential) will be collected as described in Table 2.  Approximately 20 mL of blood 
will be collected for the clinical laboratory assessments at the specified times.  Serum pregnancy 
tests will be performed as described inTable 4.  A positive pregnancy test prior to dosing will 
exclude the patient from enrolment in the study.  See Section 8.3.7 for requirements regarding 
pregnancies during the study.  Values for the following parameters will be obtained: 
Table 2 
Non-fasting blood and urine specimens (Measurements and evaluation of 
clinical chemistry, hematology/coagulation, urinalysis, and pregnancy 
hormones)  
HEMATOLOGY 
CLINICAL CHEMISTRY 
URINALYSIS  
Hemoglobin 
Hematocrit 
Platelet Count 
White Blood Cell Count 
Differential, including: 
Neutrophils 
Lymphocytes 
Basophils 
Monocytes 
Eosinophils 
Total protein 
Albumin  
Creatinine 
Uric acid 
Bilirubin (conjugated and total) 
Alkaline phosphatase 
AST(SGOT) 
ALT (SGPT) 
Glucose 
Calcium 
Phosphorus 
Bicarbonate 
Chloride 
Sodium 
Potassium 
Magnesium 
 
Color/appearance 
Specific gravity 
pH 
Protein (qualitative)* 
Glucose (qualitative) 
Ketones (qualitative) 
Bilirubin (qualitative) 
Blood (qualitative) 
Standard microscopic examination if 
above parameters are abnormal 
COAGULATION TESTS 
OTHER 
Prothrombin time (PT) or 
International Normalized Ratio 
(INR) 
Partial thromboplastin time (PTT) 
Serum Pregnancy Test (according to 
study schedule) 
 
* If Grade 2, then 24-urine must be obtained.  
 
The results of clinical laboratory tests conducted during the study must be assessed by the 
Investigator to determine each patient’s continuing eligibility for participation in the study.  If 
values are outside the normal reference range, the Investigator must determine clinical 
significance within the context of the study and the patient’s baseline.  Clinically significant 
abnormal laboratory parameters occurring during the study are reported as AEs. 
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8.3.2 
Medical History and Physical Examination 
As part of the physical examination, a medical history will be taken with particular attention to 
(1) a review of the body systems, including diagnosis of malignancy; and (2) use of prescription 
medications, including prior chemotherapy and corticosteroids, and nonprescription medications.  
 
Physical examination findings within the following categories will be assessed:  
 
! HEENT 
! pulmonary 
! cardiovascular 
! GI/abdomen 
! extremities 
! neurological 
! skin and hair  
! weight  
 
The Screening Visit will also include measurement of height. 
8.3.3 
Standard 12-lead Electrocardiograms (ECGs) 
A standard 12 Lead ECG will be performed at the times described in Table 4.  In the case of an 
abnormal ECG, the ECG should be repeated to rule out machine error or improper placement of 
leads and reviewed by a local cardiologist.  Any abnormality determined to be clinically 
significant by the Investigator should be discussed with the Medical Monitor prior to enrolment 
of the patient.  
 
Any ECGs deemed abnormal by the Investigator may be over read by a cardiologist to make a 
determination of clinical significance.  In some cases, it may be appropriate to repeat abnormal 
ECGs to rule out improper lead placement as contributing to the ECG abnormality.  It is 
important that leads are placed in the same positions each time in order to achieve precise ECG 
recordings. 
8.3.4 
Vital Signs 
Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature.  These parameters will be measured as described in Table 4.  Vital sign 
measurements will be conducted after several minutes in the sitting position. 
8.3.5 
ECOG Performance Status 
The Investigator will assess each patient’s functional status using the ECOG Performance Status 
Scale at the time points identified inTable 4.  Eligible patients must have an ECOG Performance 
Status of 0 to 2 at screening (see Appendix B). 
8.3.6 
Adverse Events 
8.3.6.1 Adverse Events (AE) and Serious Adverse Events (SAE) 
An adverse event (AE) is any untoward medical occurrence in a subject participating in a clinical 
trial. An adverse event can be any unfavorable and unintended sign, symptom or disease 
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temporally associated with the use of the study medication, whether or not considered related to 
the study medication. AEs will be collected from the start of treatment until 30 days following 
the final visit dose.  Any events occurring prior to treatment will be recorded on the medical 
history page with the event name and onset date and end date if not continuing.  Pre-existing, 
known clinically significant conditions observed at screening should be recorded as medical 
history. 
 
This definition also includes accidental injuries, reasons for any change in medication (drug 
and/or dose) other than planned titration, reasons for admission to a hospital, or reasons for 
surgical procedures (unless for minor elective surgery for a pre-existing condition). It also 
includes adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the study medication.  Any new laboratory abnormality assessed as 
clinically significant by the Investigator must be recorded as an adverse event.  
 
A treatment emergent adverse event is any adverse event occurring after start of study 
medication and within the time of residual drug effect, or a pre-treatment adverse event or pre-
existing medical condition that worsens in intensity after start of study medication and within the 
time of residual drug effect.  
 
Adverse events should be recorded as diagnoses, if available. If not, separate sign(s) and 
symptom(s) are recorded. One diagnosis/symptom should be entered per record.  
 
Note that death is not an event, but the cause of death is. An exception is the event of sudden 
death of unknown cause. Note that hospitalization is not an event; however, the reason for 
hospitalization is. Procedures are not events; the reasons for conducting the procedures are. In 
general, only the reason for conducting the procedure will be captured as an adverse event. 
However, if deemed necessary by the Investigator, a procedure can be captured along with the 
reason for conducting the procedure. 
 
An overdose or medication error is not an adverse event unless it is temporally associated with 
an unfavourable or unintended sign or symptom.   
 
Each AE is to be classified by the investigator as serious or non-serious.  A serious adverse event  
(SAE) is any untoward medical occurrence or effect that occurs at any dose:  
 
• Results in death 
• Is life-threatening (i.e., an immediate risk of death) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is associated with a congenital anomaly/birth defect 
• Is an important medical event 
 
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An adverse event caused by an overdose or medication error is considered serious if a criterion 
listed in the definition above is fulfilled. 
 
Important adverse events that may not result in death, may not be life-threatening, or do not 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject’s safety or may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
Serious adverse events also include any other event that the investigator or sponsor judges to be 
serious or which is defined as serious by the regulatory agency. 
 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial subject using concise medical terminology.  In addition, each 
trial subject will be questioned about adverse events.  The question asked will be “Since you 
began taking the study medication, have you had any health problems?” 
 
8.3.6.2 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
It is the responsibility of the Investigator to assess the clinical significance of all abnormal 
laboratory values. The Investigator will exercise medical judgment in deciding whether abnormal 
laboratory values are clinically significant and represent AEs.  In some cases, significant changes 
within the range of normal will require similar judgment by the Investigator. 
 
If an abnormal laboratory value or assessment is clearly related to a medically defined diagnosis 
or syndrome, the diagnosis or syndrome will be recorded on the AE page, not the individual 
laboratory values.  Clinically significant abnormal laboratory values should not be listed on the 
AE page of the eCRF, unless clinical signs or symptoms are present.  
 
All clinically significant abnormal laboratory results or assessments will be followed until they 
return to normal or become stabilized (up to 30 days after end of study drug administration). 
8.3.6.3 Procedures for Assessing, Recording, and Reporting Adverse Events 
and Serious Adverse Events 
Throughout the duration of the study, the Investigator will closely monitor each subject for 
evidence of drug intolerance and for the development of clinical or laboratory evidence of 
adverse events.  All adverse events (expected or unexpected) which occur during the course of 
the study, whether observed by the Investigator or by the subject, and whether or not thought to 
be drug-related, will be reported and followed until resolution or until they become stable. 
The Investigator will evaluate AEs according to the following guidelines: 
• 
NCI CTCAE Version 4.0.  The Investigator must assign a CTC Grade for each AE 
(Appendix A) 
• 
Description of event (if the event consists of a cluster of signs and symptoms, a diagnosis 
must be recorded [e.g., flu syndrome] rather than each sign and symptom) 
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• 
Onset Date  
• 
Stop Date  
• 
Seriousness (see definition of SAEs, Section 8.3.6.1)  
The Investigator must record whether or not the AE meets the definition of serious.  If the 
event is serious, the Investigator must complete a Serious Adverse Event report form (see 
Section 8.3.6.4).  CASI Pharmaceuticals or designee will monitor the completeness and 
accuracy of these forms. 
• 
Relationship to Study Medication 
The Investigator must assess the relationship between the AE and the study medication as 
either not related or having a possible, probable, or definite relationship to the study 
medication.  
• 
Outcome 
Outcome of AEs should be recorded based on the status of the AE at discontinuation from 
the study (includes 30 days post last dose) as resolved, resolved with sequelae, ongoing or 
death.  If an AE is not resolved at the time of discontinuation, the AE should be followed 
until resolution (return to normal or baseline values) or until judged by the Investigator to 
be no longer clinically significant. 
• 
Action Taken (None, AE Required Treatment, Temporarily Interrupted or Permanent 
Discontinuation of Study Medication) 
• 
Patient Status (i.e., Was patient prematurely discontinued due to AE?) 
Events will be coded into one of the following causality categories as defined below: 
Category 
Definition 
Unrelated 
Clearly and incontrovertibly due only to extraneous causes, and does 
not meet criteria listed under possible or probable. 
Unlikely 
Does not follow a reasonable temporal sequence from administration. 
May have been produced by the subject’s clinical state or by 
environmental factors or other therapies administered. 
Possible 
Follows a reasonable temporal sequence from administration, but 
may have been also produced by the subject’s clinical state, 
environmental factors or other therapies administered. 
Probable 
Clear-cut temporal association with administration with improvement 
on cessation of investigational medicinal product or reduction in 
dose. Reappears upon rechallenge. Follows a known pattern of 
response to the investigational medicinal product. 
 
Adverse events with the causality assessed as unrelated or unlikely are categorized as not related 
to study medication. 
 
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Adverse events with the causality assessed as possible or probable are categorized as related to 
study medication and are called adverse drug reactions. 
8.3.6.4 Reporting of Serious Adverse Events 
An AE that is serious or potentially serious requires the following additional detailed reports and 
follow-up and should be recorded in the CRF.  The content of these detailed reports should 
address the Investigator’s (or in some cases, the Sponsor’s) estimate of causality, and whether or 
not the AE is identified in nature, severity, and frequency in the Investigator’s Brochure or in 
other risk information that has been supplied to the Investigator. 
 
Sponsor Notification 
Any SAE that occurs after starting study drug administration must be reported to the Clinical 
Study Monitor or Project Manager as soon as information is available.  In turn, the Clinical 
Study Monitor/Project Manager must immediately inform the Medical Monitor of the event and 
document the notification in a telephone/contact report.  The urgency for reporting a SAE is 
three-fold:  (1) to facilitate discussion (and implementation, if necessary) by the Sponsor and the 
Investigator of appropriate follow-up measures; (2) to facilitate Investigator reporting of 
unanticipated problems involving risk to human patients to the IRB/REB; and (3) to enable the 
Sponsor to fulfil the requirements to the appropriate regulatory authority. 
 
Any non-fatal or non-life-threatening SAE, regardless of expectedness or causality, or fatal or 
life-threatening SAE must be immediately reported to the Clinical Study Monitor or Project 
Manager by telephone or facsimile, and a written report (Serious AE Report Form) signed by the 
Investigator must be provided to the Clinical Study Monitor or Project Manager promptly, but no 
later than the timelines outlined in Table .  This documentation will be forwarded to the Medical 
Monitor immediately to facilitate the prompt detection by the Medical Monitor of any changes in 
the nature, severity, or frequency of serious AEs, and allow the Sponsor to meet reporting 
requirements of the appropriate regulatory agency.  
 
 
Table 3 
Serious Adverse Event Reporting Requirements for Protocol 2076-CL-006 
Communication 
Initial Reports 
Follow-Up Reports 
Fatal or Life-
Threatening SAE 
Other SAEs 
Any SAE 
Vendor SAE Portal*/ 
Telephone/Fax/Email 
Immediately** 
Vendor SAE Portal*/ 
Telephone/Fax 
Within 24 hours** 
Vendor SAE Portal*/ 
Telephone/Fax/Email 
Prompt notification 
required no later than 
48 hours** 
Update Vendor SAE 
Portal 
Written 
Within 48 hours** 
Vendor SAE Portal 
Within 48 hours** 
Vendor SAE Portal 
*If the SAE Portal is not available, alternative modes of communication must be used to report within the 
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specified time frames. 
**The time period for notification of an SAE begins when the Investigator or any site personnel obtains 
knowledge of the event. 
 
Institutional Review Board Notification 
The Investigator must also promptly notify the IRB/REB of the SAE, including any follow-up 
information in accordance with local institutional policy. 
 
If a given SAE is associated with the study medication and is unexpected, CASI Pharmaceuticals 
will forward an Investigational New Drug application (IND) Safety Report to the regulatory 
authorities and to the Investigator(s).  In accordance with FDA regulations, it is the Investigator’s 
responsibility to promptly inform the IRB/REB of the IND Safety Report. 
 
Significant or Unexpected Toxicities 
CASI Pharmaceuticals, the Medical Monitor, and the involved Investigator will monitor the 
safety experience of all patients treated.  Significant or unexpected toxicities that, in the 
judgment of the Investigator, the Sponsor, or the Medical Monitor, presents an unacceptable 
consequence or risk to the patient will result in discontinuation of the patient from further study 
participation.  The Investigator will notify CASI Pharmaceuticals immediately of any significant 
or unexpected toxicities.  The Investigator, CASI Pharmaceuticals, or the Medical Monitor will 
notify other investigators and all institutional review committees of important or unexpected 
toxicity.  Treatment may be delayed to allow recovery from treatment-related toxicities and to 
consider if dose reductions are appropriate for continued therapy with ENMD-2076.  A delay of 
up to 3 weeks is allowed for patients to return to baseline or Grade 1 from any treatment-related 
side effect.  Treatment delays for events such as intercurrent illnesses will be discussed with the 
Investigator and Medical Monitor to determine if a patient may remain on study if a delay of 
more than two weeks is required. 
 
Post Study Adverse Events 
Investigators are not obligated to actively seek information on AEs or SAEs in former study 
participants who completed the end of study visit.  However, the Investigator should promptly 
notify CASI Pharmaceuticals, or designee, if the Investigator learns of any SAE or death of a 
study patient within 30 days after a patient has discontinued study drug administration, and such 
event(s) is (are) reasonably related to the study medication. 
Investigators should promptly notify CASI Pharmaceuticals, or designee, if they become aware 
of a former study participant who is one of the parents of a subsequently conceived child with a 
congenital anomaly (see below). 
8.3.6.5 Follow-up of Adverse Events and Serious Adverse Events and Other 
Investigations 
All SAEs must be followed until they are resolved (return to normal or baseline values), 
stabilized, or the patient is lost to follow-up and cannot be contacted.  Supplemental 
measurements and/or evaluations may be necessary to fully investigate the nature and/or 
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causality of an AE or SAE.  This may include additional laboratory tests, diagnostic procedures, 
or consultation with other healthcare professionals.  If the patient dies during the study or within 
30 days following the End of Study Drug Administration/Discontinuation, any postmortem 
findings (including histopathology) must be provided to CASI Pharmaceuticals, or designee.  
CRF data should be updated with any new information as appropriate. 
8.3.7 
Pregnancy Information 
A serum pregnancy test will be performed on females to determine pregnancy status at the time 
points outlined inTable 4.  If any female patient becomes pregnant while enrolled in the clinical 
trial, she will be withdrawn immediately.  Any dispensed study medication must be returned to 
the clinical site.  The Investigator must notify CASI Pharmaceuticals or designee by telephone 
within 24 hours of learning about the pregnancy.  The Investigator must diligently follow the 
patient until delivery or termination of the pregnancy, providing necessary updated information 
to CASI Pharmaceuticals or designee.  Generally, follow-up will occur within six to eight weeks 
following the estimated delivery date.  Any premature termination of the pregnancy will also be 
reported. 
 
Although pregnancy occurring in a clinical trial is not considered to be an AE or SAE, any 
pregnancy complication or elective termination of a pregnancy for medical reasons will be 
recorded as an AE or SAE and will be followed as such.  A spontaneous abortion is always 
considered to be an SAE.  
 
 
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9. 
STUDY PROCEDURES AND FLOW CHART 
A brief description of the chronological flow of the study is provided in the following sections.   
 
A detailed time and event schedule is provided inTable 4.  Time 0 is defined as the precise time 
of the first ENMD-2076 administration on Day 1.  All other time points in this study are relative 
to these definitions. 
 
Screening Period (Day -28 to Day 1): 
Prior to the initiation of any protocol-specific screening assessments not generally performed as 
part of routine patient care; the patient must be given a complete explanation of the purpose and 
evaluations of the study.  Subsequently, the patient must sign and receive a copy of an Informed 
Consent Form that was approved by the IRB.  Once informed consent has been obtained, the 
eligibility of the patient will be determined, and Screening Period assessments will be performed. 
 
Treatment Period (before dosing on Day 1 up to Day 28): 
On Day 1 before the initiation of the treatment, patients will be evaluated and baseline values for 
the specific assessments will be obtained.  Thereafter during the initial Treatment Period, 
patients will visit the clinic for evaluation of tolerability, safety, and efficacy.  Evaluation visits 
will be scheduled as described inTable 4. 
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Table 4 
Schedule of Assessments 
Measurement/Treatment 
Screening 
Baseline 
Follow-up after study drug administration a 
Days 
–28 to 1 
Day 1 
(prior to 
dose) 
Cycle 1 
Cycle 2 
Cycle 3 + 
Subject 
Discontinuation l 
Day 
1 
Day 
8 
Day 
15  
Day 1 (day 
29) 
Day 1 
(of Cycle 3+) 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
Informed Consent and HIPAA 
Authorization  
X  
 
 
 
 
 
 
 
Medical/Cancer History  
X 
 
 
 
 
 
 
 
Echocardiogram or MUGA  
X 
 
 
 
 
XJ 
XJ 
XJ 
Physical Examination c 
X 
X b 
 
 
 
X 
Xi 
X 
Vital Signs (HR, temp, RR, BP) 
X 
X b 
 
X 
X 
X 
Xi 
X  
12-lead ECG 
X 
X b 
X m 
 
 
X m 
X m,n 
X 
ECOG Performance Status 
X 
X b 
 
 
 
X 
X 
X 
RECIST Assessment 
X 
 
 
 
 
 
Xk 
X 
Histological q or cytological evidence 
for diagnosis 
X 
 
 
 
 
 
 
 
Archived specimens for biomarker 
analyses and genomic testing r 
X 
 
 
 
 
 
 
 
Tumor Biopsy s for subsequent 
biomarker analyses 
X 
 
 
 
 
 
X 
X 
Retained Plasma Sample with biopsy t 
X 
 
 
 
 
 
X 
X 
Hematology c 
X 
X b 
 
X 
X 
X  
X  
X  
Clinical Chemistry c 
X 
X b 
 
X 
X  
X 
X  
X  
Coagulation Tests c 
X 
X b 
 
 
 
 
X j 
 
TSH level  
X 
X b 
 
 
 
X 
 
 
Urinalysis c,d 
X 
X b 
 
 
 
X 
 
X 
Pregnancy Test e 
X 
X b 
 
 
 
X 
 
 
Dispense ENMD-2076 
 
 
X 
 
 
X 
Xi 
 
Tumor Marker AFPf 
 
X 
 
 
 
X 
Xk 
X  
Ammonia 
 
X 
 
 
 
X 
Xk 
X 
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CT g (or MRI) of chest, abdomen, 
pelvis   
X 
  
 
 
 
 
Xg 
X 
AE Monitoring 
 
X 
X 
X 
X 
X 
Xi 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Xi 
X 
Follow-up Phone calls 
 
 
 
 
 
 
 
Xp 
Retained Plasma Sample 
Pharmacokinetics o  
 
 
X  
X  
X  
X  
X  
 
AE = adverse event; BP = blood pressure; DCE-MRI = dynamic contrast enhanced magnetic resonance imaging; HIPAA = Health 
Insurance Portability and Accountability Act; HR = heart rate; RR = respiratory rate; TSH = thyroid stimulating hormone. 
a. Each visit following Day 1 must be completed with ±3 days of the indicated visit day and each monthly visit must be completed 
within ±7 days of the indicated visit day. 
b. Repeated only if more than 72 hours since screening assessments. 
c. Specific tests are listed in the protocol.   
d. If a patient develops 2+proteinuria, then a 24-hour urine collection is required for quantification and a repeat urinalysis should occur 
every week until resolution. 
e. Women of childbearing potential only. 
f. Tumor markers need to be assessed within 3 days of Cycle 1 Day 1, on Cycle 2, Cycle 3, Cycle 5, etc, and at the end of treatment, but 
optional on even cycles after Cycle 2. 
g. Baseline scans must be done within 28 days prior to entering study and performed two months after Cycle 1 Day 1 and every two 
months after (+/- 7 days window). CT Scan can be either liver tri-phasic or liver 4-phase but should be consistant throught the study. 
h. AEs and concomitant medications are monitored continually while on study.  (Patients are instructed to call with AE symptoms 
between scheduled visits). 
i. Completed on Day 1 at each new cycle. 
j. Completed if clinically indicated and by discretion by the Investigator. 
k. Completed at Cycle 2 and every 2 cycles after baseline (ie. Day 1 of Cycle 3, Cycle 5, etc). 
l. These procedures should be done if a patient reaches disease progression (which may occur at a scheduled visit) or if a patient 
withdraws for other reasons. For subjects that withdraw for other reasons a CT scan is required every two months until disease 
progression or death. 
m. Electrocardiogram should be performed on Day 1 of each Cycle pre-dose and 4-6 hours post dose. 
n. For Cycle 4 and beyond, Electrocardiogram may be omitted if all previous ECGs have been clinically insignificant by investigator 
discretion. 
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o. Blood samples for pharmacokinetic analysis will be drawn and processed in all patients prior to dosing on Day 1, Day 8 and Day 15 
of Cycle 1, and Day 1 of Cycle 2 and Cycle 3, respectively. 
p. After subject discontinues, a follow-up call should be done every three months for confirming survival. 
q. This review will be conducted by a pathologist at the participating site to confirm the diagnosis. If there is a discrepancy, a review of 
a different archived specimen if available (heterogeneity is common) and/or identify a liver pathologist at another site who can 
provide independent review. 
r. Tissue for biomarker study and genomic testing:  
- For archived tissue, 10-12 slides or a tissue block should be provide;  
- For tissue biopsy, multiple strips that is sufficient for biomarker study and genomic testing should be provided; 
- The tissue should be shipped to Memorial Sloan Kettering Cancer Center for subsequent biomarker study. 
s. Tumor Biopsy: Tumor biopsy (optional) baseline up to 30 days prior to initiation of dosing if patient had a biopsy after any 
previous treatments, they would be exempt of this biopsy and at the end of treatment Cycle 2 (or Day 1 of cycle 3) in line with the 
imaging for tumor measurement  An additional optional biopsy at the time of disease progression will be performed in patients who 
have complete response, partial response or stable disease for > 16 weeks. 
Tumor biopsy for minor patients will only occur if medically indicated and not solely for research purposes.  If available, a sample of 
tumor tissue from any surgical resection or biopsy during treatment or at time of progression will be requested for biomarker and 
genomic testing on this study. The biopsy after cycle 2 and the optional biopsy at completion of therapy only refers to patients 18 
years of age or older. 
t. Retained Plasma Sample with biopsy: At the same time the biopsy is performed, i.e. at baseline and at the end of treatment Cycle 2 
(or Day 1 of cycle 3).
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9.1 
Study Periods 
9.1.1 
Screening Period (Days –28 to –1) 
Prior to performing any study procedures, the Investigator, or designee, will obtain written 
informed consent from the patient as described in Section 3.3.  The patient’s consent must be 
confirmed at the time of signature by the dated signature of the person conducting the informed 
consent discussions.  A copy of the signed consent document must be given to the patient or the 
patient’s legally authorized representative.  “Legally authorized representative” means an 
individual or judicial or other body authorized under applicable law to consent on behalf of a 
prospective patient to the patient’s participation in the procedure(s) involved in the research.  
The Investigator will retain the original signed consent document. 
  
The specific Screening assessments are described in Section 8.  Results of all 
assessments/evaluations must be acceptable to the Investigator and to the Sponsor or their 
designee prior to treatment with study medication.   
 
When all screening results are completed and eligibility is confirmed, the patient will be assigned 
a patient identification number. 
9.1.2 
Treatment Period 
The assessments to be performed during the Treatment Period are described in Section 8 and the 
timing of the assessments is provided inTable 4.  Assessments at each clinic visit following Day 
1 must be completed within ±3 days of the indicated visit day for Cycle 1 and each monthly visit 
(Cycle 2+) must be completed within ±7 days of the indicated visit cycle (4-weeks).  
9.1.3 
End of Cycle 6 Assessment Time point 
All patients will have radiographic assessments of their disease at 6 months/180 days unless CT 
scan has previously documented progression of their disease.  For patients who are continuing to 
receive study drug at this time point, this radiographic assessment may be combined with their 
regular visit and list of assessments for the cycle. 
9.1.4 
End of Study Drug Administration Visit 
End of study drug administration assessments will be completed for each patient as indicated 
inTable 4. 
 
9.2 
Study Procedures 
 
9.2.1 
Pharmacokinetic analysis 
 
Blood samples will be drawn from all the patients enrolled prior to the dosing at Day 1, Day 8 
and Day 15 (steady state) of Cycle 1, and day 1 of Cycle 2, and Cycle 3, respectively as outlined 
in Table 4.  
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4 mL blood will be collected in tubes containing heparin sodium. Following blood collection, 
samples will be cooled in an ice bath and centrifuged (at approximately 1500 rpm for 10 
minutes) under refrigeration at a temperature of approximately 4°C within 30 minutes of 
collection. Plasma samples will be divided into2 aliquots of approximately equal volume and 
stored in suitably labelled tubes at -80±15°C (within 45 minutes of blood sample collection), 
pending assay. Samples will remain in an ice bath until placement in a freezer. 
Plasma samples will be retained and plasma concentrations of ENMD-2076 and its major active 
metabolite ENMD-2060 will be analysed.  The effects of gender, age, body weight and CLcr 
(creatinine clearance) on the steady state plasma concentrations will be evaluated to explore the 
drug’s exposure-response relationships.  
(A manual for the Pharmacokinetic analysis will be provided) 
 
9.2.2 
Tissue biomarker analysis: 
Formalin-fixed paraffin embedded archival surgical tumor tissue samples obtained from patients 
will be used for immunohistochemical analysis of key markers of proliferation (phospho-histone 
H3 [pHH3], Ki67), tumour microvessels (CD31) and p53. Following paraffin removal and 
subsequent rehydration of sections 5 lm thick, antigen retrieval is performed by incubating slides 
for 10 min at 100 oC in 10 mM sodium citrate, pH 6.0 (p53, pHH3, Ki67) or 10 mM Tris, 1 mM 
ethylene diamine tetra-acetic acid (EDTA), pH9 (CD31). Slides are blocked in 10% donkey 
serum in phosphate buffered solution (PBS) for 1 h then incubated for 1 h with primary antibody 
diluted in 2% donkey serum-PBS. Antibodies and dilutions to be used are as follows: p53 mouse 
monoclonal clone DO-1 (1:2000), Santa Cruz; pHH3 (Ser10) mouse monoclonal (1:1000), Cell 
Signalling; Ki67 mouse monoclonal clone MIB-1 (1:200), Dako; CD31 mouse monoclonal clone 
JC70A (1:500), Dako.  
 
Slides are incubated overnight with biotin conjugated donkey anti-mouse IgG (Jackson 
ImmunoResearch, 1:200), followed by incubation with horseradish peroxidase-conjugated 
streptavidin (Jackson, 1:200) for 1 h. After washing in PBS, slides are developed with 3,3’ 
diaminobenzidine (Dako), followed by counterstaining with haematoxylin (Dako). All slides are 
digitally scanned using the ScanScope XT brightfield scanner (Aperio Technologies), with an 
Olympus 20 X/0.75NA objective lens (resolution 0.5 microns/pixel). Images are visualized 
and analyzed using ImageScope (Aperio). Cells positive for pHH3 and Ki67 staining are counted 
using the accompanying Nuclear_v9 algorithm. The CD31 microvessel density (MVD) count is 
determined by locating three CD31- dense hotspots in each section and counting the number of 
CD31-positive loci in a high-power field area for each hotspot, then representing the average as 
number of microvessels (MV) per mm2. 
 
The tissue should be shipped to Memorial Sloan Kettering Cancer Center for subsequent 
biomarker studies and possibly other research.. 
9.2.3 
Genomic testing 
Paraffin embedded tumor tissue sections and one whole blood sample will be collected and 
processed for a 410 gene panel DNA sequencing analyses. The treatment and preservation of 
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tumor tissue will follow the routine operation procedures in pathology. Tissue blocks with high 
levels of tumor cells should be selected (weight 100~500 mg, diameter >5 mm). At least 15-20 
unstained and charged slides should be provided, with a thickness of 10µm, along with one HE 
stained paraffin sections with a thickness of 5µm. Slides should be cut from the same source. The 
predicted tumor cells should be more than 50%. The tissue section samples will be shipped to 
MSKCC after collection for further testing and analysis. The tumor cell DNA will be extracted, 
sequenced and analyzed based on standard operational procedures at the MSKCC research 
laboratory. One whole blood sample should be collected in a 3mL EDTA lavender top tube and 
send to MSKCC. MSKCC’s Center of Molecular Oncology will run its Integrated Mutation 
Profiling of Actionable Cancer Targets (IMPACT) battery of 410 cancer genes on all samples 
provided. This information will be collected for research purposes only. 
 
9.2.4 
Tumor biopsy: 
Tumor biopsies will be performed as per local institutional guidelines.  Tumor biopsy (optional) 
baseline up to 30 days prior to initiation of dosing if patient had a biopsy after any previous 
treatments, they would be exempt of this biopsy and at the end of treatment Cycle 2 (or Day 1 
of cycle 3) in line with the imaging for tumor measurement  An additional optional biopsy at the 
time of disease progression will be performed in patients who have complete response, partial 
response or stable disease for > 16 weeks.   If either the baseline or post-treatment biopsy is 
unable to be obtained due to technical issues (after consenting the patient and making a 
reasonable effort), the patient is still eligible to participate in the study.  A third optional biopsy 
will take place at the time of disease progression for patients who have complete response, 
partial response, or stable disease for > 16 weeks. Biopsy samples obtained pre- or after 
treatment will also be used for biomarker analysis using immunohistochemistry methods as 
described above. For tissue biopsy, multiple strips that are sufficient for biomarker study should 
be provided.  
A 3mL blood sample will be collected at each time the biopsy is performed. The blood will be 
drawn in an EDTA tube and MSKCC’s Center of Molecular Oncology will run the sample on its 
Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) battery of 410 cancer 
genes. The sample may also be used to identify predictive biomarkers of response, sensitivity 
and clinical benefit to ENMD-2076.  
 
Tumor biopsy for minor patients will only occur if medically indicated and not solely for 
research purposes.  If available, a sample of tumor tissue from any surgical resection or biopsy 
during treatment or at time of progression will be requested for biomarker and genomic testing 
on this study. The biopsy after cycle 2 and the optional biopsy at completion of therapy only 
refers to patients 18 years of age or older. 
 
(A manual for the Pathology tissue and Tumor biopsy will be provided) 
 
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10. STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
10.1 Subject Populations 
All enrolled patients who receive at least one dose of study medication will constitute the safety 
population.  The safety population will be used for all demographic and baseline characteristics 
analyses and for all safety analyses.   
 
The per-protocol population will include all evaluable patients in the safety population who do 
not have a major protocol deviation.  Efficacy assessments will be analyzed for the safety and 
per-protocol population.  The analysis on the safety population should be considered primary. 
10.2 Subject Disposition 
This study is an open-label trial; patients will be allowed to continue study drug treatment until 
disease progression or toxicity occurs.  Patients will remain on study for at least 6 months/180 
days.  No interim analysis or data safety monitoring beyond that described above will be 
conducted for this study. 
10.3 Demographics and Baseline Characteristics 
Demographics and baseline characteristics of subjects will be summarized with descriptive 
statistics. 
10.4 Efficacy Analysis 
 
We have designed this study using a Simon’s Optimal two-stage design to allow for an early 
interim analysis to determine potential futility and an overall final analysis with criteria 
established to allow for sufficient power and type 1 error rate to provide results to support a 
submission of the study as a pivotal trial.    
 
For the primary endpoint, the overall response rate will be examined using the RECIST v 1.1 
criteria.  Patients will first be examined in one of 4 categories – CR, PR, SD, PD (Complete 
response, Partial Response, Stable Disease, or Progressive disease, respectively).  Next, patients 
will be dichotomized as responders (CR/PR versus non-responders). The null hypothesis that the 
true response rate is 2% will be tested against a one-sided alternative that the true response rate is 
15%. In the first stage, 16 patients will have reached study endpoints of response s per RECIST 
1.1 criteria after two cycles of treatment. If there are zero responses in these 16 patients, the 
study will be stopped. Otherwise, 13 additional patients will be accrued for a total of 29. The null 
hypothesis will be rejected if 2 or more responses are observed in 29 patients. This design yields 
a type I error rate of 9.4% and power of 90% when the true response rate is 15%. The probability 
of early termination due to drug inefficacy is 72%. 
 
After the primary efficacy analysis is performed, a one-sided 95% confidence interval will be 
calculated using the Clopper-Pearson exact method for the response rate.  This will determine the 
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lower bound for the response rate.  If 2 or more patients respond out of 29 then the lower bound 
will exceed 1.2% providing evidence that the drug is active (i.e. ruling out 0% response). 
For each of the secondary endpoints, exploratory analyses will be performed.  Progression Free 
Survival rate at 6 months (PFS6) and three time-to-event measures will be calculated. Time to 
Progression, progression free survival and overall survival.  A Kaplan-Meier survival plot will be 
calculated for each of these measures and median time to event (i.e. survival) will be calculated 
for each measure. 
10.5 Safety Analysis 
Safety will be assessed by evaluation of adverse events and clinical laboratory results. 
10.5.1 
Adverse Events 
Adverse events will be coded to system organ class and preferred term using MedDRA version 
16.0 or higher.  All adverse events occurring after the initiation of the study treatment (treatment 
emergent adverse events) will be reported, including events present at baseline that worsened 
during the study. 
 
Adverse events will be summarized by treatment group to provide visual comparison among the 
treatment groups with respect to incidence of adverse events (the number of subjects reporting at 
least one episode of a specific adverse event), incidence of adverse events by severity within 
body system, incidence of adverse events by attribution within body system, and incidence of 
adverse events causing withdrawal and incidence of serious adverse events.  Regarding severity 
and attribution summaries, the most extreme outcome (highest severity and closest to study drug 
related) will be used for those subjects who experience the same adverse event on more than one 
occasion.  
 
Written narratives will be provided for all serious, unexpected or other significant adverse events 
that are judged to be of special interest because of their clinical importance. 
10.5.2 
Clinical Laboratory 
Clinical laboratory results will be summarized with descriptive statistics at baseline each study 
timepoint and with shifts from baseline. 
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11. QUALITY CONTROL AND QUALITY ASSURANCE 
10.6 Source Data and Records 
Source data are all the information in original records and certified copies of original records of 
clinical findings, observations, laboratory reports, data sheets provided by the sponsor or other 
activities in the study, which are necessary for the reconstruction and evaluation of the study. 
The investigator will permit study-related monitoring, audit(s), IRB review(s) and regulatory 
inspection(s), with direct access to all the required source records. 
All study records will be retained for a period of time as defined by the regulatory authority and 
per ICH E6 section 4.9 for the country in which the investigation is conducted.  Generally, this 
means at least 2 years following the date on which the drug is approved by the regulatory 
authority for marketing for the purposes that were the subject of the investigation.  In other 
situations (e.g., where the investigation is not in support of or as part of an application for a 
research or marketing permit), a period of 2 years following the date on which the entire clinical 
program is completed, terminated or discontinued or the investigational application under which 
the investigation is being conducted is terminated or withdrawn by the regulatory authorities. 
In the event the Investigator retires, relocates or for any other reason withdraws from the 
responsibility for maintaining records for the period of time required, custody of the records may 
be transferred to any other person who will accept responsibility for the records.  Notice of such 
a transfer must be given in writing to the Sponsor.  The Investigator must contact the Sponsor 
prior to disposal of any records related to this study.  
10.7 Reporting of Results 
The Case Report Form (CRF) is an integral part of the study and subsequent reports.  The CRF 
must be used to capture all study data recorded in the patient’s medical record.  The CRF must 
be kept current to reflect patient status during the course of the study.  Only a patient screening 
and randomization number and patient initials will be used to identify the patient.   
 
The monitor is responsible for performing on-site monitoring at regular intervals throughout the 
study to verify adherence to the protocol; verify adherence to local regulations on the conduct of 
clinical research; and ensure completeness, accuracy, and consistency of the data entered in the 
CRF. 
 
CASI Pharmaceuticals, Inc. or a designated CRO will monitor completed Case Report Forms 
(CRFs).  A case report form will be provided for each screened patient. 
 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in paper CRF or the Target e*CRF™, an Internet-based electronic 
data collection system, which is 21CFR Part 11 compliant..  All details of the CRF completion 
and correction will be explained to the investigator.  The management module of Target 
e*CRF™ , if used, includes edit check and query systems that seamlessly integrate with the data 
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entry system.  All modifications to the data in the eCRF are tracked by an electronic audit trail 
(date and identity of the person making the change are instantaneously recorded). The actual date 
(and time, if applicable) of each assessment should always be entered in the CRFs  
If the Investigator authorizes other persons to make entries in the CRF, the names, positions, and 
signatures of these persons must be indicated on the Site Delegation Log. 
 
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected, preferably on the same day that a study patient is seen for an 
examination, treatment, or any other study procedure.  Any outstanding entries must be 
completed immediately after the final examination.  By design, an explanation must be provided 
for all missing data, altered data, and/or out of range data. 
 
The completed case report form must be reviewed and signed by the Investigator named in the 
study protocol or by a designated sub investigator after all the data was monitored and verified as 
final by the designated study monitor. 
 
Final monitored and audited CRFs will be provided by the Sponsor to the sites at the end of the 
study in the format of a PDF file. 
10.8 Confidentiality of Subject Data 
The investigator will ensure that the confidentiality of the subjects' data will be preserved. In the 
CRF or any other documents submitted to the sponsor, the subjects will not be identified by their 
names, but by an identification system, which consists of their initials and number in the study. 
The investigator will maintain documents not meant for submission to the sponsor, e.g., the 
confidential subject identification code and the signed informed consent forms, in strict 
confidence. 
 
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11. REPORTING AND PUBLICATION 
11.1 Confidentiality of Study Data 
Any information relating to the study product or the study, including any data and results from 
the study, will be the exclusive property of the sponsor. The investigator and any other persons 
involved in the study will protect the confidentiality of this proprietary information belonging to 
SPONSOR. 
11.2 Publication Policy 
SPONSOR agrees to make the report of the multicenter study results available to investigators 
for preparing a publication of the results in meeting abstract or medical journal form.  SPONSOR 
will have 30 days to review any proposed publication of the data for accuracy and proprietary 
information. The Study Chair has the first right of refusal of both first and last authorship 
position on manuscripts and meeting presentations. 
12. REFERENCES 
Asada N, Tanaka Y, Hayashido Y, Toratani S, Kan M, Kitamoto M, Nakanishi T, Kajiyama G, 
Chayama K, Okamoto T. Expression of fibroblast growth factor receptor genes in human 
hepatoma-derived cell lines. In Vitro Cell Dev Biol Anim. 2003;39:321-8. 
 
El-Serag HB, Mason AC: Rising incidence of hepatocellular carcinoma in the United States. N 
Engl J Med 1999; 340:745-50. 
 
El-Serag HB: Current Concepts: Hepatocellular Carcinoma. N Engl J Med 2011;365:1118-27. 
 
El Serag HB, Davila JA: Is fibrolamellar carcinoma different from hepatocellular carcinoma? - a 
US population-based study. Hepatology 2004;39:798–803. 
 
Honeyman JN, Simon EP, Robine N, Chiaroni-Clarke R, Darcy DG, Lim IIP, Gleason CE, 
Murphy JM, Rosenberg BR, Teegan L, Takacs CN, Botero S, Belote R, Germer S, Emde A-K, 
Vacic V, Bhanot U, LaQuaglia MP, Simon SM: Detection of a recurrent DNAJB1-PRKACA 
chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 2014; 343, 1010-1014; 
 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D.  Global cancer statistics. CA Cancer 
J Clin 2011;61:69-90. 
 
Moreno-Luna LE, Arrieta O, Garcia-Leiva J, et al: Clinical and pathologic factors associated 
with survival in young adult patients with fibrolamellar hepatocarcinoma. BMC Cancer 
2005;5:302-142. 
 
Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol. 2004;41:864-80. 
 
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Siegel R, Ma J, Zou Z, Jemal A. Cancer Statistics, 2013. CA Cancer J Clin 2013;63:11-30. 
 
Sooklim K, Sriplung H, Piratvisuth T: Histologic subtypes of hepatocellular carcinoma in the 
southern Thai population. Asian Pac J Cancer Prev 2003;4:302–306. 
 
Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR, D'Angelica M, Abou-Alfa G, Blumgart LH, 
DeMatteo RP.  Outcome of patients with fibrolamellar hepatocellular carcinoma. Cancer. 
2006;106:1331-8. 
 
Yen JB, Chang KW. Fibrolamellar hepatocellular carcinoma- report of a case. Chang Gung Med 
J. 2009;32:336-9.
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13. APPENDIX A  
 
National Cancer Institute Common Terminology Criteria for Adverse Events v. 4.03 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
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14. APPENDIX B 
 ECOG Performance Status 
 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
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15. APPENDIX C 
 
New Response Evaluation Criteria in Solid Tumors: Revised RECIST guideline (version 
1.1) 
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New Response Evaluation Criteria in Solid Tumors: Revised RECIST guideline (version 1.1). 
Eur J Cancer, 45:228-247, 2009. 
 
 
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16. APPENDIX D 
 
Appendix D. Selected Inhibitors and Inducers of CYP3A4 
 
Inhibitors 
Inducers 
Protease inhibitors: 
ritonavir 
indinavir 
nelfinavir 
saquinavir 
Anticonvulsants, mood stabilizers: 
phenytoin (anticonvulsant) 
carbamazepine 
oxcarbazepine 
Macrolide antibiotics: 
erythromycin 
telithromycin 
clarithromycin 
Barbiturates: 
    Phenobarbital 
Azole antifungals: 
fluconazole 
ketoconazole 
itraconazole 
Non-nucleoside reverse transcriptase 
inhibitors: 
efavirenz 
nevirapine 
etravirine 
Nefazodone (psychoactive and 
antidepressant) 
Rifampicin & rifabutin (bactericidal) 
Bergamottin (constituent of 
grapefruit juice) 
Modafinil (stimulant) 
Quercetin (nutritional supplement) 
Hyperforin (constituent of St Johns Wort) 
Aprepitant (antiemetic) 
Cyproterone (antiandrogen, progestin) 
Verapamil & diltiazem (calcium channel 
blocker) 
Pioglitazone & troglitazone 
(antidiabetics) 
Chloramphenicol (antibiotic) 
 
 
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