Phase I/II Trial of MGCD516 Combined With Nivolumab in Patients With Advanced Clear Cell Renal Cell Cancer That Progressed on Prior VEGF-Targeted Therapy
Phase: PHASE1
Conditions: Clear Cell Renal Cell Carcinoma, Metastatic Kidney Carcinoma, Stage III Renal Cell Cancer AJCC v7, Stage IV Renal Cell Cancer AJCC v7
Sponsor: M.D. Anderson Cancer Center

Protocol 2016-0332 
May 24, 2021 
Page 1 of 62 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2016-0332 
Protocol Title 
Phase I/II trial of MGCD516 combined with nivolumab in patients 
with advanced clear cell renal cell cancer that progressed on prior 
VEGF-targeted therapy 
Protocol Phase 
I/II 
Protocol Version 
19 
Version Date 
05/24/2021 
Protocol PI 
Pavlos Msaouel MD, PhD 
Department 
Genitourinary Medical Oncology 
U.T. M. D. Anderson Cancer Center 
1155 Pressler Street, Unit 1374 
Houston, TX 77030 
Telephone: (713) 792-0067 
Fax: (713) 745-1625 
Statitician 
Department 
Peter Thall, PhD 
Biostatistics  
IND Sponsor 
MD Anderson Cancer Center 
IND # 
132907 
Supporter 
Mirati Therapeutics Inc 
The University of Texas 
M.D. Anderson Cancer Center
Lead Institution: 
The University of Texas M. D. Anderson Cancer Center 
Protocol Version Tracking 
Pre-submission version 
02/26/2016 
Pre-submission version 
03/31/2016 
V00 for submission 
05/03/2016 
V01 for submission 
07/25/2016 
V02 for submission 
08/27/2016 
V03 for submission 
09/27/2016 PDOL v03 
V04 for resubmission 
12/05/2016 PDOL  v04 
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V05 for resubmission  
04/07/2017 PDOL v05 
V06 for resubmission  
05/26/2017 PDOL 06 
V06 for resubmission  
05/26/2017 PDOLv07 
V08 for resubmission  
08/16/2017 PDOL v08 
V09 for resubmission 
10/06/2017 PDOL v09 
Submission error 
10/06/2017PDOL v10 
V10 for resubmission 
04/13/2018 PDOL v11 
V11 for resubmission 
05/14/2018 PDOL v12 
V11 for resubmission 
05/14/2018 PDOL 13 
V13 for resubmission 
03/26/2019 
V14 For resubmission 
04/15/2019 
V15 For resubmission 
04/30/2019 
V16 For resubmission 
06/11/2019 PDOL v21 
V17 For Submission 
03/11/2020 MOD 003 
V18 For Submission 
03/27/2020 MOD 004 
V19 for submission 
5/24/2021 MOD005 extended access 
 
 
 
 
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TABLE OF CONTENTS 
Page 
1.0 
Research Hypothesis 
5 
2.0 
Objectives 
5 
3.0 
Background and Rationale 
5 
4.0 
Eligibility Criteria 
19 
5.0 
Treatment Plan 
23 
6.0 
Study Medications 
25 
7.0 
Correlative Studies 
34 
8.0 
Discontinuation of Therapy 
34 
9.0 
Pre-treatment Evaluation 
37 
10.0 
Evaluation During Treatment 
38 
11.0 
Criteria for Response or Progression 
43 
12.0 
Criteria for Removal from Protocol Treatment 
45 
13.0 
Safety Assessments and Reporting Requirements 
46 
14.0 
Statistical Considerations / Data Analysis 
49 
15.0 
Data and Protocol Management 
53 
16.0 
References 
54 
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Table 1. LIST OF ABBREVIATIONS 
 
 
Abbreviation 
Term 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
APC 
Antigen-presenting cell 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BTLA 
B- and T-cell Lymphocyte Attenuator 
ccRCC 
Clear-Cell Renal Cell Cancer 
Cmax 
Maximum Concentration 
CPK 
Creatine Phosphokinase 
CR 
Complete Response 
CTL 
CD8+ cytotoxic T lymphocyte 
CTLA-4 
Cytotoxic T Lymphocyte Antigen-4 
DN 
Dose Normalized 
FDA 
United States Food and Drug Administration 
FMCS 
Finding Meaning in Cancer Scale 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
HGF 
Hepatocyte Growth Factor 
HIF 
Hypoxia-Inducible Factor 
HPF 
High Power Field 
IC50 
Half maximal inhibitory concentration 
IC90 
90% maximal inhibitory concentration 
irAE 
Immune-related Adverse Event 
irRC 
Immune related Response Criteria 
IV 
Intravenous 
LAG-3 
Lymphocyte Activation Gene-3 
LFT 
Liver Function Test 
LMW 
Low Molecular Weight 
M1 macrophages 
Classically activated macrophages 
M2 macrophages 
Alternatively activated macrophages 
mAb 
Monoclonal Antibody 
MDSC 
Myeloid-Derived Suppressor Cell 
MERTK 
MER Proto-Oncogene Tyrosine Kinase 
mRCC 
Metastatic Clear-Cell Renal Cell Cancer 
MSC 
Mesenchymal Stem Cell 
MTD 
Maximum Tolerated Dose 
mTOR 
Mammalian Target of Rapamycin 
NCI 
National Cancer Institute 
NCCN 
National Comprehensive Cancer Network 
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NK 
Natural Killer cells 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Pharmacodynamic 
PD-1 
Programmed Death Receptor-1 
PD-L1 
Programmed Death-ligand 1 
PD-L2 
Programmed Death-ligand 2 
PDGF 
Platelet-Derived Growth Factor 
PDGFRA 
Platelet-Derived Growth Factor Receptor Alpha Polypeptide 
PFS 
Progression-Free Survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PO 
Per Os (By Mouth) 
PR 
Partial Response 
QOL 
Quality of Life 
 
RBC 
Red Blood Cells 
RCC 
Renal Cell Cancer 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RTK 
Receptor Tyrosine Kinase 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
sMET 
Soluble MET Ectodomain 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
T1/2 
Half Life 
TH1 
CD4+ T helper 1 cell 
TH2 
CD4+ T helper 2 cell 
TH17 
CD4+ T helper 17 cell 
TAM receptors 
Tyro3, Axl, and Mer receptors 
TEN 
Toxic Epidermal Necrolysis 
TIM-3 
T Cell Immunoglobulin and Mucin Protein-3 
TKI 
Tyrosine Kinase Inhibitor 
Tmax 
Time of Maximum concentration observed 
Tmin 
Time of Minimum Observed Concentration 
Treg 
Regulatory T cell 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR2 
Vascular Endothelial Growth Factor Receptor 2 
VHL 
von Hippel-Lindau 
VISTA 
V-domain Ig Suppressor of T-cell Activation 
WBC 
White Blood Cells 
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1.0 
RESEARCH HYPOTHESIS 
 
The receptor tyrosine kinase inhibitor MGCD516 can be safely administered in combination with 
an anti-PD1 antibody (nivolumab) and augment immunological and clinical responses in patients 
with metastatic renal cell carcinoma who have been previously treated with drugs targeting the 
vascular endothelial growth factor (VEGF) pathway. 
 
 
2.0 
OBJECTIVES 
 
Primary objective: 
• To determine the toxicities (defined as a grade 3 or 4 NCI CTCAE non-hematologic or 
hematologic adverse event, within 12 weeks from treatment initiation), and efficacy (defined 
as achieving complete remission, partial remission, or stable disease within 6 weeks) of 
MGCD516 when administered PO daily in combination with standard dose nivolumab  240 
mg IV every 2 weeks. 
 
Secondary objectives: 
• To estimate the overall survival (OS), progression-free survival (PFS) times, objective 
response rates (ORR), and quality of life (QOL) of patients with advanced clear cell RCC 
treated with the combination 
of MGCD516 and nivolumab 
• Evaluate potential biomarkers for patient stratification and treatment response, including 
genetic analysis, serum cytokines and chemokines, as well as tumor antigen-specific immune 
.responses, such as antibody and T cell responses, as surrogates for anti-tumor activity 
 
 
Extended Access objective (long term extension phase):  
• Provide continued access to MGCD516 (sitravatinib) in combination with nivolumab, with 
continued collection of serious adverse events, for patients enrolled on trial and continue to 
benefit from this combination regimen.  
 
3.0 
BACKGROUND AND RATIONALE 
 
 
3.1 
Introduction 
Renal cell cancer (RCC) is the 7th most common cancer in U.S. men and the 9th most common 
cancer in U.S women. An estimated 61,560 new cases and 14,080 deaths are expected in 2015.1 
Approximately 30% of patients will have metastatic RCC at the time of diagnosis,2 and a similar 
proportion of newly diagnosed RCC patients will later on develop metastasis.3 Clear-cell RCC 
(ccRCC) is the most common RCC histologic type, comprising 83%-90% of all RCCs.4,5 An 
improved understanding of ccRCC tumor biology has led to major advances in the treatment of 
metastatic ccRCC (mRCC) over the last decade. Subsequently, immunomodulating cytokines 
such as interleukin-2 and interferon alfa, which were the mainstay therapy for mRCC for two 
decades, have recently been replaced by agents targeting the VEGF or the mammalian target of 
rapamycin (mTOR) pathways.6 
 
ccRCC is associated with inactivating mutations of the von Hippel-Lindau (VHL) tumor 
suppressor gene. This leads to upregulation of hypoxia-inducible factors (HIF) and to 
downstream upregulation of VEGF, resulting in increased angiogenesis, which is commonly 
noted in ccRCC.7 Gene mutations that activate the mTOR pathway are also frequently found in 
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both hereditary and sporadic forms of ccRCC.8 Tyrosine kinase inhibitors (TKIs) targeting the 
VEGF pathway that have been approved by the United States Food and Drug Administration 
(FDA) for use in mRCC include sorafenib, sunitinib, pazopanib, and axitinib. Bevacizumab, a 
monoclonal antibody that binds to VEGF also has efficacy against mRCC. Two mTOR 
inhibitors, temsirolimus and everolimus, have received FDA approval for use in mRCC. The 
most recent targeted agents to improve survival in mRCC are cabozantinib, a TKI that targets the 
VEGF, Axl and c-MET pathways, and nivolumab, a monoclonal antibody that targets the 
programmed death-1 (PD-1) immune checkpoint receptor.9,10 
 
Although targeted agents prolong survival, resistance eventually develops for most patients. 
Therefore, there is a clear need for therapies that can produce complete and durable tumor 
responses with an acceptable toxicity profile. Immune checkpoint inhibition is a new treatment 
strategy that has garnered much attention after demonstrating impressive durable clinical 
responses in many solid tumors, including mRCC.9,11 The interplay between malignant cells and 
the various components of the immune network can either suppress or foster tumor growth. 
CD8+ cytotoxic T lymphocytes (CTL), CD4+ T helper 1 cells (TH1), natural killer (NK) cells and 
classically activated (M1) macrophages mainly suppress tumor development. However, other 
immune components such as CD4+ T helper 2 cells (TH2), CD4+ T helper 17 cells (TH17), 
myeloid-derived suppressor cells (MDSC), alternatively activated (M2) macrophages, and 
CD4+CD25+Foxp3+ Induced Regulatory T cells (Treg) can paradoxically protect tumor cells 
from immunosurveillance.12 Effective immunotherapies should simultaneously enhance anti- 
tumor immunity and inhibit tumor-promoting immune factors. Novel combination strategies with 
other targeted agents may intensify the antitumor effects of immune checkpoint therapy by 
inducing immunogenic cell death, by sensitizing tumor tissues to killing by effector cells, and by 
suppressing crucial components of the immune network that hinder immunosurveillance.12 
 
3.1 
Background on MGCD516 
 
MGCD516 is a potent inhibitor of the catalytic activity of a subset of closely related recombinant 
human receptor tyrosine kinases (RTKs) including the Axl family, c-MET, KIT, FLT3, RET and 
the VEGFR, PDGFR, DDR, Trk families as well as selected Eph family members and selected 
target oncogenic variants (Table 2).13 To confirm that inhibition of enzymatic activity, as 
measured using recombinant protein assays, translated into inhibition of target kinases in cells, 
MGCD516 biochemical specificity was evaluated in cell-based assays with half maximal 
inhibitory concentration (IC50) values ranging from <10 to 181 nmol/L (Table 2). Many of the 
targets inhibited by MGCD516 are known driver kinases in mRCC. 
 
 
 
 
 
 
 
Table 2. In vitro kinase inhibition profile of MGCD51613 
RTK target 
Biochemical Specificity (IC50 nmol/L) 
Axl 
1.5 
MER 
2 
c-MET 
20 
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VEGFR2 (KDR) 
5 
VEGFR1 (FLT1) 
6 
VEGFR3 (FLT4) 
2 
FLT3 
8 
c-KIT 
6 
PDGFRA 
30 
DDR1 
29 
DDR2 
0.5 
RET 
44 
TRKA (NTRK1) 
5 
TRKB (NTRK2) 
9 
EPHA2 
44 
EPHA3 
1 
EPHA4 
76 
EPHB2 
10 
EPHB4 
12 
FYN 
339 
RON 
43 
ROS 
59 
SRC 
156 
TIE2 
274 
YES 
298 
PYK2 
364 
BTK 
304 
EPHB3 
249 
INSR 
5550 
HCK 
1109 
FER 
1589 
fdsLTK 
1938 
FES 
2010 
FMS 
2290 
ABL 
2987 
IGF1R 
3980 
ARG 
4098 
FGFR1 
>5000 
FGFR2 
>5000 
FGFR3 
>5000 
FGFR4 
>5000 
ITK 
>5000 
ERBB1 
>5000 
ERBB2 
>5000 
ERBB4 
>5000 
EPHA1 
>10000 
EPHB1 
>10000 
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FAK 
>10000 
JAK1 
>10000 
JAK2 
>10000 
JAK3 
>10000 
ALK 
>10000 
SYK 
>10000 
ZAP70 
>10000 
 
3.1.1 Pharmacology of MGCD516 
 
The following is the chemical name and structure of MGCD516: 
 
MGCD516 Free Base 
 
H 
H 
N 
N 
 
O 
O 
O 
F 
S 
F 
 
NH 
N 
N 
O 
 
 
 
Chemical Formula: 
MGCD516 Free Base: C33H29F2N5O4S 
Molecular Weight: 
MGCD516 Free Base: 629.68 
In MGCD516 toxicity studies in dogs, no target organs were identified, despite overt decreases  
in body weight and food consumption.  In the rat, however, target organs included the adrenal 
gland, Brunner’s glands in the duodenum, femur and sternum (bone and bone marrow), spleen, 
lymph nodes, thymus, ovaries, kidneys (glomerulopathy, tubular necrosis, increased basophilic 
tubules), pancreas, and tongue.  MGCD516-related microscopic changes in the adrenal gland, 
Brunner’s glands in the duodenum, femur and sternum (bone and bone marrow), spleen, lymph 
nodes, thymus, ovary, kidney, pancreas, and tongue were consistent with those previously 
described in rats administered anti-angiogenic (anti-VEGF) compounds in preclinical studies.14-16 
All effects, except those in the kidney and pancreas, either fully resolved or showed partial 
recovery. 
 
Some of the effects seen preclinically and clinically from VEGF signaling inhibitors include 
hypertension, proteinuria, impaired wound healing, gastrointestinal (GI) perforation, 
hemorrhage/thrombosis, posterior reversible leukoencephalopathy, cardiac impairment, thyroid 
dysfunction, ovarian follicular atresia, and decreased corpora lutea.17 As noted above, some of 
the MGCD516 target organs in animal correlate with typical clinical effects seen with VEGF 
inhibitors. Kidney effects (nephrotic syndrome) have been reported predominantly with 
bevacizumab and not the small molecule TKIs.17 Thus, previous experience with other VEGF 
pathway TKIs indicates that it is unlikely that the adrenal/kidney effects seen in MGCD516- 
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treated rats (≥ 10 mg/kg/day) will translate into clinical toxicities in patients.  Hypertension has 
been observed with all VEGF pathway inhibitors, and mild increases in intravascular pressure 
were indeed observed with MGCD516.  Decreased corpora lutea and follicular atresia were 
observed in the ovary, and these effects have also been seen preclinically with sunitinib and 
bevacuzumab.15   Cyclic endometrial growth is dependent on its ability to regenerate a vascular 
capillary network. Therefore, inhibition of the VEGF pathway likely contributes to the effects of 
MGCD516 on reproductive organs. Genotoxicity studies of MGCD516 indicate a lack of 
potential to induce point mutations, chromosomal aberrations, or to interact with or damage 
DNA. Therefore, it is unlikely that MGCD516 poses a genotoxic risk to humans. 
 
The pharmacokinetic properties of MGCD516 have been examined in mice, rats, and dogs, in 
single-dose pharmocokinetic (PK) studies (Table 3) and in rats and dogs in good laboratory 
practice (GLP) toxicokinetic studies. Single dose PK studies show that MGCD516 is absorbed, 
with an absolute oral bioavailability of 20-72%, a half-life (t1/2) of 3.6-7.1 hours, and with the 
maximum concentration (Cmax) and area under the curve (AUC) increasing generally in a dose- 
dependent manner. 
 
Table 3. Mean Single Dose Pharmacokinetic Parameters for MGCD516 
 
Route 
Parameters 
Mean 
(unit) 
Mouse 
(CD-1, Female) 
Rat 
(Sprague-Dawley, 
Female) 
Dog 
(Beagle, Male) 
IV 
Dose (mg/kg) 
(n) 
2.5 
(3) 
5.0 
(2) 
1.0 
(2) 
DN C0 (µmol/L)/(mg/kg) 
((µg/mL)/(mg/kg)) 
0.63 
(0.394) 
10.6 
(6.67) 
0.99 
(0.620) 
DN AUC0-t (µmol hr/L)/(mg/kg) 
((µg.hr/mL)/(mg/kg)) 
1.11 
(0.702) 
5.7 
(3.59) 
0.99 
(0.622) 
t½ (h) 
6.23 
3.56 
7.11 
CL (L/h/kg) 
1.38 
0.279 
1.49 
V (L/kg) 
6.28 
0.980 
11.1 
PO 
Dose (mg/kg) 
(n) 
2.0 
(3) 
5.0 
(3) 
5.0 
(2) 
DN Cmax  (µmol/L)/(mg/kg) 
((µg/mL)/(mg/kg)) 
0.081 
(0.0511) 
0.105 
(0.0660) 
0.043 
(0.0272) 
DN AUC0-t (µmol hr/L)/(mg/kg) 
((µg.hr/mL)/(mg/kg)) 
0.80 
(0.505) 
0.25 
(0.156) 
0.50 
(0.312) 
tmax (h) 
6 
6 
4 
F (%) 
72.2 
19.6 
56.4 
Abbreviations: DN C0 – dose normalized back-extrapolated plasma drug concentration at time zero following bolus 
intravenous injection; DN AUC0-t  – dose normalized area under the plasma concentration versus time curve from 
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time zero to the time of the last measurable concentration (t=24 h for all reported values except for DN AUC0-t in  
rats after 2 mg/kg oral dose t=6 h); t½ – half life; CL – total clearance; V – volume of distribution; DN Cmax – dose 
normalized maximum plasma concentration; F – absolute bioavailability calculated as (DN AUC0-∞ oral / DN AUC0-∞ 
IV), tmax – time to maximum observed concentration. 
 
Toxicokinetic studies using oral MGCD516 dosing were conducted in rats for 7 days (12.5-75 
mg/kg/day) and 4 weeks (2.5-25 mg/kg/day) and dogs for 7 days (1-8 mg/kg/day) and 4 weeks 
(0.3-3 mg/kg/day).  The time to maximum observed concentration (Tmax) ranged between 4 to 12 
hours in rats and 2 to 6 hours in dogs.  Mean t1/2 ranged between 2.96 to 8.65 hours in rats and 
3.19 to 6.16 hours in dogs.  In all studies, increases in Cmax and AUC0-24 values were roughly 
dose proportional on Day 1 and at the end of study indicating no accumulation. Female rats had 
consistently higher Cmax and AUC0-24 values than did males at nearly all dose levels on Day 1, 
however values were generally comparable at Day 27 at the evaluable dose levels.  In dogs, 
consistent sex differences were not observed.  No evidence for accumulation was observed in 
either rats or dogs. 
 
3.1.2 Preclinical efficacy data of MGCD516 
 
A series of in vivo experiments with MGCD516 were performed to 1) demonstrate inhibition of 
its kinase targets (e.g., c-MET, Axl, RET, EPHA2) in tumors and establish the PK and 
pharmacodynamic (PD) parameters of c-MET inhibition; 2) demonstrate anti-tumor efficacy in 
rodent models of cancer; 3) demonstrate the dose- and time-dependent relationship of inhibition 
of RTK targets, such as c-MET, with anti-tumor efficacy. 
 
The anti-tumor efficacy of MGCD516 was evaluated in a variety of human tumor xenograft 
models (total of 17) representative of cancers known to exhibit dysregulation of RTKs targeted 
by MGCD516.  MGCD516 demonstrated significant anti-tumor efficacy compared with vehicle 
control across all evaluated models at dose levels ranging from 1.25 to 20 mg/kg/day depending 
on the model tested (see the Investigator’s Brochure for full details). Anti-tumor efficacy was 
generally dose-dependent for models for which multiple dose levels were evaluated. MGCD516 
was generally well tolerated with minimal overt toxicity or weight loss at dose levels up to 20 
mg/kg/day for up to 18 days of administration.  The 20 mg/kg/day dose level was the maximum 
dose for comparative purposes across all models utilized for efficacy studies. At this dose, anti- 
tumor efficacy ranged from stable disease to robust tumor regression, with the minimum 
proportion of stable tumors observed being 77% (DU145 prostate and HCT-116 colon), which 
was significantly higher compared with vehicle control.  MGCD516 consistently produced either 
stable disease or tumor response (>90% of cases) in the majority of models evaluated at the 
20 mg/kg/day dose with multiple models exhibiting frank tumor regressions at this dose level. 
Highly sensitive models exhibiting tumor regressions at 20 mg/kg/day MGCD516 included the 
MKN45 gastric adenocarcinoma model (41% tumor regression), NCI-H1437 lung 
adenocarcinoma (24% tumor regression), CTG-0838 lung adenocarcinoma (43% tumor 
regression), and MV4-11 leukemia (minor tumor regression).  Interestingly, several of these 
models have an underlying genetic alteration of at least one MGCD516 RTK target including 
focal amplification of the MET gene (MKN45), linear amplification of a region of chromosome 
4, which includes the PDGFRA, KIT and KDR gene loci, along with a R988C MET mutation 
(NCI-H1437), a KIF5B-RET oncogenic gene fusion event (CTG-0838); and a FLT3-ITD gene 
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mutation (MV4-11). This observation supports the specificity of MGCD516 for tumors 
exhibiting genetic alterations in select RTK targets. 
 
Antitumor Efficacy of MGCD516 in NCI-H1437 (Left Panel) and CTG-0838 (Right 
Panel) Human Lung Adenocarcinoma Xenograft Models Implanted 
Subcutaneously in Athymic Mice 
 
 
Tumor volume reported as median. 
 
In addition, MGCD516 has demonstrated anti-tumor efficacy, including evidence of tumor 
regression, in the MKN45 gastric adenocarcinoma xenograft model known to be resistant to the 
VEGF receptor TKI sunitinib (40 mg/kg daily).  These data suggest that MGCD516 has the 
ability to circumvent resistance to clinically used inhibitors of the VEGF pathway likely due to 
its broader RTK target profile. 
 
Antitumor Efficacy of MGCD516 in the MKN45 Human Gastric Adenocarcinoma 
Xenograft Model Following Progression During Sunitinib Administration 
 
MKN45 tumors were established at 250 mm3 and subsequently mice received oral sunitinib at 40 mg/kg/day until 
tumors progressed to approximately 600 mm3 at which point mice were randomized into 2 cohorts A) continued 
treatment with sunitinib at 40 mg/kg/day or B) initiation of oral administration of MGCD516 at 10 mg/kg/day. 
Tumor volume reported as median. 
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3.1.3 Dose Rationale for MGCD516 
The PK/PD of MGCD516 was evaluated using the c-MET-dependent MKN45 gastric 
adenocarcinoma tumor model.  Plasma concentrations of MGCD516 were determined using 
liquid chromatography–mass spectrometry, and phosphorylation of c-MET in MKN45 tumors 
was determined by ELISA at several dose levels and time points on Day 4 of administration. 
The anti-tumor efficacy of MGCD516 was also evaluated in the MKN45 model over a broad 
range of doses by calculating the tumor volume change relative to Day 1 in a 14-day repeat-dose 
study.  These studies suggested that the anti-tumor efficacy of MGCD516 in the MKN45 model 
depended on the extent and duration of c-MET inhibition.  This model was further used to define 
the target plasma concentration, i.e., the projected efficacious plasma level IC50 and 90% 
maximal inhibitory concentration (IC90).  The IC90 value for inhibiting c-MET phosphorylation 
corresponded to the IC50 values of stable disease or tumor response suggesting that near- 
complete inhibition of c-MET phosphorylation (> 90%) is needed to inhibit tumor growth (> 
50%). 
Because the antitumor activity of MGCD516 may be mediated by other RTKs in addition to c- 
MET, the determination of human target efficacious exposure is based on PK/PD modeling of 
anti-tumor efficacy as opposed to only c-MET inhibition.  In terms of systemic exposure, the 
daily exposure (AUC0-24,ss) that is associated to 50% maximum tumor growth inhibition was 
estimated at 2.5 µmol·h/L (1.57 µg·h/mL) which was thus established as the minimum target 
efficacious exposure in the clinical setting based on this model. The corresponding average 
plasma concentration at steady-state (Cave,ss) was estimated at 0.1 µmol/L (0.0630 µg/mL). 
3.1.3.1 Clinical Experience to Date: Data from the Phase 1/1b 516-001 study 
The 516-001 trial was a Phase 1/1b dose escalation study that explored the safety, PK, and 
optimal MGCD516 dose ranges. The following is a summary of experience generated in this 
first-in-human study.  Data collection is ongoing, thus all data reported are preliminary. 
The modified toxicity probability interval (mTPI) method18 was used to guide dose escalation. 
The assumptions applied in establishing the mTPI methodology were: 
•
the Maximum Tolerated Dose (MTD) was defined to have a 0.3 probability of dose limiting
toxicity; and
•
the acceptable variance around the MTD was ± 0.05 (i.e., the region of the MTD was 25% to
35% incidence of dose limiting toxicity).
Dose escalation in cohorts of patients started at 10 mg MGCD516 daily and proceeded through 
20, 40, 80, 110, 150 and 200 mg daily.  Cohorts included 4 to 7 patients. A total of 32 patients 
were accrued, and in November 2015, the dose of 200 mg MGCD516 administered daily was 
determined to exceed the MTD. 
The observed safety profile for MGCD516 was manageable and, in most respects, expected for 
small molecule tyrosine kinase inhibitors that inhibit VEGFR.  Adverse events (AEs) reported to 
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be treatment-related in more than 10% of patients included hypertension, fatigue, diarrhea, 
nausea, vomiting, rash, and stomatitis. Grade 3 treatment-related AEs reported in one or more 
patients included hypertension (which was manageable), diarrhea, serum amylase increase, 
palmar-plantar erythrodysesthesia, decrease in left ventricular ejection fraction (LVEF) and 
pulmonary embolism. Dose Limiting Toxicities reported during the first cycle of treatment with 
MGCD516 included Grade 3 palmar-plantar erythrodysesthesia in 1 of 6 evaluable patients 
enrolled in the 80 mg cohort, as well as Grade 2 intolerable neuropathy, fatigue and stomatitis, 
each in 1 of 3 patients treated at the 200 mg dose level.  In all cases, dosing was interrupted until 
improvement in the AE and then treatment was restarted with reduction by one dose level. Two 
Serious Unexpected Suspected Adverse Reaction (SUSAR) have been reported: 1) a patient in 
the 150 mg dose level cohort developed Grade 3 decrease in LVEF, without clinical symptoms 
of congestive heart failure, following two cycles of treatment; 2) a patient in the 150 mg dose 
level cohort who developed Grade 3 diarrhea after two cycles of treatment at 150 mg and 4 
cycles of treatment at 110 mg. No other serious adverse events related to MGCD516 treatment 
were reported. 
 
With regards to the clinical efficacy of MGCD516, as of 11/18/2016, 32 patients were enrolled 
in the Phase 1 dose escalation portion of the Phase 1/1b 516-001 study, of which 27 patients had 
at least one imaging study. Of these 27 patients, 17 showed stable disease (SD) and 10 showed 
progressive disease (PD) as best response. The phase 1b portion is treating patients with a 
starting dose of 150 mg as the MTD based on the dose escalation portion. It has enrolled 35 
patients, of which 25 patients have had at least one imaging study. Of these 25 patients, 4 have 
shown partial response (PR), 17 have shown SD, and 4 have shown PD as best response. Out of 
the 4 patients that have demonstrated PR, one has metastatic ccRCC refractory to prior anti- 
VEGF therapy and has achieved a durable response, one has metastatic castration-resistant 
prostate cancer, one has refractory breast cancer with RET mutation, one has previously treated 
non-small cell lung cancer with RET rearrangement. A total of 8 patients with RCC have been 
treated to date. The majority have had some degree of tumor reduction but only the 1 case 
mentioned above has achieved PR by Response Evaluation Criteria in Solid Tumors (RECIST) 
criteria. 
The updated Investigator’s Brochure (IB) issued on 25 August 2015 includes preliminary PK and 
PD data collected in the 10 mg to 110 mg cohorts. After single dose administration, MGCD516 
reaches peak concentration in a median time of 3 to 9 hours. Exposure parameters (maximum 
concentration [Cmax] and area under the curve [AUC]) are dose proportional with doses up to 110 
mg.  Mean elimination half-life varies between 40 and 53 hours.  The steady state PK is reached 
in a mean time of 11 to 15 days.  Drug accumulation is observed after administration of multiple 
doses and averages 4.2-fold for Cmax and 4.7-fold for AUC0-24. Preliminary PK data generated 
since the IB update indicate that increase in exposure continues to be dose proportional through 
the 200 mg daily dose level, the highest dose administered. 
 
As described in the IB update, the PD effects of MGCD516 treatment are examined by analyzing 
VEGFA, soluble VEGF-R2 and soluble MET ectodomain (sMET) levels in plasma samples 
collected before and after MGCD516 administration.  Preliminary PD analyses showed a 
concentration dependent modulation of each biomarker that approached near maximal level 
(based on historical data for TKIs) for VEGF-A (~300% increase), sVEGF-R2 (~35% decrease), 
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and sMET (~60% increase). Average MGCD516 steady state concentration values observed in 
patients receiving 80 mg and 110 mg QD were 64.2 ng/mL and 123 ng/mL, respectively. 
3.2 
Background on Nivolumab (BMS-936558) 
3.2.1 Mechanism of Action 
Immune checkpoints are regulatory signals that can affect immune activation and self-tolerance. 
Immune checkpoint signaling is crucial for preventing autoimmunity and for protecting host 
tissues from immune-mediated collateral damage. Checkpoint inhibitory molecules including 
cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), lymphocyte 
activation gene-3 (LAG-3), T cell immunoglobulin and mucin protein-3 (TIM-3), B7-H3 (also 
designated as CD276), B- and T-cell lymphocyte attenuator (BTLA), and the V-domain Ig 
suppressor of T-cell activation (VISTA) are frequently expressed on tumor-infiltrating T cells.19
Although the exact signaling pathways associated with these molecules remain to be fully 
elucidated, it is clear that they regulate immune activity by different mechanisms and at different 
levels. 
PD-1 is the first immune checkpoint receptor to be targeted in clinical practice against mRCC.9
In contrast to CTLA-4, which is near exclusively expressed on T cells, PD-1 is more broadly 
expressed and can limit the activity of both T- and B-lymphocytes, NK cells, and certain myeloid 
cells when bound to either of its two known ligands, PD-L1 and PD-L2.20 PD-L1 and PD-L2 
have distinct expression profiles.20 PD-L1 is expressed not only on antigen-presenting cells 
(APCs), but also on non-hematopoietic cells, including tumor cells. Expression of PD-L2 is 
largely restricted to APCs including macrophages and myeloid dendritic cells, as well as mast 
cells. PD-L1 can be aberrantly produced in cancer tissues resulting in tumor-induced immune 
dampening via the PD-1 signaling pathway.21 Therefore, whereas CTLA-4 regulation occurs 
mainly in lymphoid tissues, PD-1 is predominantly activated within the tumor 
microenvironment. 
The role of PD-1 as a negative regulator of T cells was demonstrated in PD-1 deficient mice 
which developed significant autoimmunity with elevated titers of autoantibodies.22,23 In addition, 
blocking antibodies against PD-1 activated immune responses that reduced tumor metastasis and 
tumor growth in a number of experimental tumor models.24,25 Consistent with the 
immunosuppressive role of PD-1/PD-L1/2 signaling, forced expression of PD-L1 in murine 
tumor cell lines allows increased tumor growth in vivo, previously kept in check by T cells. This 
inciting effect of PD-L1 on tumor growth is reversed by blocking anti-PD-L1 antibodies.26 In 
ccRCC, high surface expression levels of PD-L1 on tumor cells correlate with tumor 
aggressiveness.27,28 
The first anti-PD-1 agent to be approved for clinical use was nivolumab, a fully humanized IgG4 
(kappa) isotype anti-PD-1 monoclonal antibody (mAb). It has received accelerated FDA 
approval for use in metastatic or unresectable melanoma, metastatic non-small cell lung cancer, 
and metastatic renal cell cancer based on its proven clinical efficacy in these settings.9,29-32
Immune reactivation by nivolumab produces long-term responses that persist even after 
treatment cessation.33 Toxicity data derived from trials of PD-1/PD-L1 blockade suggest that this 
approach produces less toxicity compared with CTLA-4 targeting.29-32,34,35 This may be due to 
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the expression of CTLA-4 in lymphoid organs leading to lower treatment specificity compared 
with the more localized intratumoral expression of PD-1/PD-L1. 
 
3.2.2 Nivolumab Pharmacokinetics 
The PK of single-dose nivolumab was assessed in patients with multiple tumor types in the 
CA209001 trial, using a dose range of 0.3 to 10 mg/kg. The time of maximum concentration 
observed (Tmax) across single dose levels ranged from 1.6-3.0 hours with individual values 
ranging from 0.9 to 7.0 hours. Nivolumab has a linear PK in the range of 0.3 to 10 mg/kg with 
dose- proportional increase in the maximum concentration observed and in the area under the 
curve from zero to infinity, with low to moderate inter-subject variability observed at each dose 
level, i.e., a coefficient of variation ranging from 7%-45%. The geometric mean clearance after a 
single IV dose of nivolumab ranges from 0.13-0.19 mL/h/kg, whereas the mean volume of 
distribution ranges from 83-113 mL/kg across doses. The mean terminal half-life of nivolumab is 
17-25 days, which is in accordance with the half-life of endogenous IgG4 antibodies, indicating 
that they share a similar elimination mechanism. The elimination and distribution of nivolumab 
is dose-independent in the dose ranges studied. 
 
The PK of multiple nivolumab doses is being investigated in the CA209003 trial. A preliminary 
population pharmacokinetic model has been developed using nonlinear mixed effect modeling 
using data from 350 patients accrued in the CA209001, CA209002, and CA209003 trials. Dosing 
based on normalizing by body weight produces relatively constant trough concentrations over a 
wide range of body weights, and is therefore appropriate for trials of nivolumab. 
 
3.2.3 Nivolumab in Renal Cell Carcinoma 
Nivolumab monotherapy has been tested in multiple ongoing and completed trials that accrued 
patients with mRCC, including the Phase 1 single-ascending dose, dose-escalation CA209001 
trial, the Phase 1 multiple-ascending dose, dose-escalation CA209003 study which assessed 
multiple tumor types (including mRCC), the exploratory CA209009 study which investigated the 
immunomodulatory activity of nivolumab in mRCC, and the Phase 2 dose ranging CA209010 
study. Of note, the efficacy of nivolumab compared with the mTOR inhibitor everolimus was 
evaluated in the pivotal phase 3 randomized multicenter CheckMate 025 study.9 In addition, 
CA209016 is an ongoing phase I dose-escalation study of nivolumab in combination with either 
sunitinib, pazopanib or the CTLA-4 inhibitor ipilimumab. 
 
3.2.3.1 Safety of Nivolumab in Renal Cell Carcinoma 
Patients enrolled in clinical trial CA209001 (n=39) received a single dose of nivolumab with 
potential retreatment in 3 months. The most common AEs were fatigue (56%), nausea (44%), 
proteinuria (38%), constipation (33%), back pain (33%), dry mouth (28%), vomiting (28%), rash 
(26%) and dyspnea (26%). No correlation was identified between nivolumab dose levels (0.3, 1, 
3, or 10 mg/kg IV) and AE incidence or severity. All patients had at least one AE, and 32 
patients (82%) had Grade 3 or 4 AEs. The three treatment-related severe AEs reported were 
Grade 2 hypothyroidism, Grade 2 anemia, and Grade 3 colitis. No drug-related deaths were 
noted. 
 
Nivolumab-related AEs of any grade occurred in 75.2% of patients in the CA209003 trial (n = 
306).36  The most common drug-related AEs occurring in ≥ 5% of patients included fatigue 
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(28.1%), rash (14.7%), diarrhea (13.4%), pruritus (10.5%), nausea (9%), decreased appetite 
(9%), and fever (6%). The majority of AEs were low grade, and only 14% of patients developed 
Grade 3/4 drug-related AEs. The most common Grade 3/4 drug-related AEs occurring in ≥ 1% of 
patients were fatigue (2%), pneumonitis (1%), diarrhea (1%), and AST/ALT increase (0.3% 
each). Drug-related serious adverse events (SAEs) occurred in 17% of patients. Grade 3/4 drug- 
related SAEs occurring in ≥ 1% of patients were pneumonitis (1.3%), and diarrhea (1%). The 
spectrum, incidence, and severity of nivolumab-related AEs was overall similar across the 
different dose levels used. Less common drug-related AEs included vitiligo, hepatitis, 
hypophysitis, and thyroiditis. 
 
Treatment interruption and administration of corticosteroids were used to manage hepatic or 
gastrointestinal AEs, which overall were fully reversible. Hormone replacement therapy was 
used to manage endocrine AEs. Several patients with these AEs successfully restarted nivolumab 
therapy. Drug-related pneumonitis was noted in 3% of patients. Grade ≥ 3 pneumonitis 
developed in only 3 patients (1%). There was no clear relationship between the occurrence of 
pneumonitis and dose level, dose number, or tumor type. Low-grade pneumonitis generally 
resolved with discontinuation of treatment and administration of corticosteroids. Infliximab 
and/or mycophenolate were used as additional immunosuppressants in 3 patients, but it remains 
uncertain whether this provided additional benefit. Three drug-related deaths (1%) due to 
pneumonitis were noted. In two of these cases, early and aggressive intervention such as 
systemic corticosteroid therapy was not initiated, and this likely significantly contributed to the 
fatal event, whereas in the 3rd patient, concomittant administration of other anti-cancer agents 
(erlotinib and vinorelbine) may have aggravated toxicity. 
 
In the CheckMate 025 study using the now established nivolumab dose of 3 mg/kg every 2 
weeks, following a median duration of treatment of 5.5 months (range, <0.1 to 29.6), treatment- 
related AEs of any grade occurred in 319/406 patients (79%). The most frequent treatment- 
related AEs were fatigue (33%), nausea (14%), and pruritus (14%). Grade 3/4 treatment-related 
AEs occurred in 19% of patients, with the most common Grade 3/4 AE being fatigue (2%). 
Treatment-related AEs leading to nivolumab discontinuation were noted in 8% of patients. There 
were no nivolumab-related deaths.9 
 
3.2.3.2 Clinical Activity of Nivolumab in Renal Cell Carcinoma 
In the CA209001 trial, partial response (PR) to nivolumab therapy was noted in 3/39 patients 
(7.7%), one of which had mRCC and was treated at a dose level of 3 mg/kg. The other two 
partial responders had melanoma and mRCC respectively and were both treated at a dose level of 
10 mg/kg. Stable disease (SD) was seen in 10/39 patients (25.6%), and was maintained for > 6 
months in 2/10 patients. In the CA209003 trial, 34 patients with pre-treated mRCC received 
nivolumab and achieved objective response rates of 5/18 (27.8%) and 5/16 (31.3%) for dose 
levels 1 mg/kg and 10 mg/kg, respectively. The PFS at 24 weeks was 50% in the 1 mg/kg and 
67% in the 10 mg/kg dose groups. 
 
In the CheckMate 025 phase 3 trial, patients treated with nivolumab at a dose level of 3 mg/kg 
every 2 weeks demonstrated a median OS of 25.0 months, which was significantly higher 
compared with the mTOR inhibitor everolimus (p=0.002). This benefit was retained among 
different prognostic subgroups. The median PFS in the nivolumab group was 4.6 months. The 
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objective response rate (ORR) of patients treated with nivolumab was 25%, with PR seen in 24% 
and CR in 1% of patients respectively. The median time to response was 3.5 months (range, 1.4- 
24.8) and the median duration of response was 12.0 months (range, 0-27.6).9 
 
3.3 
Rationale for Combining MGCD516 with Immune Checkpoint Therapy 
MGCD516 is a TKI that targets multiple closely related receptor tyrosine kinase pathways 
including VEGF, platelet-derived growth factor (PDGF), c-KIT, c-MET, and the Tyro3, Axl, and 
MER (TAM) family.  There is a strong rationale for targeting these pathways in mRCC due to 
their role in aberrant tumor angiogenesis (VEGFR and PDGFR), tumor growth and metastatic 
progression (c-MET), and evasion of immune surveillance (VEGFRs, c-KIT, TAMs). VEGF, c- 
KIT, c-MET, and Axl signaling activates cells and molecules that limit the ability of immune 
checkpoint therapy to fully harness the immune system and achieve consistent, durable anti- 
tumor activity. 
 
The TAM receptor tyrosine kinases Axl and MER Proto-Oncogene (MERTK) are expressed by 
selected innate immune cell subpopulations including macrophages and dendritic cells,37 and 
cooperate to create an immunosuppressive tumor microenvironment. MERTK suppresses the 
classically activated (M1) macrophage pro-inflammatory cytokine response involving IL‑  12, 
IL 6 and TNF, and enhances M2 macrophage anti-inflammatory cytokine production involving 
IL‑  10, IL-4, TGFβ, and HGF.38,39 The ability to initiate an antitumor M1 macrophage response 
is impeded by the MERTK-dependent M2 macrophage response within the tumor 
microenvironment. In addition, Axl is required for the termination of Toll-like receptor 
dependent inflammatory response in dendritic cells.40 Studies in TAM receptor null mice have 
implicated Axl and MERTK in the regulation of innate immune responses mediated by pro- 
inflammatory signaling.41 TAM pathway inhibition facilitates the ability of APCs to drive TH1 
responses through increased production of pro-inflammatory cytokines.42 The inhibition of Axl 
and MERTK can therefore enhance anti-tumor immunity mediated by CTLs stimulated by TH1- 
type cytokines. Accordingly, Axl neutralizing antibodies can attenuate tumor growth by 
modulating immune cell function in a mouse breast cancer model.42 In addition, implantation of 
syngeneic breast and melanoma tumors in MERTK null mice results in decreased tumor growth 
due to an enhanced innate immune response.43 
 
The implantation of MERTK-null bone marrow in irradiated wild-type mice produces a M1- 
polarized tumor macrophage phenotype that inhibits the growth of breast tumors via immune 
responses mediated by MERTK-null hematopoetic cells.  Both Axl and MERTK are expressed 
by NK cells and negatively regulate NK cell activity in the tumor microenvironment as part of a 
feedback regulatory mechanism that decreases NK cell antitumor activity and enhances tumor 
progression and metastasis in mouse cancer models.44   Tumors implanted into null mice for the 
MERTK and Axl ligand Gas6 grow more slowly, likely due to the inhibition of MERTK on 
macrophages, Axl on dendritic cells, and both Axl and MERTK on NK cells.45  Collectively, 
these data implicate Axl and MERTK as key regulators of the innate immune system within the 
tumor microenvironment, and indicate that inhibition of these TAM RTKs by TKIs such as 
MGCD516 can reverse tumor-protective immune pathways. 
 
The c-MET RTK also modifies anti-tumor immune responses by regulating APC function and by 
promoting immunosuppressive pathways within the tumor microenvinronment. c-MET is 
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expressed by immature CD14+ monocytes which can acquire an immunosuppressive phenotype 
when exposed to the c-MET ligand hepatocyte growth factor (HGF) secreted by tumor stromal 
and mesencymal stem cells (MSCs).46 Depletion of CD14+ monocytes or neutralization of HGF 
secretion by MSCs reverses the suppression of effector T-cell proliferation and triggers a shift 
back toward a TH1-activated T-cell phenotype.46  MSCs are also implicated in the expansion of 
immunosuppressive MDSCs which is also dependent on the secretion of HGF.47   APCs, such as 
dendritic cells, also express c-MET which can be activated by HGF and subsequently suppress 
APC function including both antigen presenting capacity and antigen-dependent T-cell responses 
in vitro and in vivo.48-50  HGF neutralization increases APC antigen-presenting capacity and 
triggers an antigen-mediated and T cell-directed immune response in vivo in selected mouse 
models of inflammatory response.48,50 
 
Of all the MGCD516 RTK targets, the most comprehensive preclinical and clinical data 
demonstrating immunostimulatory activity are available for Vascular endothelial growth factor 
receptor 2 (VEGFR2) and c-KIT. Inhibition of these receptors results in depletion of 
immunosuppressive cellular subsets, including Tregs and MDSCs. VEGF neutralizing antibodies 
and VEGF receptor small molecule inhibitors reduced the percentage of intratumoral Tregs in a 
syngeneic mouse cancer model.51 Neutralizing antibodies against VEGFR2 expressed on Tregs 
attenuate the proliferation of these cells in tumor-bearing mice.51 Depletion of Tregs in 
peripheral blood and tumor tissue has also been observed in both mouse models and in clinical 
trials of VEGF receptor TKIs including sunitinib, sorafenib, and cabozantinib.51-55 MDSCs 
notably express both c-KIT and VEGFR1 and the inhibition of these RTKs, using pharmacologic 
or genetic approaches, reduces MDSC viability in vitro and depletes this cell population in 
mouse tumor models.52,56,57 
 
Preclinical data with MGCD516 indicate that it can increase expression of PD-L1 on tumor cells 
in vitro and in vivo.  Pilot studies in syngeneic mouse tumor models also suggest that MGCD516 
increases the proliferation and fraction of systemic/spleen CD4+ and CD8+ T lymphocytes and 
reduces the number of systemic MDSCs.  Additional studies to investigate the effects of 
MGCD516 in the tumor microenvironment are ongoing. 
 
Since MGCD516 and immune checkpoint inhibitors, such as nivolumab, use distinct 
mechanisms for immune activation we hypothesize that combination therapy with MGCD516 
plus nivolumab will have acceptable safety profile and may lead to high clinical response rate 
and long-term survival for patients with mRCC. Treatment of mRCC with MGCD516 may 
produce rapid tumor cell death and release of tumor associated antigens, as well as 
simultaneously enhance the ability of APCs to present tumor antigens. This would prime anti- 
tumor T cell responses, which can then be enhanced and sustained by nivolumab. In addition, 
because multiple MGCD516 RTK targets are also implicated in the evasion of immune 
surveillance and resistance to immune checkpoint inhibitors there is a strong mechanistic 
rationale for the combination of these classes of agents. 
 
3.3.1 Studies Using Other TKIs 
Cabozantinib targets multiple RTKs, including the VEGFR family, c-KIT, c-MET, and TAM 
receptors.  Cabozantinib-treated mice exhibit increased splenic CD4+ T cells.55 Both 
cabozantinib alone and its combination with a cancer vaccine significantly increase the 
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percentage of CD8+ T cells. Treatment with cabozantinib also reduces the percentage of splenic 
Tregs and MDSCs. Cabozantinib-treated Tregs are not able to suppress CD4+ T cell proliferation 
indicating the normal regulatory function of these cells was eliminated. Collectively, the 
favorable change in the effector T-cell to Treg/MDSC ratio establishes an immune stimulatory 
environment.55 Clinically, a reduction in immunosuppressive immune cell subsets, including 
Tregs and MDSCs, has also been observed in patients treated with cabozantinib.58 
 
Sunitinib blocks the tyrosine kinase activities of multiple receptors including the VEGF receptor 
family, c-KIT, and the platelet-derived growth factor receptor alpha polypeptide (PDGFRA). 
Sunitinib increases CD8+ T cells and decreases circulating Tregs and MDSCs in vivo thus 
improving the ratio between CD8+ T effector cells and suppressor cell populations.51,54,56 
Functional analysis studies indicate that sunitinib alone or combined with a vaccine strategy 
decreases the ability of circulating Tregs57 and MDSCs to inhibit T CD8+ cell proliferation.59 In 
addition, sunitinib in combination with the immunomodulatory molecules IL-12 and/or 4-1BB 
agonist significantly improved the survival of tumor-bearing mice.56 The expansion of tumor T 
effector cell populations and reduction of Tregs and MDSCs by sunitinib has been observed in 
mRCC and other cancer patients treated with sunitinib.51-53 
  
3.4 Updated results from the present protocol 
 
From May 2017 through February 2020, 42 patients were enrolled in the present trial. At data 
cutoff (September 21, 2020), 12/42 patients (28.6%) continued to receive trial treatment. The 
median follow-up time was 18.7 months (95% CI 13.5 to 24.3). Sitravatinib (MGCD516) starting 
doses of 60, 80, 120, and 150 mg daily were selected according to the late-onset efficacy-toxicity 
(LO-EffTox) design for 0, 15 (35.7%), 24 (57.1%), and 3 (7.1%) patients. Overall, regardless of 
sitravatinib starting dose, the combination of sitravatinib plus nivolumab yielded an objective 
response rate (ORR) of 35.7% (15/42 patients) and a disease control rate (DCR) of 88.1% (37/42 
patients). Complete response was noted in one patient (2.4%), who received a sitravatinib starting 
dose of 80 mg. The posterior mean for the median progression free survival (PFS) was 11.7 months 
[95% credible interval (CrI) 8.2 to 16.6]. Median overall survival (OS) was not reached, and 34/42 
patients (80.1%) were alive at the time of data cutoff. Because we designed our trial to reflect the 
patient population enrolled in the CheckMate 025 phase III trial of nivolumab monotherapy in 
advanced ccRCC, we performed historical comparisons with CheckMate 025 using conservative 
Bayesian non-informative priors. Combining the three sitravatinib dose groups, the posterior 
probabilities that sitravatinib plus nivolumab yielded higher ORR and longer PFS than those 
reported for nivolumab monotherapy in CheckMate 025 were 96% and 100%, respectively.  
 
Dose-limiting toxicities (DLTs) were noted in all three patients treated with 150 mg daily. The 120 
mg dose produced an ORR of 37.5% (9/24 patients) compared with the ORR of 26.7% (4/15 
patients) observed with 80 mg. The 80 mg dose was associated with fewer DLTs (4/15 patients; 
26.7%) compared with the 120 mg dose (10/24 patients; 41.7%). The estimated EffTox desirability 
scores were 0.622, 0.787, 0.755, and 0.630 for the 60, 80, 120, and 150 mg doses, respectively. 
Because the 80 and 120 mg doses had nearly identical estimated trade-off desirability scores, we 
compared them using additional criteria. The Bayesian posterior probabilities of sitravatinib 120 
mg producing a higher ORR and longer PFS, compared with 80 mg were 80.7% and 68.3% 
respectively. The posterior probabilities of sitravatinib 120 mg yielding lower level of depression, 
higher quality of life, and higher hope for the future scores at 3 months compared with sitravatinib 
80 mg were 92.7%, 82.6%, and 90.5%, respectively. Thus, all metrics favored the sitravatinib 
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starting dose of 120 mg.  
 
Adverse events (AEs) requiring dose reduction of sitravatinib throughout the treatment course were 
noted in 22/42 patients (52.4%) . The primary reason for treatment discontinuation was disease 
progression (25/42 patients [59.5%]). Treatment discontinuation due to AEs was noted in 4/42 
patients (9.5%). Death due to toxicity occurred in one patient who developed respiratory failure 
from myasthenia gravis. High-dose glucocorticoids (prednisone ≥ 40 mg/day or equivalent) for the 
management of immune-related AEs were administered in 8/42 patients (19%). Additional 
immunosuppressive strategies such as infliximab were needed in 2/42 patients (4.8%).  
 
In conclusion, this is the first study to evaluate the safety and efficacy of sitravatinib (MGCD516) 
plus nivolumab in ccRCC. Higher ORR and longer PFS with sitravatinib plus nivolumab in 
patients with ccRCC that progressed on prior antiangiogenic therapies were seen, compared to 
historical studies with nivolumab or TKI monotherapies in this setting. Furthermore, we found that 
the sitravatinib starting dose of 120 mg demonstrated the optimal tradeoff between efficacy, 
toxicity, and quality of life. The present trial provided a strong rationale for larger ongoing clinical 
trials utilizing sitravatinib 120 mg in combination with anti-PD1 therapy across multiple tumor 
types. 
 
 
 
4.0 
ELIGIBILITY CRITERIA 
 
4.1 
Signed written informed consent 
 
1.   Patients must give written informed consent prior to initiation of therapy, in keeping with the 
policies of the institution. Patients with a history of major psychiatric illness must be judged 
able to fully understand the investigational nature of the study and the risks associated with 
the therapy. 
 
4.2 
Inclusion criteria: 
 
1. Patients with histologically or cytologically confirmed metastatic/advanced clear cell RCC, 
or RCC with a clear cell component, who have received 1 or 2 prior anti-angiogenic therapy 
regimens (+/- cytokine therapy with interleukin-2 or interferon-alfa) in the advanced or 
metastatic setting. Examples of anti-angiogenic agents include, but are not limited to, 
sorafenib, sunitinib, pazopanib, axitinib, and bevacizumab. 
 
2. There must be evidence of progression on or after last treatment regimen received and within 
6 months of enrollment. 
 
 
3. Patients must have at least one measurable site of disease, defined as a lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) and 
measures ≥ 15 mm with conventional techniques or ≥ 10 mm with more sensitive techniques 
such as MRI or spiral CT scan. If the patient has had previous radiation to the marker 
lesion(s), there must be evidence of progression since the radiation. 
 
 
4. Karnofsky performance status ≥70 
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5. Age ≥ 18 years 
 
6. Patients must have adequate organ and marrow function prior to study entry as defined 
below: 
• Hemoglobina 
≥ 9 g/dl (treatment allowed) 
• absolute neutrophil count 
≥1,500/µL 
• platelets 
≥100,000/µL 
• total bilirubin 
≤ 1.5 mg/dl 
• AST(SGOT) or ALT (SGPT) 
≤2.5 X institutional uln, 
except in known hepatic 
metastasis, wherein may 
be < 5 x ULN 
• Serum Creatinine 
< 1.5 x ULN (as long as 
patient does not require 
dialysis) 
a May receive transfusion 
bIf creatinine is not <1.5×ULN, then calculate by Cockcroft-Gault methods 
or local institutional standard and CrCl must be ≥40 mL/kg/1.73 m2 
 
7. INR and PTT ≤ 1.5 x ULN prior to study entry. Therapeutic anticoagulation with warfarin is 
allowed if target INR ≤ 3 on a stable dose of warfarin or on a stable dose of low molecular 
weight (LMW) heparin for > 2 weeks (14 days) at the time of enrollment. 
 
8. Female patients of childbearing potential (not postmenopausal for at least 12 months and not 
surgically sterile) must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) before study entry. Pregnancy test must be repeated if 
performed > 14 days before starting study drug. 
 
9. Women must not be breastfeeding 
 
10. Patients with a history of major psychiatric illness must be judged (by the treating physician) 
able to fully understand the investigational nature of the study and the risks associated with 
the therapy. 
 
11. Patients with controlled brain metastases are allowed on protocol if they had solitary brain 
metastases that was surgically resected or treated with radiosurgery or Gamma knife, without 
recurrence or edema for 1 month (4 weeks). 
 
4.3 Exclusion criteria: 
 
1. Patients must not have any other malignancies within the past 2 years except for in situ 
carcinoma of any site, adequately treated (without recurrence post-resection or post- 
radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of the 
skin, or active non-threatening second malignancy that would not, in the investigator's 
opinion, potentially interfere with the patient's ability to participate and/or complete 
this trial. Examples include but not limited to: urothelial cancer grade Ta or T1, 
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adenocarcinoma of the prostate treated by active surveillance. 
 
2. Patients currently receiving anticancer therapies or who have received anticancer therapies 
within 2 weeks (14 days) from enrollment into this study (including chemotherapy and 
targeted therapy) are excluded. Also, patients who have completed palliative radiation 
therapy more than 14 days prior to the first dose of MGCD516 are eligible. 
 
3. Patients, who have had a major surgery or significant traumatic injury (injury requiring > 4 
weeks (28 days) to heal) within 4 weeks (28 days) of start of study drug, patients who have 
not recovered from the side effects of any major surgery (defined as requiring general 
anesthesia) or patients that are expected to require major surgery during the course of the 
study. 
 
4. Patients who have been previously treated with mTOR inhibitors such as everolimus and 
temsirolimus, or with c-MET inhibitors such as cabozantinib 
 
5. Patients who have organ allografts. 
 
6. Known or suspected autoimmune disease.  Patients with a history of inflammatory bowel 
disease (including Crohn’s disease and ulcerative colitis) and autoimmune disorders such as 
rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus 
Erythematosus or autoimmune vasculitis [e.g., Wegener’s Granulomatosis] are excluded 
from this study.  Patients with a history of Hashimoto’s thyroiditis only requiring hormone 
replacement, Type I diabetes, or psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are allowed to participate. 
 
7. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). 
8. Any underlying medical condition, which in the opinion of the Investigator, will make the 
administration of study drug hazardous or obscure the interpretation of adverse events, such 
as a condition associated with frequent diarrhea, uncontrolled nausea, vomiting, 
malabsorption syndrome or small bowel resection that may significantly alter the absorption 
of MGCD516. 
 
9. Patients must not have received prior anticancer therapy with any immune checkpoint 
inhibitors such as anti-CLTA-4, anti-PD1, or anti-PD-L1. 
 
10. Patients receiving any concomitant systemic therapy for renal cell cancer are excluded. 
 
11. Patients must not be scheduled to receive another experimental drug while on this study. 
 
12. Patients who are on high dose steroid (e.g., > 10mg prednisone daily or equivalent) or other 
more potent immune suppression medications (e.g., infliximab). Topical, inhaled, intra- 
articular, ocular, or intranasal corticosteroids (with minimal systemic absorption) are 
allowed. A brief course (<48 hours) of systemic corticosteroids for prophylaxis (eg, from 
contrast dye allergy) is permitted. 
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13. Patients who have any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation in the study such as: 
• Symptomatic congestive heart failure of New York heart Association Class III or IV 
• unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction 
within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any 
other clinically significant cardiac disease 
• severely impaired lung function as defined as 02 saturation that is 88% or less at rest on 
room air 
• uncontrolled diabetes as defined by blood glucose >200 mg/dl (11.1 mmol/l) 
• Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as 
exhibiting ongoing signs/symptoms related to the infection and without improvement) 
despite appropriate antibiotics or other treatment 
• Liver disease such as cirrhosis or chronic active hepatitis; Positive test for hepatitis B 
virus (HBV) using HBV surface antigen (HBV sAg) test or positive test for hepatitis 
C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating 
acute or chronic infection. 
 
14. Patients must not have history of other diseases, metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving reasonable suspicion of a disease 
or condition that contraindicates the use of MGCD516 or nivolumab or that might affect the 
interpretation of the results of the study or render the subject at high risk from treatment 
complications. 
 
15. Patients should not receive immunization with attenuated live vaccines within one week (7 
days) of study entry or during study period. 
 
16. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require 
glucocorticoids for brain or leptomeningeal metastases. 
 
17. Female patients who are pregnant or breast feeding, or adults of reproductive potential who 
are not using effective birth control methods. If barrier contraceptives are being used, these 
must be continued throughout the trial by both sexes. Hormonal contraceptives are not 
acceptable as a sole method of contraception.  (Women of childbearing potential must have 
a negative urine or serum pregnancy test within 14 days prior to study entry.  Pregnancy test 
must be repeated if performed > 14 days before administration of MGCD516). 
 
18. Any patients who cannot be compliant with the appointments required in this protocol must 
not be enrolled in this study. 
 
19. Concurrent therapy with medications known to significantly prolong the QT interval and/or 
associated with increased risk for Torsade de Pointes arrhythmia. The Principal 
Investigator (PI) is the final arbiter in questions related to eligibility. 
 
20. Patients with LVEF < 40% 
 
4.4 Inclusion of Women and Minorities 
 
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This trial is open to women and men and members of all races and ethnic groups. 
 
 
 
 
 
5.0 TREATMENT PLAN 
 
5.1 
Patient Enrollment 
All patients or legally acceptable representatives must personally sign and date, and receive a 
copy of the informed consent form (ICF) before any study specific screening procedures are 
performed. Standard medical practice procedures (CT, MRI, physical exam, blood tests) 
performed within the specified screening period may be used for screening. 
 
Patients will be registered by the responsible study nurse or research coordinator. All patients 
will be registered in the approved Office of Research Administration (ORA) database at MD 
Anderson. 
 
All patients who sign an informed consent will be identified by a unique patient number. This 
number will be used to identify the patient throughout the clinical study and must be used on all 
study documentation related to that patient. The patient identification number must remain 
constant throughout the entire clinical study. 
 
A patient is considered enrolled when study medication is administered on Day 1. 
 
 
5.2 
Data Collection 
 
Data will be entered into MD Anderson institutionally approved and compliant database(s) 
Prometheus and CORe. The database(s) have secure portal that requires users to login with 
validated credentials, uses approved encryption protocols as defined by institutional 
information security standards. Systems have granular data access controls to ensure that the 
minimal amount of information required to complete a task is presented, can handle de-
linking and de-identification of patient information to maintain patient confidentiality if 
necessary. The system(s) are 21 CFR 11 compliant. Standard data collection, storage procedures, 
and quality assurance procedures will be followed, to ensure integrity and auditability of all 
information entered. 
 
All patients will be registered in the University of Texas M. D. Anderson Cancer Center CORe 
database. Registration will occur following informed consent process and prior to initiation of 
investigational intervention(s). All eligibility criteria must be satisfied. 
 
 
 
5.3 Study Design and Duration 
 
This is a phase I–II dose-finding trial to determine the optimal dose of the targeted oral agent 
MGCD516 when combined with immunotherapy via intravenous Nivolumab at fixed dose 240 
mg IV every 2 weeks, in patients with metastatic renal cell carcinoma with a clear cell 
component who have progressed following treatment with anti-VEGF agents. The goal of the 
study is to determine an optimal oral MGCD516 dose level among the four levels 60, 80, 120 
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and 150 mg/day given orally daily until toxicity or progressive disease. Dose-finding will be 
done using the sequentially adaptive phase I-II late-onset EffTox (Lo-EffTox) trade-off-based 
design of Jin et al.60-62   To determine the optimum dosage, efficacy is defined as achieving 
complete response (CR), partial response (PR), or stable disease (SD) within 6 weeks, and the 
occurrence of any of the following toxicities within 12 weeks from the start of therapy will be 
considered a dose-limiting toxicity (DLT), if judged by the Investigator to be clinically relevant 
and related (possibly or probably) to administration of either or both study drug(s): 
 
• Hematologic DLTs: 
o Grade ≥ 3 febrile neutropenia (ANC < 1.0 x 109/L with either a single 
temperature≥ 38.3ºC or a sustained temperature of  ≥ 38ºC for more than 1 hour) 
o Grade 3 thrombocytopenia (platelets < 50.0 x 109/L > 25.0 x 109/L) if associated 
with: 
 A bleeding event that requires an elective platelet transfusion, OR 
 A life-threatening bleeding event which results in urgent intervention and 
admission to an Intensive Care Unit 
o 
Grade 4 thrombocytopenia (platelets < 25.0 x 109/L) 
 
• Non- Hematologic DLTs: 
o Any Grade 4 non-hematological toxicity 
o Grade ≥ 2 drug-related uveitis that does not respond to topical therapy OR 
requires systemic treatment 
o Grade 3 overlapping toxicities of nivolumab and MGCD516, including diarrhea, 
rash, fatigue, or elevation of serum amylase/lipase, lasting > 3 days despite 
optimal supportive care with the exception of: 
 Grade 3 fatigue lasting ≤5 days 
 Grade 3 rash that resolves to ≤ Grade 1 within 3 weeks 
 Grade 3/4 elevation in serum amylase and/or lipase that are not associated 
with clinical or radiological evidence of pancreatitis 
o Any other Grade 3 non-hematologic toxicity lasting > 3 days despite optimal 
supportive care with the exception of: 
 Grade 3 tumor flare (defined as local pain, irritation or rash localized at 
sites of known or suspected tumor) 
 A transient (resolves within 6 hours of onset) Grade 3 infusion-related AE 
 Grade 3 hypertension that can be controlled with medical therapy 
o Any clinically meaningful Grade 3 non-hematologic laboratory value if: 
 Medical intervention (other than electrolyte repletion) is required to treat 
the patient, OR 
 The abnormality leads to hospitalization, OR 
 The abnormality persists for > 1 week. 
 
Beginning on day 1 of the study, patients will each be treated with a pre-specified daily oral dose 
of MGCD516 determined by the Lo-EffTox method. Following 2 weeks of MGCD516 
monotherapy, nivolumab will additionally be initiated at a dose of 240 mg intravenously (IV) 
every 2 weeks. Patients who have received at least 6 infusions of nivolumab 240 mg IV every 2 
weeks with no DLTs related to nivolumab, will be allowed as an option to transition to the 
nivolumab schedule of 480 mg IV every 4 weeks. No other dose or schedule modifications will be 
allowed for nivolumab. A maximum of 60 patients will be treated in up to 20 cohorts of size 3, 
with the first cohort treated at the pre- specified dose of 80 mg of MGCD516 per day. All 
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successive doses will be chosen by the Lo- EffTox method, and no untried dose level will be 
skipped when escalating. The Lo-EffTox design will be implemented using the specialized 
computer program developed by Jin et al.60 The study biostatistician Peter Thall, Ying Yuan, or 
Xuemei Wang in the Biostatistics Department should be consulted as necessary during trial 
conduct. Secondary outcomes will include progression-free survival (PFS) time, overall survival 
(OS) time, objective response rate (ORR), and quality of life (QOL). 
 
Patients will receive baseline staging studies with CT or MRI and be assessed for treatment 
response (RECIST 1.1) by CT or MRI at week 6 (+/- 7 days) as detailed on Sections 9 and 10 of 
the protocol. 
 
Patients will continue to receive combination therapy of MGCD516 plus nivolumab on protocol 
until disease progression or unacceptable treatment-related toxicity. Patients will be allowed to 
continue study therapy after initial investigator-assessed RECIST 1.1-defined progression if they 
are deemed by the investigator to be deriving clinical benefit and tolerating study drug(s), as 
described in Section 8.3. 
 
 
 
6.0 STUDY MEDICATIONS 
 
6.1 
Nivolumab (Anti-PD1) 
 
Nivolumab is a fully human, IgG4 (kappa) isotype, monoclonal antibody that binds PD-1. 
Nivolumab will be supplied in vials of 100 mg (10 mg/mL) and packaged in an open-label 
fashion. Ten nivolumab vials (each 10 mL) will be packaged within a carton. The vials are not 
subject specific although there will be specific vial assignments by subject distributed by the 
Pharmacy in order to track drug usage and re-supply. 
 
6.1.1 
Dose Calculation of nivolumab 
 
Nivolumab will be 240 mg (every 2 weeks) or 480 mg (every 4 weeks), flat dose per infusion. 
Dose adjustment is not allowed. 
 
6.1.2 
Preparation and Dispensing of Nivolumab 
 
The product storage manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the Investigator 
Brochure. If concerns regarding the quality or appearance of the study drug arise, do not 
dispense the study drug and contact the sponsor immediately. 
 
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (e.g. required diluents, administration sets). 
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Nivolumab vials must be stored at a temperature of 2°C to 8°C and should be protected from 
light. If stored in a glass front refrigerator, vials should be stored in the carton. Recommended 
safety measures for preparation and handling of nivolumab include laboratory coats and gloves. 
Nivolumab will be obtained through commercial sources as the trial is being conducted in the 
salvage setting that nivolumab is FDA-approved for and its use is in accordance with the 
National Comprehensive Cancer Network (NCCN) guidance. Care must be taken to assure 
sterility of the prepared solution as the product does not contain any anti-microbial preservative 
or bacteriostatic agent. No incompatibilities between nivolumab and polyolefin bags have been 
observed. 
 
Nivolumab is to be administered as a 60 +/- 15 minute IV infusion, using a volumetric pump 
with a 0.2/0.22 micron in-line filter at the protocol-specified dose. The drug can be diluted with 
0.9% normal saline for delivery but the total drug concentration of the solution 1 mg/ml to 10 
mg/ml. It is not to be administered as an IV push or bolus injection. At the end of the infusion, 
flush the line with a sufficient quantity of normal saline. 
 
6.1.3 Administration of nivolumab 
 
Each treatment cycle will last 2 weeks (or 4 weeks if the patient is switched to the nivolumab 
schedule of 480 mg IV every 4 weeks). During the first treatment cycle, patients will be treated 
with MGCD516 only. The 1st infusion of nivolumab will be given on day 1 of the 2nd treatment 
cycle. Patients will receive nivolumab as a 60 +/- 15 minute IV infusion on Day 1 of a treatment 
cycle every 2 weeks until disease progression or intolerability. There will be no nivolumab dose 
escalations or reductions allowed. Patients may be dosed no less than 12 days from the previous 
dose. If a subject cannot receive a following dose of the cycle within the designated time frame, 
it will be omitted and the next dose received will be considered Day 1 of the next cycle. 
 
Nivolumab should be administered under the supervision of a physician experienced in the use of 
IV agents. Nivolumab is administered as an IV infusion only. 
 
Patients may receive nivolumab at the MDACC local Regional Cancer Centers or local physician 
office. However, initial screening, workup, the first dose of nivolumab, restaging, and biological 
sample collection must be done at the MDACC main campus. The participating oncologists will 
be advised to order pre- and post-treatment evaluations according to the protocol with a written 
memo. Patients with local physicians who agree to manage standard infusions must agree to 
perform required tests, send all related medical records to MDACC, and allow the MDACC 
investigator to direct dose adjustments. The patients are required to return to MDACC for 
evaluation at weeks 4 (+/- 3 days), 6 (+/- 3 days) from the day of study treatment initiation, and 
then at least every 12 weeks (+/-7 days) for those that are progression-free during the first 2 years, 
and then every 6 months for those that progression-free for more than 2 years. 
 
 All study related treatment decisions will be made by the MD Anderson PI or designee. 
 
Calculate Total Infusion Volume as follows: 
 
(Total nivolumab dose in mg ÷ 10 mg/mL) + dilution volume = total infusion volume in mL 
Calculate Total Drug Concentration as follows: 
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Total nivolumab dose in mg ÷ Total infusion volume nivolumab dose in ml = total infusion 
volume in mg/mL. 
Total concentration cannot be below 1 mg/mL. 
 
Calculate Rate of Infusion as follows: 
Total infusion volume in mL ÷ 60 minutes = rate of infusion in mL/min. 
 
6.1.4 
Patient Monitoring During Infusion 
 
Patients will be monitoring by standard of care vital signs during nivolumab infusion.  
 
6.1.5 
Treatment of nivolumab Related Infusion Reactions 
 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- 
or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should 
be reported within 24 hours to the BMS and reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE (version 4.0) guidelines. 
 
Treatment recommendations for nivolumab related infusion reactions are provided below and 
may be modified based on MD Anderson treatment standards and guidelines, as appropriate: 
 
For Grade 1 symptoms (Mild reaction; infusion interruption not indicated; intervention not 
indicated): 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or acetaminophen 325 to 1000 mg at least 30 minutes before additional 
nivolumab administrations. 
 
For Grade 2 symptoms (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g. antihistamines, non-steroidal anti- 
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤ 24 hours): 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg; remain at 
bedside and monitor subject until resolution of symptoms. Corticosteroid or bronchodilator 
therapy may also be administered as appropriate. If the infusion is interrupted, then restart the 
infusion at 50% of the original infusion rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
subject closely. If symptoms recur then no further nivolumab will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the subject until 
resolution of symptoms. The amount of study drug infused must be recorded on the case report 
form (CRF). The following prophylactic premedications are recommended for future infusions: 
Diphenhydramine 50 mg (or equivalent) and/or acetaminophen 325 to 1000 mg should be 
administered at least 30 minutes before additional nivolumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be 
used. 
 
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For Grade 3 or Grade 4 symptoms [Severe reaction, Grade 3: prolonged (i.e. not rapidly 
responsive  to  symptomatic  medication  and/or  brief  interruption  of  infusion);  recurrence  of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
(e.g. renal impairment, pulmonary infiltrates), Grade 4: life-threatening; pressor or ventilatory 
support indicated]: 
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and treat 
the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly 
for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV 
(or equivalent), as needed. Subject should be monitored until the investigator is comfortable that 
the symptoms will not recur. Nivolumab will be permanently discontinued. Institutional 
guidelines will be followed for the treatment of anaphylaxis. Remain at bedside and monitor 
subject until recovery from symptoms. In the case of late-occurring hypersensitivity symptoms 
(e.g.  appearance  of  a  localized  or  generalized  pruritus  within  1  week  after  treatment), 
symptomatic treatment may be given (e.g. oral antihistamine or corticosteroids). 
 
6.2 
MGCD516 
 
MGCD516 is an orally-available, potent small molecule inhibitor of a closely related spectrum of 
tyrosine kinases including MET, Axl family, VEGFR family, PDGFR family, KIT, FLT3, Trk 
family, RET, DDR2, and selected Eph family members. MGCD516 targets several clinically 
validated ccRCC pathways including VEGF and c-MET. 
 
6.2.1 
Formulation and Packaging 
 
MGCD516 will be provided by Mirati as 10 and 40 mg unit dose strength capsules.  Please refer 
to the drug label for formulation and handling information. The composition of the drug product 
consists of a blend of MGCD516 free base drug substance, microcrystalline cellulose (Avicel® 
PH302) and polysorbate 80 (Tween® 80). The blend is filled into either  Size 1 Light Blue 
Opaque (10 mg strength) or Size 1 Swedish Orange Opaque (40 mg strength), hard gelatin 
capsules. 
 
MGCD516 drug product is packaged in 30 count, high-density polyethylene (HDPE), white 
opaque, round bottles.  The 1 mg unit dose capsules are packaged into 30 cc bottles while the 2, 
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 used for all 4 dosage strengths. Each bottle is labeled with 
contents, product lot number, required storage conditions, and regional specific cautionary 
statement “New Drug-Limited by Federal Law to Investigational Use.” 
 
The drug will be provided free of charge by Mirati Therapeutics.  Up to 2 or 3 month drug supply 
will be provided to patients in long term extension phase.  Depending on the return appointment.  
 
6.2.2 
Dose 
 
Beginning on day 1 of the study, each patient will be treated with a daily oral dose of MGCD516 
determined by the Lo-EffTox method60 among the four levels 60, 80, 120 and 150 mg/day. The 
first cohort will be treated at the pre-specified dose of 80 mg of MGCD516 per day. All 
successive doses will be chosen by the Lo-EffTox method, and no untried dose level will be 
skipped when escalating. Patients 
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will continue to receive MGCD516 daily until disease progression or unacceptable treatment- related 
toxicity. 
 
6.2.3 Administration of MGCD516 
 
MGCD516 will be self-administered by the patients. The investigator will instruct the patient to take 
the study drugs exactly as specified in the protocol. MGCD516 will be administered orally as a once 
daily dose. MGCD516 capsules should be taken in the fasted state, at least 2 hours after the previous meal 
and 1 hour before the next meal. 
 
6.2.4 
Compliance 
 
Patients will be required to return all empty bottles of study medication at the beginning of every other 
cycle, for destruction. Patients will keep a drug diary to document administration compliance. The 
completed diaries will be brought to clinic for review. Self-administered medications must be accounted 
for and destroyed per applicable Institutional and Departmental policy. Instructed intervals and dosing 
will be documented in the medical record. Compliance (individual drugs) within 80% of instructed dose 
and schedule is expected of participants during each cycle. Variations in dosing within expected 
compliance will not constitute a protocol deviation or violation. Missed dosed may be documented in 
the electronic case report form.   
 
6.2.5 Drug Storage and Drug Accountability 
The investigator, or an approved representative, e.g. pharmacist, will ensure that all study 
medications are stored in a secured area, under recommended storage conditions and in accordance 
with applicable regulatory requirements. All study drug supplies must be kept in a locked limited 
access room. The study drug must not be used outside the context of this protocol.  Bottles of 
MGCD516 are to be stored at room temperature (suggested range is 15- 30°C or 59-86°F). 
 
The investigator must maintain adequate records documenting the receipt, use, loss, or other deposition 
of the investigational product. The records must identify the investigational product, including batch 
or code numbers, and account for its disposition on patient-by-patient basis, including specific dates 
and quantities. 
 
6.2.5.1 MGCD516 Destruction 
Investigational MGCD516 (expired or end of study) should be destroyed on site according to the 
institution’s standard operating procedure. 
 
6.2.6 Management of MGC516 toxicity 
 
6.2.6.1 Management of stomatitis/oral mucositis/mouth ulcers 
 
Stomatitis/oral mucositis/mouth ulcers due to study drug should be treated using local supportive care. 
Please note that investigators in earlier trials have described the oral toxicities associated with study drug 
as mouth ulcers, rather than mucositis or stomatitis. If your examination reveals mouth ulcers rather than 
a more general inflammation of the mouth, please classify the adverse event as such. Please follow the 
paradigm below for treatment of stomatitis/oral mucositis/mouth ulcers: 
 
1. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouth wash or salt 
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water (0.9%) mouth wash several times a day until resolution. For more severe toxicity (Grade 2 in 
which case patients have pain but are able to maintain adequate oral alimentation, or Grade 3 in 
which case patients cannot maintain adequate oral alimentation), the suggested treatments are 
topical analgesic mouth treatments (i.e., local anesthetics such as benzocaine, butyl aminobenzoate, 
tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
 
2. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents. 
 
3. Antifungal agents must be avoided unless a fungal infection is diagnosed. In particular, systemic 
imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should be avoided in all 
patients due to their strong inhibition of metabolism of study drug, thereby leading to higher drug 
level exposures. Therefore, topical antifungal agents are preferred if an infection is diagnosed. 
Similarly, antiviral agents such as acyclovir should be avoided unless a viral infection is 
diagnosed. 
 
Note:  Stomatitis/oral mucositis should be appropriately graded using the functional grading given on 
the NCI CTCAE for adverse events, version 4.0. 
 
6.3 Concomitant Therapies 
 
The following considerations apply during the entire duration of the study: 
• No other approved or investigational anticancer treatment will be permitted during the study 
period, including chemotherapy, biologic agents, hormone therapy or immunotherapy except for 
bisphosphonates.  No other investigational drug may be used during treatment on this protocol, and 
concurrent participation in another therapeutic clinical trial is not allowed. 
• No anticancer agents other than the study medications should be given to patients. If such 
agents are required for a patient then the patient must first be withdrawn from the study. 
• Surgery or radiation therapy for palliation purposes or management of intercurrent illness which, 
in the judgement of the treating physician, is not related to disease progression. After the patient 
has received at least 2 infusions of nivolumab and 6 weeks (42 days) of oral MGCD516 then 
further therapy on protocol can be held for up to 4 weeks (28 days) to allow 
for recovery from surgical or other interventions. 
• Growth factors (e.g.G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) are not to be 
administered prophylactically but may be prescribed by the investigator for rescue from severe 
hematologic events, if this is thought to be appropriate. 
• No chronic treatment with systemic steroids or other immunosuppressive agents. Topical or 
inhaled corticosteroids are allowed. 
• Live vaccines should be avoided while a patient is on protocol. 
• The co-administration of MGCD516 and oral warfarin is possible but should be subject to 
verification of coagulation (INR) once steady state is reached (after one week’s treatment). 
• Patients who develop venous thromboembolism (pulmonary embolisms or deep venous 
thrombosis) may be treated as indicated by LMW heparin and stay on protocol at the 
discretion of the treating physician. 
• The patient will provide a list of concurrent medications related to co-morbidity (e.g. 
hypertension, diabetes, etc.), including over the counter agents, taken prior to enrollment. The list 
will be updated during clinic visits while on treatment and will be maintained in the medical 
record.  
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• In vitro experiments indicate that MGCD516 is a potential inducer of CYP 2B6 and 3A4, as well as a 
potential inhibitor of CYP 2C8, 2D6, and 3A4, though neither time dependent nor metabolism 
dependent inhibition has been observed. Medications that are substrates for CYP 2C8, 2D6 or 3A4 
and are either sensitive substrates or have a narrow therapeutic index should be used with caution during 
treatment with MGCD516. 
• In vitro experiments in microsomes and recombinant human P450 enzymes suggest that MGCD516 
is metabolized by several cytochromes including CYP 3A4, 2B6, 2D6, and with a low risk of any 
one CYP demonstrating 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 the cytochrome P450 system. 
• The solubility of MGCD516 is pH dependent. For this reason, medications that are associated with 
sustained increase in gastric pH should be avoided during treatment with MGCD516. Patients 
requiring gastric pH medications should switch from use of proton pump inhibitors or H2 antagonists to 
use of antacids. 
• 
MGCD516 is an inhibitor of BCRP and P-gp transporters based on in vitro studies. Medications that 
are substrates for BCRP or P-gp transporters should be avoided during treatment with 
MGCD516. 
• 
Medications with QTc Prolonging Activity: The risk of QTc prolongation in patients receiving sitravatinib 
has not been characterized. Use of medications known to prolong QTc and pose risk of Torsades de 
Pointes (listed in Appendix E) is to be avoided. 
 
6.4 
Dose Modifications and Interruptions 
 
 
There will be no intra-subject dose reduction or escalation of nivolumab during the study. Patients 
will continue to receive MGCD516 daily along with nivolumab 240 mg IV every 2 weeks until 
disease progression or unacceptable treatment-related DLT. Patients who have received at least 6 
infusions of nivolumab 240 mg IV every 2 weeks with no DLT related to nivolumab, will be allowed 
to transition to the equivalent nivolumab schedule of 480 mg IV every 4 weeks. If one agent 
(MGCD516 or nivolumab) is interrupted or discontinued, administration of the other agent may 
continue at the discretion of the Investigator and patient. 
 
There are four possible dose levels for MGCD516 in this study: 60, 80, 120, and 150 mg per day. 
Depending on safety observations, the MGCD516 dose during subsequent cycles of treatment may be 
reduced to the next lower dose level at the discretion of the Investigator and patient. Specifically, for 
grade ≥ 3 hematologic and non-hematologic DLTs or Grade ≥ 2 drug-related uveitis that does not respond 
to topical therapy OR requires systemic treatment (as described in section 5.3) attributed to MGCD516 
then treatment should be held until resolution to ≤ Grade 1 or baseline, and then MGCD516 can be 
restarted at the next lower dose level. If toxicity recurs (second time or third time) at Grade ≥3 (or Grade 
≥ 2 drug-related uveitis that does not respond to topical therapy OR requires systemic treatment), then 
hold MGCD516 until resolution to ≤ Grade 1 or baseline and restart at next lower dose level. If the patient 
develops a DLT related to MGCD516 at the 60 mg dose level then MGCD516 should be discontinued. 
Dose reductions of MGCD516 will also be allowed on a case-by-case basis at the discretion of the 
Investigator and patient in patients with toxicity related to MGCD516 that does not meet the DLT criteria 
outlined in section 5.3. Once the dose has been reduced, re-escalation is generally not recommended but 
may be considered on a case-by-case basis. If the administration of MGCD516 is interrupted for reasons 
other than toxicity, then treatment with MGCD516 may be resumed at the same dose. Only the data from 
the originally planned MGCD516 dose will be used for the dose-finding late-onset EffTox (Lo-EffTox) 
calculations, described in section 14. 
 
Dosing interruptions > 4 weeks that occur for non-drug-related reasons may be allowed if approved by the 
Principal Investigator. Prior to re-initiating treatment in a subject with a dosing interruption lasting > 4 
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weeks, the UTMDACC IND Office must be notified. Tumor assessments should continue as per protocol 
even if dosing is interrupted. 
 
As described above, after the patient has received at least 2 infusions of nivolumab and 6 weeks (42 
days) of oral MGCD516 then further combination treatment can be held for up to 4 weeks (28 days) to 
allow for recovery from surgery, radiation therapy, or other interventions for palliation purposes or 
management of intercurrent illness which, in the judgement of the treating physician, is not related to 
disease progression. 
 
Immune-related Adverse Events (irAEs) are defined in the nivolumab label as those occurring during 
nivolumab therapy, often necessitate immunosuppression and have no other alternate etiology. The 
nivolumab package insert (http://packageinserts.bms.com/pi/pi_opdivo.pdf) provides detailed 
evaluation and management guidelines for the following types of ir-AEs: pneumonitis, colitis, hepatitis, 
endocrinopathies, nephritis/renal dysfunction, rash, and encephalitis. As a general principle, nivolumab 
should be withheld or permanently discontinued in patients with moderate or severe irAEs. Depending 
on the nature of the irAE, it should be managed with corticosteroids and/or hormone-replacement 
therapy. The corticosteroids should be tapered down upon improvement of the irAE to Grade ≤1. 
Depending on the severity of the irAE, restarting of nivolumab may be considered. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 28 days, the UT MDACC IND Office must 
be consulted. Tumor assessments should continue as per protocol even if dosing is interrupted. 
 
Patients experiencing any Grade 4 non-hematological toxicity should be taken off study. MGCD516 
can be held in patients experiencing, despite optimal supportive care, persistent non- overlapping 
toxicities attributed to MGCD516, such as hypertension, palmar-plantar erythrodysesthesia, peripheral 
neuropathy, or stomatitis. The Principal Investigator must be consulted prior to re-initiating treatment in 
a subject with a dosing interruption lasting > 4 weeks. 
 
With regards to the management of potential overlapping toxicities of the two drugs: 
• Patients experiencing Grade 3 fatigue for > 5 days despite optimal supportive care should be 
taken off study with discontinuation of the combination therapy. 
• In patients experiencing Grade 3 rash or Grade 2/3 diarrhea, both oral MGCD516 and 
nivolumab should be held until improvement to Grade ≤1. Topical and/or systemic steroids 
can be given as needed. If no improvement to ≤ Grade 1 after combination treatment has been 
held for >3 weeks then the patient should be taken off study. Dosing interruptions for 
prolonged steroid tapers >6 weeks to manage drug-related adverse events are allowed. The 
Principal Investigator must be consulted prior to re-initiating treatment in a patient with a 
dosing interruption lasting > 4 weeks. 
• Patients experiencing Grade 3/4 elevation in serum amylase and/or lipase levels associated 
with clinical or radiological evidence of pancreatitis, with no other alternate etiology, should 
be taken off study with discontinuation of the combination therapy. 
 
Discontinuation criteria for nivolumab and MGCD516 are described in sections 8.1 and 8.2, 
respectively. 
 
 
6.5 Quality of Life Evaluation 
 
Measuring quality of life (QOL) outcomes in cancer patients has become an important mandate for 
clinical trials.  It is especially important to assess QOL in phase II cancer clinical trials that are likely to 
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move into the phase III setting.  The extent to which treatment impairs QOL is information the patients 
need when making treatment decisions.  It is also important to try and identify factors that are associated 
with better adjustment to help us identify patients at risk for adjustment problems and translate this 
information into the clinical setting to individualize intervention programs.  In addition, elucidating 
protective and risk factors will help identify individuals at greater risk for medical complications, disease 
progression, and recurrence. 
 
Patients will experience somewhat different symptoms when they receive the different therapies.  In 
order to assess the effects of combining these treatments, we will assess multidimensional aspects of 
QOL over the treatment course. 
 
QOL evaluations will not be performed during the long term extension phase of the trial.  
 
6.5.1 Assessment Schedule 
 
All patients will complete a full assessment battery at baseline, prior to treatment.  Patients will then 
complete a brief assessment battery at week 2, week 4, week 6, and then every 12 weeks (see Table 4). 
 
 
Table 4:  Data collection sessions for psychosocial measures 
BASELINE 
 
FOLLOW-UP   
• FACT 
• SF-12 
• Depression (CES-D) 
• Social Provisions Scale 
• History of depression 
• FMCS 
• FACT 
• SF-12 
• CES-D 
• FMCS 
 
 
Several measures used previously in our work on chronic stress and QOL will be used in the proposed 
study.  In all cases, they have proven to be useful and sensitive measures of stress and QOL, have proven 
to be stable, reliable, and valid with groups of people who are and are not suffering from major 
depression or other psychiatric disorders. All surveys will be completed electronically using e-tablets 
and response data will be collected using the HIPAA-compliant Qualtrics software platform. 
 
Quality of Life:   
 
The Functional Assessment of Cancer Therapy (FACT) is a cancer-specific measure of health-related 
quality of life.  This instrument was able to discriminate between individuals with metastatic and non-
metastatic disease, as well as between patients at different stages of illness.  The scale has been found to 
have good concurrent validity, high internal consistency (0.89), and good test re-test reliability (0.82 to 
0.88).  The FACT will be completed at each assessment. 
 
General QOL – General QOL will be assessed using the Medical Outcomes Study 12-item short-form 
survey (SF-12).  Responses are based on a Likert-type scale. The SF-12 is a health-related QOL measure 
that is responsive to minor versus major medical problems as well as psychiatric problems. It has good 
test-retest reliability (coefficients for various subscales range from 0.60 to 0.81) and good internal 
consistency (coefficients range from 0.78 to 0.93).  The SF-12 will be completed at each assessment. 
 
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Depression:   
  
Depression will be assessed using the Centers for Epidemiologic Studies - Depression (CES-D) (3).  The 
CES-D is a well-validated 20-item self-report measure of depression that focuses on affective components 
of depression.  Cut-off scores of 16 for screening clinical depression have been recommended.  Internal 
consistency is high in the general population and in patient populations.  It also has been demonstrated to 
possess adequate convergent validity with other measures of depression.  The CES-D will be completed at 
baseline and at each subsequent assessment. 
 
Lifetime history of Major Depressive Disorder (MDD) will be measured using the two cardinal items 
from the Structured Clinical Interview for DSM-IV Disorder (SCID) that assess lifetime presence of 
depressed mood or anhedonia for two weeks or more. Patients are considered to have lifetime MDD if 
they endorse one or both of the items. These two questions will only be completed at the first assessment. 
 
Social Support: 
Perceived availability of social support will be measured using the 24-item Social Provisions Scale that 
includes subscales for attachment, social integration, opportunity for nurturance, reassurance of worth, 
reliable alliance, and guidance.  The SPS will only be completed at baseline. 
 
Hope for the future:  
Finding meaning in cancer will be measured using the Finding Meaning in Cancer scale (FMCS).  This 
17-item scale assesses benefits in different domains, including accepting life’s imperfections, changing 
priorities, and developing a sense of purpose in life. The scale is scored as a single factor, has good 
internal consistency (0.95), and has shown moderate association with psychological well-being.   
 
7.0 
CORRELATIVE STUDIES 
 
We will perform immune monitoring, including but not limited to the evaluation of CD4 and CD8 T 
cells in available tumor tissue and peripheral blood samples as previously published.63-66 Peripheral 
blood and tumor tissue samples (optional) will be obtained within 14 days pretreatment, 2 weeks after 
MGCD516 monotherapy, following 2 infusions of Nivolumab, and upon disease progression. All 
samples will be collected and analyzed per a separate IRB-approved protocol. In addition, another IRB-
approved protocol, separate from the aforementioned immunotherapy analyses, will be used to 
investigate in the blood and tumor tissues, a panel of cytokines, chemokines, cell-free DNA, and other 
relevant angiogenic factors, biological receptors, ligands, nucleotides and proteins. 
 
Up to one hundred (150) ml of blood will be drawn at the visits outlined in Sections 9 and 10. These 
samples will be labeled with confidential identification numbers and provided to the 
Immunotherapy platform for immunological assessments. A detailed laboratory manual highlighting 
the blood collection and processing procedures will be prepared. All blood collection will be 
compliant with institutional safety standards and will not exceed the maximum blood draw per 
venipuncture policy. 
 
Blood and tissue collections for correlative studies will not be performed during the long term extension 
phase of the trial. The only exception is optional collection of blood or tissue samples for those patients 
taken off therapy due to disease progression to assess causes of disease progression. 
 
 
 
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8.0 
DISCONTINUATION OF THERAPY 
 
Patients MUST be discontinued from study therapy AND withdrawn from the study for the 
following reasons: 
 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• 
Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the opinion 
of the Investigator, indicates that continued treatment with study therapies is not in the best 
interest of the subject 
• 
Termination of the study by MD Anderson Cancer Center 
• 
Imprisonment or the compulsory detention for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness. 
• 
Progressive disease:  Patients, who develop rapidly progressive disease (clinically or by 
RECIST) before the scheduled evaluations, may be taken off protocol treatment at the 
discretion of the investigator. Patients can continue to receive their assigned targeted 
agent, even if they develop progressive disease radiographically, as long as in the 
judgment of the treating physician, they are benefitting from their targeted agent.  
 
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value suspected to be related to study drug must be followed at least weekly until 
the adverse event or abnormal laboratory resolves or returns to grade 1. This may be done by telephone 
correspondence. If a patient requires a dose delay of > 28 days from the intended day of the next 
scheduled dose, then the patient must be discontinued from the study. If one agent (MGCD516 or 
nivolumab) is interrupted or discontinued, administration of the other agent may continue at the 
discretion of the Investigator and patient. 
 
8.1 
Discontinuation Criteria of Nivolumab 
 
Nivolumab administration should be discontinued for the following: 
 
• 
Any Grade ≥ 2 drug-related uveitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period OR 
requires systemic treatment 
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for laboratory abnormalities, drug-related bronchospasm, hypersensitivity 
reactions, and infusion reactions: 
− 
Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
 Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation. 
 Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation: 
• 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5- 10x 
upper limit of normal (ULN) for > 2 weeks 
• 
AST or ALT > 10x ULN 
• 
Total bilirubin > 5x ULN 
• 
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN 
 
− 
Grade 3 drug-related bronchospasm, hypersensitivity reaction, or infusion reaction of 
any duration requires discontinuation 
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• 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
− 
Grade 4 neutropenia ≤ 7 days 
− 
Grade 4 lymphopenia or leukopenia 
− 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset. 
− 
Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis. It is recommended to consult with the PI for Grade 4 
amylase or lipase abnormalities. 
• 
Any dosing interruption lasting > 4 weeks with the following exceptions: 
− 
Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing interruption 
lasting > 4 weeks, the Principal Investigator must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted. 
− 
Dosing interruptions > 4 weeks that occur for non-drug-related reasons may be allowed if 
approved by the Principal Investigator. Prior to re-initiating treatment in a subject with a 
dosing interruption lasting > 4 weeks, the UTMDACC IND Office must be notified.  
Tumor assessments should continue as per protocol even if dosing is interrupted. 
• 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab dosing. 
• 
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase or lipase, AST, ALT, or total bilirubin: Grade 3 amylase or lipase 
abnormalities that are not associated with symptoms or clinical manifestations of pancreatitis 
do not require a dose delay. It is recommended to consult with the PI for Grade 3 amylase or 
lipase abnormalities. 
• 
Any Grade 3 colitis, neurologic toxicity, symptomatic pancreatitis, or pneumonitis. 
• 
Any Grade ≥3 Stevens-Johnson Syndrome of Toxic Epidermal Necrolysis (TEN). 
 
 
8.2 
Discontinuation Criteria of MGCD516 
 
General or specific changes in the patient’s condition which render the patient unacceptable for 
further treatment in the judgment of the investigator. Patients may discontinue from study treatment or 
from the study at any time at their own request, or they may be discontinued at any time at the 
discretion of the investigator for safety, or behavioral reasons, or the inability of the patient to 
comply with the protocol required schedule of study visits or procedures at a given study site. 
 
Criteria that may be used to discontinue patients from receipt of study medication will include, but 
will not be limited to: 
 
• Objective disease progression according to RECIST 1.1 as determined by the investigator, 
(patients who may derive clinical benefit may continue on treatment at the discretion of the 
investigator); 
• Global deterioration of health status requiring discontinuation; 
• Adverse event; 
• Significant protocol violation; 
• Lost to follow-up; 
• Refusal for further treatment; 
• Study terminated by Sponsor; 
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• Death. 
 
Reasons for discontinuation from study follow-up may include: 
• Completed study follow-up; 
• Study terminated by Sponsor; 
• Lost to follow-up; 
• Refusal for further follow-up for survival; 
• Death. 
 
If a patient does not return for a scheduled visit, every effort should be made to contact the patient.  At 
least 2 attempts should be made to contact the patient and each attempt should be recorded in the 
source documents.  In any circumstance, every effort should be made to document patient outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request the patient to return 
for a final visit, and if applicable follow-up with the patient regarding any unresolved adverse events. 
 
If the patient withdraws from the study treatment, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be collected. 
The investigator may retain and continue to use any data collected before such refusal for further follow-
up. 
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8.3 
Continued Treatment beyond Progression of 
Disease 
 
Accumulating evidence indicates a minority of patients treated with immunotherapy may 
derive clinical benefit from continued treatment despite initial evidence of progressive 
disease.67 For this reason, patients will be permitted to continue study therapy beyond 
initial investigator- assessed RECIST 1.1-defined progression as long as they meet the 2 
criteria listed below. 
 
• Investigator-assessed clinical benefit, 
and 
• Subject is tolerating study 
drug 
 
The assessment of clinical benefit should take into account whether the subject is 
clinically deteriorating and unlikely to receive further benefit from continued treatment. 
 
All decisions to continue treatment beyond initial progression must be discussed with the 
MDACC IND Office and documented in the study records. 
 
Patients should discontinue study therapy upon evidence of further progression, defined 
as an additional 10% or greater increase in tumor burden from time of initial progression 
(including all target lesions and new measurable lesions). 
 
New lesions are considered measurable at the time of initial progression if the longest 
diameter is at least 10 mm (except for pathological lymph nodes, which must have a short 
axis of at least 15 mm). Any new lesion considered non-measurable at the time of initial 
progression may become measurable and therefore included in the tumor burden 
measurement if the longest diameter increases to at least 10 mm (except for pathological 
lymph nodes, which must have an increase in short axis to at least 15 mm). 
 
For statistical analyses that include the investigator-assessed progression date, patients 
who continue treatment beyond initial investigator-assessed RECIST 1.1-defined 
progression will be considered to have investigator-assessed progressive disease at the time 
of the initial progression event. 
 
 
9.0 
 
 
 
 
PRE-TREATMENT 
EVALUATION 
 
 
 
9.1 Within 28 days of study 
entry 
• Signed and dated informed consent. 
• Physical Exam and updated medical history 
• Updated evaluation of concurrent non-malignant diseases and recent medical 
therapy (within the thirty days prior to the evaluation). 
• Imaging: CT scan of chest, abdomen, and pelvis (MRI of abdomen and pelvis may 
substitute CT abdomen/pelvis). CT scan or MRI of the brain. 
• Plain films of bones/skeletal survey and bone scan will be ordered only if clinically 
indicated 
• 12-lead ECG 
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9.2 Within 14 days (+/- 3 days) of study 
entry 
• Confirmation of the eligibility of patients (see Section 4 for detailed 
Inclusion/Exclusion criteria) 
• Histologic diagnosis/confirmation of RCC with clear cell component 
• Baseline signs and symptoms 
• Current medications 
• Interim history 
• Assessment of Karnofsky performance status, weight, temperature, blood 
pressure, heart rate, respiratory rate, oxygen (O2) saturation 
• Physical Examination 
• Laboratory testing: 
o CBC with differential & platelets 
o Chemistry panel including electrolytes (Na, K, Cl, CO2), albumin, 
alkaline phosphatase, ALT, AST, calcium, LDH, total bilirubin, BUN, 
creatinine, 
Phosphorus 
o INR/PTT 
o Lipid profile 
o Blood glucose 
o Serum amylase and lipase, 
o Serum free T4 and TSH. 
o Serum ACTH and Cortisol 
o Blood samples for Immune Testing and Correlative Studies 
o Urinalysis: Gross examination including specific gravity, protein, glucose, 
and 
blood; microscopic examination including white blood cells / high power 
field 
(WBC/HPF), red blood cells / high power field (RBC/HPF) and any 
additional findings. 
 If urine protein ≥ 100 mg/dL then obtain random 
urine protein/creatinine ratio 
o Serum or urine pregnancy test for females of childbearing potential 
• Collect fresh biopsy (optional / up to 14 days prior) 
• Complete e-tablet QOL assessments (FACT, SF-12, CES-D, Social Provisions 
Scale, FMCS, History of Depression) 
 
9.3 Within 6 months (180 days) of study 
entry 
• Doppler echocardiogram  
 
9.4 Treatment can not start until at least 1 week after any minor surgical 
procedure, excluding placement of a vascular access device and core biopsies. 
 
10.0 
EVALUATION DURING 
TREATMENT 
 
10.1 
A cycle of treatment is defined as 2 weeks (+/- 3 days), or 4 weeks +/- 3 days if the 
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patient is switched to the nivolumab schedule of 480 mg IV every 4 weeks. The 
following must be performed on Day 1 of each course. If assessment and tests were 
completed within 7 days of Course 1 Day 1, procedures will not be repeated. Patients 
are required to come to MD Anderson at the beginning of every course. 
 
• Interim history 
• Assessment of Karnofsky performance status, weight, temperature, 
blood pressure, heart rate. 
• Physical examination 
• Assessment of all concomitant medications and treatments taken since the 
last assessment. Concurrent medications related to co-morbidity (e.g. 
hypertension, diabetes, etc.) will be recorded in the database. The name, 
dose, date start and stop (as accurately as possible) along with indication 
of the medication will be collected. 
• Assessment of adverse events and tumor-related signs and symptoms 
• Assessment of treatment related toxicities 
• Laboratory testing: 
o CBC with differential & platelets 
o Chemistry panel including electrolytes (Na, K, Cl, CO2), 
alkaline phosphatase, ALT, AST, calcium, total bilirubin, 
BUN, creatinine 
o Blood for correlative studies 
o Tissue sample 
 
10.2 
After 2 weeks (± 3 days) of MGCD516 monotherapy: collect blood samples as well 
as optional fresh biopsy for immune testing and correlative studies to assess treatment 
response to MGCD516 monotherapy. 
 
10.3 
The following labs will additionally be obtained at 6 weeks (42 days +/- 3 days), 12 
weeks (84 days +/- 7 days), and every 12 weeks (84 days +/- 7 days)for as long as 
patients are receiving therapy on protocol : 
o Lipids 
o Blood glucose 
o Serum amylase and lipase 
o Serum free T4 and TSH. 
o Serum ACTH and Cortisol 
o Chemistry panel including electrolytes (Na, K, C1, CO2), albumin,  alkaline 
phosphatase, ALT, AST, calcium, LDH, total bilirubin, BUN, creatinine, 
phosphorus 
o Urinalysis: Gross examination including specific gravity, protein, glucose, and 
blood; microscopic examination including white blood cells / high power field 
(WBC/HPF), red blood cells / high power field (RBC/HPF) and any additional 
findings. 
 If urine protein ≥ 100 mg/dL then obtain random urine 
protein/creatinine ratio. 
o Optional: on the 4th week (± 3 days) of therapy on protocol (following at 
least 1 infusion of nivolumab): collect blood samples for immune testing and 
correlative studies to assess treatment response to combination therapy. 
 
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10.4 
Imaging scans (CT of chest and CT scan or MRI of abdomen/pelvis) will be 
performed to determine disease response at 6 weeks (42 days)(+/- 3 days), 12 weeks 
(84 days +/- 7 days), and every 12 weeks (84 days +/- 7 days), for as long as 
patients are receiving therapy on protocol.  A follow-up CT or MRI of the brain will 
only be ordered if clinically indicated. 
 
10.5 
Echocardiogram will be obtained on the 12th week (± 14 days) of therapy on 
protocol and then repeat every 6 months (± 1 month) or as clinically indicated. 
 
10.6 
Complete e-tablet QOL assessments (FACT, SF-12, CES-D, FMCS) at 2 weeks (± 
7 days), 6 weeks (± 7 days), 12 weeks (± 7 days) and every 12 weeks (± 7 days) 
thereafter. 
 
 
10.7 
End of Treatment Evaluation:  Adverse events and tumor-related signs and 
symptoms will be assessed.  For patients who develop toxicity related to study drug 
necessitating discontinuation of protocol therapy before restaging to assess tumor 
response, physicians treating these patients will make every effort to repeat the 
appropriate imaging studies if feasible and indicated to assess tumor response at the 
time the patients are taken off protocol treatment. For patients taken off protocol 
therapy due to disease progression, blood samples and tumor biopsy (optional at the 
physician's discretion) will be collected within 28 days from the time that disease 
progression is first confirmed and used for immune testing and correlative studies. 
 
10.8 
Long-term Follow-Up: Patients will be followed for survival every 3 months (90 
days ± 1 month or 28 days) by record review or telephone correspondence.  Patients 
in long term follow up at the time of Long Term Extension Phase approval will be 
assessed for survival every 6 months (180 days +/- 1 month or 28 days) 
 
10.9 
Long term Extension Phase 
Upon analysis of primary endpoints, the Investigator, sponsor and supporter may 
agree to notify patients of the status of the clinical trial and allow patients on study 
medication if they agree and consent. The supporter will continue to supply the 
MGCD516 (sitravatinib) drug until the treating physician determines to withdraw 
study medication due to adverse events progression or patient decision.   
Data collection will include visit date, assessment of compliance per patient 
statement, preferable with a medication recorded on study calendar.  Patients who 
choose not to record doses on a medication calendar will not constitute a deviation or 
violation of the protocol. Patients will be asked to return to MD Anderson every 2 to 
3 months (8 to 12 weeks) for resupply of study medication.  The return appointment 
timing is at the discretion of the treating physician.  MGCD516 will not be mailed 
except when acts of nature make it impossible to travel, such as hurricanes, other 
natural storms (such as snowstorms) or in the case of manmade disasters such as fire.    
Patients may remain on MGCD516 even if nivolumab is withdrawn.  As the 
nivolumab is per standard of care dose and schedule the infusions may be scheduled 
locally with the instruction of a local physician letter (“dear doctor” letter).  Serious 
adverse events will be reported and assessed by the MD Anderson study team.   
 
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a. 
During Pre-Study, must be within six months of study entry. 
STUDY CALENDAR 
 
 
 
Pre- 
Study 
 
Day  
+1 
 
Day+15 
(C2D1) 
Each 14 or 28 
day cycle 
(+/- 3 days)z 
4 weeks (28 
days)(+/- 3 days) 
from day+1 
6 weeks (42 
days)(+/- 3 days) 
from day+1 
Every 12 weeks 
(84 days +/- 7 
days)  
 
End of 
treatment 
Informed Consent 
Xm 
 
 
 
 
 
 
 
Confirmation of 
eligibility 
Xn
 
 
 
 
 
 
 
 
Histologic 
diagnosis/confirmation 
X
 
 
 
 
 
 
 
 
Medical History 
Xm 
 
 
 
 
 
 
 
Interim History 
Xn
 
 
X 
 
X 
X 
X 
Physical Examination 
Xn
 
 
X 
 
X 
X 
X 
Imaging 
Xb,m
 
 
 
 
             Xb 
Xb 
Xj 
Echocardiogram   
Xa 
 
 
 
 
 
Xu 
 
Weight, temperature, 
blood pressure, heart rate 
and respiratory rate 
Xn
 
 
 
 
Xh
 
 
 
 
X 
 
X 
 
O2 saturation 
Xn
 
 
 
 
 
 
 
CBC with differential & 
platelets 
   Xc,n
 
 
 
Xc
 
 
Xc
 
Xc
 
 
Chemistry Panel 
Xd,n 
 
 
Xg
 
Xd
Xd
 
INR/PTT 
Xd,n 
 
 
 
 
 
 
 
Serum Free T4 + TSH 
Xn 
 
 
 
 
X 
X 
 
Serum ACTH and 
Xn 
 
 
 
 
X 
X 
 
Urinalysis 
Xn,o 
 
 
 
 
Xo 
Xo 
 
Pregnancy Test 
Xn,f 
 
 
 
 
 
 
 
Lipid Profile 
Xn 
X 
X 
Blood glucose 
Xn 
X 
X 
Amylase and Lipase 
Xn 
X 
X 
12-Lead ECG 
Xm 
Karnofsky Performance 
Status 
Xn 
X 
X 
X 
X 
Concomitant 
Medications 
Xn 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
Initiate daily oral 
MGCD516 
Xp 
Initiate IV nivolumab 
Xq 
QOL assessment 
Xn,x 
 
Xy 
 
 
Xy 
Xy 
 
Long Term Follow Up 
 
 
 
 
 
 
 
Xk 
Optional Procedures 
Blood for correlative 
studies 
Xn 
Xe 
Xr 
Xs 
X 
Xv 
Tissue Sample 
Xn,i 
Xl 
Xt 
Xw 
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b. CT scan of chest, CT scan or MRI of abdomen/pelvis at 6 weeks (42 days)(+/- 3 days) from 
study day 1, then every 12 weeks (84 days)(+/- 7 days) after day 1. CT scan or MRI of the 
brain only at baseline (within 28 days of study entry), and can be repeated if clinically 
indicated. Plain films of bones/skeletal survey and bone scan will not be ordered routinely 
on all patients but only if clinically indicated; any follow-up CT scan or MRI will be ordered 
if clinically indicated. 
c. 
Differentials include neutrophils, lymphocytes, monocytes, eosinophils and basophils 
d. Includes electrolytes (Na, K, Cl, Co2), albumin, alkaline phosphatase, ALT, AST, 
calcium, LDH, total bilirubin, BUN, creatinine, phosphorus, glucose, INR/PTT 
(pre-study only)  
e. 
After 2 weeks (± 3 days) of MGCD516 monotherapy: collect blood sample for 
correlative studies to assess treatment response to MGCD516 monotherapy 
f. 
Only for women of childbearing potential. May be serum or urine. 
g. Only includes electrolytes (Na, K, Cl, Co2), alkaline phosphatase, ALT, AST, calcium, total bilirubin, BUN, 
and creatinine 
h. Only blood pressure and heart rate 
i. 
Optional fresh biopsy at the physician’s discretion (up to 14 days prior) 
j. 
For patients who develop toxicity related to study drug necessitating discontinuation of 
protocol therapy before restaging to assess tumor response, physicians treating these 
patients will make every effort to repeat the appropriate imaging studies if feasible and 
indicated to assess tumor response at the time the patients are taken off protocol treatment. 
k. Patients will be followed for survival every 3 months (90 days ± 1 month or 28 days) 
by record review or telephone correspondence.  Patients in long term follow up at the 
time of Long Term Extension Phase approval will be assessed for survival every 6 
months (180 days +/- 1 month or 28 days) 
l. 
After 2 weeks (± 3 days) of MGCD516 monotherapy: collect fresh biopsy 
(optional at the physician’s discretion) to assess treatment response to MGCD516 
monotherapy 
m. Within 28 days of study entry 
n. Within 14 days (+/- 3 days) of study entry 
o. If urine protein ≥ 100 mg/dL on urinalysis then obtain random urine protein/creatinine ratio 
p. Patients will continue to receive MGCD516 daily until disease progression or 
unacceptable treatment-related toxicity 
q. Patients will receive nivolumab as a 60 +/- 15 minute IV infusion on Day 1 of a treatment 
cycle every 2 weeks until disease progression or intolerability. Patients may be dosed no 
less than 12 days from the previous dose. Patients who have received at least 6 infusions of 
nivolumab 240 mg IV every 2 weeks with no DLTs related to nivolumab, will have the 
option to transition to the equivalent nivolumab schedule of 480 mg IV every 4 weeks. 
r. 
On the 4th week (± 3 days) of therapy on protocol (following at least 1 infusion of nivolumab): collect 
blood sample (optional at the physician’s discretion) for correlative studies to assess treatment response to 
combination therapy 
s. 
On the 6th week (± 3 days) of therapy on protocol (following at least 2 infusions of nivolumab): collect 
blood sample for correlative studies to assess treatment response to combination therapy 
t. 
On the 6th week (± 3 days) of therapy on protocol (following at least 2 infusions of nivolumab): collect 
fresh biopsy (optional at the physician’s discretion) to assess treatment response to combination therapy 
u. Obtain an echocardiogram  on the 12th week (+14 days) of therapy on protocol and then repeat every 6 
months ( + 1 month) 
v. In patients taken off therapy due to disease progression, collect blood sample for correlative studies to 
assess causes of disease progression 
w. In patients taken off therapy due to disease progression, collect fresh biopsy (optional at the physician’s 
discretion) to assess causes of disease progression. 
x. Complete e-tablet QOL assessments (FACT, SF-12, CES-D, Social Provisions Scale, FMCS, History of 
Depression) within 14 days (+/- 7 days) of study entry 
y. Complete e-tablet QOL assessments (FACT, SF-12, CES-D, FMCS) at 2 weeks (± 7 days), , 6 weeks (± 7 
days), 12 weeks (± 7 days) and every 12 weeks (± 7 days) thereafter 
z.   patients who switch to nivolumab 480mg will, from that time onwards, have physical exam, CBC and 
chemistry panel every 4 weeks (28 days +/- 3 days) instead of every 2 weeks (14 days +/- 3 days) 
 
 
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Long Term Extension Phase Schedule of Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a In patients taken off therapy due to disease progression, collect optional blood and tissue 
sample for correlative studies to assess causes of disease progression 
 
11.0 CRITERIA FOR RESPONSE OR PROGRESSION 
 
11.1 Efficacy Assessments 
Progression-free survival (PFS) and objective response rate (ORR), each based on RECIST 
1.1 criteria, are two of the primary efficacy assessments of this study. 
 
Evaluation of response will follow the Response Evaluation Criteria in Solid Tumors 
(RECIST). All tumor measurements must be recorded in centimeters. 
 
• 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 
(those with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically).  A sum of the longest 
diameter for all target lesions will be calculated and reported as the baseline sum longest 
diameter. The baseline sum of longest diameters will be used as the reference by which 
the objective tumor response is characterized. 
 
• Non-target Lesions: 
All other lesions (or sites of disease) up to 2 lesions per site and 5 lesions in total 
should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up. 
 
Event 
Every 8 to 12 weeks 
(56 to 84 days +/- 7 
days) 
 
End of treatment Plus 
30 days post last dose 
 Follow up exam with physician or delegated 
advance practice provider  
X 
X 
Assessment of serious adverse events 
X 
X 
Disease assessment per the discretion of the 
treating physician  
X 
X 
daily oral MGCD516 
 
 
IV nivolumab *every 4 weeks per standard of 
care 
X* 
X 
Routine laboratory assessment per the 
discretion of the treating physician 
 
 
 Blood and tissue for correlative studies 
 
Xa 
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11.2 Evaluation of Target Lesions: 
• Complete Response (CR): 
The disappearance of all target lesions. 
• Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter of target lesions, taking as 
reference the baseline sum longest diameter. 
• Progressive Disease: 
At least a 20% increase in the sum of the longest diameter of target lesions, taking as 
reference the smallest sum longest diameter recorded since the treatment started or the 
appearance of one or more new lesions. 
• Stable 
Disease: 
Insufficient shrinkage to qualify for partial response, or insufficient increase to qualify for 
progressive disease, taking as reference the smallest sum longest diameter since the 
treatment started. 
 
11.3 Evaluation of Non-target Lesions: 
• Complete Response: 
The disappearance of all non-target lesions. 
• Incomplete Response/Stable Disease: 
The persistence of one or more non-target lesion(s) 
• Progressive Disease: 
The appearance of one or more new lesions and/or unequivocal progression of existing 
non-target lesions. 
 
 
11.4 Evaluation of Best Overall Response: 
 
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
Evaluation of Best Overall Response (RECIST) 
 
Target 
Lesions 
Non-target lesions 
New lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR= complete response; PR= partial response; SD= stable disease; and PD= progressive 
disease 
 
 
11.5 Immune related Response Criteria (irRC) 
 
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New, measurable lesions 
Incorporated into tumor burden 
New, non- measurable lesions 
Do not define progression (but precludes 
irCR) 
Non-index lesions 
Contribute to defining irCR (complete 
disappearance is required 
Complete response (CR) 
Disappearance of all lesions in two 
consecutive observations not less than 4 
weeks apart 
Partial response (PR) 
≥50% decrease in tumor burden compared 
with baseline in two observations at least 4 
weeks apart 
Stable disease (SD) 
50% decrease in tumor burden compared 
with baseline cannot be established nor 
25% increase compared with nadir 
Progression of disease (PD) 
≥25% increase in tumor burden compared 
with nadir (at any single time point) in two 
consecutive observations at least 4 weeks 
apart 
 
 
Note: According to the irRC, disease progression of non-index lesions or appearance of 
new non-measurable lesions will not classify the subject as PD, and therefore the subject 
may stay in the study if it is the in the subject’s best interest. A confirmatory tumor 
assessment may be performed no less than 4 weeks after the first indication of progression 
to provide additional data for the investigator to decide if the subject should stay in the 
trial or be discontinued due to clinical progression based on the investigator’s decision. 
 
 
 
11.6 Time -to- Event Assessment of Response 
 
Time to Response: From the start of study drug to the first observation of a response (the 
first of two confirmatory measurements). 
 
Duration of Response: From the first observation of a response (the first of the two 
confirmatory statements) to the first observation of progressive disease, or to death due to 
any cause, or early discontinuation of treatment due to progressive disease. 
Time to Progression: From the start of study drug to the first evidence of progression. 
Progression-free survival (PFS): Time from the start of the study drugs until disease 
progression (based on RECIST 1.1 criteria) or death 
 
Survival:  Survival will be calculated from the start of the study drugs to death due to any 
cause. 
 
Patients in Long Term Extension Phase will not have formal RECIST measurements.  The 
treating physician will evaluate patient for overall continued benefit.   
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12.0 CRITERIA FOR REMOVAL FROM PROTOCOL TREATMENT 
 
• Progressive disease:  Patients, who develop rapidly progressive disease (clinically or 
by RECIST) before the scheduled evaluations, may be taken off protocol treatment at 
the discretion of the investigator. Patients can continue to receive their assigned 
targeted agent, even if they develop progressive disease radiographically, as long as in 
the judgment of the treating physician, they are benefitting from their targeted agent.  
• Intercurrent illness that prevents continuation of treatment. 
• Unacceptable adverse event(s), or delay of treatment for > 4 weeks due to treatment-
related toxicity. Note: Patients who require emergency surgery (e.g. for appendectomy or 
because of trauma complications) or who require a procedure (e.g. 
Kyphoplasty/vertebroplasty) may remain on trial, even if administration of the targeted 
agent is interrupted, as long as the targeted agent is resumed within 4 weeks from date of 
interruption. 
• Death 
• Patient non-compliance with therapy. 
• Decision of the patient to withdraw from the study 
• Lost to follow-up 
• Imprisonment or the compulsory detention for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness. 
 
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. 
 
 
 
13.0 SAFETY ASSESSMENTS AND REPORTING REQUIREMENTS 
13.1 
All patients will be evaluated for safety.  The safety parameters include all laboratory 
tests and hematological abnormalities, physical examination findings, and spontaneous 
reports of adverse events reported to the investigator by patients.  An adverse event is 
any untoward or unfavorable medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, 
or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research.  All 
adverse events encountered after the patient has provided informed consent and until 4 
weeks after the patient has stopped treatment will be evaluated according to the NCI 
Common Toxicity Criteria (CTCAE) version 4.0.  Prior treatment associated toxicities 
present at the time of informed consent but before study treatment initiation, will be 
recorded as baseline abnormalities and graded according to NCI CTCAE version 4.0 
criteria. 
 
Information about all adverse events, whether volunteered by the subject, discovered 
by investigator questioning, or detected through physical examination, laboratory test 
or other means, will be collected and reported  as described in the data submission 
schedule 
 
Reporting Responsibilities of Investigators under 21 CFR 312.64(b) and 
Sponsors under 21 CFR 312.32(c)(1)(i) for Serious and Unexpected Suspected 
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Adverse Reactions 
 
Term 
Investigator 
Responsibility 
Sponsor 
Responsibility 
Final Determination 
Responsibility 
Serious 
(or life-
threatening) 
Yes 
(Investigator must 
report all serious 
adverse events to 
the sponsor 
immediately) 
Yes 
An event is considered 
serious or life-threatening, 
based on either the 
investigator’s or 
sponsor’s opinion. 
Unexpected 
No 
(No requirement to 
assess 
“expectedness”) 
Yes 
The sponsor is 
responsible for 
determining whether 
event meets the definition 
of “unexpected,” based on 
whether the event is listed 
in the investigator 
brochure; or if an 
investigator brochure is 
not required or available, 
is not consistent with the 
risk information described 
elsewhere in the general 
investigational plan or 
elsewhere in the current 
application. 
Suspected 
Adverse 
Reaction – 
(causality 
assessment 
standard - 
“reasonable 
possibility”) 
Yes  
(Investigator must 
provide sponsor 
with an assessment 
of causality)  
Yes (Sponsor’s 
assessment 
determines 
reportability, 
regardless of 
investigator’s 
assessment)  
 
The sponsor is 
responsible for 
determining whether there 
is a reasonable possibility 
that the drug caused the 
adverse event, taking into 
consideration the 
investigator’s assessment. 
 
↓  
The sponsor 
reports serious 
and unexpected 
suspected adverse 
reaction to the 
FDA and all 
participating 
investigators. 
 
13.2Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse event reaction is considered “serious” if, in 
the view of either the investigator or the sponsor, it results in any of the following 
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outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse experience as it occurred. It does not include 
experience that, had it occurred in a more severe form, might have caused 
death. 
• Inpatient hospitalized or prolongation of existing hospitalization. 
• A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, IND 
Office. 
 
• All events occurring during the conduct of a protocol and meeting the definition 
of a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, regardless 
of attribution (within 5 working days of knowledge of the event). 
 
• All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office. 
 
 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. 
 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical 
recovery is complete and laboratory tests have returned to baseline, progression of 
the event has stabilized, or there has been acceptable resolution of the event. 
 
 
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• Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 
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13.3 
Reporting to FDA 
 
• Serious adverse events will be forwarded to FDA by the IND MD Anderson 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
Investigator Communication with Supporting Companies: 
 
13.4 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious 
adverse experiences will be forwarded to the product manufacturer by the investigator. 
 
13.5 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
 
13.6 Long Term Extension Phase 
Patients will continue to be assessed for serious adverse events in the long term extension. 
Routine and expected AEs will not be collected in the case report form.  Reporting of 
events to sponsor and supporter will remain as above.   
 
 
14.0  STATISTICAL CONSIDERATIONS / DATA ANALYSIS 
 
14.1 Phase I-II Dose-Finding Design 
 
This is a phase I–II dose-finding trial to determine the optimal dose of the targeted oral agent 
MGCD516 when combined with immunotherapy via Nivolumab at fixed dose 240 mg IV every 
2 weeks, in patients with metastatic renal cell carcinoma with clear cell component who have 
had prior treatment with anti-VEGF agents. The scientific goal of the trial is to determine an 
optimal MGCD516 dose level among the four levels 60, 80, 120, 150 mg/day given orally each 
day until toxicity of progressive disease. Dose-finding will be done using the sequentially 
adaptive phase I-II late-onset EffTox (Lo-EffTox) trade-off-based design of Jin et al.60-62 For the 
goal of determining an optimum dose, dose limiting Toxicity within 12 weeks from the start of 
therapy is defined as described in section 5.3, and Efficacy is defined as achieving CR, PR, or 
stable disease within 6 weeks. Patients who have received at least 6 infusions of nivolumab 240 
mg IV every 2 weeks with no DLTs related to nivolumab, will have the option to transition to 
the equivalent nivolumab schedule of 480 mg IV every 4 weeks. Because such a change will 
occur after at least 12 weeks from study initiation the endpoints are not affected for the purpose 
of dose escalation and de-escalation. 
 
Each cohort will include no more or less than 3 patients. A maximum of 60 patients will be 
treated in up to 20 cohorts of size 3, with the first cohort treated at 80 mg/day, all successive 
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doses chosen by the Lo-EffTox method, and no untried dose level skipped when escalating. 
Enrollment will continue without delay except, we also require at least one patient’s toxicity 
outcome to have been observed at the current dose (which takes a maximum of 12 weeks) before 
enrolling the next cohort of patients. For the two Lo-EffTox dose acceptability rules, the upper 
limit on the probability of toxicity is .40, the minimum probability of Efficacy .50, and cut-offs 
.10 will be used for both stopping probability criteria.  If the lowest dose level is found to be 
unacceptable in terms of either high toxicity or low efficacy, the trial will be terminated and no 
dose level will be selected. The three equivalent trade-off probability pairs used for computing 
the trade-off contours are (.50, 0), (.70, .25), (1, .65). The prior hyper-parameters were computed 
based on the assumed prior means Prob(Efficacy | dose) = .25, .30, .35, .50  and Prob(Toxicity | 
dose) = .20, .25, .30, .40. respectively, at the four MGCD-516 dose levels.  The overall prior 
effective sample size = 1. 
 
The Lo-EffTox design will be implemented using the specialized computer program developed 
by Jin et al.60 The study biostatistician Peter Thall, Ying Yuan, or Xuemei Wang in the 
Biostatistics Department should be consulted as necessary during trial conduct. Secondary 
outcomes will include progression-free survival (PFS) time, overall survival (OS) time, objective 
response rate (ORR), and quality of life (QOL). Unadjusted distributions of the time-to-event 
outcomes will be estimated using the method of Kaplan and Meier68 and their relationship to 
prognostic covariates will be evaluated by Bayesian piecewise exponential survival regression.69 
 
A Toxicity/Efficacy Summary will be submitted to IND Office Medical Monitor; every three 
patients, after the first twelve weeks of study therapy or administration is discontinued, 
whichever comes first, until 60 patients have completed study therapy. 
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14.2 Design Operating Characteristics 
 
Operating characteristics of the design are summarized below, based on simulations with1000 
replications per scenario. In the simulations, it is assumed that the times to toxicity and efficacy 
follow Weibull distributions, the percentage of toxicity (or efficacy) events occurring in the later 
half of each evaluation interval is 50%, and the accrual rate is 2 cohorts per month. 
 
Scenario 
Dose (mg/day) 
60 
80 
120 
150 
None 
1 
True pT, pE 
.20, .25 .30, .45 .40, .70 .50, .95 
- 
Trade-off Value 
-0.83 
-0.58 
-0.24 
0.12 
- 
% selected 
0 
11.5 
41.0 
41.0 
6.5 
# Patients Treated 
3.5 
8.7 
18.8 
27.6 
- 
2 
True pT, pE 
.20, .40 .30, .65 .60, .70 .90, .75 
- 
Trade-off Value 
-0.53 
-0.18 
-0.55 
-0.91 
- 
% selected 
8.4 
75.5 
1.4 
0 
14.7 
# Patients Treated 
8.0 
31.1 
10.6 
6.2 
- 
3 
True pT, pE 
.30, .65 .60, .72 .65, .75 .70, .78 
- 
Trade-off Value 
-0.18 
-0.51 
-0.52 
-0.54 
- 
% selected 
78.4 
10.3 
0.1 
0 
11.2 
# Patients Treated 
27.5 
18.5 
6.8 
3.9 
- 
4 
True pT, pE 
.10, .15 .15, .20 .20, .25 .25, .30 
- 
Trade-off Value 
-0.87 
-0.85 
-0.83 
-0.81 
- 
% selected 
0 
0 
0 
3.8 
96.2 
# Patients Treated 
3.2 
3.3 
4.3 
22.2 
- 
5 
True pT, pE 
.50, .25 .60, .35 .70, .45 .80, .56 
- 
Trade-off Value 
-1.30 
-1.26 
-1.21 
-1.14 
- 
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% selected 
0 
0 
0 
0 
100 
# Patients Treated 
4.2 
6.2 
4.9 
5.4 
- 
 
 
14.3 
Additional analyses 
 
Demographics: For each treatment group (control, experimental), summary statistics will be 
provided for age, baseline disease status and prior treatments. 
 
Toxicity:  Adverse effects that will be evaluated include, but are not limited to infections, renal 
toxicity, hepatic toxicity, and pulmonary toxicity.  Methods of assessment will include 
monitoring blood counts, and performing laboratory tests as indicated by clinical signs and 
symptoms. Evidence of toxicity or adverse events will be recorded at all clinic visits. All 
observed adverse effects will be graded for all patients and the degree of association of each with 
therapy assessed. 
 
Quality of Life: Prior to inferential procedures, extensive descriptive analyses will be conducted 
for each of the measures obtained at each session.  Descriptive statistics (e.g., means, ranges, 
standard deviations) will be computed, together with ninety-five percent confidence intervals for 
the means.  Proportions of subjects falling outside normative ranges for the stress and QOL 
measures will also be calculated.  Values for the standardized scales will be compared to 
normative data and patients receiving other types of cancer therapy.  Graphical methods (e.g., 
boxplots and histograms) will be employed to more closely examine the distributions of the 
measures at each time point.  Change scores for the stress and QOL measures will be computed as 
the simple differences between the baseline measure and subsequent evaluations.  Bivariate 
associations between the raw scores, the change scores, optimism, social support, and 
demographic variables will be evaluated using Pearson’s product moment correlation coefficients 
together with scatterplots where appropriate.  These procedures will allow us to thoroughly 
characterize the stress and QOL profiles of this patient population across the sessions.  
 
In this study, numerous models will be constructed to analyze the data and, therefore, the results 
will be treated as hypothesis generating and interpreted with caution.  Inferential statistics will 
comprise paired t-tests of the stress and QOL measures.  Significant test results (p < .05) will be 
interpreted as indicating significant changes in stress and QOL associated with the treatment.  
Linear regression analyses will then be used to construct prediction models using a composite 
stress and QOL score.  In these analyses, the composite stress and QOL score will be regressed 
onto spirituality and social support at the start of the trial, and interaction terms will be calculated 
to determine whether these factors moderate stress and quality of life.  Potential confounders 
include the stress and QOL measures obtained at baseline and demographic and treatment 
characteristics.  Backwards step-wise regression will be employed to construct the final models, 
with a rejection criteria of p > .05.   Multivariate methods, including repeated measures analyses, 
will be employed to further explore the potential changes in the stress and QOL measures over 
time.  Standard residual based diagnostic procedures will be used to evaluate model assumption 
and normalizing transformation made as appropriate. 
 
 
 
 
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15.0 DATA AND PROTOCOL MANAGEMENT 
 
Protocol Compliance: All required interim and pretreatment data should be available, and the 
physician must assess tumor response and must provide a detailed description of toxicity, when 
appropriate.  If dose modifications or treatment interruptions are necessary, the details must be 
carefully documented.  Performance status must be documented at each toxicity assessment. 
 
 
Data Capture: Data will be entered in the MD Anderson institutionally approved database(s). 
Registration data entry will occur prior to initiation of therapy. All eligibility criteria must be 
satisfied. 
 
Accuracy of Data Collection: The MD Anderson Principal Investigator will be the final arbiter of 
response and toxicity, should a difference of opinion exist. 
 
Monitoring: The trial will be monitored throughout the study with the assistance of the MD 
Anderson IND office. The study will be performed in accordance with ethical principles and 
follow federal, institutional, and departmental policy and or regulation. Every effort will be made 
to maintain patient confidentiality in accordance with federal regulation and institutional policy. 
 
Chain of custody of biological samples:  The chain of custody will be maintained for all samples 
throughout to completion and close out of the trial.  A record of storage location will be 
documented. Records will be available for monitoring and audit as requested. 
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Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression after radical 
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Tilki D, Nguyen HG, Dall'Era MA, et al. Impact of histologic subtype on cancer-specific 
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Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and 
prognostic features among histologic subtypes of renal cell carcinoma. The American journal of 
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Moch H, Montironi R, Lopez-Beltran A, Cheng L, Mischo A. Oncotargets in different 
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Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth 
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Guo H, German P, Bai S, et al. The PI3K/AKT Pathway and Renal Cell Carcinoma. 
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Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced 
Renal-Cell Carcinoma. The New England journal of medicine 2015;373:1803-13. 
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Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced 
Renal-Cell Carcinoma. The New England journal of medicine 2015;373:1814-23. 
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Pennock GK, Chow LQ. The Evolving Role of Immune Checkpoint Inhibitors in Cancer 
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Lakshmi Narendra B, Eshvendar Reddy K, Shantikumar S, Ramakrishna S. Immune 
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Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK. Significant blockade of 
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Inomata A, Nakano-Ito K, Fujikawa Y, et al. Brunner's gland lesions in rats induced by a 
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Patyna S, Arrigoni C, Terron A, et al. Nonclinical safety evaluation of sunitinib: a potent 
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Hall AP, Westwood FR, Wadsworth PF. Review of the effects of anti-angiogenic 
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Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for 
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