Clinical trial NCT02978859
Conditions: Liposarcoma Metastatic Liposarcoma
Keywords: MGCD516 Sarcoma Liposarcoma Unresectable Liposarcoma Metastatic Liposarcoma Sitravatinib
Sponsor: Columbia University
Start date: 2016-11-01; Completion date: 2021-12-20
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate Sitravatinib, an oral small molecular receptor tyrosine kinase inhibitor, for the treatment of advanced liposarcoma.

Detailed description:
Sarcomas are a group of cancers which arise from connective tissue and bone, of which more than 50 subtypes exist. Approximately 12,000 people are diagnosed with sarcoma annually in the United States.

Liposarcoma is one of the more common types of soft tissue sarcoma. The primary treatment for liposarcoma is surgery when possible. When liposarcoma is not amenable to surgery, various systemic treatments, including chemotherapy, are used. However, the effectiveness of existing treatments for liposarcoma is limited.

Sitravatinib is an oral, targeted drug which inhibits receptor tyrosine kinases. Receptor tyrosine kinases are proteins on the surface of the liposarcoma cell which play a role in cancer growth. In laboratory work, Sitravatinib effectively suppressed the growth of liposarcoma models. The purpose of this study is to evaluate the safety and efficacy of Sitravatinib in patients with liposarcoma which cannot be removed by surgery.

Arms: arm 1: Patients with locally advanced and unresectable or metastatic sarcoma will receive MGCD516 at the discretion of the principal investigator until disease progression, unacceptable toxicity or adverse event(s) or withdrawal of consent.
Interventions: intervention 1: MGCD516
Intervention descriptions: intervention 1: Administered at 150 mg orally, daily, in continuous 21 day cycles. An orally available, potent small molecular inhibitor of several related receptor tyrosine kinases.

Protocol documents:
Prot_SAP_000.pdf: 
MGCD516 Sarcoma Phase II 
1
A Phase II Trial of Sitravatinib (MGCD516), a Multi-
receptor Tyrosine Kinase Inhibitor, in Advanced 
Liposarcoma and Other Soft Tissue Sarcomas
Herbert Irving Comprehensive Cancer Center Protocol 
CUMC IRB#:  AAAQ8661 
IRB approval date: 09/28/2016  
NCT02978859


MGCD516 Sarcoma Phase II 
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TITLE:  A phase II trial of Sitravatinib (MGCD516), a multi-receptor tyrosine kinase 
inhibitor, in advanced liposarcoma and other soft tissue sarcomas 
Coordinating Center: 
Columbia University Medical Center 
Sponsor-Investigator: 
Benjamin Izar, MD 
650 W. 168th Street 
BB17-1706D 
New York NY 10032 
Email address: bi2175@cumc.columbia.edu 
Statistician: 
Shing M. Lee, PhD 
722 West 168th Street 
6th Floor, Room 645 
New York, NY 10032  
Telephone: 212-342-1266 
     Email address: sml2114@columbia.edu 


MGCD516 Sarcoma Phase II 
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Funding Source: 
Mirati Therapeutics 
9393 Towne Center Drive, Suite 200 
San Diego, CA 92121 
Telephone: 858-332-3410 
Study Agent: 
MGCD516 


MGCD516 Sarcoma Phase II 
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Affiliate Institutions: 
Site Principal Investigator and Contact Information: 
Massachusetts General Hospital 
Principal Investigator:  
Edwin Choy, MD, PhD 
Hematology/Oncology 
55 Fruit Street 
Boston MA, 02114-2696 
Phone 1: 617-724-4000 
Fax: 617-643-1915 
Email address: echoy@partners.org 
Washington University in St. Louis 
Principal Investigator:  
Brian Van Tine, MD, PhD 
Medical Oncology, Barnes and Jewish Hospital 
660 S. Euclid Ave. 
St. Louis, MO 63110 
Phone 1: 314-747-3096 
Email address: bvantine@wustl.edu 


MGCD516 Sarcoma Phase II 
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Protocol Synopsis 
Title 
A phase II trial of MGCD516, a multi-receptor tyrosine kinase inhibitor, 
in advanced liposarcoma and other soft tissue sarcomas  
Short Title 
MGCD516 in advanced liposarcoma and other soft tissue sarcomas 
Protocol Number 
AAAQ8661 
Phase 
Phase II 
Methodology 
Open-label, single-arm, Simon 2-stage 
Study Duration 
60 months (estimated) 
Study Center(s) 
Multi-center, 3 sites. 
Objectives 
This study will assess the efficacy of the oral, small molecule, multi-
receptor tyrosine kinase (RTK) inhibitor MGCD516 in patients with 
unresectable or metastatic well-differentiated and de-differentiated 
liposarcoma by evaluating the progression free rate at 12 weeks as 
compared historical controls. Secondary objectives include assessment 
of overall response rate, overall survival, progression free survival and 
safety parameters. One correlative objective will measure changes in 
total and phospho-protein expression of MGCD516 RTK targets 
between baseline and on-treatment tumor biopsies using reverse phase 
protein array technology in a subset of liposarcoma patients. Another 
correlative objective will use next generation sequencing to assess 
liposarcoma pre-treatment tumor specimens for genetic changes in 
MGCD516 targets and evaluate the effect of such changes on drug 
efficacy. If the study fails to show evidence of efficacy during stage 1 
(liposarcoma patients), a set of other sarcoma subtypes suggested 
sensitive by preclinical studies will be evaluated for preliminary signs 
of efficacy.  
Number of Subjects 29 patients 
Diagnosis and Main 
Inclusion Criteria 
Eligible patients for stage I include those 18 years or older with 
histologically confirmed, unresectable or metastatic well-differentiated 
or de-differentiated liposarcoma with measurable disease by RECIST 
criteria who have received one prior line of systemic therapy and have 
demonstrated evidence of disease progression prior to enrollment.  If the 
study does not meet its endpoint in the 13 liposarcoma patients during 
stage I of the Simon 2-stage design, an additional 16 patients will be 
enrolled, composed of 4 patients each with malignant peripheral nerve 
sheath tumor, synovial sarcoma, alveolar rhabdomyosarcoma and 
alveolar soft part sarcoma to evaluate for potential signs of efficacy in 
those subtypes.  
Study Product, 
Dose, Route, 
Regimen 
MGCD516 120 mg orally daily in continuous 21 day cycles 


MGCD516 Sarcoma Phase II 
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Duration of 
administration 
Continuous, 21-day cycles 
Reference therapy 
Not applicable 
Statistical 
Methodology 
The primary endpoint is the progression free rate (PFR) at 12 weeks. 
This corresponds to the number of patients who are alive and without 
evidence of disease progression at 12 weeks out of all evaluable 
patients. On the basis of historical controls (see section 15), a PFR 
greater than 40% at 12 weeks is associated with active second line 
agents in sarcoma and considered promising, whereas a PFR less than 
20% at 12 weeks is associated with inactive agents and considered not 
promising.  
We will use a Simon optimal 2-stage design. The study will enroll 13 
liposarcoma patients in the first stage. If 3 or more liposarcoma 
patients meet the endpoint in the first stage, the study will be expanded 
to a total of 29 liposarcoma patients. If a total of 9 or more liposarcoma 
patients demonstrate the PFR endpoint, the agent will be considered 
promising in liposarcoma and worthy of further study. This design 
provides for a type 1 error of 0.10 and type 2 error of 0.14. The study 
design has a power of 85% to detect a difference between a PFR of 
20% versus 40% at 12 weeks.  
If the study does not meet its endpoint in liposarcoma patients during 
stage I, an additional 16 patients will be enrolled, composed of 4 each 
of MPNST, synovial sarcoma, alveolar rhabdomyosarcoma and 
alveolar soft part sarcoma as exploratory cohorts to evaluate for 
potential signs of efficacy in those subtypes to inform further clinical 
study.  


MGCD516 Sarcoma Phase II 
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Protocol Schema 


MGCD516 Sarcoma Phase II 
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Table of Contents 
Protocol Signature Page ...................................................................................................................6 
Protocol Synopsis.............................................................................................................................7 
1.
INTRODUCTION AND RATIONALE ............................................................................13
1.1 
Sarcoma and receptor tyrosine kinases. .................................................................13 
1.2 
MGCD516, a novel small molecular RTK inhibitor .............................................16 
1.3 
Preclinical rationale for MGCD516 in sarcoma ....................................................16 
1.4 
Rationale for Selection of Subtypes .......................................................................25 
1.5 
Clinical Experience with MGCD516 .....................................................................26 
2.
STUDY OBJECTIVES ......................................................................................................26
2.1 
Primary Objective ..................................................................................................26 
2.2 
Secondary Objectives.............................................................................................26 
2.3 
Correlative Science Objectives ..............................................................................27 
3.
INVESTIGATIONAL AGENT .........................................................................................28
3.1 
Preclinical Data ......................................................................................................28 
3.2 
Clinical Data to Date ..............................................................................................31 
4.
STUDY DESIGN...............................................................................................................34
4.1 
General Design.......................................................................................................34 
4.2 
Dose Limiting Toxicities .......................................................................................36 
4.3 
Number of Patients ................................................................................................36 
5.
SUBJECT SELECTION AND WITHDRAWAL .............................................................36
5.1 
Inclusion Criteria ...................................................................................................36 
5.2 
Exclusion Criteria ..................................................................................................37 
5.3 
Inclusion of Women and Minorities ......................................................................38 
5.4 
Subject Recruitment ...............................................................................................39 
5.5 
Early Withdrawal of Subjects ................................................................................39 
6.
REGISTRATION PROCEDURES ...................................................................................40
6.1 
CUMC Research Participant Registration .............................................................40 
7.
TREATMENT PLAN ........................................................................................................42
7.1 
Agent Administration.............................................................................................42 
7.2 
General Concomitant Medication and Supportive Care Guidelines ......................42 
7.3 
Duration of Therapy ...............................................................................................43 
7.4 
Duration of Follow Up ...........................................................................................44 
7.5 
Criteria for Removal from Study ...........................................................................44 
7.6 
Approach to COVID-19 Related Treatment Interruptions ....................................44 
8.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................44
8.1 
Dose Levels ............................................................................................................45 
8.2 
Management Advice for Non-Hematologic Adverse Events ................................45 


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8.3 
Management Options for Hematologic Adverse Events .......................................48 
9.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................50
9.1 
Adverse events .......................................................................................................50 
9.2 
Definitions..............................................................................................................50 
9.3 
Recording of Adverse Events ................................................................................53 
9.4 
Reporting of Serious Adverse Events ....................................................................53 
9.5 
Reporting Process ..................................................................................................55 
10.
PHARMACEUTICAL INFORMATION ..........................................................................55
10.1 
Description .............................................................................................................55 
10.2 
Treatment Regimen ................................................................................................56 
10.3 
Method for Assigning Subjects to Treatment Groups ...........................................56 
10.4 
Preparation and Administration of Study Drug .....................................................56 
10.5 
Subject Compliance Monitoring ............................................................................56 
10.6 
Prior and Concomitant Therapy .............................................................................56 
10.7 
Packaging ...............................................................................................................56 
10.8 
Blinding of Study Drug ..........................................................................................56 
10.9 
Receiving, Storage, Dispensing and Return ..........................................................57 
11.
STUDY CALENDAR .......................................................................................................58
12.
MEASUREMENT OF EFFECT........................................................................................60
12.1 
Antitumor Effect – Solid Tumors ..........................................................................60 
12.2 
Disease Parameters ................................................................................................60 
12.3 
Methods for Evaluation of Measurable Disease ....................................................61 
12.4 
Response Criteria ...................................................................................................64 
12.5 
Duration of Response .............................................................................................65 
12.6 
Progression-Free Survival ......................................................................................66 
12.7 
Response Review ...................................................................................................66 
12.8 
Unblinding Procedures...........................................................................................66 
12.9 
Stopping Rules .......................................................................................................66 
13.
CORRELATIVE STUDIES ..............................................................................................66
13.1 
Proteomics studies .................................................................................................66 
(5) Material should be labeled, accessioned and stored consistent with standard of care policies 
and procedures at the participating institution. ..................................................................69 
13.2 
Genomic studies .....................................................................................................72 
14.
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................74
14.1 
Data Collection ......................................................................................................74 
14.2 
Data Reporting .......................................................................................................75 
14.3 
Data and Safety Monitoring Committee ................................................................75 
14.4 
Quality Control and Quality Assurance .................................................................75 
14.5 
Confidentiality .......................................................................................................76 
14.6 
Source Documents .................................................................................................77 


MGCD516 Sarcoma Phase II 
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14.7 
Case Report Forms .................................................................................................77 
14.8 
Records Retention ..................................................................................................77 
15.
STATISTICAL CONSIDERATIONS...............................................................................78
15.1 
Study Design/Endpoints.........................................................................................78 
15.2 
Size/Accrual Rate...................................................................................................79 
15.3 
Stratification Factors ..............................................................................................79 
15.4 
Analysis of Secondary Endpoints ..........................................................................79 
15.5 
Analysis of Correlative Science Endpoints............................................................79 
15.6 
Reporting and Exclusions ......................................................................................80 
16.
PROTECTION OF HUMAN SUBJECTS ........................................................................81
17.
STUDY FINANCES ..........................................................................................................81
17.1 
Conflict of Interest .................................................................................................81 
17.2 
Subject Stipends or Payments ................................................................................81 
18.
PUBLICATION PLAN .....................................................................................................81
19.
GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER STUDIES......82
19.1 
Multi-site Communication .....................................................................................82 
19.2 
New Protocol Distribution, IRB Submission, Modifications, Renewals ...............82 
19.3 
Regulatory Documents...........................................................................................82 
19.4 
Site activation.........................................................................................................83 
19.5 
Central Registration Procedures -  Participant Registration Process .....................83 
19.6 
Protocol Deviation/Subject Waiver Request for Affiliate Sites ............................85 
19.7 
Guidelines for Affiliate Site Monitoring................................................................85 
19.8 
Dose Level Determinations....................................................................................86 
19.9 
Adverse event reporting .........................................................................................87 
19.10 Confidentiality .......................................................................................................88 
19.11 Data Reporting Plan ...............................................................................................89 
19.12 Data Acquisition and Submission ..........................................................................89 
19.13 Record Keeping and Record Retention ..................................................................89 
20.
APPENDICES ...................................................................................................................91
20.1 
Appendix 1: Supplementary List of Potential Drug Interactions...........................91 
21.
REFERENCES ..................................................................................................................93


MGCD516 Sarcoma Phase II 
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1. INTRODUCTION AND RATIONALE
This document is a protocol for a human research study. This study is to be conducted according 
to US and International standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Columbia University Medical Center institutional research policies and procedures.  
1.1 
Sarcoma and receptor tyrosine kinases. 
Sarcomas comprise a heterogeneous group of uncommon solid tumors of mesenchymal origin, 
of which more than 50 subtypes have been defined. In 2015, approximately 11,930 people will 
be diagnosed with sarcoma, and 4,870 will die of the malignancy1 
The most common subtypes of soft tissue sarcoma include gastrointestinal stromal tumor 
(GIST), liposarcoma, leiomyosarcoma, synovial sarcoma and malignant peripheral nerve sheath 
tumor (MPNST). The more common bone tumors include osteosarcoma, chondrosarcoma and 
the Ewing’s family of tumors. The primary management for most localized sarcomas is surgical 
resection when feasible. Unfortunately, therapeutic options for patients with metastatic or 
unresectable disease remain limited. The various subtypes of sarcoma differ greatly in their 
clinical and molecular characteristics as well as response to traditional cytotoxic agents and 
radiotherapy.  Outcomes are generally poor in advanced disease, with doxorubicin or the 
combination of gemcitabine and docetaxel eliciting objective responses in about 25% of patients, 
with median overall survival from the diagnosis of metastatic disease limited to 12 to 18 
months2. The recent approval of trabectedin for advanced liposarcoma and leiomyosarcoma3, 
and pazopanib for advanced non-adipocytic sarcomas4, has resulted in modest improvements in 
progression free survival for these disease subtypes with no demonstrated benefit in overall 
survival. Molecular characterization of certain subtypes of sarcoma has permitted some progress 
in targeted systemic therapy, most notably with the discovery of activating KIT mutations in 
GIST, and amplification of CDK4 and MDM2 in well-differentiated/de-differentiated 
liposarcomas5. However, for the majority of patients with advanced sarcomas, outcomes remain 
disappointing, and new approaches are urgently needed. 
Complex organisms rely on cell-cell communication, largely conveyed by small proteins termed 
growth factors, to convey critical messages, including those related to growth, division, survival, 
motility and changes in cell shape. Receptor tyrosine kinases (RTKs) play the critical role in 
transducing these extracellular signals into the cell where they elicit an array of biologic 
responses. The prototypical RTK includes an N terminal domain extending into the extracellular 
space which functions in ligand binding. The middle segment of the RTK protein contains a 
transmembrane domain composed of hydrophobic amino acids. The C-terminal domain extends 
into the cytoplasm and contains the RTK’s tyrosine kinase activity, which phosphorylates 
tyrosine residues on various cytoplasmic proteins, resulting in activation of various signaling 
pathways and downstream processes. Most RTKs function as heterodimers or homodimers, with 
dimerization often induced by extracellular ligand binding. The cytoplasmic kinase domains then 
phosphorylate each other resulting in a change in the conformation of the catalytic cleft, allowing 
substrates to bind.  
RTKs may be dysregulated by gene amplification, point mutations, increased transcription or 


MGCD516 Sarcoma Phase II 
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translation, autocrine growth factor secretion from neoplastic cells and by other means. These 
dysregulated RTKs have been shown to play an important role in tumor development across 
nearly all cancer types through their effects on cell growth, differentiation, migration, 
angiogenesis and apoptosis, among other phenotypes on which cancer cells depend. RTK-
targeted therapies, both small molecular inhibitors and antibodies, have proven efficacious in the 
clinic for numerous cancers, as evidenced by  regulatory approval of a growing list of such 
agents, including imatinib, sorafenib, sunitinib, pazopanib, regorafeninb, trastuzumab, 
cetuximab, erlotinib and gefitinib, among others. The efficacy of these RTK-based therapies in 
human cancer have been thoroughly reviewed elsewheref6. In some cases, a tyrosine kinase 
inhibitor has been indicated for use in a disease subset with a defined genetic abnormality in that 
RTK, such as crizotinib for ALK-translocated non-small cell lung cancer or imatinib in KIT-
mutant GIST. In other cases, the agent was studied and approved in a broader disease 
subpopulation, such as pazopanib for non-adipogenic soft tissue sarcomas, without a predefined 
genetic alteration, but with upregulation of RTKs and downstream pathways associated with 
drug target.  
There is substantial evidence to implicate numerous RTKs in sarcomagenesis. The most 
prominent example of aberrant RTK activity in sarcomagenesis is reflected by activating 
mutations in the KIT gene in GISTs. KIT binds its ligand stem cell factor and exerts important 
downstream effects on the development of a variety of cell types, including gut motility cells, 
from which GISTs are thought to arise. Mutations in KIT result in constitutive, ligand 
independent activation of the RTK and downstream signaling. GISTs are responsive to the KIT 
inhibitor imatinib. In the initial phase II study of this agent in advanced GIST, 53% of patients 
demonstrated objective tumor shrinkage7 and, following the introduction of imatinib, median 
overall survival in advanced GIST improved from 11 to 57 months8. Patients progressing on 
imatinib benefit when treated with the multi-targeted RTK inhibitor sunitinib, which acts on 
vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor 
alpha (PDGFRa), c-KIT and FLT39.  
The RTKs VEGFR and PDGFR play an important role in angiogenesis, and are often 
dysregulated by tumors to enhance vascular supply and ameliorate conditions of hypoxia. 
Moreover, PDGFR plays an important role in normal cells of mesenchymal origin. A number of 
studies have documented VEGF and VEGFR overexpression in various sarcomas and expression 
often correlates with clinical outcomes10. Bevacizumab, a monoclonal antibody against VEGFR, 
has received regulatory approval for its activity in various settings, including advanced colon 
and lung cancers. Solitary fibrous tumor, previously termed hemangiopericytoma, is an 
uncommon soft tissue sarcoma that characteristically demonstrates prominent ectatic blood 
vessels and is traditionally resistant to cytotoxic chemotherapy. A phase II study of the 
combination of bevacizumab and temozolomide demonstrated favorable results in this sarcoma 
subtype, with a median progression free survival of 10 months, highly favorable as compared 
historical controls and chemotherapy11. Pazopanib is an orally available small molecule inhibitor 
of VEGFR and PDGFR among other RTKs. This agent was studied in a phase III trial of patients 
with various advanced soft tissue sarcomas, excluding adipocytic sarcomas and GIST, 
demonstrating progression on at least one prior regimen. The drug demonstrated an improvement 
in progression free survival as compared placebo, leading to its FDA approval12.  
Aside from VEGFR and PDGFR, numerous RTKs have been implicated in tumorigenesis across 


MGCD516 Sarcoma Phase II 
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the various soft tissue and bone sarcomas, including IGF1-R, MET, Axl, RET and others. The 
role of RTKs in sarcoma has been reviewed in detail elsewhere13. In numerous cases, 
overexpression of these various RTKs correlates with worsened clinical outcomes. In 
undifferentiated pleomorphic sarcoma, for example, overexpression of MET has been observed 
in up to 40% of tumors and dysregulation of the downstream targets MEK and AKT is 
associated with worse survival14. Using expression profiling and tissue microarray validation 
linked to patient clinical data, expression of RET, IGF-1 and IGF-2 was found to correlate with 
clinical outcomes in myxoid liposarcoma.15 Phosphorylated forms of KIT and PDGFRb are 
overexpressed in synovial sarcoma16. The role of IGF-1R in bone tumors, such as osteosarcoma 
and Ewing sarcoma, has been supported by various in vitro and in vivo models17. Axl has 
recently been shown to be overexpressed in Ewing sarcoma where this RTK  plays a role in cell 
viability and migration18. Furthermore, Axl, EphB2, FGFR2 and RET were recently implicated 
in osteosarcoma pathogenesis in addition to established roles for PDGFR and VEGFR.19 In clear 
cell sarcoma, the EWS-ATF1 fusion gene has been shown to activate transcription of MET, and 
MET inhibition has shown important clinical effects in preclinical models20.  
One recent study attempted to identify a role for driver receptor tyrosine kinases in sarcoma cell 
lines and xenografts using a novel phosphoproteomics strategy21. Phosphotyrosine peptide 
immunoprecipitation was followed by LC MS/MS to identify phosphorylated tyrosine kinases in 
a collection of sarcoma cell lines including osteosarcoma (MNNG, U2OS, MG63, Saos2), 
rhabdomyosarcoma (RD18, A204), leiomyosarcoma (SK-LMS1), fibrosarcoma (HT1080), and 
Ewing’s sarcoma (RD-ES and A673). In this analysis, numerous phosphorylated receptor 
tyrosine kinases were identified including EGFR, several Eph and FGFR receptors, IGF-1R, 
KIT, MET and PDGFRa, among others, with expression levels confirmed by Western blot. A 
panel of existing TKIs was then used against particular cell lines based on the 
phosphoproteomics results and siRNA techniques were used to demonstrate the driver role for 
the proposed kinases. Using this approach, PDGFRa was implicated in rhabdomyosarcomas, 
MET in osteosarcomas, and IGF-1R in Ewing’s sarcoma.  
Nonetheless, antibodies and small molecule inhibitors of RTKs have not always been successful 
in clinical trials in sarcoma. In a single center study of 36 patients with advanced soft tissue or 
bone sarcoma treated with the anti-EGFR monoclonal antibody cetuximab, progression-free 
survival (PFS) was poor, even in the subgroup of patients demonstrating EGFR overexpression 
by immunohistochemistry, where 4-month PFS was just 4%22. In a multi-arm phase II study 
cohorted by disease subtype and using a Simon two-stage design, clinical activity of sorafenib 
was suggested only in angiosarcomas, with minimal evidence of activity in other sarcoma 
subtypes23. The use of anti-IGF-1R agents, including the monoclonal antibodies cixutumumab 
and R1507, have also demonstrated unimpressive results24.  
Explanations for these modest results likely include the activation of compensatory pathways to 
overcome inhibition by a narrowly targeted RTK inhibitor and failure to select for a subgroup of 
tumor types most likely to respond to the targeted agent. This experience suggests that a more 
broadly targeted agent demonstrating clinically relevant inhibition of a selected group of RTKs 
strongly implicated in tumorigenesis may be more clinically effective, and also reinforces the 
need for correlative studies to understand mechanisms of drug action and resistance.  


MGCD516 Sarcoma Phase II 
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1.2 
MGCD516, a novel small molecular RTK inhibitor 
MGCD516 is an orally available, potent, small molecule inhibitor of a group of related tyrosine 
kinases including MET, Axl, VEGFR, PDGFR, KIT, FLT3, Trk, RET, DDR2 and a subset of 
Eph receptors. These tyrosine kinases are known to play important roles in tumor growth, 
survival, invasion and angiogenesis. Activation of signaling through some of these RTKs may 
represent resistance mechanisms following inhibition of others, as has been suggested for MET 
in the case of VEGFR.  
In biochemical kinase assays, MGCD516 was shown to potently inhibit the catalytic activity of 
these RTKs, with IC50 values between 0.5 and 76 nanomolar. Activity was confirmed in RTK-
dependent cell-based assays with IC50 ranging from less than 10 to 181 nanomolar. MGCD516 
also demonstrated clinical activity against several clinically relevant MET mutants. The drug did 
not show significant inhibitory activity of intracellular tyrosine kinases or serine threonine 
kinases.  
The anti-tumor efficacy of MGCD516 was studied in 17 human tumor xenograft models in 
human cancer types with dysregulation of receptor tyrosine kinases. The drug showed tumor 
growth regression or inhibition as compared vehicle control in all of these models evaluated at 
doses ranging from 1.25 to 20 mg/kg/day, with all dose levels well tolerated. Drug efficacy 
ranged from partial growth inhibition to robust cytoreduction. At the 20 mg/kg/day dose, near 
complete tumor growth inhibition was seen in several models, several of which had underlying 
genetic alterations in at least one of the drug’s targets. Anti-tumor efficacy and frank regression 
were also observed at lower dose levels. 
1.3 
Preclinical rationale for MGCD516 in sarcoma 
The efficacy of MGCD516 in sarcoma has been thoroughly evaluated in the preclinical setting in 
the laboratory of Dr. Gary Schwartz25. These preclinical studies first aimed to identify RTKs 
highly expressed in common sarcoma subtypes, followed by an evaluation of MGCD516 both in 
vitro and in vivo. In an initial analysis, basal expression of a set of receptor tyrosine kinases was 
assessed by Western immunoblotting in a subset of sarcoma cell lines. These sarcoma cell lines 
included osteosarcoma (Saos2), Ewing sarcoma (A673, CHP100), dedifferentiated liposarcoma 
(DDLS, LS141), malignant peripheral nerve sheath tumor (MPNST) and synovial sarcoma 
(SYO-1).  
A range of RTKs were tested for basal expression and included Axl, PDGFR, IGF-1R, FGFR2, 
KIT, Eph, VEGFR, RET and MET, among others. Basal expression levels are shown in figure 
1A across the cell types. Based on basal expression patterns, five cell lines were chosen for 
further study based on their expression of the most RTKs: A673, DDLS, LS141, MPNST and 
Saos2. All of these five cell lines showed expression of EphA1, EphB4 and VEGFR1, but 
expression of the other tested RTKs varied by cell line. For example, DDLS, LS141 and Saos2 
appeared to showed relatively high levels of IGF-1R expression, MPNST showed significant 
levels of PDGFRa. LS141, and to a lesser extent, A673 and MPNST, expressed PDGFRb.  
Basal phosphorylation was then studied using a phospho-RTK proteome profiler kit. Results are 
shown in figure 1B. A673, LS141 and Saos2 showed high levels of phosphorylated IGF1-R.  


MGCD516 Sarcoma Phase II 
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Two cell lines, DDLS and MPNST, showed high basal phosphorylated MET. DDLS, LS141 and 
MPNST showed evidence of phosphorylated EGFR.  
Figure 1 A (left) and B (right) 
The antiproliferative activity of MGCD516 was then explored in the five chosen cell lines: 
A673, DDLS, LS141, MPNST and Saos2. All cell lines were found to be sensitive to the drug in 
a concentration-dependent manner (figure 2a). IC50 values for the three sensitive cell lines 
(DDLS, MPNST, and LS141) ranged from 250-750 nmol/L, and for the less sensitive cell lines 
(A673 and Saos2) ranged from 1.5-2.0 micromolar/L.  


MGCD516 Sarcoma Phase II 
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Figure 2A 
In order to demonstrate the proposed mechanism, MGCD516 was shown to inhibit 
phosphorylation of target kinases within these cell lines at low nanomolar concentrations by 
Western blotting. Complete inhibition of phosphorylation of IGF1-R, PDGFRb and MET was 
demonstrated, as was downregulation of the downstream pathway member pAKT (figure 2B). 
Figure 2B 


MGCD516 Sarcoma Phase II 
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This inhibition of phosphorylation of target kinases was also confirmed by phospho-RTK 
proteome profiler analysis (figure 3). Again, MGCD516 demonstrated significant inhibitory 
effects on multiple RTKs including PDGFRa, PDGFRb, IGF1-R and MET, as shown in figure 3, 
with effects also noted on Axl and ALK. Interestingly, IGF1-R and ALK were not potently 
inhibited by MGCD516 in initial RTK enzymatic assays, suggesting that the inhibitor effects for 
these kinases may be mediated by an alternative mechanism, such as heterodimerization with 
direct RTK targets of the drug.   
Figure 3 


MGCD516 Sarcoma Phase II 
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The efficacy of MGCD516 was then compared against imatinib and crizotinib, two other multi-
kinase inhibitors with some target RTK overlap with MGCD516 (figure 4). MGCD516 was 
evaluated as compared these agents in the DDLS, LS141 and MPNST cell lines using 500 
nanomolar of each agent. MGCD516 showed enhanced efficacy as compared either agent in all 
cell lines tested except for MPNST, where the effects of imatinib and MGCD516 appeared 
similar. Moreover, across all three cell lines, MGCD516 was at least as effective as combination 
treatment with imatinib and crizotinib. Furthermore, using Western blot, MGCD516 showed 
better inhibition of downstream targets such as pAKT as compared the other two drugs.  
Figure 4 
MGCD516 was further compared against pazopanib. Pazopanib is a multi-angiogenesis RTK 
inhibitor approved for use in non-adipocytic sarcomas on the basis of a multi-center randomized 
phase III trial which demonstrated improved progression free survival as compared placebo. The 
drug is also approved in advanced renal cell carcinoma. A cell viability assay was performed in 
MPNST, LS141 and DDLS cell lines treated with 500 or 1000 nanomolar of either agent. 
MGCD516 showed enhanced anti-tumor efficacy as compared pazopanib in all cell lines, with 
the most profound differences seen in the dedifferentiated liposarcoma cell line (figure 5). 


MGCD516 Sarcoma Phase II 
21
Figure 5 
To demonstrate a driver role in tumorigenesis for the proposed kinases, siRNA mediated kinase 
knockdown was carried out in the various cell lines and compared with the effects of MGCD516 
itself (figure 6).  
DDLS and MPNST showed higher basal levels of MET and PDGFRb, whereas the LS41 cell 
line showed higher basal levels of IGFR-1 and PDGFRb. Therefore, siRNA mediated 
knockdown was performed for MET and PDGFRb in DDLS and MPNST, and for IGF1-R and 
PGDFRb in LS141, alone or in combination. 
Cell viability assays showed that combined knockdown of the driver kinases by siRNA had a 
significant antiproliferative effect in all three cell lines. This suggests an important 
pathophysiologic role for these RTKs in tumor proliferation. MGCD516 demonstrated a similar 
antiproliferative effect as compared siRNA mediated knockdown of these kinases. Interestingly, 
in MPNST, combined knockdown of MET and PDGFRb resulted in a lesser anti-proliferative 
effect as compared knockdown of PDGFRb alone, possibly as a result of compensatory 
activation of alternative pathways.  


MGCD516 Sarcoma Phase II 
22
Figure 6 


MGCD516 Sarcoma Phase II 
23
The effect of MGCD516 was studied in mouse xenograft models of MPNST and LS141 and 
treatment was compared against imatinib and crizotinib. The treatment resulted in no toxicity to 
the animals as measured by weight loss (figure 7b and 7c). In both xenograft models, treatment 
with MGCD516 resulted in profound suppression of tumor growth as compared vehicle and also 
resulted in enhanced anti-proliferative effects as compared imatinib and crizotinib (figure 8a and 
8b). Tumor tissue was analyzed by Western immunoblotting after 3 weeks of treatment. This 
analysis demonstrated greater inhibition of driver kinases by MGCD516 as compared imatinib or 
crizotinib. Moreover, Ki-67 assessed in tumor biopsies at 3 weeks showed substantially lower 
Ki-67 in the MGCD516 treated animals as compared the vehicle controls.  
Figure 7 


MGCD516 Sarcoma Phase II 
24
Figure 8 


MGCD516 Sarcoma Phase II 
25
1.4 
Rationale for Selection of Subtypes 
Clinical trials in sarcoma must balance the biological heterogeneity of over fifty subtypes with 
the feasibility of conducting clinical trials in rare diseases and the availability of funding and 
industry support to conduct such trials. The preclinical data obtained at CUMC and by Mirati 
Therapeutics support liposarcoma as a sarcoma subtype especially responsive to MGCD516 on 
the basis of in vitro and in vivo data. Our preclinical studies established IGF-1R, MET and 
PDGFR are important for liposarcoma tumorigenesis, and MGCD516 is active against these 
targets. In addition to the encouraging preclinical data, we have also chosen to focus this study 
on liposarcoma because:  
(1) Liposarcoma is the most common sarcoma subtype. This would facilitate accrual of the study 
and enhance the clinical utility of the agent if found to be active. 
(2) Liposarcoma is in urgent need of active therapies. There are only 2 FDA-approved agents for 
this disease, the chemotherapeutic agents eribulin and trabectedin, both of which have limited 
clinical activity and considerable toxicity.  
(3) There is currently no approved receptor tyrosine kinase inhibitor for liposarcoma. Pazopanib, 
a small molecule receptor tyrosine kinase inhibitor, was approved in non-adipocytic sarcomas 
and phase II studies found the drug ineffective in liposarcoma. Our correlative studies may help 
elucidate the basis for the variable sensitivity of liposarcoma to pazopanib. Our preclinical data, 
and work by others, suggests that liposarcoma depends upon MET, IGF1-R and PDGFR 
signaling; notably, pazopanib is inactive against the first two of these RTKs, whereas MGCD516 
has considerable activity. The broader profile of MGCD516 targets may also abrogate activation 
of compensatory signaling pathways, a well characterized mechanism of resistance to RTK 
inhibitors.  
Preclinical studies at CUMC and Mirati have suggested efficacy for MGCD516 in numerous 
other sarcoma subtypes aside from liposarcoma. In view of this and the limited resources 
available for clinical trials in sarcoma, we have proposed a Simon 2 stage design in which stage I 
will accrue liposarcoma patients and will continue to stage 2 and complete accrual in 
liposarcoma alone if the study meets the stage I endpoint. If, however, the study fails in stage I, 
we will enroll an additional 16 patients across 4 other sarcoma subtypes found promising on the 
basis of preclinical data as an exploratory cohort which will be hypothesis generating for future 
clinical studies, including phase II trials. This design allows for maximal use of resources and 
only enrolls patients whose disease subtype is suggested sensitive on the basis of the available 
preclinical data. In view of our preclinical data and the Mirati data, the exploratory subgroup 
would include MPNST, synovial sarcoma, alveolar rhabdomyosarcoma and alveolar soft part 
sarcoma.  
In the CUMC preclinical studies MPNST was among the most sensitive to MGCD516 in cell 
line viability assays (figure 2A above) and treatment of an MPNST xenograft with MGCD516 
showed complete suppression of tumor growth (figure 8A above) and compared favorably with 
imatinib and crizotinib, RTK inhibitors of KIT/PDGFR and MET, respectively. Synovial 
sarcoma cell lines were also responsive to MGCD516 (figure 2A above). 


MGCD516 Sarcoma Phase II 
26
In preclinical studies performed by the Mirati Therapeutics, MGCD516 was evaluated in 3-day 
cell viability assays across a panel of over 550 cancer cell lines characterized for cancer type and 
genomic characteristics with the intention of identifying patterns of cell line sensitivity and 
resistance to treatment and linking these response patterns to tumor cell line phenotypic and 
genotypic characteristics.  This cell line panel also contained 57 cell lines derived from sarcoma 
and was comprised of over 8 different sarcoma sub-types.  Among the sarcoma cell lines the top 
4 most sensitive subtypes (lowest IC50 values and greatest degree of lethality) were comprised 
of liposarcoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, and malignant 
peripheral nerve sheath tumor derived cell lines. In contrast, leiomyosarcoma, osteosarcoma, and 
Ewing’s sarcoma were among the more resistant subtypes in the Mirati studies. Alveolar 
rhabdomyosarcoma and alveolar soft part sarcoma are thus included on the basis of the Mirati 
studies.  
1.5 
Clinical Experience with MGCD516 
MGCD516 is currently being evaluated in the first in human study 516-001, a phase 1 dose 
escalation study in solid tumors. Data was recently updated at the European Cancer Conference 
in September 2015. Safety and pharmacokinetic data from this study were favorable and are 
discussed in section 3. With respect to efficacy, prolonged disease stabilization was observed, 
with 6 patients completing at least 5 cycles of therapy, including one patient with liposarcoma 
completing 8 cycles.  Pharmacodynamic studies in human plasma confirmed modulation of 
circulating biomarkers, including VEGFR and sMET. The study will proceed to a phase 1b 
which will enroll patients with non-small cell lung cancer and other tumors with genetic 
alterations in RET, TRK, and other MGCD516 targets to further evaluate clinical activity at the 
recommended phase 2 dose.  
2.
STUDY OBJECTIVES
This is an open-label, multi-center, single-armphase II study of the oral small molecular multi-
receptor tyrosine kinase inhibitor MGCD516 in adult patients with unresectable and metastatic 
well-differentiated and de-differentiated liposarcoma who have received one prior line of 
systemic therapy and who demonstrate evidence of disease progression prior to study entry. . The 
study will use a Simon optimal 2-stage design, but if liposarcoma fails in the first stage, the study 
will enroll additional patients with other sarcoma subtypes found promising on the basis of 
preclinical data in an exploratory cohort.   
2.1 
Primary Objective 
To assess the efficacy of MGCD516 in patients with advanced liposarcoma by evaluating the 
progression free rate at 12 weeks as compared historical controls. 
2.2 
Secondary Objectives 
2.2.1 
To further evaluate the safety profile of MGCD516 by assessing adverse event 
rates (according to National Cancer Institute CTCAE version 4.0 criteria) in 


MGCD516 Sarcoma Phase II 
27
patients treated with this agent. 
2.2.2 
To assess the efficacy of MGCD516 in patients with advanced liposarcoma by 
evaluating the overall response rate (according to RECIST 1.1 criteria), progression 
free survival and overall survival in patients treated with this agent. 
  2.2.3 
If MGCD516 fails to show efficacy in the first stage of the study (liposarcoma 
patients), to evaluate a cohort of other sarcoma subtypes (malignant peripheral nerve 
sheath tumor, synovial sarcoma, alveolar rhabdomyosarcoma and alveolar soft part 
sarcoma), for preliminary signs of efficacy to inform future studies.  
2.3 
Correlative Science Objectives 
2.3.1 
To use reverse phase proteomic arrays (RPPA) to evaluate changes in total and 
phosphorylated MGCD516 target RTK expression in tumor specimens from a 
subset of liposarcoma patients at baseline and while on treatment with the study 
agent to confirm evidence of on-target effects and evaluate potential predictive 
biomarkers. 
2.3.2 
To use next generation sequencing techniques to evaluate pre-treatment tumor 
biopsies from liposarcoma patients for a defined set of genetic alterations involving 
MGCD516 targets, and to assess the relationship between the presence of such 
genetic alterations and clinical efficacy.  
For details on the reporting of the endpoints, see section 15, Statistical Considerations. 


28 
MGCD516 in Sarcoma Phase II 
3. INVESTIGATIONAL AGENT
MGCD516 is an orally available, potent small molecular inhibitor of several related receptor 
tyrosine kinases, including VEGFR, PDGFR, MET, KIT, Axl, FLT3, RET, DDR and certain 
Eph family members. These receptors have been implicated in numerous processes that support a 
malignant phenotype in human cancer.  
3.1 
Preclinical Data 
MGCD516 has been extensively studied in the preclinical setting. The following information is 
referenced from the Investigator’s Brochure for MGCD516, version 2.0, as provided by Mirati 
Therapeutics, unless otherwise referenced.  
3.1.1 Pharmacokinetics, Absorption, Distribution, Metabolism and Excretion 
The pharmacokinetics, distribution and metabolism of MGCD516 were examined in vitro and in 
mice, rats and dogs in non-good laboratory practice (GLP) pharmacokinetic studies. Plasma 
pharmacokinetics were determined after single intravenous and oral administration of the agent 
to mice, rats and dogs across a range of dose levels. After IV administration of MGCD516 at 2.5 
mg/kg in mice, 5 mg/kg in rats and 1 mg/kg in dogs, the volume of distribution was 6.28, 0.980 
and 11.1 L/kg, respectively. Total clearance values were 1.38, 0.279 and 1.49 L/h/kg. The half-
life of elimination was 6.23, 3.50 and 7.11 hours in mice, rats and dogs, respectively. Mean Cmax
and AUC generally increased in a dose-dependent fashion. After oral administration of 2, 5 and 5 
mg/kg to mice, rats and dogs, respectively, the drug was systemically absorbed with absolute 
bioavailability values of 72.2%, 19.6% and 56.4%, respectively.  
Repeat dose pharmacokinetics were conducted by oral administration of the agent in rats for 7 
days (12.5-75 mg/kg/day) or 4 weeks (2.5-25 mg/kg/day) and in dogs for 7 days (1-8 mg/kg/day) 
or 4 weeks (0.3-3 mg/kg/day).The Tmax ranged from 4 to 12 hours in rats and 2 to 6 hours in 
dogs. Mean t1/2 was 3 to 9 hours in rats and 3 to 6 hours in dogs. Increases in Cmax and AUC0-24 
were generally dose proportional. There was no evidence of accumulation in any of these studies. 
3.1.2 Plasma protein binding 
The binding of MGCD516 to human, mouse, rat and dog plasma proteins was assessed using an 
ultracentrifugation approach with frozen K3EDTA plasma for all species. The percentage of 
MGCD516 bound to protein was 99% in mouse plasma, 99.5% in rat plasma, 99.3% in dog 
plasma and 98.6% in human plasma. Results from the positive control, warfarin, indicated 
acceptable performance for this assay. The effects of plasma from multiple species on inhibition 
of MET phosphorylation by MGCD516 in MKN45 (gastric cancer) cells was studied. The 
presence of 100% plasma increased the concentration of MGCD516 needed to achieve 50% 
MET inhibition as compared 10% plasma by a factor of 1.4 to 8.8 across species and by 1.45 in 
humans.  


29 
MGCD516 in Sarcoma Phase II 
3.1.3 Metabolism 
In-vitro metabolic profiling studies were performed in mouse, rat, dog, monkey and human 
hepatocytes and 8 putative metabolites were identified, with none unique to humans. After 120 
minutes of incubation with human hepatocytes, 88% of the drug remained. Phenotyping of the 
drug in human liver microsomes and recombinant human P450 enzymes suggested that multiple 
enzymes contributed to the metabolism of MGCD516 including CYP1A2, CYP2A6, CYP2B6, 
CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4. In rat and dog studies, no phase II 
metabolites were detected.  
3.1.4 Enzyme Interactions 
Primary cultures of cryopreserved human hepatocytes were treated with MGCD516 and 
expression of cytochrome P450 enzymes was assessed. Treatment of human hepatocytes with up 
to 30 micromolar MGCD516 resulted in little or no induction of CYP1A2 activity or mRNA 
levels, or of CYP3A4 activity. MGCD516 at doses of 3 and 10 micromolar did cause 
concentration dependent increases in CYP2B6 activity, CYP2B6 mRNA levels and CYP3A4 
mRNA levels.  
There was no substantial evidence of direct inhibition of CYP1A2, CYP2A6 or CYP2E1, and no 
substantial evidence of time or metabolism dependent inhibition of any of the CYP systems 
evaluated. The drug did demonstrate evidence of direct inhibition of CYP2C8, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4/5 with IC50 values of 2.9, 11, 10, 1.9 and 11 micromolar, 
respectively. About 50% direct inhibition of CYP2B6 was observed with 20 micromolar 
MGCD516.  
Because the potency of MGCD516 against is receptor tyrosine kinase targets is generally less 
than 0.1 micromolar, it is unlikely that MGCD516 at therapeutic levels will result in clinically 
significant inhibition or induction of the cytochromes at dosing that will be clinically used.  
3.1.5 Toxicology 
Toxicology of MGCD516 was evaluated in 7-day dose range-finding studies and 4-week oral 
toxicity and toxicokinetic studies (followed by 2 week recovery period) in both rats and dogs. 
Studies in rats 
In a 7-day repeat dosing study, rats were administered MGCD516 at doses of 0, 12.5, 25, 50 and 
75 mg/kg/day by oral gavage (3/sex/group for control, 9/sex/group for treated). One male 
administered a dose of 75 mg/kg was found dead on day 7 with autopsy evidence of adrenal 
cortical hemorrhage. Pathologic findings were evaluated at the 12.5 mg/kg and 75 mg/kg dose 
levels. At the 12.5 mg/kg dose level, findings were of minimal to slight severity and included: 
adrenal cortex (congestion/hemorrhage), duodenum (villi blunting/fusion), bone marrow 
(osteodystrophy, congestion/hemorrhage), and thymus (apoptosis/necrosis). These findings were 
also seen in animals administered 75 mg/kg/day but with increased frequency and severity and 
further included kidney (tubular necrosis) and pancreas (apoptosis, increased lymphocytes).  


30 
MGCD516 in Sarcoma Phase II 
For the 4 week toxicity and toxicokinetic study, male and female rats were assigned to four 
groups (15/sex/group) and doses administered via oral gavage for 29 days followed by a 14 day 
recovery period. Doses of 2.5, 10 or 25 mg/kg/day in control article or a control article alone 
were evaluated. Effects were studied on the respiratory and nervous systems. In summary, the 
dose level of 25 mg/kg/day was not tolerated and resulted in mortality, adverse clinical 
observations and considerable changes in body weight. The no observed adverse effect level was 
found to be 2.5 mg/kg/day. Two animals given 10 mg/kg/day and 9 animals given 25 mg/kg/day 
were sacrificed in moribund condition during the dosing phase, with the cause of death assessed 
as adrenal hemorrhage in at least 8, and septicemia in 1. There were no changes in hematologic, 
coagulation or chemistry parameters of significance. Autopsy demonstrated findings generally 
consistent with other studies of anti-angiogenic compounds, and most such findings were 
reversible. Organs with changes that did not reverse at the recovery sacrifice included changes in 
the kidney, ovary, testes and epididymis. No effects were seen on the respiratory and nervous 
systems.  
Studies in dogs 
In a 7-day dose range-finding study in dogs, MGCD516 was administered at 0, 12.5, 25, 50 or 
100 mg/kg/day, but was not tolerated at any dose level. Therefore, a second study was conducted 
in dogs at doses of 0, 1, 2, 4 and 8 mg/kg/day. The 8 mg/kg/day was not tolerated requiring 
sacrifice of 3 animals in moribund condition, with weight loss and liquid/mucoid feces observed 
in a fourth. No adverse microscopic changes were seen at a dose of 4 mg/kg/day, but a decrease 
in body weight and food consumption was observed at this dose level.  
A toxicity and toxicokinetic study was carried out in dogs. Animals received a control article or 
MGCD516 at doses of 0.3, 1 or 3 mg/kg/day daily for 4 weeks by oral gavage followed by a 2-
week recovery phase. All animals survived to scheduled sacrifice. One animal administered 3 
mg/kg/day had dosing discontinued on day 8 due to anorexia, dehydration, liquid feces, vomit 
and marked body weight loss. Other clinical observations were limited to thin appearance and 
discolored or liquid feces in animals given 3 mg/kg/day. No adverse changes in hematology, 
chemistry, coagulation or urinalysis were seen. There were no effects on ophthalmic or 
electrocardiogram studies and there were no adverse macroscopic or microscopic findings. In 
summary, the 3 mg/kg/day dose was not tolerated and the no adverse effect level was felt to be 1 
mg/kg/day.  
3.1.6 Cardiovascular Effects 
Telemetry-instrumented male beagle dogs were administered MGCD516 at doses of 0, 0.5, 1 and 
4 mg/kg by oral gavage in a Latin square dosing design. No qualitative ECG abnormalities were 
observed at any dose level. Significantly higher systolic (up to 12 mmHg), diastolic (up to 14 
mmHg) and mean arterial (up to 14 mmHg) pressures were seen with doses above 1 mg/kg 
which persisted fifteen hours post dose. At the 4 mg/kg dose level, heart rates were significantly 
lower, which persisted through 25 hours post dosing, likely due to a compensatory mechanism. 
Although mild prolongation of PR and QT intervals was seen, there was no change in the qTC 
interval. Although all of these effects were mild, they were attributed to MGCD516 owing to 


31 
MGCD516 in Sarcoma Phase II 
dose dependency, and, with respect to cardiovascular toxicity, the no observed-adverse effect 
level was determined as 4 mg/kg. 
3.1.7 Genotoxicity 
MGCD516 was evaluated in a standard array of GLP genotoxicity studies. In a bacterial 
mutagenicity assay, MGCD516 was found to be non-mutagenic at doses up to 5000 micrograms 
per plate. The agent was also considered negative for inducing chromosomal aberrations in 
cultured human hepatocytes. An in vivo rat micronucleus assay was conducted at dose levels of 
0, 375, 750 and 1500 mg/kg/day and the agent was negative for inducing micronuclei in the bone 
marrow of male Sprague-Dawley Rats.  
3.1.8 Carcinogenicity 
None performed. 
3.1.9 Developmental and Reproductive Toxicity 
None performed. 
3.2 
Clinical Data to Date 
MGCD516 is being evaluated in a first-in-human study, 516-001, a multi-center, open-label 
phase 1/1b clinical trial evaluating the safety, metabolism, pharmacokinetics and 
pharmacodynamics of this agent in patients with advanced solid tumors. The phase 1 portion of 
this study is a dose escalation study in unselected patients using a modified toxicity probability 
interval design. Key inclusion criteria include advanced metastatic or unresectable solid tumor 
malignancies, an ECOG performance status of 0 or 1 and no history of symptomatic or 
uncontrolled brain metastases. The initial starting dose was MGCD516 at 10 mg once daily, 
based on one-tenth of the severely toxic dose observed in 10% of animals, derived from the 4 
week toxicology study in rats described in section 3.1. Cohorts of 3-5 patients were enrolled per 
dose level.  
As of 11/2015, a total of 32 unselected patients had been accrued to the phase 1 dose escalation 
phase, including 5 with soft tissue sarcoma. 6 dose cohorts were evaluated ranging from 10 mg 
to 200 mg orally daily. Dose escalation proceeded through three dose levels (10, 20 and 40 mg) 
without a dose limiting toxicity. At the 80 mg level, one dose limiting toxicity of grade 3 palmar 
plantar erythrodysesthesia was noted. Subsequently, 3 additional patients were added with no 
further DLTs observed. The dose was escalated to 200 mg with no dose limiting toxicities seen 
at 110 or 150 mg. However, at the 200 mg dose level, 3 DLTs were observed: grade 2 intolerable 
neuropathy, fatigue and stomatitis, each in 1 of 3 patients treated at this dose level. The patient 
who experienced neuropathy had been previously treated with the chemotherapy agent docetaxel. 
A maximum tolerated dose/recommended phase 2 dose of 150 mg orally daily was established. 


34 
MGCD516 in Sarcoma Phase II 
Single dose pharmacokinetic parameters were evaluated in 24 patients, and steady state 
parameters in 20 patients. Plasma samples for pharmacokinetic analyses were collected over a 
168-hour period following single dose administration and a 24-hour period following repeat dose 
administration. Drug concentrations were determined using a validated LC MS/MS method. 
After single administration, the drug reached peak concentration over a median time of 3 to 9 
hours. Plasma exposure levels were found to increase in a dose proportional fashion.  Mean 
elimination half-life varied between 40 and 53 hours. Steady state pharmacokinetics were 
reached in 11-15 days. Drug accumulation was observed following multiple dosing, averaging 
4.2-fold for Cmax and 4.7-fold for AUC0-24. Mean value for peak to trough fluctuation was 
53.8%. At the 100 mg dose level, mean steady state Cavg was 123 ng/mL, Cmax was 151 ng/mL 
and AUC was 2590 ng*h/mL.  
On 2/6/2018, Mirati Therapeutics provided updated guidance to investigators participating on the 
industry sponsored phase 1/1b study of Sitravatinib in solid tumors. In this study, Sitravatinib 
appeared to have improved long-term tolerability at a dose of 120 mg based on assessment of 
toxicities observed in patients starting at this dose, and in patients dose reduced from 150 to 120 
mg. Furthermore, analysis of pharmacokinetic data suggest plasma concentrations for 
Sitravatinib are comparable at the 120 and 150 mg dose levels. Therefore, the recommended 
starting dose of Sitravatinib for the phase 1/1b study was modified to 120 mg, which has also 
been adopted in this study effective in 5/2018. Patients already enrolled on this study may 
continue at the 150 mg dose level, or reduce the 120 mg level, as determined by the treating 
investigator.  
4. STUDY DESIGN
4.1 
General Design 
This is a phase II, single-arm, open-label, Simon optimal 2-stage study evaluating the efficacy of 
MGCD516 in patients with unresectable or metastatic well-differentiated or de-differentiated 
liposarcoma who have received treatment with at least one prior systemic therapy and 
demonstrate evidence of disease progression prior to study enrollment. If the study fails to reach 
its endpoint in the stage I liposarcoma cohort, it will enroll additional patients with other sarcoma 
subtypes which may be responsive on the basis of preclinical data as an exploratory cohort which 
may inform future clinical studies.   
The study will be conducted at two institutions. All subjects will be treated with the same agent 
and dose, MGCD516, at 120 mg in continuous 21 day cycles. Patients will receive treatment at 
the discretion of the principal investigator until disease progression, unacceptable toxicity or 
adverse event(s) or withdrawal of consent. 
The primary endpoint is the progression free rate (PFR) at 12 weeks, which will be evaluated 
against historical controls for active and inactive agents in sarcoma. Secondary endpoints include 
overall survival, progression free survival, overall response rate and safety profile. Correlative 
science endpoints will be exploratory and hypothesis generating. A subset of liposarcoma 
patients will undergo baseline and on-treatment tumor biopsies. Reverse phase protein arrays 
will be used to assess for changes in total and phospho-protein RTK targets of the drug between 
these biopsies. In another correlative study, all liposarcoma patient’s existing tumor specimens 


35 
MGCD516 in Sarcoma Phase II 
will be assessed by next generation sequencing to identify a panel of predefined genetic 
alterations in MGCD516 RTK targets.  
We will use a Simon optimal 2-stage design. The study will enroll 13 liposarcoma patients in the 
first stage. If 3 or more liposarcoma patients meet the PFR endpoint described above in the first 
stage, the study will be expanded to a total of 29 liposarcoma patients. If a total of 9 or 
liposarcoma more patients demonstrate the PFR endpoint, the agent will be considered promising 
in liposarcoma. This design provides for a type 1 error of 0.10 and type 2 error of 0.14. The 
study has a power of 85% to detect a difference between PFS of 20% versus 40% at 12 weeks.  
If the study does not meet its endpoint in liposarcoma patients during stage 1 of the Simon 2-
stage design, an additional 16 patients will be enrolled, composed of 4 each of MPNST, synovial 
sarcoma, alveolar rhabdomyosarcoma and alveolar soft part sarcoma, to evaluate for potential 
signs of efficacy in those subtypes as part of an exploratory cohort which may inform the design 
of future phase 2 studies.  
For further details regarding the study design, see the following sections: 
Section 5: 
Inclusion and exclusion criteria 
Section 7: 
Treatment plan 


36 
MGCD516 in Sarcoma Phase II 
Section 11: 
Study calendar 
Section 13: 
Correlative studies 
Section 15: 
Statistical considerations 
4.2 
Dose Limiting Toxicities 
Not applicable. 
4.3 
Number of Patients 
The study size is 29 patients. 
5.
SUBJECT SELECTION AND WITHDRAWAL
This clinical trial can fulfill its objectives only if appropriate patients are enrolled. All clinically 
relevant considerations should be made when deciding whether this protocol is appropriate for a 
particular patient. Waivers to eligibility requirements cannot be granted by any party. In order to 
be considered eligible, a patient must meet all of the inclusion criteria and be free of all of the 
exclusion criteria as stated below.  
5.1 
Inclusion Criteria 
5.1.1 
Stage 1: Histologically confirmed well-differentiated or dedifferentiated 
liposarcoma. If stage 1 of the Simon II stage design fails to meet its endpoint for 
liposarcoma patients, an additional 16 patients will be enrolled, composed of 4 each 
of MPNST, synovial sarcoma, alveolar rhabdomyosarcoma and alveolar soft part 
sarcoma (otherwise, an additional 16 patients with well-differentiated or de-
differentiated liposarcoma would be enrolled). Pathology review occurs at the 
center enrolling the patient on this trial.  
5.1.2 
Disease must be locally advanced and unresectable or metastatic. Disease which 
may be resected but with an associated level of morbidity deemed unacceptable by 
the treating clinician is considered eligible.  
5.1.3 
Patients must have measurable disease by RECIST criteria version 1.1. 
5.1.4 
Patients must evidence of disease progression, either clinically or radiographically, 
within the 12 weeks prior to study enrollment, as determined by the investigator 
enrolling the patient on the study. 
5.1.5 
Patients must have been treated with at least one prior systemic regimen for 
sarcoma. Neoadjuvant or adjuvant systemic therapy qualify as prior therapy for the 
purposes of this study. There is no upper limit on previous lines of therapy 
received. A prior line of systemic therapy may include prior investigational agents 
received as part of other clinical studies.  
5.1.6 
Patients must be age 18 years or older. Because no dosing or adverse event data are 
currently available for MGCD516 in patients less than 18 years of age, children are 
excluded from the present study, but will be eligible for future pediatric trials. 


37 
MGCD516 in Sarcoma Phase II 
5.1.7 
Patients must demonstrate an ECOG performance status of 0 or 1. 
5.1.8 
Patients must demonstrate normal organ and marrow function as defined below: 
Absolute neutrophil count (ANC) 
≥ 1,500/mm3 
Platelet count 
≥ 100,000/mm3 
Creatinine 
≤ 1.5 times upper limit of normal OR 
Calculated creatinine clearance 
> 45 mL/min* 
Total bilirubin 
≤ 1.5 times upper limit of normal** 
AST/ALT 
≤ 1.5 times upper limit of normal** 
Notes: 
Upper limit of normal is defined by the clinical laboratory performing the test. 
* Using the lean body mass formula only (Modified Cockcroft Gault)
** If transaminase elevation and/or bilirubin elevation is attributed to the presence 
of liver metastases, a total bilirubin ≤ 2.5 times the upper limit of normal and an 
AST and ALT ≤ 2.5 times the upper limit of normal are permissible. Patients with 
an elevated bilirubin level that is attributed to an inherited disorder, such as 
Gilbert’s disease, may be enrolled at the discretion of the principal investigator. 
5.1.9 
Patients must demonstrate adequately controlled blood pressure at the time of study 
entry, as defined by a blood pressure ≤ 150/100 mmHg at study screening on at 
least one of two screenings conducted at least 24 hours apart. If blood pressure 
meets these guidelines on initial measurement, no subsequent measurement for 
screening is needed. Blood pressure may be assessed by automated or manual 
methods by an appropriately trained clinician or nurse.   
5.1.10 
Patients must have normal left ventricular systolic function, as demonstrated by a 
transthoracic echocardiogram or MUGA scan showing a normal left ventricular 
ejection fraction. 
5.1.11 
The effects of MGCD516 on the developing human fetus are unknown.  For this 
reason, women of child-bearing potential and all men must agree to use adequate 
contraception (hormonal or barrier method of birth control, abstinence) prior to 
study entry and for the duration of study participation.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately.  Men treated or 
enrolled on this protocol must also agree to use adequate contraception prior to the 
study, for the duration of study participation, and 4 months after completion of 
MGCD516 administration. If patients do not agree to the above, they are not 
considered eligible.  
5.1.12 
Ability to understand and willingness to sign a written informed consent document. 
5.2 
Exclusion Criteria 
5.2.1 
Patients must not have received treatment with any chemotherapy, immunotherapy, 
radiotherapy or an investigational agent for malignancy within the 28 days 


38 
MGCD516 in Sarcoma Phase II 
preceding study registration. Patients may not have received treatment with 
nitrosureas or mitomycin within the 42 days prior to study registration. Patients 
may not have received treatment with a small molecule targeted agent (including 
off-label or investigational use) within 14 days preceding study registration, 
provided this represents at least 7 half-lives for that agent. Toxic effects from any 
prior therapy (except alopecia) must have resolved to grade 1 or less according to 
NCI CTCAE v4.0 or to the patient’s baseline by the time of registration.  
5.2.2 
Patients may not be receiving any other investigational agent for any purpose 
concurrently. Patients may not require ongoing treatment with (a) gastric pH 
modifying medications including proton pump inhibitors or H2 blockers (patients 
may switch to antacids), (b) medications which are known to be sensitive substrates 
or substrates with a narrow therapeutic index for the P-gp and BCRP transporters 
and/or (c) medications known to cause QTc prolongation with risk of Torasades. 
Please see Appendix 1 for a list of such prohibited concomitant medications at 
study entry.  
5.2.3 
Patients may not have a history of allergic reaction or hypersensitivity to 
microcrystalline cellulose (Avicel PH302) or polysorbate 80 (Tween 80), which are 
components of the drug product MGCD516.   
5.2.4 
Patients may not have uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, uncontrolled cardiac arrhythmia, uncontrolled diabetes mellitus or 
uncontrolled psychiatric illness that would limit compliance with study 
requirements in the opinion of the principal investigator. Additionally, patients 
must be free of any impairment in the ability to swallow and absorb the oral study 
drug. 
5.2.5 
Patients may not be pregnant or nursing. Pregnant women are excluded from this 
study because the teratogenic effects of MGCD516 have not been adequately 
studied. A negative pregnancy test must be documented 7 days or less prior to 
registration. Because there is an unknown but potential risk for adverse events to 
nursing infants secondary to treatment of the mother with MGCD516, 
breastfeeding must be discontinued prior to registration for this clinical trial.  
5.2.6 
Patients may not have known HIV infection. HIV-positive patients on combination 
antiretroviral therapy are ineligible because these patients are at increased risk of 
lethal infections when treated with potentially marrow suppressive therapy. 
Although marrow suppression was not an observed toxicity in the phase 1 trial of 
this agent, this side effect has been observed with other pan-receptor tyrosine 
kinase inhibitors.  
5.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. In accordance with 
the NIH guidelines on the inclusion of women and minorities as subjects in clinical research, the 
Department of Health and Human Services (HHS) requires that all pilot, phase 1, phase 2, and 
phase 3 trials must include accrual targets for males, females, and minorities. The accrual targets 


39 
MGCD516 in Sarcoma Phase II 
reflect the expected accrual over the life of the study.  
5.4 
Subject Recruitment 
Patients will be recruited from investigator and co-investigator practices. 
5.5 
Early Withdrawal of Subjects    
5.5.1 When and How to Withdraw Subjects 
Patients will be removed from this study for failure to adhere to protocol requirements, 
withdrawal of consent, disease progression, unacceptable toxicity, global deterioration in health 
status, study termination or death. There is no evidence to suggest that abrupt withdrawal of this 
study agent would result in adverse clinical effects and therefore there is no taper of study drug 
in the event of withdrawal.  
5.5.2 Data Collection and Follow-up for Withdrawn Subjects 
Although subjects may be withdrawn prematurely from the study, follow-up will continue for all 
such subjects. Subjects withdrawn because of unacceptable adverse events will be followed-
until resolution or stabilization of the adverse event. An attempt will be made to obtain survival 
information for all subjects for a period of at least 3 years following the time of registration or 
until death, whichever comes first. For more information, see section 11, study calendar. This 
will include attempts to contact subjects via telephone and by certified letter using information 
available to the investigators and the study team. When possible, at least two attempts will also 
be made to contact the subject’s next of kin to obtain such information while observing relevant 
privacy laws, where applicable.  


40 
MGCD516 in Sarcoma Phase II 
6. REGISTRATION PROCEDURES
6.1 
CUMC Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures, along with applicable institutional policies and federal regulations. 
Only Investigators/Research personnel properly trained and delegated to consent subjects for this 
protocol will participate in the consenting process. Furthermore, properly delegated/trained 
Physician Investigators (e.g., MD, MD PhD) are required to sign/verify a protocol specific 
Eligibility Checklist for each subject enrolled on the study, in addition to providing the relevant 
source documentation confirming subject eligibility. 
All participants must be centrally registered through the Central Registration Office 
within Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of study 
treatment. 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding 
holidays and weekends). Same day patient registrations (and after hour registrations) will be 
accommodated on a case by case basis provided that the study team has expressed all time 
sensitive registration concerns/cases in a timely manner to the Central Registration Office.  
CPDM Central Registration Procedures: Within 48 hours of obtaining consent (excluding 
holidays and weekends), a completed/signed IRB approved informed consent HIPAA form, and 
demographics forms must be submitted to the CPDM Central Registration Office via an email to 
CPDMRegistration@columbia.edu or fax to 212.305.5292, with the subject line “Protocol 
Number: Pending Subject Registration Request (PHI)”.  Upon receipt, applicable subject 
information as well as a “pending eligibility” status will be entered into HICCC’s institutional 
database.  This status will remain until further source documentation is made available to 
confirm overall patient eligibility. Required materials for all pending registration submissions are 
as follows: 
•
Completed/signed IRB approved/stamped Informed Consent Forms, including
additional study ICFs (e.g., tissue, DNA, etc.), as applicable.
•
The completed/signed IRB approved HIPAA Authorization form
•
Completed/signed CPDM ICF checklist


41 
MGCD516 in Sarcoma Phase II 
•
Completed/signed HICCC personal census form
•
Completed/signed CPDM Demographics Note to File
In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 
•
The completed/signed study specific Eligibility Checklist (signed by a
Physician level Investigator)
•
Copies of source documentation necessary for each item to be verified on the
CPDM specific Eligibility Checklist, including but not limited to:
Copy of required laboratory test and procedure reports (e.g., hematology, 
serum chemistry, pregnancy test when applicable, MRI reports, CT/bone 
scans, etc.) 
Copy of pathology and surgical reports 
Copy of clinic note(s) or other appropriate medical records capturing the 
consent process information, along with providing source documentation of 
any other items needed for screening/eligibility that are not captured in other
source document forms (e.g., positive investigator statements of unique 
eligibility items not captured via other direct source documentation, 
concomitant medication lists, etc.) 
Protocol deviation/waiver approvals (if applicable) 
Please note: subject line of email or fax should include the following: “AAAQ8661: Complete 
Subject Registration Request (PHI)”. 
Upon receipt of the above mentioned documentation, participant eligibility information will be 
verified by a qualified Central Registration Registrar. If any questions arise during the review 
process, queries in the form of emails will be addressed to the applicable study team personnel 
for clarification prior to enrollment. All applicable finalized registration/eligibility information 
will then be entered into HICCC’s institutional CTMS database by the Central Registration 
Registrar.  Upon completion, an official subject registration notification email will be sent to the 
PI/research team which will include eligibility/enrollment status, as well as subject ID 
information.  Protocol therapy may not be initiated prior to receipt of this notification from the 
Central Registration Office. 
All screen fail/ineligible subjects, as well as subjects who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 


42 
MGCD516 in Sarcoma Phase II 
7. 
  TREATMENT PLAN 
7.1 
 Agent Administration 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks for MGCD516 are described in Section 10.  Appropriate dose modifications for MGCD516 
are described in Section 9.  No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient's malignancy. 
REGIMEN DESCRIPTION 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
MGCD516 
None 
120 mg 
Orally 
Daily 
21 days 
The patient will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each cycle of treatment.  
The drug will be administered in the fasted state, at least 2 hours after the previous meal, and 1 
hour before the next meal. The capsules will be taken in the morning hours (1 hour before 
breakfast or 1 hour before lunch). The study capsules will be taken with at least 200 mL (1 cup) 
of water. No predefined prophylactic or supportive care medications will be administered with 
the study agent for patients newly starting therapy. However, prophylactic or supportive care 
may be initiated in the event of toxicity as described in section 9. 
7.2 
 General Concomitant Medication and Supportive Care Guidelines 
MGCD516 has the potential to interact with certain other drugs which study patients may be 
taking, which could result in unforeseen toxicities. The case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies. Patients 
should be asked at each study-related clinical visit about new medications, including herbal 
medications or supplements, which they are taking. 
7.2.1 Medications affecting the cytochrome system 
In vitro experiments indicate that MGCD516 is a potential inducer of CYP2B6 and CYP3A4 as 
well as a potential inhibitor of CYP2C8, CYP2D6 and CYP3A4, although neither time 
dependent nor metabolism dependent inhibition have been observed. Nonetheless, medications 
that are substrates for CYP2B6, CYP2C8, CYP2D6 or CYP3A4 and are either sensitive 
substrates or have a narrow therapeutic index should be used with caution during treatment with 
MGCD516. An alternative agent should be employed if possible; otherwise, patients should be 
monitored at each study visit for signs or symptoms suggestive of subtherapeutic or 
supratherapeutic levels of these agents. A list of substrates for CYP2B6, CYP2C8, CYP2D6 and 
CYP3A4 which are either sensitive substrates or have a narrow therapeutic index is provided in 
Appendix 1 for reference.  


43 
MGCD516 in Sarcoma Phase II 
Furthermore, in vitro experiments in microsomes and recombinant human P450 enzymes suggest 
that MGCD516 is itself metabolized by several cytochromes including CYP3A4, CYP2B6 and 
CYP2D6, although with a low risk of any single CYP having a disproportionate contribution to 
its metabolism. Caution should therefore be used when administering MGCD516 to patients 
taking medications that are strong inhibitors or inducers of these cytochromes. A list of such 
medications is provided in Appendix 1.   
7.2.2 Medications affecting gastric pH 
The solubility of MGCD516 is pH dependent, therefore medications that are associated with a 
sustained increase in gastric pH should be avoided. Upon registration to the study, patients on 
PPIs or H2 agonists should attempt to discontinue use of these agents. Patients should pursue 
lifestyle modifications and may switch to the use of as needed antacids (including gaviscon) 
and/or carafate. If patients continue to experience significant GERD symptoms, a PPI or H2 
blocker may be reinstituted at the discretion of the principal investigator and should be given 12 
hours apart from the Sitrvatinib whenever possible.  
7.2.3 Medications acting on the BCRP and P-gp transporters 
MGCD516 is an inhibitor of the breast cancer resistance protein (BCRP) and P-glycoprotein (P-
gp) transporters based on in vitro studies. Therefore, medications that are known substrates for 
the BCRP or P-gp transporters with a sensitive and/or narrow therapeutic index are prohibited. A 
list of such medications is provided in Appendix 1. 
7.2.4 Medications affecting the qTC interval 
The risk for qTC prolongation in patients receiving treatment with MGCD516 has not been 
adequately characterized in humans. Therefore, use of medications known to prolong the QTc 
interval and pose a risk of Torsades are prohibited during treatment with MGCD516. The use of 
medications known to prolong the QTc and pose a conditional risk of Torsades should be used 
with caution. Please see Appendix 1 for a list of medications to be avoided and used with caution 
in this setting. 
7.3 
 Duration of Therapy 
Treatment with the study drug will continue until one of the following applies: 
•
Disease progression
•
Intercurrent illness that prevents further administration of treatment
•
Unacceptable adverse event
•
Patient’s decision to withdraw from the study
•
General or specific changes in the patient's condition render the patient unacceptable for
further treatment in the judgment of the investigator
Patients whose disease status remains complete response, partial response or stable disease may 


44 
MGCD516 in Sarcoma Phase II 
continue on therapy indefinitely until one of the above conditions applies. 
7.4 
 Duration of Follow Up 
Patients who do not progress while on study treatment will be followed every 3 months after 
completion of study treatment for the first 12 months of follow up and then every 6 months for 
both survival and disease status until death or for a period of at least 3 years, whichever comes 
first. For patients who are taken off therapy due to progression, information on survival will also 
be collected every 3 months after completion of study treatment for the first 12 months of follow 
up and then every 6 months until death or for a period of at least 3 years, whichever comes first.  
Patients removed from study for unacceptable adverse events will also be followed for 
information on resolution or stabilization of the adverse event. 
7.5 
 Criteria for Removal from Study 
Patients will be removed from the study when any of the criteria listed in Section 7.3 applies.  
The reason for study removal and the date the patient was removed will be documented in the 
Case Report Form. 
7.6 
Approach to COVID-19 Related Treatment Interruptions 
Patients whose protocol treatment is interrupted because of COVID-19 infection and/or COVID-
19-related effects on the conduct of this study may resume resume treatment at the discretion of 
the treating investigator if the investigator believes the potential benefits outweigh risks. In this 
situation, the patient’s clinical situation, previous benefit from study treatment, and other 
available treatment options should be considered.  
This applies to subjects whose treatment is delayed beyond the protcol allowed timeframe of 28 
days and also to subjects whose study-specified restaging imaging performed around the time of 
treatment interruption shows disease progression, and this progression can reasonably attributed 
to the period treatment was withheld.  
In these situations, the treating investigator will document the specifics of the situation and 
consideration of risk/benefit in the electronic medical record.  
8.
DOSING DELAYS/DOSE MODIFICATIONS
This section provides guidance on the management of adverse events and on dose delays and 
modifications for MGCD516. In the event of adverse events attributed to MGCD516 and deemed 
intolerable to the investigator, treatment may be temporarily or permanently discontinued. For 
patients who temporarily discontinue treatment, treatment may resume following resolution of 
treatment-related adverse events to grade 1 or baseline at a reduced dose level. Recommended 
dose modification algorithms are included for commonly observed adverse events. Adverse 
events are classified and graded according to CTCAE version 4.0. The following guidelines 
should also be observed:  


45 
MGCD516 in Sarcoma Phase II 
•
If a patient experiences multiple adverse events and there are conflicting
recommendations as to management, the investigator should use the recommended dose
adjustment that reduces the dose to the lowest level of the available options.
•
Any patient who requires a delay in therapy exceeding 28 days should be removed from
the study. Any patient who requires more than three dose reductions should also be
removed from the study.
•
Patients should receive all relevant supportive care during the study, including, but not
limited to: blood product support, antibiotic treatment, and management of other newly
diagnosed medical conditions. All blood products and concomitant medications (such as
antiemetics, analgesics, antidiarrheals) received from the first day of study drug treatment
until 30 days after the final dose of study drug treatment must be recorded.
•
Patients who require radiation therapy while on study must be removed from the study.
•
Patients who require surgery while on study may proceed with surgery provided resection
or removal of sarcoma is not part of the surgery. However, if a dose delay of more than
28 days is required, the patient must be removed from the study.
•
Blood products and growth factors should be used as clinically warranted and in
accordance with institutional policy at the institution where the patient is being treated.
Specifically, the use of erythropoietin is permitted at the discretion of the treating
physician. The use of filgrastim and related medications to avoid dose reductions or
delays is discouraged. The use of these agents in the setting of complications from
therapy, such as severe infection, is permitted and must be documented.
8.1 
Dose Levels 
Dose Level 
MGCD516 Dose 
-3 
Off protocol therapy 
-2 
80 mg orally daily 
-1 
100 mg orally daily 
0 
120 mg orally daily* 
* Note: The starting dose of Sitravatinib was modified from 150 to 120 mg daily in 5/2018.
Patients already enrolled on the study at the time of this modification may continue at the 150 
mg dose level, or reduce to the 120 mg dose level, at the discretion of the treating investigator. 
For patients continuing at 150 mg, 120 mg represents dose level -1, and so on. 
8.2 
Management Advice for Non-Hematologic Adverse Events 
Hypertension 
Management/Next Dose for MGCD516 
≤ Grade 1 
No change in dose 


46 
MGCD516 in Sarcoma Phase II 
Hypertension 
Management/Next Dose for MGCD516 
Grade 2 
Continue therapy. Institute anti-hypertensive agent or alter dose of 
existing anti-hypertensive agent.  
Grade 3 
Hold therapy. Institute anti-hypertensive agent or alter dose of 
existing agent. Resume therapy when hypertension resolved to grade 
2 or less. For subsequent occurrences at grade 3, hold therapy until 
blood pressure resolves to grade 2 or lower, and reinstitute at one 
dose level lower, at investigator’s discretion. 
Grade 4 
Off protocol therapy. 
When anti-hypertensive therapy is indicated, the agent employed should be based upon review 
of the patient’s clinical history to determine the most appropriate agent, with cardiology 
consultation as needed. The use of dihydropyridine calcium channel blockers such as 
nifedipine, amlodipine and nicardipine can be considered as first line agents, in the absence of 
contraindications.  
Palmar Plantar 
Erythrodysesthesia 
Management/Next Dose for MGCD516 
≤ Grade 1 
No change in dose. Counsel on measures to mitigate the effects of 
palmar plantar erythrodysesthesia and institute topical therapies as 
described below.  
Grade 2 
Hold until ≤ Grade 1, counsel on measures to mitigate the effects of 
palmar plantar erythrodysesthesia, and resume at one dose level lower. 
Grade 3 
Hold until ≤ Grade 1, counsel on measures to mitigate the effects of 
palmar plantar erythrodysesthesia, and resume at one dose level lower, 
at investigator’s discretion. 
Grade 4 
Not applicable. 
Signs and symptoms of palmar plantar erythrodysesthesia include redness, swelling, pain and 
blistering on the palms of the hands and soles of the feet. Patients should be counseled to avoid 
exposure of hands and feet to hot water and other sources of heat, to avoid activities causing 
force or friction, and to avoid contact with harsh chemicals. Treatment includes the use of 
moisturizing agents, topical anesthetics, topical anti-inflammatory medications, and topical 
corticosteroids.  
Proteinuria 
Management/Next Dose for MGCD516 
≤ Grade 1 
Continue therapy with close monitoring by urinalysis at least every 
cycle.  
Grade 2 
Hold protocol therapy. Perform 24 hour urine collection to confirm 
degree of proteinuria. May reinstitute at one dose level lower if and 
when protein levels decrease to 2g in 24 hours, at the discretion of the 
principal investigator.  
Grade 3 
Off protocol therapy. 
Grade 4 
Not applicable. 
Patients who develop more than 2g proteinuria should undergo 24 hour urine collection for 
definitive assessment of urine protein. Patients who develop nephrotic syndrome should be 


47 
MGCD516 in Sarcoma Phase II 
Proteinuria 
Management/Next Dose for MGCD516 
taken off protocol therapy and referred for further management by a nephrologist. ACE 
inhibitor therapy is permitted in study patients as clinically indicated. 
Diarrhea 
Management/Next Dose for MGCD516 
≤ Grade 1 
No change in dose. Evaluate for infectious etiology if clinically 
indicated. Institute anti-diarrheal therapy.   
Grade 2 
No change in dose. Evaluate for infectious etiology if clinically 
indicated. Institute anti-diarrheal therapy. If diarrhea persists at grade 2 
or higher for more than 5 days despite supportive care, hold protocol 
therapy and manage supportively. Reinstitute at same dose when 
symptoms improve to ≤ grade 1. On subsequent occurrences at grade 2, 
consider dose reduction when therapy reinstated.  
Grade 3 
Hold until ≤ Grade 1.  Evaluate for infectious etiology if clinically 
indicated. Institute anti-diarrheal therapy. Reinstitute at one dose level 
lower when symptoms improve to ≤ grade 1.   
Grade 4 
Off protocol therapy. 
If clinically indicated, evaluate patients for an infectious etiology of diarrhea using appropriate 
test for Clostridium difficile, stool cultures, and PCR for GI pathogens, where available. Treat 
infection as clinically indicated. First line supportive care should be instituted with the anti-
diarrheal loperamide.  
Fatigue 
Management/Next Dose for MGCD516 
≤ Grade 1 
No change in dose. 
Grade 2 
No change in dose. 
Grade 3 
Hold until ≤ Grade 2.  Resume at same dose level. If recurs at grade 3, 
hold until ≤ Grade 2 and then resume at one dose level lower. 
Grade 4 
Not applicable. 
Fatigue is commonly associated with receptor tyrosine kinase inhibitors. Evaluate and treat for 
other conditions which can manifest as fatigue, including but not limited to thyroid 
dysfunction, infection and anemia.  
Left ventricular 
systolic dysfunction 
Management/Next Dose for MGCD516 
≤ Grade 1 
Not applicable.  
Grade 2 
Not applicable.  
Grade 3 
Off protocol therapy.  
Grade 4 
Off protocol therapy.  


48 
MGCD516 in Sarcoma Phase II 
Liver Function 
Abnormality 
Management/Next Dose for MGCD516 
ALT or AST  3x 
ULN but  5x ULN 
AND TB  2x ULN 
Continue study drug. Monitor liver function testing weekly until tests 
return to normal or baseline, or demonstrate stabilization (if tests 
demonstrate stability in the opinion of the investigator, monitoring may 
be changed to every 2-3 weeks.) If liver function testing worsens, 
follow applicable instructions below.  
ALT or AST  5x 
ULN AND TB  2x 
ULN 
Hold study drug.  Monitor liver function testing weekly until tests 
return to normal or baseline. Reinstitute therapy at one dose level lower 
and monitor liver function testing at least weekly for a minimum of 4 
weeks after restarting therapy. If ALT or AST again  5x ULN, 
discontinue further protocol therapy.  
TB  2x ULN but  
3x ULN regardless 
of AST/ALT 
Hold study drug.  Monitor liver function testing weekly until tests 
return to normal or baseline. Reinstitute therapy at one dose level lower 
and monitor liver function testing at least weekly for a minimum of 4 
weeks after restarting therapy. Note: If patient enters the study with TB 
between ULN and 1.5x ULN (because attributed to presence of 
metastatic disease), no intervention is required unless increase in TB 
represents a change from baseline.  
TB  3x ULN 
regardless of 
AST/ALT 
Discontinue study drug. 
Protocol modifications of 6/8/2017 reflect the lack of clinically significant hepatotoxicity 
observed in the phase 1/1b study of Sitravatinib in solid tumors (grade 3/4 AST/ALT observed 
in less than 3% of patients, no grade 3/4 TB abnormalities observed. (TB = total bilirubin). 
All Other Non-
Hematologic Events 
Management/Next Dose for MGCD516 
Treatment delay 
Dose Modification 
≤ Grade 1 
No delay 
No change in dose 
Grade 2 
In general, hold until ≤ grade 1 
or return to baseline 
Not required 
Grade 3 or 4 
manageable with 
supportive care. 
Hold until ≤ grade 1 or return to 
baseline 
Not required 
Grade 3 or 4 
not manageable with 
supportive care. 
Hold until ≤ grade 1 or return to 
baseline 
Resume at one dose level lower 
than dose inducing toxicity. 
Modifications apply to toxicities deemed related to study drug. 
Appropriate supportive care should be instituted. 
8.3 
Management Options for Hematologic Adverse Events 
Neutropenia 
Grade 1 (ANC < 1500 to < LLN) 
Maintain dose level 


49 
MGCD516 in Sarcoma Phase II 
Grade 2 (ANC 1000 to < 1500) 
Maintain dose level 
Grade 3 (ANC 500 to < 1000) 
Hold therapy until resolved to ≤ grade 2, then: 
 If resolved in ≤ 7 days, maintain dose level 
 If resolved in > 7 days, reduce by 1 dose level 
Grade 4 (ANC < 500 or febrile neutropenia) Hold therapy until resolved to ≤ grade 2, then 
restart at one dose level lower. 
Thrombocytopenia 
Grade 1 (PLT 750000 to < LLN) 
Maintain dose level 
Grade 2 (PLT 50000 to < 75000) 
Hold therapy until resolved to ≤ grade 1, then: 
 If resolved in ≤ 7 days, maintain dose level 
 If resolved in > 7 days, reduce by 1 dose level 
Grade 3 (PLT 25000 to < 50000) 
Hold therapy until resolved to ≤ grade 1, then 
restart at one dose level lower.  
Grade 4 (PLT < 25000) 


50 
MGCD516 in Sarcoma Phase II 
9.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS
9.1 
Adverse events 
A summary list of reported treatment-related treatment-emergent adverse events for MGCD516 
is provided below. For a detailed list of all treatment emergent adverse events reported in the 
phase 1 trial of MGCD516 in solid tumors, please see section 3.2. Based on the most recently 
available information the phase 1/1b study (as of 7/2016 and representing 61 patients treated 
with the drug), the following treatment-related treatment-emergent adverse events were reported: 
Likely (>20%) 
Less Likely (5-20%) 
Rare but Serious (<3%) 
•
Diarrhea
•
Fatigue (feeling tired)
•
Hypertension (high
blood pressure)
•
Blood clots, in the veins or
lungs
•
Change in voice
•
Constipation
•
Cough
•
Decreased appetite
•
Dry mouth
•
Low thyroid level
(hypothyroidism)
•
Nausea
•
Mucosal inflammation
and/or irritation, including
mouth pain
•
Rash
•
Swelling and/or redness
and/or pain of the hands
and feet
•
Vomiting
•
Weakness
•
Weight loss
•
Decrease in heart
function or heart
pumping
•
Fever with low
white blood cells
(infection fighting
cells)
•
Increase in
pancreas-related
enzymes
•
Increase in heart rate
(tachycardia)
•
Increase in liver
function tests
(possible liver
damage)
•
Protein in the urine
•
Weakness,
numbness and/or
pain due to nerve
injury (neuropathy)
MGCD516 is a small molecule multi-receptor tyrosine kinase inhibitor of a range of RTKs. As 
such, it may share some similar properties with other small molecule RTK inhibitors, although 
adverse events associated with the drugs are likely to vary based on the particular RTKs 
selectively inhibited.  
9.2 
Definitions 
Adverse Event: An adverse event (AE) is any untoward or unfavorable medical occurrence in a 
human subject, including abnormal sign, symptom or disease, temporally associated with the 
subject’s participation in research, whether or not considered related to the subject’s participation 
in the research. Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality, results in study withdrawal, is associated with a serious adverse event, is 


51 
MGCD516 in Sarcoma Phase II 
associated with clinical signs or symptoms, leads to additional treatment or to further diagnostic 
tests, is considered by the investigator to be of clinical significance 
Serious Adverse Event: Adverse events are classified as serious or non-serious.  A serious 
adverse event is any AE that is:  
•
fatal
•
life-threatening
•
requires inpatient hospitalization/prolongation of existing hospitalization,
unless: (1) routine treatment  or monitoring of the studied indication, not
associated with any deterioration in condition (procedures such as central line
placements, paracentesis, pain control); (2) elective or pre-planned treatment
for a pre-existing condition that is unrelated to the indication under study and
has not worsened since the start of study drug; (3) treatment on an emergency
outpatient basis for an event not fulfilling any of the definitions of an SAE
given above/below and not resulting in hospital administrations; (4) social
reasons and respite care in the absence of any deterioration in the patient’s
general condition
•
results in persistent or significant disability or incapacity
•
a congenital anomaly or birth defect
•
an important medical event. An important medical event is one that may not be
immediately life threatening but is clearly of major clinical significance. It may
jeopardize the subject, and may require intervention to prevent one of the other
serious outcomes noted above. For example, drug overdose or abuse, a seizure
that did not result in inpatient hospitalization, or intensive treatment of
bronchospasm in an emergency department would all typically be considered
serious.
Unanticipated Problem: An unanticipated problem is any incident, experience or outcome 
involving risks to subjects or others in any human subjects research that meets all of the following 
criteria: 
•
unexpected (in terms of nature, severity or frequency) given (a) the research
procedures that are described in the IRB-approval protocol and informed
consent document, and (b) the characteristics of the subject population being
studied;
•
related or possibly related to participation in such research (e.g., there is a
reasonable possibility that the incident, experience or outcome may have been
caused by the procedures involved in such research); and


52 
MGCD516 in Sarcoma Phase II 
•
suggests that the research places subjects or others at a greater risk of harm
(including physical, psychological, economic or social harm) than was
previously known or recognized.
Adverse Event Reporting Period: The study period during which adverse events must be 
reported is normally defined as the period from the initiation of any study procedures (after the 
first dose of study treatment) to the end of the study treatment (last dose of study treatment) and 
follow-up.  For this study, the study treatment follow-up period is defined as 28 days following 
the last administration of study treatment. 
Baseline/Preexisting Condition: A baseline/preexisting condition is one that is present at the 
start of the study. A preexisting condition should be recorded as an adverse event if the 
frequency, intensity, or if the character of the condition worsens during the study period. 
General Physical Examination Findings: At screening, any clinically significant abnormality 
should be recorded as a preexisting condition.  At the end of the study, any new clinically 
significant findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event.  
Post-study Adverse Event: All unresolved adverse events should be followed by the 
investigator until the events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained.  At the last scheduled visit, the investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study.   
Abnormal Laboratory Values: A clinical laboratory abnormality should be documented as an 
adverse event if any one of the following conditions is met:  
•
The laboratory abnormality is not otherwise refuted by a repeat test to confirm
the abnormality
•
The abnormality suggests a disease and/or organ toxicity
•
The abnormality is of a degree that requires active management (e.g., change of
dose, discontinuation of the drug, more frequent follow-up assessments, further
diagnostic investigation, etc.).
Hospitalization, Prolonged Hospitalization or Surgery: Any adverse event that results in 
hospitalization or prolongation of hospitalization should be documented and reported as a serious 
adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for an adverse event.  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
•
Hospitalization or prolonged hospitalization for diagnostic or elective surgical
procedures for a preexisting condition.  Surgery should not be reported as an


53 
MGCD516 in Sarcoma Phase II 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful. 
•
Hospitalization or prolonged hospitalization required to allow efficacy
measurement for the study.
•
Hospitalization or prolonged hospitalization for therapy of the target disease of
the study, unless it is a worsening or increase in frequency of hospital
admissions as judged by the clinical investigator.
9.3 
Recording of Adverse Events 
Signs or symptoms of the patient’s cancer diagnosis and/or comorbidities at baseline will be 
recorded beginning on day 1. At each contact with the subject, the investigator must seek 
information on adverse events by specific questioning and, as appropriate, by examination.  
Assessment of adverse events will include type, incidence, severity (as graded by CTCAE 
version 4), timing, seriousness, and relatedness to study treatment. For each adverse event, the 
investigator will determine and document whether there exists a reasonable possibility that the 
study drug treatment caused or contributed to the adverse event. When the investigator does not 
know whether or not the study treatment is causally-related to the event, reporting for study 
purposes will be as “related” to study treatment.  
Information on all adverse events should be recorded immediately in the source document, and 
also in the appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should recorded in the source 
document, though should be grouped under one diagnosis. 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period must be followed to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
9.4 
 Reporting of Serious Adverse Events 
9.4.1 IRB Notification by Sponsor-Investigator 
Reports of all events (including follow-up information) that meet the definition of an unanticipated 
problem posing risk to subjects or others must be submitted to the IRB within one week (5 business 
days) following the occurrence of the unanticipated problem or the principal investigator’s 
acquiring knowledge of the unanticipated problem  in accordance with IRB policy. Additionally, 
the sponsor-investigator will submit a summary of all unanticipated problems that occurred since 
the beginning of the study at the time of continuing review. Copies of each report and 
documentation of IRB notification and receipt will be kept in the Regulatory binder. 


54 
MGCD516 in Sarcoma Phase II 
9.4.2 FDA Notification by Sponsor-Investigator 
Columbia University Medical Center will be responsible for all communication with the FDA. 
Columbia University Medical Center will report to the FDA, regardless of the site of occurrence, 
any adverse event that is serious, unexpected and for which there is evidence to suggest a causal 
relationship between the drug and the adverse event. These must be reported to the FDA and any 
affiliate sites as soon as possible, but in no case later than 15 calendar days after the sponsor 
determines that the information qualifies for reporting.  Columbia University Medical Center 
will also submit an IND annual report to the FDA in accordance with 21.CFR 312.33. 
Columbia University Medical Center must report to the FDA and any affiliate site investigators 
as follows:  
•
Any unexpected fatal or life-threatening event must be reported as soon as
possible, but no later than 7 calendar days after the sponsor investigator initial
receipt of the information
•
Any findings from epidemiological studies, pooled analysis of multiple studies,
or clinical studies, whether or not conducted under an IND, and whether or not
conducted by the sponsor-investigator, that suggest a significant risk in humans
exposed to the drug  must be reported as soon as possible but no later than 15
calendar days after the sponsor-investigator determines that the information
qualifies for reporting
•
Any findings from animal or in vitro testing whether or not conducted under an
IND, and whether or not conducted by the sponsor-investigator, that suggest a
significant risk in humans exposed to the drug  must be reported as soon as
possible but no later than 15 calendar days after the sponsor-investigator
determines that the information qualifies for reporting
•
Any clinically important increase in the rate of a serious suspected adverse
reactions  over that listed in the protocol or Investigator Brochure
•
Expected SAEs and AEs will be included in the IND Annual Reports.
Follow-up information to a safety report should be submitted as soon as the relevant information 
is available.  However, if the results of a sponsor’s investigation show that an adverse drug 
experience not initially determined to be reportable are so reportable, the sponsor investigator 
must report such experience as soon as possible, but no later than 15 calendar days after the 
determination is made. 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but in no event later than 15 calendar days after initial 
receipt of the information. 


55 
MGCD516 in Sarcoma Phase II 
9.4.3 DSMC Reporting by the Sponsor Investigator 
Serious adverse events not constituting unanticipated problems are to be reported to the HICCC 
DSMC. Reporting should occur within 24 hours of knowledge of the SAE occurring at our 
institution or affiliate sites. 
9.4.4 Reporting to Drug Manufacturer by Sponsor-Investigator 
All Suspected Unexpected Serious Adverse Reactions (SUSARs)  will be submitted to Mirati 
Therapeutics on a MedWatch Form 3500A within the timelines as follows:  
•
Reports of fatal or life threatening Serious Adverse Drug Reactions will be forwarded
within five (5) calendar days of Receipt Data
Reports of Serious Adverse Drug Reactions (other than fatal or life threatening) will be 
forwarded within twelve (12) calendar days of Receipts Date. 
Please FAX IND Safety Reports (SUSARS) to 1-888-488-9697.  For FAX problems call 1-800-
201-8725 to report the event via phone. 
In addition, all reports prepared for FDA submission will be submitted to Mirati Therapeutics prior 
being submitted to the FDA. If no comment is received by Mirati Therapeutics within 48 hours, 
the report will be submitted to the FDA in its original form, so as to ensure timely submission of 
documentation. 
9.5 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A, the HICCC DSMC Serious Adverse 
Event Reporting Form, or in a narrative format. If supplied as in a narrative format, the minimum 
information to be supplied is noted above at the beginning of section 10.  At the time of IRB 
renewal or at the request of the manufacturer, the Sponsor-Investigator will submit a summary of 
all serious adverse events that have occurred during the study to the manufacturer.  
10.
PHARMACEUTICAL INFORMATION
10.1 
Description 
MGCD516 is an orally available small molecular inhibitor of several closely related receptor 
tyrosine kinases. Detailed information on the drug’s mechanism of action, as well as preclinical 
and clinical safety information, is provided in Section 4. The drug is currently supplied as 10 and 
40 mg capsules. The composition of the drug product includes a blend of the free base substance 
MGCD516 with microcrystalline cellulose (Avicel PH302) and polysorbate 80 (Tween 80). The 
blend is filled into size 1 light blue opaque (10 mg) or size 1 Swedish orange opaque (40 mg) 
hard gelatin capsules. The 10 and 40 mg capsules are packaged into 60 cc bottles.  


56 
MGCD516 in Sarcoma Phase II 
10.2 
Treatment Regimen 
The treatment regimen consists of MGCD516 at a dose of 120 mg orally daily in continuous 21 
day cycles. This dose will be administered as three (3) 40 mg capsules. The drug will be 
administered in the fasted state, at least 2 hours after the previous meal, and 1 hour before the 
next meal. The capsules will be taken in the morning hours (1 hour before breakfast or 1 hour 
before lunch). The study capsules will be taken with at least 200 mL (1 cup) of water. 
10.3 
Method for Assigning Subjects to Treatment Groups 
Not applicable. All study participants will be treated with the same treatment regimen. 
10.4 
Preparation and Administration of Study Drug 
The study drug is an oral capsule which will be packaged, shipped and stored as described 
below. The drug will be received by the Research Pharmacy of Columbia University Medical 
Center, stored in a secure location and according to all institutional policies, and will be released 
to the research nursing staff who will distribute the agent to the patient. No other specific 
preparation of the drug is needed at the study site.  
10.5 
Subject Compliance Monitoring 
Study subjects will complete a medication journal documenting compliance with the study drug. 
The medication journal will be reviewed after each cycle. Patients who are non-complaint with 
the treatment regimen may be removed from the study at the discretion of the principal 
investigator. 
10.6 
Prior and Concomitant Therapy 
Information will be collected on all prior anti-cancer therapies. Patients may not receive any 
other agent which could be considered treatment for the primary neoplasm or which might affect 
the primary endpoint during their participation in the study. For other restrictions on concomitant 
medication use, see section 7.2.  
10.7 
Packaging 
The MGCD516 drug product is packaged in 30 count, high-density polyethylene (HDPE) white 
opaque round bottles. The 10 and 40 mg unit dose capsules are packaged into 60 cc bottles. A 
tamper-proof heat induction seal and a child resistant closure are employed. Each bottle is labeled 
with contents, product lot number, required storage conditions and a regional specific cautionary 
statement.  
10.8 
Blinding of Study Drug 
Not applicable. This is an open-label study. 


57 
MGCD516 in Sarcoma Phase II 
10.9 
Receiving, Storage, Dispensing and Return 
10.9.1 Receipt of Drug Supplies 
The study drug will be shipped by Mirati Therapeutics to the Research Pharmacy of Columbia 
University Medical Center. Upon receipt of the of the study treatment supplies, an inventory will 
be performed and a drug receipt log filled out and signed by the person accepting the shipment.  
The designated study staff will count and verify that the shipment contains all the items noted in 
the shipment inventory.  Any damaged or unusable study drug in a given shipment will be 
documented.  The investigator must notify the agent manufacturer of any damaged or unusable 
study treatments that were supplied to the investigator’s site. 
10.9.2 Storage 
Bottles of MGCD516 will be stored at room temperature, within a range of 15 to 30 degrees 
Celsius. The storage area should be secure with limited access. Only qualified personnel who are 
familiar with procedures that minimize undue exposure to them and to the environment should 
undertake the preparation, handling and safe disposal of small molecule chemotherapeutic agents 
such as MGCD516. 
10.9.3 Dispensing of Study Drug 
Regular study drug reconciliation will be performed to document drug assigned, drug consumed, 
and drug remaining.  This reconciliation will be logged on the drug reconciliation form and 
signed and dated by the study team. Drug inventory forms will record the batch or lot numbers 
for disposition on a patient by patient basis and signed by the person dispensing the drug. 
Patients will receive study drug on the first day of each cycle while they remain on study. 
Sufficient supply will be provided for the cycle and up to 2 additional days in case of delayed 
clinic visits or lost capsules. Study site personnel will provide each patient with written dosing 
information. Patients will record their daily dosing on a provided form and report any missed 
doses or lost capsules.  
10.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining.  This reconciliation will be logged on the drug reconciliation 
form, signed and dated.  Any discrepancies noted will be investigated, resolved, and documented 
prior to return or destruction of the study drug.  


58 
MGCD516 in Sarcoma Phase II 
11. 
STUDY CALENDAR 
Procedure 
Screening 
(1) 
Cycle 1(9) 
Cycle 2 (9) 
Cycle 3 + (9) 
End of 
study 
(8) 
1 
8 
15 
1 
8 
15 
1 
8 
15 
Informed consent 
X 
Medical history 
X 
Pathology confirmation 
X 
Physical examination and vital signs
X 
X 
X 
X 
X 
X 
X 
Height and weight 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
ECG (1)
X 
X 
Echocardiogram (1) 
X 
X 
CBC w/differential (1,3) 
X 
X 
X 
X 
X 
X 
X 
Comprehensive metabolic panel (1,3,4) 
X 
X 
X 
X 
X 
X 
X 
Thyroid function tests (1, 3, 11) 
X 
X 
X 
Lipase (1, 3, 11) 
X 
X 
X 
Serum or urine pregnancy test (1) 
X 
Urinalysis (1) 
X 
X 
(10) 
X 
CT or MRI of chest, abdomen, pelvis (2) 
X 
X 
X 
Tumor specimen submitted for next 
generation sequencing (5) 
X 
Fresh tumor biopsy for RPPA studies (6)
X 
X 
Follow-up telephone contact (7) 
X 
(1): History and physical, all laboratory studies, urinalysis and single EKG must be completed 14 
days or less prior to registration, with the exception of the serum or urine pregnancy test, which 
must be performed 7 days or less prior to registration. The echocardiogram must be completed 
within 56 days of registration, unless there is clinical suspicion for a change in cardiac status 
since that time, in which case it should be repeated. An echocardiogram will be repeated at any 
point during week 1 of cycle 3. Protocol-specific screening procedures that are performed as part 
of standard of care and are within these specified timeframes may be used for screening 
purposes.  
(2) Baseline imaging can include either (a) CT, spiral CT or MRI, or (b) FDG-PET with 
diagnostic CT performed with IV and oral contrast and CT acquired with 5 mm or less slice 
thickness. Imaging studies used for baseline tumor measurements must be obtained 28 days or 
less prior to registration. Imaging studies performed as part of standard care and within this 


59 
MGCD516 in Sarcoma Phase II 
timeframe may be used for screening purposes. Imaging studies are performed every 2 cycles (6 
weeks, 42 days) for the first 36 weeks of study treatment, and then every 3 cycles (9 weeks, 63 
days) thereafter. Imaging studies may be performed +/- 5 days from the required date. In the 
event of dose delays/holds, imaging studies should still be obtained at the scheduled timepoints 
as determined from registration, without delays to account for the dose delays/holds. 
Confirmatory scans must be obtained at least 4 weeks after the documentation of an objective 
response as discussed in section 12. It is acceptable to perform confirmatory assessments at the 
next appointed evaluation per protocol.  Response assessment should include assessment of all 
sites of disease and use the same imaging method as used at baseline whenever possible.  
(3) All laboratory studies may be performed +/- 3 days from the required date. 
(4) Comprehensive metabolic panel is to include albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, glucose, potassium, total protein, 
AST, ALT and sodium. 
(5) Applies to liposarcoma patients only: All patients will have their most recent available biopsy 
material submitted for next generation sequencing to assess for genetic alterations of MGCD516 
targets. See section 13 for more information on sample collection, processing and analysis. In 
cases were institutional policy or availability of prior specimens preclude this analysis, these 
studies will not be performed for that patient.  
(6) Applies to liposarcoma patients only: A subset of 10 patients will undergo baseline and on-
treatment tumor biopsies for RPPA studies. The first 10 patients with lesions amenable to biopsy 
who are enrolled to the study (beginning with the first patient enrolled in stage I) will undergo 
these biopsies. See section 13 for information on sample collection, processing and analysis. The 
baseline biopsy specimen will be obtained at any point between day -14 and the date of first 
treatment with the study drug (cycle 1, day 1) provided consent is obtained and the other eligibility 
criteria are met. The on-treatment biopsy specimen will be performed with a target timepoint of 
cycle 1 day 15 (with a window of cycle 1 days 15 through 20). Biopsies will be obtained from the 
site of disease. If the study fails in stage I and proceeds to the exploratory cohort, no further 
RPPA analyses will be performed.  
(7) A post-study follow-up contact via telephone by research staff will be conducted every 3 
months during the first year after the end of study participation, and then every 6 months 
thereafter. For patients who do not progress on study treatment, information is obtained on 
disease status, survival status, and new anti-cancer therapy received. For patients who do 
progress on treatment, information is obtained on survival status and new anti-cancer therapy 
received. Follow-up continues for at least 3 years as measured from the date of study registration 
or until death, whichever comes first.  
(8) The end-of-study visit must be scheduled 28 days after the last dose of study drug (+/- 7 
days) and before starting any new anti-neoplastic therapy. Imaging studies are only performed at 
this time if they would otherwise be indicated by that patient’s study calendar.  
(9) Clinical assessments will occur on days 1, 8 and 15 of cycle 1, and then on day 1 of all cycles 


60 
MGCD516 in Sarcoma Phase II 
thereafter. Clinical assessments may occur +/- 3 days from the target date. 
(10) The urinalysis is repeated on cycle 3 day 1. If there is no evidence of proteinuria, the 
urinalysis need not be repeated in subsequent cycles. If microscopic testing shows evidence of 
proteinuria, the study should be repeated on day 1 of subsequent studies.  
(11) Thyroid function tests (TSH, reflexive free T4/free T3 if TSH is abnormal) and lipase 
should be performed at baseline, C3D1, every other cycle after C3D1 (i.e. C5D1, C7D1 etc.) and 
at end of treatment.    
12. 
MEASUREMENT OF EFFECT 
12.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients will be re-evaluated for response every 6 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
12.1.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with MGCD516. 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
12.2 
Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for 
nodal lesions) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by 


61 
MGCD516 in Sarcoma Phase II 
clinical exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. Cystic lesions thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
12.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 


62 
MGCD516 in Sarcoma Phase II 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g., for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 


 
 
63 
MGCD516 in Sarcoma Phase II 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy/Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers: Tumor markers will not be used in this study.  
 
Cytology/Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign 
of PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, 
this is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT, additional follow-up CT scans are needed to determine if 
there is truly progression occurring at that site (if so, the date of PD will be the 
date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to 
represent fibrosis or scarring.  The use of FDG-PET in this circumstance should 
be prospectively described in the protocol and supported by disease-specific 
medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET 
and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 


64 
MGCD516 in Sarcoma Phase II 
than twice that of the surrounding tissue on the attenuation corrected image. 
12.4 
Response Criteria 
12.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
12.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase. Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
12.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 


 
 
65 
MGCD516 in Sarcoma Phase II 
 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*  
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
12.5 
Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 


 
 
66 
MGCD516 in Sarcoma Phase II 
12.6 
Progression-Free Survival 
 
Progression free survival is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
12.7 
Response Review 
 
Not applicable.  
 
12.8 
Unblinding Procedures 
 
Not applicable.  
 
12.9 
Stopping Rules  
 
Adverse event stopping rule: Accrual will be temporarily suspended to this study if (a) at any 
time, 2 patients have experienced a grade 5 event considered at least possibly related to the study 
treatment and not related to disease progression or (b) more than 40% of all patients, when 
accrual is equal to or greater than 10 patients, have experienced a grade 3 or higher adverse 
event. In addition, each grade 5 event will be reviewed at the time of occurrence to determine 
whether study accrual should be suspended to protect the safety of patients. This adverse event 
stopping rule may be altered in the event of the study reopening after a temporary suspension or 
should new information become available related to the safety of the study drug.  
 
13.  CORRELATIVE STUDIES 
 
The correlative studies described below will be performed in liposarcoma patients only.  
 
13.1 
Proteomics studies 
 
Introduction 
 
Reverse phase protein array (RPPA) is a functional proteomics technology capable of profiling 
protein levels and post-translational modifications, including phosphorylation, across various 
biological specimens, including human tissue, using a miniaturized analyte-down dot-blot 
immunoassay.26 The technique allows for monitoring of protein expression across a large number 
of samples in a quantitative, high-throughput and cost-effective manner not currently 
matched by other proteomics technologies.  
 
In RPPA, analytes are immobilized on a solid phase, most often nitrocellulose, and probed with 
an affinity reagent, usually a high-affinity validated antibody. The technology is particularly well 
suited for profiling the state of cell signaling networks owing to small sample requirements, high 
sensitivity in the picomolar range and precision as demonstrated by coefficient of variance < 
15%. RPPA has been used in a range of preclinical and clinic research applications for 
identification of novel therapeutic targets and predictive biomarkers, pharmacodynamic analysis 
and monitoring of therapeutic response.27  


 
 
67 
MGCD516 in Sarcoma Phase II 
 
We aim to employ RPPA to analyze changes in total and phosphoprotein RTKs between baseline 
and on-treatment tumor biopsy specimens in order to demonstrate pharmacodynamic evidence of 
on-target activity by MGCD516, evaluate drug effects on activation/suppression of downstream 
signaling pathway components and assess for possible compensatory upregulation of alternative 
RTKs and signaling pathway components as a mechanism of acquired resistance. Specifically, we 
will study changes in total and phosphoprotein levels for the following proteins: 4E-BP1, Akt, 
AXL, EGFR, Eph family, ERK 1/2, FGFR2, IGF1-R, KIT, MEK 1/2, MET, p70 S6 kinase, RET, 
RYK, PDGFRa, PDGFRb and VEGFR1-2. Significant changes in total and phosphoRTKs will 
then be confirmed by Western Blot.  
 
Prior Clinical Studies Employing RPPA 
 
RPPA has been employed as a component of numerous clinical trials for a similar purpose, 
demonstrating the feasibility of this method in human tumor specimens obtained in a clinical trial 
setting. One of the earliest clinical trials to employ RPPA was a phase II trial of gefitinib in 
patients with refractory or recurrent epithelial ovarian cancer28. Core needle tumor biopsies were 
obtained before treatment and after 4 weeks on drug, and RPPA was used to characterize 
expression of total and phosphorylated EGFR, AKT and ERK in microdissected tumor 
specimens. The majority of patients demonstrated changes in EGFR and pEGFR although no 
clinical benefit was noted for the drug. There was a trend for increased toxicity with greater 
changes in phosphorylation of EGFR, ERK and AKT. The same group later carried out a phase 
II trial of vandetanib, a small molecule inhibitor of VEGFR2 and EGFR, in platinum-resistant 
ovarian cancer patients. Core needle biopsies were obtained at baseline and after 6 weeks on 
treatment. RPPA was then used to assess multiple RTK and signaling pathway component 
endpoints in the paired tissue biopsy specimens. The study used a Simon II stage design, and the 
drug failed to demonstrate sufficient clinical efficacy in the first stage. Interestingly, however, 
RPPA suggested potential reasons for the drug’s lack of efficacy. A reduction in EGFR 
activation and downstream pAKT was demonstrated by RPPA but, despite measurable levels of 
total and activated VEGFR2 at baseline, no modulation of that target was seen across any of the 
paired biopsies. This was corroborated further by lack of significant changes in circulating VEGF 
levels in plasma. 
 
In another study, RPPA was used in preclinical models (cell lines and xenografts) treated with 
the selective AKT inhibitor GDC-0068 to identify evidence of signaling pathway modulation 
with this drug29. Potential biomarkers were then analyzed in patient samples treated with the 
drug. Pharmacodynamic evidence of AKT inhibition was demonstrated in human tumor 
specimens at clinically achievable doses and the degree of biomarker inhibition correlated to 
tumor growth inhibition in preclinical models. Moreover, in both the preclinical and clinical 
samples, compensatory feedback activation of ERK and HER3 was observed using RPPA 
thereby identifying possible candidates for combination therapy to optimize use of the novel 
drug. 
 
RPPA has also been employed in numerous clinical trials in breast cancer. Based on preclinical 
data showing that rapamycin synergistically enhances the cytotoxicity of paclitaxel in triple 
negative breast cancer, a randomized phase II trial was conducted in 50 patients evaluating 


 
 
68 
MGCD516 in Sarcoma Phase II 
neoadjuvant chemotherapy with or without everolimus30. RPPA was used to measure molecular 
changes in the PI3K/Akt/mTOR pathway at baseline and at 48 hours and after surgery. These 
measurements were the primary endpoint of this clinical trial. Phosphorylation of ribosomal pS6 
was significantly decreased in patients treated in the everolimus arm at 48 hours as shown by 
RPPA. A separate phase II breast cancer study randomized HER2 positive stage II or III breast 
cancer patients to trastuzumab, lapatinib or both agents with chemotherapy31. Core needle 
biopsies were obtained for RPPA analysis at baseline and after 2 weeks of anti-HER2 therapy. 
The study demonstrated a correlation between pathologic complete response at surgery and 
several protein biomarkers identified by RPPA. Mean expression levels of pEGFR Tyr1068 at 
baseline predicted response in the lapatinib treated patients. Across all treatment arms, the ratio 
of pTEN to pFOXO, and PI3K to pFOXO, correlated to likelihood of pathologic complete 
response.  
 
Tissue Procurement and Handling 
 
A subset of liposarcoma patients will participate in this correlative study with a target sample 
size of 10 patients. The first 10 liposarcoma patients enrolled on the study (beginning with the 
first patient enrolled in stage I) with tissue suitable for biopsy will participate, regardless of the 
site at which the patient is accrued. If the study fails in stage I and proceeds to the exploratory 
cohort of various tumors, no further RPPA analyses will be performed. However, if the study 
proceeds to stage 2 in liposarcoma, and additional patients are needed to reach a total sample size 
of 10 for this correlative, further liposarcoma patients will participate to accrue a total of 10 
liposarcoma patients with paired tissue biopsies.   
 
Paired (pre-treatment and on-treatment) core biopsy specimens will be obtained. The baseline 
biopsy specimen will be obtained at any point between day -14 and the date of first treatment 
with the study drug (cycle 1, day 1) provided consent is obtained and the other eligibility criteria for 
the study are met. The on-treatment biopsy specimen will be performed with a target timepoint of 
cycle 1 day 15 (with a window of cycle 1 days 15 through 20). 
 
The same tumor lesion should be biopsied at both time points whenever possible. Specimens are 
obtained using a 16-18 gauge core needle under imaging guidance by an interventional 
radiologist at the treating institution.  At least 4 cores are obtained, and up to 6-8 cores if feasible 
(with safety of the procedure prioritized in all cases). The first 4 cores are placed in FFPE and 
the subsequent 2-4 cores are cryopreserved and flash frozen. From the FFPE material, an H&E 
section should be cut for confirmation/diagnostic purposes, to be reviewed at the institution 
collecting the sample as per standard of care. These following specifications apply: 
 
(1) A 16 to 18 gauge needle is satisfactory; 
 
(2) Time from core needle biopsy (CNB) removal to initiation of fixation should be < 30 min; 
 
(3) CNB material should be immersed in sufficient volume of 10% neutral buffered formalin to 
ensure adequate fixation ( >15 to 20 times greater than estimated volume of CNB); 
 
(4) Formalin fixation to last between 6-72 hours at room temperature; and after fixation, proceed 


 
 
69 
MGCD516 in Sarcoma Phase II 
to paraffin embedding. Tissue blocks should be stored at ambient conditions. 
 
(5) Material should be labeled, accessioned and stored consistent with standard of care policies 
and procedures at the participating institution.  
 
Disposition of FFPE tissue: 
 
Following the biopsy, material will be accessioned to the pathology department at the institution 
obtaining the material as per institutional standard of care guidelines. FFPE tissue blocks should 
be stored at ambient conditions. Once all samples have been obtained and only when directed 
by the investigators, sections from the pre-treatment and on-treatment biopsies for all study 
participants will be made as described below, appropriately labeled, and sent to Theralink 
Technologies where RPPA studies will be performed. Specifically, the following steps will be 
taken: 
 
(1) Since tissue sections that are older than 6 weeks should not be used for RPPA analysis, 
prepared tissue sections should be prepared and shipped within 2 weeks to allow for 
transportation and on-site sample preparation before the 6 week expiration date. Thus this 
process should only be initiated when directed by the investigators.  
 
(2) The initial, uppermost tissue section that had been exposed to air should either be discarded, 
or used for a non-RPPA purpose such as H&E staining.  
 
(3) Six (6) sections should be prepared to a five (5) µm thickness and air-dried at room 
temperature. Do not bake. Alternatively, five (5) tissue sections and one (1) H&E-stained tissue 
section can also be supplied. Sections should be mounted onto either Fisherbrand™ Superfrost™ 
Excell™ Microscope Slides (cat# 22-037-247); or uncharged slides with no adhesives/treatment 
(e.g. poly-L-lysine). Each slide should be labeled with the study participant identification 
number and the timing of the biopsy (e.g. baseline/pre-treatment or on-treatment). This 
information will be provided by the clinical research team.  
 
(4) FFPE samples should be shipped with cold packs to Theralink Technologies, Inc. at the 
address shown below. Please provide notification of all incoming shipments to include the name 
of the courier, tracking number for the shipment, and expected date of delivery to Brian Corgiat 
via e-mail to: brian.corgiat@theralink.com.  
 
Theralink Technologies, Inc. 
15000 West 6th Avenue 
Suite 400 
Golden, Colorado, 80016 
ATTENTION: Brian Corgiat 
Telephone number: 720.800.2160 
 
 
 
 
 
 
 


 
 
70 
MGCD516 in Sarcoma Phase II 
Unused FFPE material will be returned to the sending institution. 
 
Disposition of flash frozen tissue: 
 
Cryogenic vials for flash frozen tissue should be labeled with the study number, study-assigned 
patient identification number, patient date of birth, and date and time at which the specimen was 
acquired. This tissue should be immediately placed into the labeled cryogenic vials. Tumor cores 
should be frozen individually in separate cryovials, as collected, in order to minimize the time 
between removal and freezing. Vials with tissue should be placed in liquid nitrogen for 2 minutes 
or longer until frozen solid. If obtained at CUMC, flash frozen tissue should be placed on dry ice 
and brought by a member of the clinical research team directly to the laboratory of Dr. Gary 
Schwartz where the material will be stored at -80°C until ready for further analyses. If obtained 
at a study site other than CUMC, the material should be stored at -80°C and, at the earliest 
convenience, packed on dry ice and sent by overnight shipping to the laboratory of Dr. Gary 
Schwartz by Federal Express or UPS with anticipated delivery on a Monday through Friday from 
9 am to 4 pm, excluding holidays (procedures should be scheduled if necessary to accommodate 
shipping on this timeline). Samples can be sent to: 
 
Dr. Parag Patwardahn 
 
Attention: MGCD516 Study 
 
Herbert Irving Comprehensive Cancer Center  
 
Columbia University Medical Center 
 
1130 Saint Nicholas Avenue, ICRC 207  
 
New York, NY 10032 
 
Regardless of the site at which the biopsy is obtained, an e-mail should be sent to 
ppp2115@cumc.columbia.edu at least 24 hours in advance to alert the laboratory to expect the 
arrival of a sample. All labeled flash frozen samples will be stored at -80°C in the laboratory of 
Dr. Gary Schwartz until such time as relevant correlative studies are performed.  
 
 
Analytic Procedures 
 
RPPA Tissue Study Procedures: 
 
The following procedures and analysis will be performed by Theralink Technologies, Inc.. 
Sections are analyzed for adequacy by a pathologist and specimens with predominant necrosis or 
lymphocytic infiltration are not used. Tumor cells and/or stromal cells are microdissected using 
an Arcturus PixCell IIe (Invitrogen, Life Technologies, Grand Island, NY). Microdissected cells 
are stored at –80C prior to reverse phase protein microarray printing. Microdissected cells are 
subject to lysis with a 10% (v/v) solution of Tris(2-carboxyethyl) phosphine (Pierce, Rockford, 
IL) or a 2.5% solution of 2- mercaptioethanol (Sigma) in Tissue Protein Extraction Reagent (T-
PER™, Pierce)/Tris-glycine 2X SDS buffer (Invitrogen). Cell lysates are stored at –80C prior to 
microarray construction. 
 
Cellular lysates are printed on glass backed nitrocellulose array slides (FAST Slides, Whatman, 


 
 
71 
MGCD516 in Sarcoma Phase II 
Florham Park, NJ) using an Aushon 2470 arrayer (Aushon BioSystems, Burlington, MA) 
equipped with 350-μm pins. Each array consists of microdissected tumor samples. The 
before/after pair for each patient are printed on the same array for most specimens. Samples are 
printed in duplicate in 4-point or 2-point dilution curves. Immunostaining is performed on a 
Dako Autostainer per manufacturer’s instructions (CSA kit, Dako, Carpinteria, CA). Each slide 
is incubated with a single primary antibody at room temperature for 30 minutes. Reverse phase 
protein microarray analysis of phosphorylated/total protein endpoints is then conducted for the 
RTK targets described in section 13.1.1. Antibodies were validated by Western blotting. The 
negative control slide is incubated with antibody diluent as a substitute for the primary antibody. 
Secondary antibody is goat anti-rabbit IgG H+L (1:7,500) (Vector Labs, Burlingame, CA) or 
rabbit antimouse IgG (1:10) (Dako). Subsequent signal detection is amplified via horseradish 
peroxidase mediated biotinyl tyramide deposition with chromogenic detection per 
manufacturer’s instructions (Dako). Array slides are scanned at 600dpi on a flatbed scanner 
(UMAX PowerLook) and saved in a tiff format (Adobe Photoshop). Spot intensity is analyzed 
using ImageQuant ver 5.2 (GE Healthcare). Total protein per microarray spot is determined with 
a Sypro Ruby protein stain (Invitrogen/Molecular Probes) per manufacturer’s directions and 
imaged with a CCD camera (NovaRay, Alpha Innotech, San Leandro, CA). 
 
Data compilation is performed with proprietary software for background correction and 
normalization. The mean local area background of each spot is used to assess spot intensity 
values greater than 2 S.D. above background. Replicate values are averaged. If the CV between 
replicates is >20%, the spot is flagged and a value of “CV too high” reported. Signal intensity 
from the secondary antibody alone (negative control) slide is subtracted from the signal intensity 
of the primary antibody slide. Each patient analyte sample is normalized to the corresponding 
Beta actin value. Total protein is analyzed as a quality control marker for each microarray spot. 
Total protein per spot is quantified as a means to assess overall sample and printing quality. Low 
total protein levels indicate inadequate sample quality or quantity. The results of the analysis will 
be reported to the study coordinators at CUMC along with the patient’s identification number 
and date of birth and subsequently will be added to the case report form and appropriate files. 
Unused tissue will be returned by Theralink Technologies, Inc. to the institution which 
performed the procedure to obtain them.  
 
Western Blot Procedures: 
 
These studies will be performed in the laboratory of Dr. Gary Schwartz at CUMC. We will 
attempt to confirm RPPA findings by assessing changes in total and phosphorylated MET, IGF1-
R and PDGFRb (RTKs identified as important for LPS proliferation in preclinical studies) by 
Western blot in the pre-treatment and post-treatment tumor biopsy specimens. Assessment of 
these targets in pre-treatment biopsies will also serve to evaluate whether phosphorylated 
expression of these targets demonstrated in cell lines is recapitulated in human tissue. We will 
also use Western blot to validate changes in other RTKs in which significant changes were 
identified by the RPPA analysis if available tissue permits. Briefly, protein extractions are 
prepared using a radio immunoprecipitation assay lysis buffer. Protein concentrations are 
measured using the BioRad protein assay and equal amounts loaded onto gradient gels. 
Membranes are probed with primary antibodies and bound antibodies are then detected with 
horseradish peroxidase and visualized by enhanced chemiluminescence reagents. Validated 


 
 
72 
MGCD516 in Sarcoma Phase II 
antibodies for MET, IGF1-R and PDGFRb are obtained from Cell Signaling Technology. 
Unused tissue will be returned by CUMC to the institution which performed the procedure to 
obtain them. If the tissue was obtained at CUMC, the tissue will be sent for archival in the 
Department of Pathology using the patient’s name and medical record number.   
 
13.2 
Genomic studies 
 
Introduction 
 
Genetic abnormalities are fundamental to cancer initiation and progression. Protein signaling 
networks, including RTKs, are dysregulated by multiple mechanisms, including changes at the 
genomic level, where receptor tyrosine kinase proteins and other components of downstream 
signaling networks are encoded. Point mutations (single nucleotide variations, insertions and 
deletions), gene amplification and chromosomal rearrangements all act to dysregulate the 
function of receptor tyrosine kinases.32 The emerging concept of personalized medicine relies 
upon the use of targeted therapies directed against alterations in specific genetic targets 
demonstrated in a patient’s tumor. This approach has already successfully entered the clinic, as 
exemplified by vemurafenib for BRAF mutant melanoma, cetuximab and panitumamb for RAS 
wild-type colorectal cancer, and crizotinib for ALK-translocated lung cancer, among others.  
 
Sanger sequencing, the initial method of DNA sequencing, was initially developed in the 1970s, 
and was used in modified form for the Human Genome Project. Next generation sequencing 
techniques improved upon the low throughput of Sanger methods.33 The scientific principles of 
both methodologies have been reviewed elsewhere.34 Next generation sequencing is currently 
employed in the NCI’s MATCH trial, in which tumor biopsies from 3000 patients will undergo 
next generation sequencing to identify genetic abnormalities relevant to currently available 
targeted agents. Patients will then enter a specific phase II trial with assignment based on genetic 
abnormality and not cancer subtype. 
 
There are several different types of next generation sequencing, including whole genome 
sequencing, whole exome sequencing and targeted sequencing, as well as the use of next 
generation sequencing techniques to sequence RNA via cDNA and to study epigenetic changes 
within DNA. Most recently, so-called ‘third generation sequencing’ platforms, which remove the 
need for PCR amplification of genetic material, have been developed.  
 
As discussed, genetic alterations in the RTK targets of MGCD516 have been well described in 
various cancers, including sarcoma. The use of this agent in patients with defined genetic 
alterations of these targets is central to the development of this agent as a targeted therapy in the 
era of personalized medicine. In the ongoing phase 1b study of MGCD516, enrollment criteria 
require patients to demonstrate genetic alterations in an MGCD516 target. In the present study, 
all patients are eligible for enrollment, however, we will use next generation sequencing to 
define relevant genetic alterations in baseline tumor specimens. We will then assess whether the 
presence of such an alteration predicts clinical efficacy.  
 
Sample Procurement and Handling 
 


 
 
73 
MGCD516 in Sarcoma Phase II 
This correlative study will be limited to liposarcoma patients and all such patients (including 
stage II if open to liposarcoma) will undergo the testing described herein. A custom targeted 
next-generation sequencing platform made available by ResearchDx Inc. will be employed in 
this clinical trial.  
 
The clinical research team at the institution enrolling the patient onto this clinical trial will 
identify the date of the patient’s most recent tumor biopsy and the institution at which that biopsy 
took place. If a patient underwent a new tumor biopsy for the purposes of this study (as described 
above for the proteomics section), FFPE tissue obtained from that procedure should be used for 
the genomic studies whenever possible, although RPPA studies will be prioritized. At the 
direction of the investigators, a request will be made by the clinical research team to the 
pathology department holding the relevant materials for a tumor block measuring at least 5mm3 
(5 x 1 x 1 mm) or 20 unstained slides (each at least 20 mm2 and 5 μm thickness; serial sections if 
possible). Samples should contain >20% tumor cellularity and 80% nucleated content. In 
addition, one H&E stained slide should also be obtained whenever possible. Slides will be 
labeled with the study number, study-assigned patient identification number, patient date of birth 
and date on which the specimen was initially acquired. Samples will then be packaged into the 
ResearchDx specific mailing kit which will be provided to all participating institutions and 
which contains further instructions for packing and labeling the samples. The kit will be mailed 
overnight by UPS or Federal Express at ambient temperature to: 
 
ResearchDx 
Attention: MGCD516 Study 
5 Mason Street 
Irvine, CA 92618 
 
Analytic Procedures 
 
The following procedures will be performed by ResearchDx. Genomic DNA is extracted from 
FFPE tissue, subjected to library preparation, followed by target enrichment via hybridization 
capture. Sequencing of uniquely indexed target enrichment libraries is performed using an 
Illumina MiSeq instrument, and bioinformatics analysis is performed using an assay specific 
pipeline. This assay was specifically developed and optimized to enrich specific portions of 
MET, AXL, EGFR, KRAS, ALK, BRAF, ROS, RET, NTRK1/2/3, DDR2, CBL, KIT, PDGFRa 
and KDR genes using Agilent biotinylated RNA oligomer libraries. The genes and alterations 
assayed are listed in the table below. Only variants with an allele frequency of greater than 5% 
are reported. The assay has a requirement for minimal 200x coverage to call variant at allele 
frequency less than 10%. For regions covered at a read depth of 100x-200x, variants must be 
present at greater than 10% allele frequency; although higher allele frequency variants in regions 
of reduced coverage (50-100x) may be reported as the discretion of the laboratory director. This 
assay only reports specific variants, and genomic alterations other than the below mentioned 
variants may be present. Unused material will be returned to the institution which initially 
obtained the tissue. Results will be reported to the clinical research coordinator using only the 
study assigned patient identification number as an identifier. 
 
 


 
 
74 
MGCD516 in Sarcoma Phase II 
 
14. 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements).  The Data Safety Monitoring Plan is 
described in Section 12.2. 
 
14.1 
Data Collection 
 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system (CTMS) that will be used for data collection. CRFs for the study will be 
built into the CTMS for data entry. The system has full auditing capabilities which is web-based 


75 
MGCD516 in Sarcoma Phase II 
and housed on a server in a fully HIPAA compliant server room with restricted access and video 
camera monitoring.  All users must login with their own application username and password.  
Users off campus must first access the Virtual Private Network with their assigned campus 
username and password and then use their application credentials.  Users are only able to see 
study information if they are indicated as study personnel in our electronic IRB system. Users are 
limited to access based on the role assigned in their corresponding protocol.  Subject data is 
entered directly into the system, which (in the case of Columbia subjects) confirms the correct 
identity of patients via an interface with the electronic medical patient index.  Staff with the 
appropriate IRB defined roles can run reports within the system for reporting purposes. 
14.2 
Data Reporting 
Case Report Forms will be completed for each subject enrolled into the clinical study through the 
CTMS. It is the investigator’s responsibility for ensuring that all clinical and laboratory data 
entered on the corresponding CRFs are complete, accurate and authentic. 
14.3 
Data and Safety Monitoring Committee 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on 
this protocol for toxicity. This protocol will adhere to the policies of the currently approved 
HICCC Data and Safety Monitoring Plan (DSMP), which is in accordance with NCI and 
CUMC-IRB policy and guidelines.  The committee is chair is appointed by the HICCC Director. 
The committee consists of HICCC faculty and staff with expertise in oncology, research 
pharmacy, research nursing, and data management. The DSMC convenes twice a month to 
review patient safety and the conduct of the trial. The PI will submit data and safety monitoring 
reports to the DSMC at a frequency to be determined by the DSMC based on risk to the subjects. 
At the time of renewal, the study team will submit the most recent DSMC approval letter for 
safety review to the CUMC IRB. Any modifications that are required by the DSMC to ensure 
patient safety will be submitted to the IRB. All protocol deviations, violations, and eligibility 
waivers will be submitted to and approved by the DSMC prior to being reported to the IRB. All 
study data reviewed and discussed during these meetings will be kept confidential.  
For multicenter research, the principal investigator will assure that there is a mechanism in place 
to distribute the report to all participating investigators for submission to their local IRB.  The 
report will document that a review of data and outcomes across all centers took place on a given 
date.  It will summarize the DSMC’s review of the cumulative toxicities reported from all 
participating sites without specific disclosure by treatment arm.  It will also inform site 
investigators of the study the DSMC’s conclusion with respect to progress or need for 
modification of the protocol.   
14.4 
Quality Control and Quality Assurance 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 


 
 
76 
MGCD516 in Sarcoma Phase II 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC.  Additionally, the 
Compliance Oversight Committee of the IRB at Columbia University Medical Center may audit 
the study at any time per institutional policies and procedures. The investigator-sponsor and 
Columbia University Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, number 
of subject charts, and data elements to be monitored. The Compliance Coordinator will review the 
study status and summarize enrollment, toxicities, SAEs/UPs, dose escalation, statistical endpoints 
(e.g., stopping rules), etc. for the full DSMC membership at the regularly scheduled meetings.   
 
Internal On-site Monitoring: 
 
• Initial, recurrent, and close-out on-site monitoring visits will also be conducted at 
remote clinical sites, as appropriate/feasible. Other sites will have monitoring 
performed remotely (see below for further details). 
• The study Monitoring Visit Log will be completed and signed by the monitor and 
the PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
• The Compliance Coordinator will communicate with the site coordinator/Site 
Principle Investigator to schedule the monitoring visit and arrange for access to 
study materials and documentation. 
• The assigned Compliance Coordinator will monitor IIT trials within 1 month after 
the first subject is enrolled and throughout the life of the study to ensure that the 
study is being conducted in accordance with the protocol, GCP, applicable federal 
and local regulations, and per all applicable SOPs. The Compliance Coordinator is 
responsible to notify the PI and CRNP/CRN/CRC of upcoming monitor visits and 
convey what information and documentation will be required for the visit(s).  The 
Compliance Coordinator is responsible for verifying that informed consent is 
properly obtained, eligibility is met (via the central registration process), and all 
study procedures are conducted according to the study protocol. The Compliance 
Coordinator will also verify that the data reported in the CRF’s accurately reflect 
source documents, that all toxicities have been reported to date, and that all 
SAE’s/UPs/deviations/violations have been reported according to local IRB and 
HICCC DSMC requirements. The Compliance Coordinator will issue queries and 
ensure resolution in a timely and efficient manner.  The Compliance Coordinator 
will also monitor for applicable regulatory compliance and research pharmacy 
compliance (if applicable) and communicate any deficiencies as appropriate. 
 
14.5 
Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA).  Those 


 
 
77 
MGCD516 in Sarcoma Phase II 
regulations require a signed subject authorization informing the subject of the following:  
 
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (e.g., that the subject is alive) 
at the end of their scheduled study period. 
The subject binders will be maintained with in the CPDM offices, a secured floor within the 
Herbert Irving Pavilion and only the investigator and study staff will have access to the file. 
14.6 
Source Documents 
 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents   Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
 
14.7 
Case Report Forms 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, write “N/D”.  
If the item is not applicable to the individual case, write “N/A”. 
  
14.8 
Records Retention 
 
Records relating to a specific research activity, including research records collected by 
investigators, must be maintained for at least three years after completion of the research (45 
CFR 46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum retention period applies 
whether or not any subjects were enrolled in the study. If the research is FDA regulated, records 
should be retained for at least two years after approval of the investigational agent by FDA; if it 
is not approved, records should be retained at least two years after the study is terminated and 
FDA is notified (note the additional requirement below for clinical research studies);  Clinical 
records, including consent forms that document clinical intervention or clinical diagnostic 
procedure research-related procedures, must be retained in medical records by the institution for 


78 
MGCD516 in Sarcoma Phase II 
at least seven years, per CUMC and NYP policy which is based on state law. 
15. 
STATISTICAL CONSIDERATIONS 
15.1 
Study Design/Endpoints 
This is a phase II, single arm, open label, Simon optimal 2 stage study. The primary endpoint is 
the progression free rate (PFR), at 12 weeks. This corresponds to the number of patients who are 
alive and without evidence of disease progression at 12 weeks out of all evaluable patients.  
Evidence of disease progression is defined according to RECIST criteria as established in section 
12.  
This endpoint has been employed in numerous phase II clinical trials in sarcoma. The European 
Organization for Research and Treatment of Cancer (EORTC) - Soft Tissue and Bone Sarcoma 
Group conducted a comprehensive retrospective analysis of clinical trial data to determine 
outcomes in patients with advanced sarcoma to establish PFR as an endpoint in phase II 
studies35. This study established historical controls for active and inactive agents in the second 
line setting. On the basis of this EORTC study, PFR greater than 40% at 12 weeks was 
associated with an active agent and was considered promising for second line therapy, whereas 
PFR less than 20% at 12 weeks was associated with an inactive agent and was considered not 
promising.  
These benchmarks have been used in numerous ongoing and completed phase II studies for 
targeted agents in sarcoma, including the phase II study of pazopanib, the only targeted therapy 
approved for a broad range of sarcoma subtypes. In that phase II study, 140 patients with 
advanced intermediate or high grade sarcoma were enrolled into four strata (leiomyosarcoma, 
adipocytic sarcoma, synovial sarcoma and other sarcomas) and a Simon two-stage design was 
used36. A favorable PFR was found in each subtype except for adipogenic sarcomas. In the 
adipogenic arm, PFR at 12 weeks was 26% and enrollment was closed in the first stage. 
However, PFR in the leiomyosarcoma, synovial and other cohorts was 44%, 49% and 39%, 
respectively. On the basis of this phase II study, a randomized double-blind phase III study was 
conducted with this agent in patients with non-adipogenic sarcomas previously treated with 
chemotherapy as compared placebo37. An improvement in progression free survival was 
demonstrated, and the drug subsequently received regulatory approval.  Numerous other phase II 
studies using these endpoints have been conducted, including a phase II study of the CDK4 
inhibitor palbociclib38.This study will use PFR at 12 weeks as the primary endpoint. 
We will use a Simon optimal 2-stage design. The study will enroll 13 liposarcoma patients in the 
first stage. If 3 or more patients meet the PFR endpoint in the first stage, the study will enroll an 
additional 16 patients to achieve a total of 29 liposarcoma patients. If a total of 9 or more such 
patients demonstrate the PFR endpoint, the agent will be considered promising in liposarcoma. 
This design provides for a type 1 error of 0.10 and type 2 error of 0.14. The study design has a 
power of 85% to detect a difference between PFS of 20% versus 40% at 12 weeks.  
If the study does not meet its endpoint in liposarcoma patients during stage I of the Simon 2-


79 
MGCD516 in Sarcoma Phase II 
stage design, an additional 16 patients will be enrolled composed of 4 each of MPNST, synovial 
sarcoma, alveolar rhabdomyosarcoma and alveolar soft part sarcoma, to evaluate for potential 
signs of efficacy in those subtypes as part of an exploratory cohort which may inform the design 
of future studies.  
15.2 
Size/Accrual Rate 
The sample size is 29 patients. We may enroll up to an additional 2 patients to account for 
patients declared non-evaluable and patients failing to initiate the first cycle of treatment. The 
planned accrual rate across both sites is 2-3 patients per month. Therefore, accrual is expected to 
be complete in approximately 10 to 15 months. Assuming patients are permitted to continue 
treatment for up to 1 year (12 months) and allowing 6 months for quality assurance, the 
anticipated duration of the study is approximately 28 to 33 months.   
15.3 
Stratification Factors 
There are no prespecified stratification factors for the primary endpoint. 
15.4 
 Analysis of Secondary Endpoints 
Adverse event rates: Adverse events will be recorded at each clinical visit and will be 
categorized according to NCI CTCAE version 4.0. Adverse event rates will be reported as counts 
and percentages per adverse event basis by grade.  
Overall survival and progression free survival: Overall survival is defined as the time from the 
date of first treatment with study drug to the time of death from any cause or last follow-up if 
alive. Progression free survival is defined as the time from first treatment with the study drug to 
the earliest of either disease progression or death from any cause. Patients who are alive and 
progression free will be censored at the time of their last follow-up.  The Kaplan-Meir method 
will be used to evaluate all time to event endpoints39. Median overall survival and median 
progression free survival will be reported with 95% confidence intervals.  
Response rate: Patient responses will be evaluated according to RECIST version 1.1 as described 
in section 12. The response rate is defined as the number of patients having a best objective 
tumor status of complete response or partial response lasting at least four weeks divided by the 
number of evaluable patients.  The response rate will be reported with 95% confidence intervals.  
15.5 
Analysis of Correlative Science Endpoints 
The relevant background, objectives and methodologies for the correlative studies are described 
in section 13, and statistical considerations relevant to these endpoints are considered here. 
15.5.1 Proteomic studies 
We will compare changes in the levels of specific total and phosphorylated proteins from 


80 
MGCD516 in Sarcoma Phase II 
baseline tumor samples to samples obtained during cycle 1 week 2 of treatment with the study 
agent in a subset of 10 liposarcoma patients. This endpoint is analyzed with exploratory intent 
given the limited sample size, as we expect to obtain tumor tissue from only approximately 10 
patients enrolled in the study. Spot intensity data from the RPPA platform are normalized prior 
to reporting. The RPPA technology is described in detail in section 13. If the data are normally 
distributed, a paired t-test will be employed to evaluate whether differences between the baseline 
and on-treatment spot intensity differ from zero for each protein studied.  If the data are not 
normally distributed, the Wilcoxon-signed rank test will be used.   
15.5.2 Genomic studies 
We will conduct next generation sequencing in all baseline tumor tissue from all liposarcoma 
patients (when sufficient material exists) to assess for a set of predefined genetic alterations in 
known targets of MGCD516. The genetic status of the tumor will then be considered on a binary 
basis; that is, a patient tumor specimen either has or does not have one of the predefined genetic 
alterations. We will then assess for a relationship between the presence of a genetic alteration 
with clinical outcomes. For tumor response, the two groups will be compared using Fisher’s 
exact test given the small sample sizes. Progression free and overall survival will be compared 
between the two groups by a log-rank test.   
15.6 
Reporting and Exclusions 
15.6.1 Evaluation of toxicity  
The safety population will consist of all patients who received at least one dose of study drug. 
15.6.2  Evaluation of response  
All patients included in the study who receive at least one treatment with the study drug will be 
assessed for response to treatment, even if there are major protocol deviations or if they are 
ultimately deemed ineligible.  Each patient will be assigned one of the following categories:  1) 
complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death 
from malignant disease, 6) early death from toxicity, 7) early death from other cause, or 9) 
unknown (not assessable or insufficient data).   
All of the patients who met the eligibility criteria, with the exception of those who received no 
study medication, will be included in the main analysis of the response rate.  Patients in response 
categories 4-9 are considered to have a treatment failure. An incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.   
15.6.3 Reporting of endpoints if study proceeds to exploratory cohort 
If the study fails to meet the stage I endpoint in liposarcoma and proceeds to enroll the 
exploratory cohort, the primary endpoint (progression free rate at 12 weeks) and secondary 
efficacy endpoints (overall survival, progression free survival, response rate) will be reported 
separately for the liposarcoma population and the exploratory cohort population. The individual 


81 
MGCD516 in Sarcoma Phase II 
best response of the patients in the exploratory cohort will be reported individually. The adverse 
event data will be reported in aggregate for the entire study population. 
16. 
PROTECTION OF HUMAN SUBJECTS 
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study conduct.  The decision of the IRB concerning the conduct of the study will be made in 
writing to the investigator and a copy of this decision will be obtained before commencement of 
this study.  
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure.  This consent form must be 
signed by the subject or legally acceptable surrogate, as outlined in the IRB approved protocol, 
and the investigator-designated research professional obtaining the consent.  
17. STUDY FINANCES
17.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the Columbia University Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved prior to participation 
in this study.  All CUMC investigators will follow the University conflict of interest policy. 
17.2 
Subject Stipends or Payments 
No stipends or payments will be given to subjects. 
18. PUBLICATION PLAN
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 


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MGCD516 in Sarcoma Phase II 
19. GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER STUDIES
19.1 
Multi-site Communication 
The CPDM Office at CUMC provides administration, data management, and organizational 
support for the affiliate sites in the conduct of a multicenter clinical trial.  The CPDM Office will 
coordinate regularly scheduled conference calls with affiliate sites.  
The following issues will be discussed, as appropriate: 
•
Enrollment information
•
Cohort updates (e.g., DLTs)
•
Adverse events (e.g., new adverse events and updates on unresolved adverse events and new
safety information)
•
Protocol violations
•
Other issues affecting the conduct of the study
19.2 
New Protocol Distribution, IRB Submission, Modifications, Renewals 
•
Protocol specific documents are distributed to affiliate sites once CUMC IRB approval has
been obtained.
•
The affiliate site must submit a draft of site specific revisions to protocol and/or consent form
documents for review and approval by the sponsor-investigator prior to submission to the
local IRB. Draft documents should be sent to the study specific email address. The site will
be provided confirmation that they are approved to submit to their local IRB.
•
Protocol amendments must be approved by the affiliate site’s local IRB within 90 days of
distribution to the site by the sponsor-investigator.
19.3 
Regulatory Documents 
Prior to Site Initiation, the Sponsor-Investigator will ensure that proper requests are made of sites 
and that the following documentation is collected, prior to the initiation of an affiliate site.   
•
CV of PI, Co-I’s and other research staff listed on FDA 1572 (signed and dated copy
within 2 years)
•
Medical Licenses of PI and Co-I’s (current copy)
•
Human subjects training certificates for PI and Co-I’s
•
CLIA/Laboratory  Certifications for Local Laboratories listed on FDA 1572
•
Local Laboratory Director’s CV and License
•
Local Laboratory Reference Ranges
•
IRB roster or statement of compliance
•
FDA Form 1572, if applicable (wet ink originals required)
•
Financial Disclosure forms for all members listed on FDA 1572 (wet ink originals
required)


83 
MGCD516 in Sarcoma Phase II 
Ongoing Regulatory Documentation:  Sponsor-Investigator will ensure that proper requests are 
made of sites and that the following documentation is collected throughout the course of the study. 
•
IRB approval letters for all protocol modifications and all renewals
•
IRB-approved consent forms
•
Current IRB roster, if statement of compliance is not provided as part of site initiation
•
FDA Form 1572, if applicable as updates are required
•
Updated investigator and site information where relevant (e.g., CV, medical licensure
and Financial Disclosure for new sub-investigator, local laboratory information)
Regulatory documents may be sent to  AAAQ8661@columbia.edu or to the following address if 
wet ink originals are required: 
Clinical Protocol & Data Management Office 
161 Fort Washington Ave. 
Herbert Irving Pavilion 
Mezzanine Level, M-203 
New York, NY 10032 
19.4 
Site activation 
Columbia University will schedule a site initiation visit once IRB approval has been submitted 
from the affiliate site.  
19.5 
Central Registration Procedures -  Participant Registration Process 
All Affiliate Institutions must register subjects with the coordinating center (CUMC) prior to any 
administration of study drug/intervention/local institution registration.  Please see instructions 
below: 
1.
Within 48 hours of obtaining consent (excluding holidays and weekends), the Affiliate
Institution CRN and/or CRC is required to submit the following documents to the
coordinating 
center’s 
Multicenter 
Trials 
Core 
and 
the 
study 
email
AAAQ8661@columbia.edu.  The Multicenter Trials Core will review the documents for
accurateness, and subsequently submit the documents to the CPDM Central Registration
Office via email, with a request to register the patient “pending eligibility.” The title of the
email should read, “AAAQ8661Pending Subject Registration Request (PHI)”.  The
following documents should be submitted with the pending registration request, as
applicable:
a.
Redacted Completed/signed IRB approved/stamped Informed Consent Forms,
including additional study ICFs (e.g., tissue, DNA, etc.), as applicable
b. Redacted Signed HIPAA (or institutional equivalent)
c.
MCT CPDM Velos Note to File form
2.
The Affiliate Institution’s investigator/research nurse/data manager/coordinator must
contact the coordinating center’s designee (CUMC’s Multicenter Trials Core) via
telephone or email to communicate the following:


84 
MGCD516 in Sarcoma Phase II 
a.
Notify of pending registration request
b. Confirm method of registration request submission (email or fax)
c.
Communicate expected time-line of registration request submission (e.g., same
day, next day, within the hour, etc.)
3.
To complete registration, the Affiliate Institution’s investigator/research nurse/data
manager/coordinator should then submit the following documents to the CUMC
Multicenter Trials Core via email at AAAQ8661@columbia.edu:
a.
A signed Affiliate Site Eligibility Checklist (signed by the investigator)
b. Copies of redacted source documentation necessary for each item to be verified on
the CUMC specific Eligibility Checklist, including but not limited to:
i. Copy of required laboratory test and procedure reports (e.g., hematology,
serum chemistry, pregnancy test when applicable, MRI reports, CT/bone
scans, etc.)
ii. Copy of pathology and surgical reports
iii. Copy of clinic note(s) capturing the consent process information, along with
providing source documentation of any other items needed for
screening/eligibility that are not captured in other source document forms.
(e.g., positive investigator statements of unique eligibility items not
captured via other direct source documentation, concomitant medication
lists, etc.)
c.
Please note: subject line of email or fax should include the following:
“AAAQ8661Complete Subject Registration Request (PHI)”.
4.
Upon receipt of the above mentioned documents, the designated study specific Clinical
Research Coordinator will review all documents and verify patient eligibility.  If any questions
arise during the review process, queries in the form of emails will be addressed to the
applicable affiliate site study team personnel for clarification prior to enrollment.  Upon
verification, the CUMC study specific designee will then forward all documents to the CPDM
Central Registration Office for central registration (as described above). The CPDM Central
Registration Registrar will review all applicable documents and communicate to the CUMC
study specific designee in order to clarify any items.  The CUMC study specific designee will
communicate with the applicable site study team personnel for additional clarifications
necessary prior to enrollment.
5.
Upon receipt of the subject registration notification email, the CUMC study specific designee
will forward the notification email (which will include the study specific patient ID) to the
affiliate site’s Principal Investigator, Consenting Professional, and applicable research
personnel.  This notification should be filed in the patient research binder accordingly.
Protocol therapy may not be initiated prior to receipt of this notification from the coordinating
center.
6.
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to
enrollment/initiation of protocol therapy must be submitted to the Central Registration Office


85 
MGCD516 in Sarcoma Phase II 
in a manner analogous to the procedures noted above. Applicable source documentation will 
be required within the corresponding submissions. 
19.6 
Protocol Deviation/Subject Waiver Request for Affiliate Sites 
The Affiliate site MUST submit a prospective deviation request to the CUMC lead PI for review 
and submission to the HICCC DSMC and CUMC IRB. Approvals must be obtained from all 
entities prior to implementation at the Affiliate site.  If a prospective protocol deviation request is 
submitted for review (from an Affiliate site), the PI/site memo(s), HICCC DSMC approval(s) and 
correspondence and CUMC IRB eligibility deviation approval letter(s)/correspondence should be 
forwarded to the Affiliate site for documentation. The Affiliate site is also required to obtain 
prospective local IRB approval as per institutional policies/procedures prior to implementing the 
proposed deviation. All documents and determinations must be clearly documented in the study 
subject’s medical record, research chart and regulatory binder, as described. Please note that the 
HICCC DSMC will no longer be approving deviations to eligibility criteria. 
19.7 
Guidelines for Affiliate Site Monitoring 
On-Site MCT Monitoring: 
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at Affiliate
sites, as appropriate/feasible. Other sites will have monitoring performed remotely (see
below for further details).
a.
The study Monitoring Visit Log will be completed and signed by the monitor and
the PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder.
2. The Compliance Coordinator will communicate with the Affiliate site coordinator/Site
Principle Investigator to schedule the monitoring visit and arrange for access to study
materials and documentation.
3. The Compliance Coordinator will monitor IIT trials within 1 month after the first subject
is enrolled at the Affiliate site and throughout the life of the study to ensure that the study
is being conducted in accordance with the protocol, GCP, applicable federal and local
regulations, and per all applicable SOPs. The Compliance Coordinator is responsible to
notify the participating site PI and CRNP/CRN/CRC of upcoming monitor visits and
convey what information and documentation will be required for the visit(s).  The
Compliance Coordinator is responsible for verifying that informed consent is properly
obtained, eligibility is met (via the central registration process), and all study procedures
are conducted according to the study protocol. The Compliance Coordinator will also
verify that the data reported in the CRF’s accurately reflect source documents, that all
toxicities have been reported to date, and that all SAE’s/UPs/deviations/violations have
been reported according to Coordinating Center, local IRB and HICCC DSMC
requirements. The Compliance Coordinator will issue queries and ensure resolution in a
timely and efficient manner.  The Compliance Coordinator will also monitor for applicable
regulatory compliance and research pharmacy compliance (if applicable) and communicate
any deficiencies as appropriate.


86 
MGCD516 in Sarcoma Phase II 
4. An SIV (or) teleconference will be scheduled and conducted prior to study drug being made
available (if applicable) and before any subjects are enrolled on a study at the Affiliate site.
Remote MCT Monitoring: 
•
When necessary (due to logistical constraints), Affiliate sites will be monitored remotely
by a designated Compliance Coordinator. Sites will be informed of this remote monitoring
process on a site by site basis.
•
Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory level,
as well as a clinical data/source documentation review level.
•
Redacted source documents (applicable to supporting the protocol specific CRF data
requirements) will be sent to the designated Compliance Coordinator via fax or secure
email for all subjects enrolled at Affiliate sites. Timelines for submission procedures will
be defined on a case by case basis.
•
The Compliance Coordinator will review all submitted redacted source documents against
the data entered on the protocol specific CRFs. The Compliance Coordinator will issue
queries when/if necessary.
•
The Affiliate site research staff will respond to queries within 30 days. If queries remain
outstanding, the Compliance Coordinator will send a delinquent query reminder for the
outstanding items.
•
The remote monitoring procedures will include review of applicable redacted source
documentation and supporting applicable documents to determine compliance regarding:
a.
Informed consent procedures
b. Eligibility criteria
c.
Protocol specific treatment compliance
d. Protocol specific toxicity/outcome documentation/compliance
e.
Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on study,
follow-up)
f.
Participating site IRB documents (e.g., IRB amendment approvals, annual
renewals, SAE/UP submissions, violation/deviation submissions, INDSR
submissions, etc.).
g. Required specimen submissions (e.g., tissue specimens, research blood specimens,
etc.)
h. Pharmacy accountability records
i.
Adherence to the CRF submission timeframes to CUMC (within the protocol
specified timeframes)
•
Affiliate site remote monitoring reports will be sent to the lead PI, HICCC DSMC, and
Affiliate sites after each remote monitoring review. Reports will include information
regarding data submission timeliness/accuracy, protocol adherence items, query resolution
status, regulatory status, and overall Affiliate site performance. These reports will be
generated by the Compliance Coordinator and reviewed with the Compliance Core
Manager prior to dissemination.
19.8 
Dose Level Determinations 
Not applicable. 


87 
MGCD516 in Sarcoma Phase II 
19.9 
Adverse event reporting 
Sponsor reporting: It is the responsibility of the study sponsor to notify all affiliate sites, in a 
written IND safety report, of any adverse event associated with the use of the drug that is both 
serious and unexpected, as well as any finding from tests in laboratory animals that suggest a 
significant risk for human subjects.  Additionally, sponsors are also required to identify in IND 
safety reports all previous reports concerning similar adverse events and to analyze the 
significance of the current event in light of the previous reports. 
Serious Adverse Event Reporting: Each participating investigator is required to abide by the 
reporting requirements set by Columbia University Medical Center. The study must be 
conducted in compliance with FDA regulations, local safety reporting requirements, and 
reporting requirements of the principal investigator. 
Participating investigators must report each serious adverse event to the Columbia University 
Medical Center Overall Principal Investigator within 24 hours of learning of the occurrence using 
the SAE Report Form. In the event that the participating investigator does not become aware of 
the serious adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it and document 
the time of his or her first awareness of the adverse event. Report serious adverse events by 
telephone, email or facsimile to: 
Matthew A. Ingham, MD 
177 Fort Washington Avenue 
Milstein Hospital Building Suite 6GN-435 
New York, NY 10032 
Telephone: 212-305-7115 
Email:  AAAQ8661@columbia.edu 
Within the following 5 business days, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the participant will 
continue or discontinue study participation. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or progression 
of the original event should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the subject continued or withdrew from study participation or if 
study drug was interrupted or discontinued. 
If the SAE is not previously documented in the Investigator’s Brochure for the study drug (new 
occurrence) and is thought to be related to the investigational agent, the sponsor-investigator may 
urgently require further information from the investigator for reporting to Health Authorities. 


88 
MGCD516 in Sarcoma Phase II 
Non-Serious Adverse Event Reporting: Non-serious adverse events will be reported to the 
Columbia University Medical Center Overall Principal Investigator on the toxicity Case Report 
Forms. 
Reporting to the Institutional Review Board (IRB) and the Data and Safety Monitoring 
Committee: All Unanticipated Problems (UPs) will be reported to the CUMC IRB.  SAEs not 
constituting UPs will reported to the HICCC DSMC. Each affiliate site will be responsible for 
safety reporting to their local IRB.  Investigators are responsible for complying with their local 
IRB’s reporting requirements, though must submit the required reports to their IRB no later than 
7 calendar days following the occurrence of the UP or the Principal’s Investigator’s acquiring 
knowledge of the UP.  Copies of each report and documentation of IRB notification and receipt 
must be included in the regulatory binder. Expected or unexpected AEs must be reported at the 
time of continuing review of a protocol. 
Guidelines for Processing IND Safety Reports: The U.S. Food and Drug Administration 
(FDA) regulations require sponsors of clinical studies to notify the FDA and all participating 
investigators of any serious and unexpected adverse experiences that are possibly related to the 
investigational agent. The CUMC Principal Investigator will review all applicable IND Safety 
Reports and has the responsibly for forwarding the IND Safety Reports to the Affiliate 
Institutions. The Affiliate Institution investigators are to review, send a copy to their IRB 
according to their local IRB’s policies and procedures, and file a copy with their regulatory 
documents. All Affiliate site INDSR submissions, along with IRB acknowledgment (per local 
policies and procedures) are to be forwarded to CUMC for placement within the trial master file. 
Reporting to Hospital Risk Management: Affiliate Site investigators will report to their local 
Risk Management Office any subject safety reports or sentinel events that require reporting 
according to institutional policy. 
19.10 Confidentiality 
Each affiliate site will be assigned a site number. Each subject that signs consent should be 
assigned a unique code number consisting of site number followed by a number with each new 
subject being assigned the next sequential number (e.g., 04-10). All sites will be required to enter 
their data in the Velos eResearch, the Clinical Trial Management System used for all Cancer-
related clinical research at CUMC. All users must login with their own application username and 
password.  Users off campus must first access the Virtual Private Network with their assigned 
campus username and password and then use their application credentials.   
Subject confidentiality must be maintained according to HIPAA regulations and GCP 
recommendations.  
Except when required by law, study information shared with persons and organizations outside of 
Columbia University Medical Center must not identify the patient by name, social security 
number, address, telephone number, or any other direct personal identifier. 
If the results of this research project are published or presented at a scientific or medical meeting, 


89 
MGCD516 in Sarcoma Phase II 
the patient not be identified. Otherwise, all results will be kept confidential and will not be divulged 
(except as required by law) without permission.  
19.11 Data Reporting Plan 
Columbia University Medical Center (CUMC) is deeply committed to research integrity and 
strong credibility when it comes to the discovery of new treatment concepts, implementation of 
new clinical research techniques, and acceptance of its researcher's findings by the medical 
establishment. In accord with these ethics, CUMC encourages and supports its investigators in the 
sharing of final research data and/or details of newly developed clinical treatments. 
CUMC's policies that pertain to patient data sharing conform to CUMC IRB rules, local and state 
laws, and HIPAA privacy regulations. The primary reason for this is to protect the privacy of 
patients who participate in clinical trials. The data can be made available for continuing review by 
federal agencies upon request and for ongoing study safety reviews by the Principal Investigator, 
Statistician, Data Safety and Monitoring Board (DSMC), and, in other instances, the CUMC IRB. 
Data collected during the course of this clinical trial will primarily be shared with other 
investigators and University staff, the IRB, FDA, and other reporting agencies, and/or transferred 
to other collaborators.  Prior to transfer, the data collected must comply with, and must be limited 
by, the CUMC's guidelines for Protecting the Rights and Privacy of Human Subjects.   
19.12 Data Acquisition and Submission 
Informed consent, including HIPPA authorization, must be obtained on all subjects prior to their 
participation. Always keep the original signed and dated consent form, with the redacted source 
documents and eligibility checklist. Velos eResearch will be used as the electronic clinical trials 
and data management system. Affiliate sites will enter data directly into Velos eResearch via 
customized case report forms for the study. The research staff will generate reports from Velos 
eResearch to ensure timely submission of data by affiliate sites. This resource allows for the timely 
analysis of particular data sets for safety analysis. 
19.13 Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends.   
The Principal Investigator is required to prepare and maintain adequate and accurate case histories 
that record all observations and other data pertinent to the investigation on each individual 
administered the investigational drug or employed as a control in the investigation. Case histories 
include the case report forms and supporting data including, for example, signed and dated consent 
forms and medical records including, for example, progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. The case history for each individual shall document that 
informed consent was obtained prior to participation in the study. 


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MGCD516 in Sarcoma Phase II 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 


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MGCD516 in Sarcoma Phase II 
20. APPENDICES
20.1 
Appendix 1: Supplementary List of Potential Drug Interactions 
The following information was obtained by from the US Food and Drug Administration Drug 
Development and Drug Interactions website40.  
20.1.1 Sensitive substrates or narrow therapeutic index for CYP 2C8, 2D6 and 3A4 
These agents should be used with caution. 
Relevant CYP 
Sensitive substrates 
Substrates with narrow therapeutic range 
CYP2B6 
Bupropion, efavirenz 
None known. 
CYP2C8 
Repaglinide 
Paclitaxel 
CYP3A 
Alfentanil, aprepitant, budesonide, 
buspirone, conivaptan, 
darifenacin, darunavir, dasatinib, 
dronedarone, eletriptan, 
eplerenone, everolimus, 
felodipine, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, 
maraviroc, midazolam, 
nisoldipine, quetiapine, 
saquinavir, sildenafil, simvastatin, 
sirolimus, tolvaptan, tipranavir, 
triazolam, vardenafil 
Alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus,  
terfenadine 
CYP2D6 
Atomoxetine, desipramine,  
dextromethorphan, metoprolol, 
nebivolol, perphenazine, 
tolterodine, 
venlafaxine 
Thioridazine 
20.1.2 Strong inducers or inhibitors for CYP 2B6, 2D6 and 3A4 
These agents should be used with caution. 
Relevant CYP 
Strong Inducers 
≥ 80% decrease in AUC 
Strong Inhibitors 
≥ 5-fold increase in AUC  
or > 80% decrease in CL 
CYP2B6 
None known. 
None known. 
CYP3A 
Avasimibecarbamazepine, 
phenytoin, rifampin, St. John’s 
wort 
Boceprevir, clarithromycin, conivaptan, 
grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir,telithromycin, 
voriconazole 
CYP2D6 
None known 
Bupropion, fluoxetine, paroxetine, quinidine 


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MGCD516 in Sarcoma Phase II 
20.1.3 Substrates of BCRP 
These agents should not be used by study participants. 
Imatinib 
Mitoxantrone 
Irinotecan 
Rosuvastatin 
Lapatinib 
Sulfusalazine 
Methotrexate 
Topotecan 
20.1.4 Substrates of P-glycoprotein 
These agents should not be used by study participants. 
Aliskiren 
Nilotinib 
Ambrisentan 
Posaconazole 
Colchicine 
Ranolazine 
Dabigatran 
Saxagliptin 
Digoxin 
Sirolimus 
Everolimus 
Sitagliptin 
Fexofenedine 
Talinolol 
Imatinib 
Tolvaptan 
Lapatanib 
Topotecan 
Maraviroc 
20.1.5 Common medications which prolong the QTc interval with risk of Torsades 
These agents should not be used by study participants. 
Amiodarone 
Dronaderone 
Pentamidine 
Anagrelide 
Droperidol 
Pimozide 
Arsenic trioxide 
Erythromycin 
Procainamide 
Azithromycin 
Escitalopram 
Quinidine 
Chloroquine 
Flecainide 
Sevoflurane 
Chlorpromazine 
Halofantrine 
Sotalol 
Citalopram 
Haloperidol 
Thioridazine 
Clarithromycin 
Ibutilide 
Vandatenib 
Cocaine 
Methadone 
Disopyramide 
Moxifloxacin 
Dofetilide 
Ondansetron (high doses, e.g. 
single dose of 32 mg IV or 
above) 


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MGCD516 in Sarcoma Phase II 
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