Conditions: Previously Treated Metastatic Colorectal Cancer
Keywords: SGI-110 irinotecan regorafenib methylation colorectal metastatic TAS-102 lonsurf
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 118
Healthy volunteers: no

Brief summary:
This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).

Detailed description:

Arms:
arm 1: Subjects receive SGI-110 on days 1-5 and irinotecan on days 8 and 15 of each 28-day cycle.

Various doses of SGI-110 are tested to determine the maximum tolerated dose in combination with irinotecan. arm 2: Subjects receive SGI-110 on days 1-5 and irinotecan on days 8 and 15 of each 28-day cycle.

Growth factor support (filgrastim and peg-filgrastim) is given during cycle 1 with option to give additional growth factor support at subsequent cycles per clinician judgement. arm 3: Subjects received either regorafenib or TAS-102 based on physician and patient preference. Subjects that had received one of these standard of care drugs (regorafenib or TAS-102) prior to enrollment received the other on study.

Regorafenib taken daily from days 1-21 of each 28-day cycle or TAS-102 taken twice daily on days 1-5 and 8-12 of each 28-day cycle.

Subjects who had disease progression on Arm B were given the option to receive Arm A study drugs after a 14 day wash-out period.

Interventions: intervention 1: SGI-110 Dose Escalation intervention 2: Regorafenib intervention 3: TAS-102 intervention 4: SGI-110 intervention 5: Irinotecan
Intervention descriptions: intervention 1: * Dose level 1 (DL1): 45 mg/m\^2 administered as a subcutaneous injection
* Dose level 1G (DL1G): 45 mg/m\^2 administered as a subcutaneous injection + growth factor support
* Dose level -1 (DL-1): 30 mg/m\^2 administered as a subcutaneous injection
* Dose level -1G (DL-1G): 30 mg/m\^2 administered as a subcutaneous injection + growth factor support intervention 2: 160 mg taken orally intervention 3: 35 mg/m\^2 taken orally intervention 4: 45 mg/m\^2 administered as a subcutaneous injection intervention 5: 125 mg/m\^2 administered IV

Protocol document:
Prot_SAP_000.pdf: 
J1369, SGI-110 + irinotecan vs. regorafenib or TAS 102 
Version 2.0 February 5, 2020 
Protocol Version Date:  February 5, 2020 
Local Protocol #: NA_00085870, J1369 
Title: A phase I study of SGI-110 combined with irinotecan followed by a randomized 
phase II study of SGI-110 combined with irinotecan versus regorafenib or TAS-102 
(lonsurf) in previously treated metastatic colorectal cancer patients 
Principal Investigator:  Nilofer Azad, MD 
Bunting-Blaustein Cancer Research Building I 
1650 Orleans Street, Room 4M10  
Baltimore, MD 21231 
(p)410-614-9169; (f)410-614-9006,
Email:  nazad2@jhmi.edu
Coordinating Center: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
USC Investigator:  
Anthony el-Khoueiry, MD (site PI) 
University of Southern California 
VUMC Investigator: 
Henk Verheul, MD PhD (site PI) 
VU University Medical Center, Netherlands 
MSKCC Investigator: 
Andrea Cercek, MD (site PI) 
Memorial Sloan Kettering Cancer Center 
Statistician: 
Marianna L. Zahurak 
Division of Oncology Biostatistics and Bioinformatics 
The Sidney Kimmel Comprehensive Cancer Center 
550 N. Broadway, Suite 1103 
Baltimore, MD 21287 
Office: 410-955-4219 
Fax: 410-955-0859 
Email: zahurma@jhmi.edu 
SKCCC Study Coordinator: 
 Tearra Miles 
 Research Coordinator  
The Sidney Kimmel Comprehensive Cancer Center at 
Johns Hopkins 
 201 North Broadway  8th floor Space   8120-43 
Baltimore, MD 21205-2009 
Phone: 410-502-5328 
Fax: 410-502-0834 
Email: tlawre18@jhmi.edu 
ClinicalTrials.gov ID: NCT01896856


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CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
SKCCC Research Nurse:   
 
 
Ellen Lilly-Foreman 
Johns Hopkins Kimmel Cancer Center  
Research Nurse-GI Oncology 
201 N. Broadway,  
Baltimore, MD 21205 
Phone: 443-287-4961 
Fax: 410-502-0834 
Email: lillyel@jhmi.edu 
 
   
Sponsor:   
 
 
 
 
 
 
 
 
Nilofer Azad, MD 
IND:  
 
 
 
 
 
 
 
 
 
 
IND 118733 
Protocol Type/Version/Version Date: Revised/ Version 1.8 / June 10, 2016 
 
SCHEMA 
 
Stage I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stage II 
 
                R 
A 
                                           N 
 mCRC                               D 
pts 
          O 
                                         M 
I 
Z 
E 
 
 
Treatment 
  ARM A: SGI-110 45mg/m2 SC D1-5 
+ Irinotecan 125mg/m2 D8,15 with 
mandatory growth factor support on cycle 1 
 
  2:1 
 
ARM B: Regorafenib 160 mg qd days 1-21 
or TAS-102 35mg/m2 BID on 
days 1-5 and 8-12 on 28 day cycle 
 
 
Start at 
dose level 1 
Treat cohort 
(3 participants) 
Number 
of DLTs 
De-
escalate 
one dose 
level 
Recruit 3 more 
participants 
Further 
DLTs? 
Stop
Escalate dose or, if 
DL2, stop at this MTD 
Yes 
No 
1 or 0 on DL2 
2 or 3 
0


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1. 
OBJECTIVES .................................................................................................................................................... 1 
1.1 
Study Design .................................................................................................................................................... 1 
1.2 
Primary Objectives .......................................................................................................................................... 1 
1.3 
Secondary Objectives ...................................................................................................................................... 1 
2. 
BACKGROUND ................................................................................................................................................ 1 
2.1 
SGI-110 ........................................................................................................................................................... 1 
2.2 
Irinotecan ........................................................................................................................................................ 6 
2.3 Regorafenib ......................................................................................................................................................... 7 
2.4 
TAS-102 (Lonsurf) ........................................................................................................................................... 8 
2.5 
Study disease: colorectal cancer ..................................................................................................................... 9 
2.6 
Rationale ....................................................................................................................................................... 10 
3. 
PARTICIPANT SELECTION ........................................................................................................................ 12 
3.1 
Eligibility Criteria ......................................................................................................................................... 12 
3.2 
Exclusion Criteria ...................................................................................................................................... 13 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................. 15 
4 
REGISTRATION PROCEDURES ................................................................................................................ 15 
4.1 
General Guidelines ....................................................................................................................................... 15 
4.2 
Registration Process ..................................................................................................................................... 15 
4.3 
 Patient assignment and randomization procedure for second cohort ........................................................ 16 
5 
TREATMENT PLAN ...................................................................................................................................... 16 
5.1 
Overall Study Design .................................................................................................................................... 16 
5.2 
Screening and pre-treatment criteria ......................................................................................................... 19 
5.3 Agent Administration ................................................................................................................................... 21 
5.4 
Definition of Dose-Limiting Toxicity .......................................................................................................... 22 
5.5 
General Concomitant Medication and Supportive Care Guidelines ............................................................. 23 
5.6 
Duration of Therapy ....................................................................................................................................... 23 
5.7 
Duration of Follow Up .................................................................................................................................. 24 
5.8 
Cross Over in Phase II .................................................................................................................................. 24 
5.9 
Criteria for Removal from Study Treatment .................................................................................................. 24 
6 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 25 
6.1 
Anticipated Toxicities .................................................................................................................................... 25 
6.2 
Toxicity Management .................................................................................................................................... 27 
6.3 
Dose Modifications/Delays ........................................................................................................................... 27 
7 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 30 


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7.1 
SGI-110 ......................................................................................................................................................... 30 
7.2 
Irinotecan ...................................................................................................................................................... 32 
7.3 
Regorafenib ................................................................................................................................................... 33 
7.4 
TAS-102 (Lonsurf) ......................................................................................................................................... 34 
8 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 36 
8.1 
Archival tissue ............................................................................................................................................... 37 
8.2 
Pharmacokinetic Studies ............................................................................................................................... 37 
8.3 
Pharmacodynamic Studies ............................................................................................................................ 39 
9 
STUDY CALENDARS .................................................................................................................................... 46 
10 
MEASUREMENT OF EFFECT..................................................................................................................... 53 
10.1 Antitumor Effect– Solid Tumors .................................................................................................................... 53 
10.2 Other Response Parameters .......................................................................................................................... 59 
11 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 60 
11.1 Definitions ..................................................................................................................................................... 60 
11.2 Procedures for AE and SAE Recording and Reporting ................................................................................. 62 
11.3 Reporting Requirements ................................................................................................................................ 62 
11.4 Reporting to the Study Sponsor ..................................................................................................................... 62 
11.5 Reporting to the Institutional Review Board (IRB) ....................................................................................... 63 
11.6 Reporting to the Food and Drug Administration (FDA) ............................................................................... 64 
11.7 Reporting to Hospital Risk Management....................................................................................................... 65 
11.8 Monitoring of Adverse Events and Period of Observation ............................................................................ 65 
12 
DATA AND SAFETY MONITORING .......................................................................................................... 65 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 11.0 (Adverse Events: 
List and Reporting Requirements). ........................................................................................................................... 65 
13 
REGULATORY CONSIDERATIONS .......................................................................................................... 66 
13.1 Protocol Review and Amendments ................................................................................................................ 66 
13.2 Informed Consent .......................................................................................................................................... 66 
13.3 Ethics and Good Clinical Practice (GCP) .................................................................................................... 66 
13.4 Study Documentation .................................................................................................................................... 67 
13.5 Records Retention ......................................................................................................................................... 67 
13.6 Data Collection ............................................................................................................................................. 67 
13.7 Multi-center Guidelines ................................................................................................................................. 68 
14 
STATISTICAL CONSIDERATIONS ............................................................................................................ 69 
14.1 Study Design/Endpoints ................................................................................................................................ 69 


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Stratification Factors .............................................................................................................................................. 75 
14.2 Reporting and Exclusions .............................................................................................................................. 75 
15 
REFERENCES ................................................................................................................................................. 76 
 
Appendix A: Performance Status Criteria .............................................................................................................. 80 
APPENDIX B:   PATIENT DIARY ......................................................................................................................... 81 
APPENDIX C:   PATIENT DIARY ......................................................................................................................... 82 
APPENDIX D: FACT-C (Version 4) ....................................................................................................................... 82 
  
 


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1 
1. OBJECTIVES 
1.1 Study Design 
 
This is a phase I/randomized phase II study of the combination of SGI-110 and irinotecan in 
previously treated metastatic colorectal cancer patients. This study will be conducted in two 
components.  First, patients will be enrolled in a phase I study of SGI-110 combined with 
irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, 
patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and 
irinotecan versus the standard of care regorafenib or TAS-102 (lonsurf). 
 
1.2 Primary Objectives 
 
Phase I Component: Stage I 
--To assess safety and tolerability of combination SGI-110 + irinotecan in colon cancer patients 
--To determine the phase II dose of the combination of SGI-110 + irinotecan 
 
Phase II Component: Stage II 
--To improve median progression-free survival from that reported with regorafenib and TAS-102 
to 4 months for SGI-110+irinotecan in previously treated metastatic colon cancer patients who 
have progressed on irinotecan. 
 
1.3 Secondary Objectives 
 
Phase I Component: Stage I 
--To assess changes in global methylation and expression at the tumor level with SGI-110 and 
irinotecan treatment 
--To assess for pharmacokinetic interactions of SGI-110 and irinotecan 
--To assess for correlation between disease response and drug exposure 
 
Phase II Component: Stage II 
--To evaluate response rate as determined by RECIST criteria 1.1  
--To evaluate concurrent SGI-110+irinotecan treatment versus regorafenib or TAS-102 alone  
--To improve median overall survival from historical rate of 6.4 months 
--To assess for potential predictive biomarkers of response and survival using baseline tissue 
 
2. BACKGROUND 
 
2.1 
SGI-110 
 
2.1.1  SGI-110 Background 
 
For further information on SGI-110 please refer to the most up to date version of the 
Investigator’s Brochure (IB).1 
 
SGI-110 is a DNA methyltransferase inhibitor (a demethylating agent). The active metabolite of 
SGI-110 (2’-deoxy-5-azacytidylyl-(3’→5’)-2’-deoxyguanosine sodium salt), a dinucleotide, is 


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2 
decitabine. SGI-110 is resistant to modification by cytidine deaminase, a common pathway of 
decitabine metabolism and deactivation.2 The molecular weight of SGI-110 and decitabine are 
580 Da and 228 Da, respectively. Therefore, the molar equivalent dose of 1 mg of decitabine is 
approximately 2.5 mg of SGI-110. SGI-110’s activity was demonstrated with the same 
preclinical pharmacodynamic assays used to demonstrate decitabine’s efficacy e.g., re-
expression of p15, p16, and MLH1 and induction of fetal hemoglobin, in vivo. In 
xenograft studies, SGI-110 demonstrates promising preclinical activity in both hematologic and 
solid tumors. 
 
In vitro evidence suggests that SGI-110 has a longer half-life than decitabine in the presence of 
cytidine deaminase. These promising observations suggest that SGI-110 has improved 
pharmaceutical properties and biological activities that expand on decitabine’s current clinical 
utility. SGI-110 has shown to be better tolerated in mice than decitabine and is as effective in 
vivo in inducing p16 expression, reducing DNA methylation at the p16 promotor region, and 
retarding EJ6 human bladder cancer tumor growth in athymic mice.3 
 
SGI-110 has been developed for subcutaneous administration. SGI-110 is pharmacologically 
active both in vitro and in vivo in a variety of tumor cells and murine xenograft models when 
administered subcutaneously. Treatment is well tolerated via the subcutaneous route in murine 
xenografts. When administered subcutaneously to non-human primates, SGI-110 releases 
decitabine slowly compared to other species, possibly prolonging the effect over longer periods. 
SGI-110 has been developed as a non-aqueous formulation to ensure formulation stability. 
 
2.1.2 Nonclinical pharmacokinetics 
 
The overall pharmacokinetic characteristics of SGI-110 are summarized as follows. The relative 
bioavailability of SGI-110 dosed subcutaneously to the rat is close to 100%. Circulating SGI-110 
levels were very low in the mouse, rat and rabbit. However, higher levels were observed in the 
monkey post subcutaneous dosing. Rapid decline in systemic exposure of SGI-110 with 
elimination plasma half-life (T1/2) in the range of 0.4-1 hours in rat and monkey was observed. 
High levels of decitabine were observed after a subcutaneous dose of SGI-110 in the mouse, rat, 
and rabbit (maximum in rat, 54 μg/mL). Levels in the monkey (maximum 463 ng/mL) were 
substantially lower. Rapid decline in systemic exposure of decitabine with elimination plasma 
T1/2 of 3.7 hour in rats and 1 hour in monkey was observed. 
 
In monkey, pharmacokinetic parameters were similar on Day 1 and Day 15 of a study in which 
they were dosed once weekly for three consecutive weeks suggesting no significant 
accumulation of the parent or the active metabolite, decitabine. 
 
The metabolic characteristics of SGI-110 are summarized as follows. SGI-110 was more stable 
in human, dog and mouse and was less stable in rat and rabbit plasma. Incubation of SGI-110 
with liver microsomes from mouse, rat, rabbit, dog and human showed little apparent 
metabolism of the compound. Incubation of SGI-110 with human hepatocytes also showed little 
apparent metabolism of the compound, based on disappearance of the parent. SGI-110 does not 
significantly bind to human plasma proteins; in vitro unbound fraction was estimated to be 91%. 
SGI-110 has poor in vitro bidirectional permeability which correlates well with its poor oral 


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absorption in vivo. SGI-110 shows no appreciable induction of CYP1A1/2, CYP2C9 and 
CYP3A4 in human hepatocytes. SGI-110 does not have any CYP450 inhibitory effect on 
CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. 
 
 
 
2.1.3 Nonclinical safety of SGI-110 
 
SGI-110 toxicity findings in rat and rabbit studies are similar to the non-clinical study findings of 
decitabine in New Drug Application (NDA) supporting Good Laboratory Practices (GLP) 
toxicology studies. Myelosuppression, decreases in thymus weight, and testicular atrophy, the 
main study findings of the SGI-110 studies, were also observed as the main study findings in 
repeat dose toxicity studies with decitabine in mice, rats, rabbits, and dogs. As with SGI-110, 
myelosuppression and thymus toxicities after decitabine administration were reversible during 
recovery periods while testicular atrophy persisted. Myelosuppression, particularly neutropenia, 
has been reported as a dose-limiting toxicity for decitabine in human clinical studies. Signs of 
testicular toxicity has not been observed in any of the published clinical studies of decitabine to 
date.4 
 
No studies have been performed to evaluate the genotoxic, mutagenic, carcinogenic or 
reproductive and developmental toxicity of SGI-110. Decitabine may have genotoxic potential; 
decitabine is mutagenic and in preclinical studies in mice and rats, decitabine was teratogenic, 
fetotoxic, and embryotoxic.4 
 
 
 
2.1.4 SGI-110 Clinical Data 
 
SGI-110 is being studied in a first-in-human, single-agent study (SGI-110-01).5 This study is 
a Phase 1/2, dose escalation, multicenter study of two subcutaneous regimens of SGI-110 in 
subjects with intermediate or high-risk myelodysplastic syndromes (MDS) or acute myeloid 
leukemia (AML). This study has two parts, a Dose Escalation Segment and a Dose Expansion 
Segment. The study seeks to evaluate the biological activity, preliminary safety, and efficacy of 
SGI-110 with two dosing schedules in intermediate to high risk MDS or relapsed or refractory 
AML subjects, while the Dose Expansion Segment further evaluates safety and efficacy at the 
recommended dose. The study is based on a 3 + 3 design within each regimen. Eligible subjects 
are being randomized to receive 1 of 2 dosing regimens of SGI-110 with the following starting 
doses: Regimen 1: 3 mg/m2/day subcutaneously on Days 1-5 of a 28-day course, Regimen 2: 
6 mg/m2 subcutaneously Weekly x 3 on Days 1, 8, 15 of a 28-day course. As of 23 April 2012, 
the study has enrolled 78 subjects into 7 dose cohorts in the Dose Escalation Segment, as shown 
below (Table 1). The minimum dose achieving maximal biological activity or biologically 
effective dose (BED) for the daily regimen has been reached at 60 mg/m2 daily on Days 1-5. 
 


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2.1.5 Human pharmacokinetics 
 
The PK of SGI-110 and decitabine are being evaluated in Study SGI-110-01. Decitabine forms 
from SGI-110 as it undergoes cleavage by phosphodiesterase (PDE) enzymes. SGI-110 after SC 
injection undergoes efficient conversion to decitabine and delivers decitabine exposures as 
measured by AUC that are equivalent or higher than those achieved by IV decitabine infusion at 
20 mg/m2, while maintaining significantly lower decitabine Cmax. It is hypothesized that lower 
Cmax may be associated with less toxicity. 
 
Due to slower release of decitabine from SGI-110, the effective half-life of decitabine after SC 
SGI-110 is prolonged and the observed decitabine exposure window is longer (8+ hrs) compared 
to IV (3-4 hrs). At Cohort 6, doses of 90 mg/m2 for the daily regimen and 125 mg/m2 for 
weekly, the observed decitabine AUCs were approximately 1.41 and 1.77 fold higher than with 
IV decitabine at the approved dose of 20 mg/m2 IV, whereas Cmax levels were only at 0.35 and 
0.44-fold for the daily and weekly regimens, respectively. It is hypothesized that longer exposure 
to decitabine may allow more drug to be incorporated into the DNA thus resulting in better 
hypomethylation and better biological activity. Clinical drug-drug interaction studies have not 
been conducted with SGI-110. In vitro, SGI-110 does not inhibit the activity nor induce levels of 
major human CYP enzymes, hence, the likelihood of CYP-mediated drug-drug interactions with 
SGI-110 is remote.5 
 
 
 
2.1.6 Clinical efficacy and biological activity of SGI-110 
 
Based on PD assessment of global hypomethylation from the first 7 cohorts in Study SGI-110- 
01, the LINE-1 demethylation data show dose dependent hypomethylation induction in the daily 
schedule reaching a plateau at Cohort 5 (60 mg/m2 SC dailyx5). The hypomethylation of the 
weekly schedule was inferior to the daily schedule and plateaued early (Figure 1). The 
Biologically Effective Dose or BED was therefore established as 60 mg/m2 dailyx5. 
 
 
 
 
 
 
 


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Figure 1: LINE demethylation 
 
There have been 5 documented major responses (2 CRs and 2 CRi, 1 CRp) all in heavily-
pretreated refractory AML subjects regardless of  prior hypomethylating agents (HMA) 
treatment : 1 CR and CRp with weekly (60 mg/m2 and 125mg/m2, respectively) 
and 2 CRi and 1 CR with daily (36/60 mg/m2 and 60 mg/m2 respectively). The major responses 
were observed in 5/19 refractory AML patients when adequate hypomethylation (>10%) was 
achieved. Five MDS patients who all received prior treatment with HMAs had hematological 
improvements or marrow CR.  
 
As of 27 March 2012, there were 54 subjects who have information in the clinical database in the 
Phase 1/2 study with single-agent SGI-110. This data cutoff date includes all subjects in both 
cohorts up to Cohort 5. 
 
Of the 54 subjects in the clinical database, 46 (85%) have reported at least 1 adverse event (AE). 
There were 26 (48%) subjects with an AE considered related by the Investigator. The most 
common related AEs, occurring in at least 3 subjects (6%) in decreasing incidence were injection 
site pain (n=12, 22%); fatigue (n=6, 11%); nausea (n=5, 9%); and thrombocytopenia, anaemia 
and diarrhea (n=3, 6%). All of these were Grade 1 or 2 AEs with the exception of 1 subject (1 in 
60 mg/m2 dailyx5) with Grade 4 thrombocytopenia and 2 subjects (1 in 3 mg/m2 dailyx5 and 1 
in 60 mg/m2 dailyx5) with Grade 3 anaemia. 
 
As of 31 May 2012, there were 156 serious adverse events (SAEs) in 66 subjects in the safety 
database regardless of relationship to the study drug. The most common SAEs (≥5%) were 
febrile neutropenia (n=24, 36%), pneumonia (n=17, 26%), disease progression (n=7, 11%), 
sepsis (n=6, 8%), pyrexia (n=5, 9%), bacteraemia and skin infection (n=4, 6% each). Most 
events were considered not related to study drug as they were expected from disease progression 
of the study population (MDS and AML). Twelve (12) subjects had SAEs considered by the 
investigator as related to the use of SGI-110: 3 subjects with febrile neutropenia, 2 subjects with 
thrombocytopenia, and 1 subject each with pseudomonal sepsis, atrial fibrillation, chest pain, 
pleural effusion, bacteraemia, sepsis and dysphagia. 
 


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As of May 2012, there have been three expedited safety reports submitted to regulatory 
authorities by the Sponsor concerning suspected adverse reactions related to SGI-110: one event 
of pleural effusion for which no other cause was established and did not return upon cessation of 
therapy (at 36 mg/m2 in the weeklyx3 regimen) and 2 events of febrile neutropenia (both at 
125 mg/m2 dailyx5), one of which was associated with sepsis that resulted in the subject’s death. 
Both febrile neutropenia cases were the only 2 cases that were considered as Dose Limiting 
Toxicities (DLTs) and they both occurred in patients with MDS in Cohort 7 (125 mg/m2 
dailyx5).The maximum administered dose (MAD) for the dailyx5 regimen is 125 mg/m2 and the 
MTD is considered to be 125 mg/m2 dailyx5 for AML patients and 90 mg/m2 dailyx5 for MDS 
based on 2 cases of febrile neutropenia that were considered as Dose Limiting Toxicities (DLTs) 
that occurred in patients with MDS in Cohort 7 (125 mg/m2 dailyx5).The MTD for the weekly 
regimen was not established as no DLTs were observed up to the 
highest dose tested of 125 mg/m2 weeklyx3 regimen. The risks of SGI-110 in humans are 
described further in Section 6, Expected Toxicities. For more detailed information, please refer 
to the IB for SGI-110. The two main drug-related adverse reactions of SGI-110 are 
myelosuppression (neutropenia, febrile neutropenia, thrombocytopenia, and anemia) and its 
consequences (such as infection, fever, and sepsis), and injection-site events such as pain, 
irritation, and inflammation. At the SGI-110 proposed in this study (30-60 mg/m2 daily on Days 
1-5), there have been no reports of drug-related myelosupression in MDS and AML subjects in 
study SGI-110-01. The recommended starting dose of 45 mg/m2 daily on Days 1-5 is 50% of the 
MTD for single-agent treatment with SGI-110 and about one-third of the MAD based on first-in-
human study SGI-110-01. 
 
Pain and burning at the injection site has been reported that are related to dose and volume of 
injection. Other than these events described above, SGI-110 has been well tolerated up to 
90 mg/m2 dailyx5 and 125 mg/m2 weekly x3. 
 
In summary, SGI-110 single agent treatment for MDS and AML patients was well tolerated up to 
125 mg/m2 weeklyx3 and 90 mg/m2 dailyx5 given every 4 weeks. DLTs of febrile neutropenia 
with bacteremia or sepsis were only observed at 125 mg/m2 dailyx5. Daily dosing achieved 
much better hypomethylation than the weekly regimen and the BED of the daily regimen was 
established at 60 mg/m2 dailyx5. At that dose there were no DLTs observed in Study SGI-110- 
01.5 
 
2.2 
Irinotecan 
   
2.2.1 Background 
 
Irinotecan is an FDA approved, commercially available topoisomerase I inhibitor with activity 
against several solid tumor cell lines including colon, lung, and ovary. Irinotecan received an 
accelerated approval in June 1996 to treat metastatic cancer of the colon or rectum that has 
recurred or progressed after standard therapy with 5-FU.  Irinotecan received full FDA approval 
in 1998 as a second-line treatment for metastatic colorectal cancer. In April, 2000, irinotecan 
received accelerated approval from the FDA as first-line treatment for metastatic colon cancer 
when combined with 5-FU and Lecovorin.   The cytotoxic effect is due to double-strand DNA 
damage produced during DNA synthesis when replication enzymes interact with the ternary 


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complex formed by topoisomerase I, DNA, and either irinotecan or SN-38 (its active 
metabolite).6  
 
2.2.2 Dose and Toxicology.   
 
The drug is given intravenously with the MTD for weekly dosing being 125 mg/m2 as a single 
agent.  The typical schedule of irinotecan administration in metastatic colon cancer is four 
consecutive weekly doses combined with 5-FU and leucovorin given every six weeks.  
Conversion of irinotecan to SN-38 (its active metabolite) occurs in the liver. Half-life for 
irinotecan is about 6 hours.  Half-life for SN-38 is about 10 hours. SN-38 is 95% bound to 
plasma proteins.   
 
Irinotecan is associated with both early (during or shortly after infusion) and late (more than 24 
hours after infusion) forms of diarrhea that may be severe. Early diarrhea may be accompanied 
by symptoms such as sweating, flushing and abdominal cramping.  Late diarrhea can be 
prolonged, life threatening, and should be treated promptly. In two Phase III trials in second line 
treatment of colorectal cancer, adverse events occurring more commonly in patients on 
irinotecan than best supportive care or 5-FU based therapy were diarrhea, nausea, vomiting and 
neutropenia. In these studies, 60 percent of patients receiving irinotecan were hospitalized at 
least once due to adverse events, compared with 63 percent receiving best supportive care alone 
and 39 percent receiving 5-FU.  Patients also experienced temporary hair loss which usually 
returned after the completion of therapy.7   
2.3 Regorafenib 
 
2.3.1 Background of regorafenib 
Various signaling pathways have been implicated in the development and progression of 
colorectal cancer, involving receptor tyrosine kinases (eg, EGFR, VEGF receptor, platelet-
derived growth factor receptor [PDGFR], and fibroblast growth factor receptor [FGFR]) and 
downstream signalling cascades (RAS-RAF-MEK-ERK and PI3K-PTEN-AKT-mTOR).8 
Regorafenib is a novel oral multikinase inhibitor that blocks the activity of several protein 
kinases, including kinases involved in the regulation of tumour angiogenesis (VEGFR1 [also 
known as FLT1], VEGFR2 [KDR], VEGFR3 [FLT4], TIE2 [TEK]), oncogenesis (KIT, RET, 
RAF1, BRAF, and BRAFV600E), and the tumour microenvironment (PDGFR and FGFR).9 In 
preclinical studies, regorafenib has shown antitumour activity, including in colorectal cancer 
models.9 
In a phase 1b study, oral regorafenib, given at a dose of 160 mg once daily for the first 3 weeks 
of each 4 week cycle, showed a tolerable toxicity profile and preliminary evidence of antitumour 
activity in 38 patients with progressive colorectal cancer who had received previous therapy for 
metastatic disease (median four lines).10 The disease control rate (partial response plus stable 
disease) was 74% (20 of 27 assessable patients). On the basis of these results and the high unmet 
need in this population of patients, the decision was made to proceed to a randomized phase 3 
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2.3.2 CORRECT trial 
From Lancet: “CORRECT was a randomized, placebo-controlled, phase 3 study involving 114 
centers in 16 countries in North America, Europe, Asia, and Australia. Patients were eligible to 
participate when they had histological or cytological documentation of adenocarcinoma of the 
colon or rectum. They had to have received locally and currently approved standard therapies 
and to have disease progression during or within 3 months after the last administration of the last 
standard therapy or to have stopped standard therapy because of unacceptable toxic effects. 
Patients were randomly assigned in a 2:1 ratio to regorafenib or placebo. 
753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety 
analyses). The primary endpoint of overall survival was met at a preplanned interim analysis. 
Median overall survival was 6ꞏ4 months in the regorafenib group versus 5ꞏ0 months in the 
placebo group (hazard ratio 0ꞏ77; 95% CI 0ꞏ64–0ꞏ94; one-sided p=0ꞏ0052). Treatment-related 
adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those 
assigned placebo. The most common adverse events of grade three or higher related to 
regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 
7%), hypertension (36, 7%), and rash or desquamation (29, 6%).”11 
Based on these results, the FDA approved regorafenib for heavily pretreated colorectal cancer 
patients on September 27, 2012.12 
2.4 TAS-102 (Lonsurf) 
2.4.1 Background of TAS-102 
For several decades, 5-FU was the only active chemotherapy in the treatment of metastatic colon 
cancer.  Since then it, and other fluoropyrimidines, have remained the backbone to chemotherapy 
regimens for colorectal maligancies.  Fluoropyrimidines act by inhibiting thymidylate synthase, 
which is necessary for the synthesis of pyrimidine nucleotides and DNA synthesis.  TAS-102 is 
an oral combination of two agents: trifluridine (thymidine-based nucleic acid analog), which 
directly incorporates into DNA, and tipiracil hydrochloride (thymidine phosphorylase inhibitor), 
which delays the breakdown of trifluridine.13 
 
In a Japanese double-blind, randomized, placebo-controlled, phase 2 trial of 169 patients with 
metastatic colorectal cancer who had been heavily pretreated (two or more prior standard 
chemotherapy regimens) and were refractory or intolerant to fluoropyrimidines, irinotecan, and 
oxaliplatin.  Patients were randomized in a 2:1 ratio to receive TAS-102 (35mg/m2) orally twice 
a day for 2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day 
rest period or placebo.  112 patients were assigned to receive TAS-102 and 57 to placebo, with 
median overall survival of 9.0 months in TAS-102 group versus 6.6 months in the placebo group 
(HR 0.56, 95% CI 0.39-0.81, p=0.0011).14  A subsequent, international Phase III trial was 
undertaken to evaluate the benefit.  
 
2.4.2 RECOURSE trial 
 
RECOURSE was a randomized, placebo-controlled, phase 3 study involving 116 centers in 13 
countries in North America, Europe, Asia and Australia.  Patients were eligible to participate if 


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they had biopsy-proven metastatic colorectal adenocarcinoma who had received at least two 
prior regimens of standard chemotherapies with subsequent progression within 3 months after 
last administration of standard therapy or intolerable side effects; or if patients had received 
adjuvant therapy, developed progression within 6 months.  Patients were randomly assigned in a 
2:1 ratio to receive TAS-102 or placebo. 
 
798 patients initiated treatment (TAS-102 n = 533; placebo n = 265; intention to treat).  All 
patients had previously received fluoropyrimidine, oxaliplatin, and irinotecan; 17% of the TAS-
102 group had previously received regorafenib.  The primary endpoint of median overall survival 
was 7.1 months in the TAS-102 group and 5.3 months in the placebo group (HR 0.68, 95% CI 
0.58-0.81; p<0.001).  The median time to an ECOG performance status of 2 or higher was 5.7 
months in the TAS-102 group versus 4.0 months in the placebo group.  Treatment-related 
adverse events occurred in 524 (98%) of patients receiving TAS-102 and in 247 (93%) of those 
receiving placebo.  370 (69%) of TAS-102 patients had grade 3 or higher adverse events, in 
comparison to 137 (52%) of those receiving placebo.  The most common adverse events of grade 
three or higher related to TAS-102 included neutropenia (38%), febrile neutropenia (4%), anemia 
(18%), thrombocytopenia (5%).  Higher grade three adverse events for those treated with TAS-
102 compared to placebo were noted for nausea (2% v 1%), vomiting (2% v <1%), and diarrhea 
(3% v <1%).15  Based on these results, the FDA approved TAS-102 for refractory metastatic 
colon cancer on September 22, 2015.16 
2.5 Study disease: colorectal cancer 
 
Metastatic colorectal cancer (mCRC) is the second leading cause of cancer death in the United 
States. In 2012, approximately 143,460 Americans will be diagnosed with CRC, and 51,690 will 
die from this disease.17 The five-year survival for all patients with metastatic disease from CRC 
is only 8.1%.18 Median survival with current generation of chemotherapies, including oxaliplatin 
or irinotecan as well as newer biologic therapies such as bevacizumab and cetuximab is only 20-
24 months. The only predictive biomarker that is currently used in clinical colorectal cancer 
practice is KRAS gene status which has only been in clinical application since 2008 when mutant 
KRAS was found to predict a lack of benefit to anti-EGFR agents. Therefore, there are currently 
only three lines of therapy for the 40% of patients with KRAS mutation (oxaliplatin-based and 
irinotecan-based regimens) with a potential added option for KRAS wildtype patients.  
 
Patients with mCRC have a 60% likelihood of responding to first-line chemotherapy with an 
oxaliplatin or irinotecan containing regimen and drops to 10% in the second line. Agents 
effective and or approved in the third line such as panitumumuab and recently reported 
regorafenib have a less than 5% response rate, and an expected median overall survival of 6.4 
months.  However, in patients with KRAS wildtype tumors who progressed on irinotecan, 
Cunningham et al. showed that retreatment with irinotecan with cetuximab resulted in a 22% 
response rate, and cetuximab is now FDA-approved for this indication.  No such irinotecan 
retreatment option exists for KRAS mutated patients. 
 
 
 
 


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2.6 Rationale 
 
Preliminary data from our group’s phase I/II study of 5-azacitidine and entinostat in non-small 
cell lung cancer has shown that, in patients who received subsequent therapy with varied agents, 
approximately one third had at least a partial response by RECIST criteria to that subsequent 
therapy.19  In CRC, as there are no subsequent therapy options for patients after 2nd or 3rd line 
therapy (based on KRAS mutational status), our group has been exploring the potential of 
DNMT inhibitor therapy to synergize subsequent therapy.  Ishiguro et al. first demonstrated that 
treatment with DAC resulted in gene re-expression of known tumor suppressor genes in CRC; 
moreover, in both in vitro and in vivo models, DAC treatment substantially decreased tumor 
growth when combined with irinotecan or SN-38 (active irinotecan metabolite) compared to 
either agent alone.20 In squamous cell cervical cancer, DAC restored SN-38 sensitivity in cells 
cultivated for SN38 resistance.21 5-aza has also been shown to increase irinotecan sensitivity in 
multiple CRC cell lines, with a synergistic effect seen in a p53-mutated cell line.22 We have 
found that pretreatment of colorectal cancer cell lines with 5-aza or decitabine has sensitized 
CRC cell lines in vitro to subsequent treatment with SN38, the active metabolite of irinotecan, by 
both MTS and clonogenic assays (Figures 1-3).  
 
Figure 1 
 
 
 
Figure 1: CRC cell lines were treated in 96 well plates with azacitidine at 500 nM for 3 days followed by two day exposure to 
SN38 and then analyzed by MTS assay. 
 
 
 
 
 
 
 
 


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Figure 2 
 
 
Figure 2: CRC cell lines were treated in 96 well plates with decitabine at 100 nM for 3 days followed by two day exposure to 
SN38 and then analyzed by MTS assay. 
 
 
Figure 3 
 
Figure 3: 105 CRC cell lines were treated with decitabine at 100 nM for 3 days and then +/- SN38 
 
 
We have seen similar effects in a primary patient-derived xenograft in vivo (Figure 4). 


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Figure 4 
 
 
 
 
 
Based on these data, we hypothesize that DNMTi therapy with SGI-110 will sensitize advanced 
colorectal cancer to treatment with Irinotecan. We propose a phase I study to assess the safety 
and tolerability of SGI-110 in combination with standard irinotecan therapy in 3rd line + 
metastatic colon cancer, followed by a randomized phase II study to evaluate efficacy of the 
combination.   
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 Participants must meet the following criteria on screening examination to be 
eligible to participate in the study: 
 
3.1.2 Participants must have histologically or cytologically confirmed 
adenocarcinoma of the colon or rectum 
3.1.3 Patients in the phase I cohort must have biopsiable disease and be 
amenable to having two research biopsies 
3.1.4 Archival tissue must be procured if available 
   
3.1.5 Participants must have measurable disease, defined as at least one lesion 
that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as > 20 mm with conventional techniques or as > 


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13 
10 mm with spiral CT scan. See section 10 for the evaluation of 
measureable disease. 
 
3.1.6 Patients in the phase II cohort must have progressed while receiving 
irinotecan therapy in the metastatic setting.  There are no limitations 
on number of prior therapies in the metastatic setting.  
 
3.1.7  Age minimum of 18 years.  
Because no dosing or adverse event data are currently available on the use of SGI-
110 in participants <18 years of age, children are excluded from this study but will 
be eligible for future pediatric trials. 
 
3.1.8 Life expectancy of greater than 12 weeks. 
 
3.1.9 ECOG performance status <1 
  
3.1.10 Participants must have normal organ and marrow function as defined 
below: 
 Leukocytes > 3,000/mcL 
 Absolute neutrophil count > 1,500/mcL 
 Platelets > 100,000/mcL 
 Total bilirubin < 1.5X institutional upper limit of normal 
 AST (SGOT)/ALT (SGPT) < 3.0 X institutional upper limit of normal  
 
with or without liver metastases 
 Creatinine < 1.5X institutional upper limit of normal or creatinine 
clearance > 50 mL/min/1.73 m2 for subjects with creatinine levels above 
institutional normal                  . 
3.1.11  
The effects of SGI-110 on the developing human fetus are unknown. For this 
reason and because oncological agents are known to be teratogenic, women of 
child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and 
for the duration of study participation. Should a woman become pregnant or suspect 
she is pregnant while participating in this study, she should inform her treating 
physician immediately. 
 
 
 
3.1.12 Ability to understand and the willingness to sign a written informed 
consent document. 
 
3.2 Exclusion Criteria 
 


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3.2.1 Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study. 
 
3.2.2 Participants who have had chemotherapy or radiotherapy within 4 weeks 
(6 weeks for nitrosoureas or mitomycin C) prior to enrolling in the 
study or those who have not recovered from adverse events due to 
agents administered more than 4 weeks earlier. 
 
3.2.3 Participants may not be receiving any other study agents. 
 
3.2.4 Participants with known brain metastases should be excluded from this 
clinical trial because of their poor prognosis and because they often 
develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other adverse events. 
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical 
or biologic composition to irinotecan, decitabine or SGI-110. 
 
3.2.6 Subjects who have received prior therapy with any 
hypomethylating agents. 
 
3.2.7 Uncontrolled intercurrent illness including, but not limited to ongoing or 
active infection, symptomatic congestive heart failure, unstable 
angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
3.2.8 Pregnant women are excluded from this study because SGI-110 is a/an 
hypomethylating agent with the potential for teratogenic or abortifacient 
effects. Because there is an unknown but potential risk of adverse events 
in nursing infants secondary to treatment of the mother with SGI-110, 
breastfeeding should be discontinued. These potential risks may also 
apply to other agents used in this study 
 
3.2.9 Individuals with a history of a different malignancy are ineligible except 
for the following circumstances: individuals with a history of other 
malignancies who have been disease-free for at least 5 years; or 
individuals with another malignancy that are deemed by the investigator 
to be at low risk for clinically meaningful recurrence (ex. cervical cancer 
in situ, definitively treated early stage prostate cancer (confined to prostate 
with Gleason 6 or below), definitely treated breast ductal or lobular 
carcinoma in situ, basal cell or squamous cell carcinoma of the skin). 
 
3.2.10 HIV-positive individuals on combination antiretroviral therapy are 
ineligible, as these individuals are at increased risk of lethal 
infections when treated with marrow-suppressive therapy. Appropriate 


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studies will be undertaken in participants receiving combination 
antiretroviral therapy when indicated 
 
3.2.11 Previous treatment with regorafenib AND TAS-102 (This applies to phase 
II only.  If patients have previously received either regorafenib OR TAS-
102, they must be able to receive the alternate regimen if randomized to 
the standard of care arm) 
3.2.12 Hospitalization for an acute medical issue within 4 weeks prior to 
screening visit that would otherwise not be managed in an infusion center 
or outpatient clinic setting (e.g., a patient admitted to complete a 
transfusion would not be ineligible.). 
3.2.13 Symptomatic bowel obstruction within 6 months prior to enrollment. 
Patients who undergo surgical correction of obstructing lesion will 
be eligible within 6 months 
 
3.3 Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Both men and women of all races and ethnic groups are eligible for this trial.  
 
 
4 
REGISTRATION PROCEDURES 
   
4.1 General Guidelines 
 
 Eligible patients will be entered on study centrally at the Sidney Kimmel 
Comprehensive Cancer Center at Johns Hopkins (SKCCC) by the Lead Study 
Coordinator. A record of patients who fail to meet entry criteria (i.e. screen failures) 
will be maintained.  Patient registration must be complete before beginning any 
treatment or study activities. 
 
Following registration, patients should begin protocol treatment within10 business 
days.  Issues that would cause treatment delays should be discussed with the Principal 
Investigator.  If a patient does not receive protocol therapy following registration, the 
patient’s registration on the study may be canceled.  The Lead Study Coordinator 
should be notified of cancellations as soon as possible. 
 
Except in very unusual circumstances, each participating institutions will order SGI-
110 agents directly from Astex pharmaceuticals.  Agents may be ordered by a 
participating site only after the initial IRB approval for the site has been forwarded to 
and acknowledged by the Coordinating Center. 
 
4.2 Registration Process 


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To register a patient, the following documents should be completed by the research 
nurse or data manager and faxed to 410-502-0834, or emailed to the Lead Study 
Coordinator at tbrown55@jhmi.edu:  
 
 Copy of required laboratory tests  
 Signed patient consent form 
 HIPAA authorization form 
 Facsimile Transmittal Page 
 Completed Registration Patient Worksheet 
 Eligibility Checklist 
 
To complete the registration process, the Lead Study Coordinator will 
 assign a patient study number 
 assign the patient a dose 
 register the patient on the study 
 Fax or email the patient study number and dose to the participating site 
 Call or email the research nurse or data manager at the participating site and 
verbally confirm registration  
 
4.3  
Patient assignment and randomization procedure for second cohort  
Each subject who satisfies the eligibility criteria and is accepted for the study will be 
assigned a unique identification number. The subject number will be used to identify the 
subject throughout the study and will be entered on all study documents.  Once the subject 
identification number has been assigned, a confirmation email will be sent to all site 
personnel.  
For the Randomized Cohort, subjects will be randomized to each treatment arm (SGI-
110+irinotecan or regorafenib/TAS-102) prior to treatment administration and should not 
exceed 1 week of the planned dose. The assignment will not be blinded.  Randomization 
will be stratified by standard treatment (Regorafenib or TAS-102) and time from last 
irinotecan treatment (> 6 months or < 6 months) through a dynamic algorithm to maintain 
balance between the arms as much as possible. For those assigned to treatment arm with 
standard of care therapy will receive regorafenib (if previously received TAS-102) or 
TAS-102 (if previously received regorafenib).  If they have never received either 
regorafenib or TAS-102, choice of therapy will be deferred to treating physician and 
patient. 
This is an open-label study. There will be no blinding of treatment assignment.  
 
5 
TREATMENT PLAN  
 
5.1 Overall Study Design 


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There will be two stages in this study: A phase I lead-in (Stage 1) followed by a randomized, 
controlled, open-label stage (Stage 2). Treatment will be administered on an outpatient basis 
 
5.1.2 Stage 1 
Stage 1 will be a traditional phase I study with a standard 3+3 design.23 A maximum of 
twenty-one eligible subjects will be enrolled to the phase I study.  Study drugs will be 
escalated per the schema to maximize the dose of drugs when given concurrently.  Patients 
will be treated with combined therapy immediately. Each cycle will last 28 days.  All patients 
enrolled at each dose level will be evaluated for DLT for the purpose of determining the 
MTD.  The dose escalation scheme is shown below. 
         
 Table 2:  Dose escalation schedule  
Dose Level 
SGI-110 (SC) 
Irinotecan (IV) 
Growth 
Factor 
Support 
with 
Filgrastim 
(or 
institutional 
equivalent) and/or Pegfilgrastim 
(SC) 
-1G 
30 mg/m2 days 1-5 
125 mg/m2 days 8 and 15 each cycle 
Filgrastim 5mcg/kg/day Cycle 1 
Days 9-14 and peg-filgrastim 6mg 
D16, additional growth factor 
support during Cycle 1 and 
subsequent cycles per clinician 
judgment 
-1 
30 mg/m2 days 1-5 
125 mg/m2 days 8 and 15 each cycle 
Per clinician judgment 
  1 (starting dose level) 
45 mg/m2 days 1-5 
125 mg/m2 days 8 and 15 each cycle 
Per clinician judgment 
1G 
45 mg/m2 days 1-5 
125 mg/m2 days 8 and 15 each cycle 
Filgrastim 5mcg/kg/day Cycle 1 
Days 9-14 and peg-filgrastim 6mg 
D16, additional growth factor 
support during Cycle 1 and 
subsequent cycles per clinician 
judgment 
2   
60 mg/m2 days 1-5 
125 mg/m2 days 8 and 15 each cycle 
Per clinician judgment 
3  
60 mg/m2 days 1-5 
125 mg/m2 days 1, 8 and 15 each cycle 
Per clinician judgment 
 
 
At least three patients will be treated at each dose level.  If 0/3 patients exhibits a dose-
limiting toxicity (DLT) after 4 weeks, the next patient will be treated at the next dose level.  
If one patient exhibits a DLT related to the study agent(s), the cohort will be expanded to up 
to 6 patients.  If 1 of 6 patients exhibits a DLT related to the study agent(s), then the next 
patient will enroll at the next dose level.  If 2 of 3-6 patients exhibit a DLT related to the 
study agent(s), the MTD is considered to have been exceeded and at least 6 patients will be 
entered at the dose level below the one at which DLT is defined. If this occurs on first dose 
level, the dose of SGI-110 will be reduced to 30 mg/m2 days 1-5 (Dose level -1). If no DLTs 
are encountered at Dose level -1, the next 3 patients will be entered at the next dose level, 
Dose level 1G. If one DLT is encountered at Dose level -1, this dose level will be expanded 
to 6 total patients at Dose level -1. And if two or more DLTs are encountered at Dose level 


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-1, at least an additional 3 patients will be enrolled at the lower dose level, Dose level -1G. 
If 0/3 or 1/6 DLTs occur on Dose level -1G, the next 3 patients will be dose escalated to 
Dose level 1G. If 2 or more DLTs out of 6 are experienced at Dose level -1G, the MTD will 
have been exceeded. Dose escalations will occur no sooner than 4 weeks after the last patient 
on the dose level has begun therapy to allow for full assessment of DLT.   
 
Table 3:  Dose escalations schema 
 
Number of Patients with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level 
will be declared the maximally administered dose 
(highest dose administered).  Three (3) additional 
patients will be entered at the next lower  dose 
level if only 3 patients were treated previously at 
that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, 
proceed to the next dose level. 
 If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared 
the maximally administered dose.  Three (3) 
additional patients will be entered at the next 
lower dose level if only 3 patients were treated 
previously at that dose. 
<1 out of 6 at highest dose level 
below 
the 
maximally 
administered dose 
This is generally the recommended phase 2 dose. 
At least 6 patients must be entered at the 
recommended phase 2 dose. 
 
Toxicity will be evaluated using the NCI Common Terminology Criteria for Adverse Events 
Active Version.  The frequency of toxicities per organ system will be tabulated using 
descriptive statistics. All patients who receive any amount of the study drug will be evaluable 
for toxicity. 
 
5.1.3 Stage 2 
The second stage of this study will be conducted as an open-label, randomized trial.24 As of 
December 2015, the maximally tolerated dose from the phase I trial was determined at level 1G:  
 SGI-110 45mg/m2 SC D 1-5 
 Irinotecan 125mg/m2 IV D 8 and 15 


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 Mandatory growth factor support during cycle 1: 
o Filgrastim (or institutional equivalent) 5mcg/kg SC C1 D 9-14 
o Peg-filgrastim 6mg SC C1 D16 
o Additional growth factor support during Cycle 1 and subsequent cycles per 
clinician judgment 
Ninety-six eligible subjects will be randomized in a 2:1 ratio to receive either (1) SGI-
110+irinotecan combination treatment in 28-day cycles (n=64) or (2) regorafenib 160 mg QD days 
1-21 in 28-day cycles or TAS-102 35mg/m2 BID days 1-5 and 8-12 in 28-day cycles as per 
physician choice (n=32). Safety data will be reviewed at least on a quarterly basis by the SRC. 
As epigenetic agents may take many months to show their benefit as seen in MDS/AML 
studies,25 in both Stage 1 and Stage 2, subjects receiving SGI-110 + irinotecan may continue 
receiving their assigned treatment if their disease progresses based on RECIST criteria, 
version 1.1 if 1) the patient is clinically stable, 2) the patient is informed of their scan results 
and agrees to continue therapy, and 3) the patient provider agrees that remaining on study 
would be appropriate for the patient.  
Crossover to the SGI-110+irinotecan combination treatment arm of the study will be permitted for 
subjects in the regorafenib/TAS-102 arm after there is evidence of disease progression.  
Response and PFS will be evaluated from images by the designated investigators at each site. 
5.2 Screening and pre-treatment criteria 
 
5.2.1 Screening Procedures 
Screening procedures and tests will be performed within 14 days before treatment administration 
with the exception of informed consent, tumor biopsy and radiologic response assessment which 
may be performed within 28 days of first dose of study drug. 
 Provision of written informed consent. The ICF must be signed and dated by the subjects before 
collection of any samples or performance of any study-specific evaluations.  
 Complete medical history, including demographics (date of birth, sex, race). A disease history, 
including the date of initial diagnosis and list of prior treatments and responses to these 
treatments, including time from last Irinotecan exposure (< or > 6 months), also will be 
recorded. Concurrent medical signs and symptoms must be documented to establish baseline 
conditions. 
 Record concomitant medications. 


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 Record all study-procedure related AEs from the time of informed consent and then treatment-
emergent AEs after the start of study drug administration (Cycle 1, Day 1) through 30 days 
after the last dose of study drug.   
 Investigator’s confirmation of eligibility. Perform all necessary procedures and evaluations to 
document that the subject meets each eligibility criterion. 
 Complete physical exam including weight and examination of the skin, eyes and fundi, ears, 
nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and 
genitourinary system.  
 Vital signs include resting systolic/diastolic blood pressure, resting heart rate, resting 
respiration rate, body temperature and pulse oximetry. Assess after the subject has rested in 
the sitting position for at least three minutes.  
 ECOG performance status.  
 12-lead ECG (rhythm, atrial rate, ventricular rate, PR interval, QRS duration, and QT/QTc, 
morphology and overall interpretation). 
 Height. 
 Sample collection for clinical laboratory tests (hematology, chemistry and urinalysis).  
 Serum or urine pregnancy test: for female subjects of child-bearing potential only. Results must 
be negative for the subject to be eligible for enrollment into the study. 
 Tumor biopsies in all phase 1 subjects on study. Additionally, tumor biopsies will be collected 
on a select number of subjects in phase 2. The following sites: SKCCC, VUMC, MSKCCC, 
and USC-Norris, will obtain biopsies on a total of 36 patients (distributed roughly evenly 
between the sites) for the first patients enrolled to the phase 2 if they have both biopsiable 
disease and are randomized to SGI-110 + Irinotecan. Optional biopsies will also be requested 
of patients with baseline research biopsies who remain on trial through Cycle 6-9. 
 Radiologic response assessment. 
 CEA 
 Quality of Life evaluation at start of study using the FACT-C questionnaire (Phase II only).   
   
5.2.2 Cycle 1, Day 1 
 
In order for patients to be treated, evaluations must meet laboratory guidelines per the eligibility 
criteria 


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5.2.3 Cycle 1 Day 8, 15 and Subsequent Cycles, Day 1, 8, 15 
In order for patients to be treated, evaluations must meet the following criteria: 
 ANC > 1250 /mcL 
 Platelet count > 75,000 /cu mm 
 Bilirubin <2 mg/dL 
 Creatinine < 2 mg/dL 
 
5.3 Agent Administration  
 
5.3.1 SGI-110 
 
SGI-110 administered SC daily on Days 1-5.   Dose level for Phase II is 45mg/m2 (modifications 
as per Section 6.3) 
SGI-110 is administered by SC injection preferably in the abdominal area. The total amount (in 
mg) of SGI-110 to be administered will be determined based on the body surface area (BSA). In 
calculating the BSA, actual heights and weights should be used. There will be no adjustments to 
“ideal” body weight. The institutional standard for calculating BSA is acceptable.  
The site(s) of SGI-110 SC injections will be captured on the dosing CRF. Additional guidelines 
regarding subcutaneous injection will be detailed in the SGI-110-02 Study Drug Reconstitution 
and Administration Manual.  
Investigators are prohibited from supplying SGI-110 to any subjects not properly enrolled in this 
study or to any physicians or scientists except those designated as sub-investigators on Food and 
Drug Administration (FDA) Form 1572. The investigator must ensure that subjects receive SGI-
110 only from personnel who fully understand the procedures for administering the study 
treatment. 
5.3.2 Irinotecan 
Irinotecan will be administered IV over 90 minutes at 125 mg/m2 per Table 3 (dose 
modifications as per Section 6.3).26 Cycles are 28 days long.  In cycle 1 irinotecan 
is given on days 8 and 15 in dose levels -1G, -1, 1, 1G, and 2, and on days 1, 8, and 
15 for dose level 3. Patients who develop acute diarrhea secondary to irinotecan 
may receive atropine and/or supportive measures per specific site’s institutional 
standard.   
Irinotecan will be diluted in 5% Dextrose injection (D5W), USP (preferred) or 
0.9% Sodium Chloride Injection (NS), USP, to a final concentration range of 0.12 


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22 
to 2.8 mg/mL (D5W, or NS). The drug will be administered intravenously over 90 
minutes, or per institutional standards 
 
5.3.3 Regorafenib 
 
Patients randomized to non-experimental therapy arm who opt for regorafenib, will 
be administered the agent as per standard dosing.27  Patients will take 160 mg once 
daily for days 1-21 of each 28 day cycle. Patients will be instructed to take the drug 
with a low-fat breakfast and to take the pills whole (not crushed). They will also be 
instructed to record drug intake on a patient pill diary (Appendix B). 
 
5.3.4 TAS-102 
 
Patients randomized to non-experimental therapy arm who opt for TAS-102, will be 
administered the agent as per standard dosing.  Patients will take 35mg/m2 (based 
on trifluridine component, with maximum single dose 80mg) twice daily for days 
1-5 and 8-12 of each 28 day cycle.16 Patients will be instructed to take the drug after 
breakfast and dinner and to take the pills whole (not crushed). They will also be 
instructed to record drug intake on a patient pill diary (Appendix C). 
 
 
5.4 Definition of Dose-Limiting Toxicity 
 
MTD will be defined based on the incidence of DLTs at each dose level. 
Dose limiting toxicity is defined as any of the following occurring through cycle 1 (Up 
to Cycle 2 day 1) of therapy related to SGI-110 or the combination of SGI-110 and 
irinotecan. The DLT is defined using the Common Terminology Criteria for Adverse 
Events (CTCAE).  
1. 
Hematologic toxicities deemed a DLT are:  
a. Grade 4 thrombocytopenia or neutropenia lasting > 7 days. 
b. Any incidence of Grade 3 or 4 febrile neutropenia. 
2. Non-hematologic toxicities deemed a DLT are:  
a. Grade ≥ 3 non-hematologic toxicity unless it could be appropriately 
managed by supportive treatment (e.g. hyperglycemia, nausea/vomiting, 
or diarrhea). 
b. Any other clinically significant adverse event which in the opinion of the 
Safety Review Committee (SRC) would place subjects at undue safety 
risk, or results in discontinuation of treatment. 


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Dose-limiting toxicity (DLT) is based on the CTEP Active Version of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE).28 
 
Management and dose modifications associated with the above adverse events are 
outlined in Section 6 (Expected Toxicities and Dosing Delays/Dose Modifications). 
 
5.5 General Concomitant Medication and Supportive Care Guidelines 
 
In general, concomitant medications and therapies deemed necessary for the supportive care and 
safety of the subject are allowed, provided their use is documented in the subject records and on 
the appropriate case report form. If toxicity occurs, the appropriate treatment per specific site’s 
institutional standard will be used to ameliorate signs and symptoms (including antiemetics for 
nausea and vomiting, anti-diarrheals for diarrhea and anti-pyretics and anti-histamines for drug 
fever). All supportive measures for optimal medical care will be given during the period of study.  
5.5.1 Antibiotics 
Antibiotics may be utilized to prevent or manage febrile neutropenia based on institutional 
standard practice. Febrile neutropenia is defined as temperature at least 38.5ºC when the ANC is 
< 1000 µL. Febrile subjects should be evaluated by physical examination, complete blood count 
(CBC) with differential, and blood culture. Subjects with febrile neutropenia or suspected sepsis 
on the basis of the physical examination are to be hospitalized for appropriate broad spectrum 
antibiotic coverage, consistent with local pathogen sensitivities.  
5.5.2 Hematopoietic Growth Factors 
Growth factor support is mandatory in cycle 1 for Phase II patients (Section 5.1.3).  Additional 
granulocyte-colony stimulating factor (GCSF) may be administered per ASCO guidelines from 
Cycle 1 onwards.29 Use of other white blood cell stimulating factors after Cycle 1 can be employed 
according to accepted practice or institutional guidelines, at the discretion of the treating physician. 
RBC transfusions can be administered at the discretion of the treating physician. 
5.5.3 Prohibited Medications 
The administration of any other anticancer agents including chemotherapy and biologic agents is 
NOT permitted. Similarly, the use of other concurrent investigational drugs is not allowed.  
5.6 Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, patients may continue on 
treatment until one of the following criteria applies: 
 Disease progression (for regorafenib or TAS-102 arm in Phase II), see 
below * regarding SGI-110 + irinotecan cohort. 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s), 


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 Participant demonstrates an inability or unwillingness to comply with the 
medication regimen and/or documentation requirements 
 Participant decides to withdraw from the study, or 
 General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
*In both Stage 1 and Stage 2, subjects receiving SGI-110 + irinotecan may continue 
receiving their assigned treatment if their disease progresses based on RECIST 
criteria if 1) the patient is clinically stable, 2) the patient is informed of their scan 
results and agrees to continue therapy, and 3) the patient’s provider agrees that 
remaining on study would be appropriate for the patient. 
 
5.7 Duration of Follow Up  
 
After removal from study, participants will be followed every three months or 
sooner until death, whichever occurs first. Participants removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event.  Post-study case report forms must be completed at least every three 
months until death and will capture information including subsequent treatments, 
response to subsequent therapy, and survival. 
  
5.8 Cross Over in Phase II  
 
As the primary endpoint of the Phase II portion of this study is PFS, patients who 
progress on standard of care treatment in phase II may crossover to the study arm A. 
The minimum washout required period is 14 days from last dose.  Subjects will be 
followed for PFS, response, and survival as well as monitored for toxicity. 
 
5.9 Criteria for Removal from Study Treatment   
 
Participants will be removed from study treatment when any of the criteria listed in 
Section 5.6 applies. The reason for study removal and the date the participant was 
removed must be documented in the study-specific case report form (CRF). 
Alternative care options will be discussed with the participant.   
 
In addition, a patient may be withdrawn by the investigator if he/she violates the study 
plan or for administrative and/or other safety reason after discussion with the sponsor.  
When a subject discontinues/withdraws prior to study completion, all applicable 
activities for the final study visit should be performed at the time of discontinuation, 
including completion of the quality of life questionnaire FACT-C for subjects enrolled 
in the phase II portion.  Any adverse experiences which are present at the time of 
discontinuation/withdrawal should be followed.  A follow-up off-study visit will occur 
within 30 days after last treatment. 
 
If a patient withdraws for non-medical reasons the following procedures will be 
followed:  
  


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 Physical examination will be performed. 
 Safety assessment (physical examination, vital signs, hematology and serum 
chemistry), performed within 30 days after last treatment  
 
6 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Active Version of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.28  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first 
dose of study treatment, throughout the study, and until the final study visit. Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
  
 
6.1 Anticipated Toxicities 
  
A list of the adverse events and potential risks associated with the agents administered 
in this study appear below and will determine whether dose delays and modifications 
will be made and/or whether the event requires expedited reporting in addition to 
routine reporting. Refer to the most recent versions of the full Prescribing Information 
for irinotecan (Camptosar®), regorafenib (Stivarga®), TAS-102 (Lonsurf®) and the 
Investigator’s Brochure for SGI-110 for further information.1,7,27  
 
6.1.1 Adverse Event Lists(s) for regorafenib 
  
The most common adverse reactions (40%) with regorafenib are fatigue, 
hypocalcemia, hypophosphatemia, palmar-plantar erythrodysesthesia, anorexia, 
diarrhea, 
transaminitis, 
hyperbilirubinemia, 
anemia, 
lymphopenia 
thrombocytopena, and proteinuria. Other adverse experiences (>10%) are 
hypertension, dysphonia, fever, pin, rash, hyponatremia, hypokalemia, and 
infection. 
 
6.1.2 Adverse Event List(s) for irinotecan 
 
The most common adverse reactions (50%) with irinotecan are alopecia, anemia, 
thrombocytopenia, leukopenia, hyperbilirubinemia, weakness, anorexia, vomiting, 
and abdominal pain and cramping.  Other adverse experiences (>10%) are 
cholinergic toxicity (47%), fever, dizziness, headache, chills, constipation, 


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mucositis, weight loss, stomatitis, cough, dyspnea, rhinitis, and diaphoresis. Prior 
studies with irinotecan have reported neutropenia and/or late diarrhea (diarrhea 
occurring more than 24 hours after irinotecan administration) as the dose-limiting 
toxicities. The aggressive use of loperamide can significantly decrease the 
incidence of severe delayed diarrhea. Other side effects include nausea, vomiting, 
anorexia, abdominal cramping, alopecia, anemia, and asthenia. An immediate onset 
diarrhea may occur in the context of a cholinergic-like syndrome which is 
characterized by diaphoresis, abdominal cramps, lacrimation, salivation, and miosis 
or other visual disturbances. Cases of colitis complicated by ulceration, bleeding, 
ileus, and infection have been observed. Additionally, isolated cases of pulmonary 
toxicity have been encountered. Finally, infrequent abnormalities of serum 
creatinine or hepatic enzymes, thrombocytopenia, mucositis, or local irritation at 
infusion sites has been noted in some patients. The use of irinotecan in the setting of 
liver dysfunction is currently under investigation. 
 
6.1.3 Adverse Event List(s) for TAS-102 
 
As per the RECOURSE trial, the most common adverse reactions (≥40%) are 
nausea, neutropenia, leukopenia, anemia, and thrombocytopenia.  Other adverse 
experiences (>10%) include vomiting, diminished appetite, fatigue, diarrhea, 
abdominal pain, fever, and asthenia. 
 
6.1.4 Adverse Event List(s) for SGI-110 
 
The most common AEs suspected by the investigators in Study SGI-110-01 to be 
related to the drug and observed to date in the MDS/AML population are: injection 
site pain, fatigue, nausea, thrombocytopenia, anemia and diarrhea. Based on the 
mechanism of action of the drug and its active form decitabine, myelosuppression 
(neutropenia, thrombocytopenia, and anemia) and the related consequences such as 
infection (e.g. pneumonia), sepsis, and bleeding are the most likely risks for the 
drug. Mucositis has also been reported. The doses of SGI-110 being studied in this 
protocol (up to 60 mg/m2 dailyx5) have not been shown to cause drug-related 
myelosuppression when the drug is used as a single agent. However, in MDS/AML 
population it is difficult to assess the relationship to the study drug since most 
patients present with myelosuppression as part of their disease condition. 
Preliminary safety data from an ongoing ovarian cancer trial in combination with 
carboplatin showed significant neutropenia and thrombocytopenia when 45mg/m2 
SGI-110 days 1-5 is combined with full dose of carboplatin (AUC 5).  
Pain and burning at the injection site has been reported that are related to dose and 
volume of injection as well as the speed of injection. Care must be taken to avoid 
intradermal injection. If injection site pain is reported upon injection, the practice 
of a slow injection (over 30-60 seconds), and the application of ice packs to the 
injection site both before and after injection (a duration of 5-10 minutes each is 
recommended) have been reported to attenuate the injection site events. If the 


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injection site events are reported at subsequent injections despite slow injection and 
the use of ice packs, pre-treatment with topical or systemic analgesics can be 
considered. 
 
6.2 Toxicity Management 
 
6.2.1 Irinotecan 
 
Patients who develop acute diarrhea secondary to irinotecan may receive atropine 
and/or supportive measures per specific site’s institutional standard.  Patients will be 
monitored until symptoms abate.  Patients who experience new or worsening 
loose stools and/or diarrhea will be recommended loperamide (or other 
equivalent anti-motility agent(s)) to take as directed following each loose 
bowel movement. Patients will be regularly evaluated by the research nurse 
until resolution of the diarrhea. Either acute or chronic diarrhea could require 
hospitalization if the patient is volume depleted or if other clinical symptoms warrant 
admission. 
 
If grade 2 or greater abdominal cramping occurs, further chemotherapy will not be 
given until the cramping has fully resolved.  The patient will also be evaluated by the 
research nurse to determine the possible etiology of the cramping.  If cramping 
secondary to irinotecan is suspected, the treatment for abdominal cramping will be 
equivalent to diarrhea (as stated above). 
 
6.3 Dose Modifications/Delays 
  
The Investigator should try to the best of his/her ability to assess whether an adverse event is 
possibly related to study treatment, and if so, attribute it to SGI-110 only, irinotecan only, or both 
SGI-110 and irinotecan, and treat the subject accordingly by only reducing the study drug that has 
most likely contributed to the individual toxicity necessitating dose reduction. This section 
provides suggested guidelines for the management of various study drug-related toxicities in 
subjects receiving both SGI-110 and irinotecan. Preferably, only one study drug should be reduced 
at any one time even if both drugs are suspected to have contributed to the toxicity (e.g. 
myelosuppression). SGI-110 should be reduced first unless an adverse event can most likely be 
attributed to irinotecan only (e.g., acute diarrhea or hyperbilirubinemia as they are not expected 
from SGI-110 treatment).  Lymphopenia of any grade that is asymptomatic will not require dose 
modification. 
During Stage 2 of the study, subjects may be randomized to receive either regorafenib or TAS-102 
versus SGI-110 and irinotecan.  Dose modifications for regorafenib or TAS-102 will be at the 
Investigator’s discretion and judgment per standard clinical practice and per most current FDA-
approved package inserts.  


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During Phase 2, treatment delays not related to adverse events (i.e. vacations) will be allowed 
beginning after cycle 4 for up to a period of 2 weeks at the discretion of the Investigator, except if 
due to a holiday that cannot be avoided.   
 
6.3.1 SGI-110 dose modifications 
In general, SGI-110 dosing should be withheld for Grade 4 myelosuppression or ≥ Grade 3 
SGI-110-related non-hematologic toxicities until toxicity has resolved to ≤ Grade 1 or baseline 
levels. Treatment with SGI-110 may then be resumed at one dose level below the administered 
dose levels (i.e., 45 mg/m2 if the patient received 60 mg/m2; or 30 mg/m2 if the patient received 
45 mg/m2. One exception is neutropenia and anemia that can be managed by growth factors, and 
transfusion in subsequent cycles. In that case dosing may be resumed at the same dose level. Dose 
reduction to less than 30 mg/m2 will not be allowed, and SGI-110 may not be omitted.  
If the subject has already received treatment with SGI-110 on Day 1 or beyond, subsequent 
treatment days (Day 2-5 in the 5-day regimen) will be withheld if the subject develops any DLT 
and the skipped doses will be missed. Dosing will also be withheld on Day 1 of any subsequent 
treatment cycles if the subject still has a DLT or other drug-related clinically significant toxicity 
that has not resolved to ≤ Grade 1 or baseline.  Dosing may restart at a lower dose level once the 
subject becomes eligible again and the DLT or other drug-related toxicity has resolved to ≤ Grade 
1 or baseline. If dosing is delayed by more than 28 days because of drug-related toxicity, then the 
subject will have SGI-110 permanently discontinued and will be taken off of Arm A.  
6.3.2 Irinotecan dose modifications 
Irinotecan dosing should be withheld for ≥ Grade 3 irinotecan-related toxicities, and resumed 
depending on the timing of recovery and number of episodes occurred (see Table 4 and 5). If 
irinotecan dosing is delayed due to irinotecan-related toxicities for > 2 consecutive  weeks despite 
supportive treatment per standard clinical practice and/or more than 2 dose reductions of irinotecan 
is required, the subject should discontinue irinotecan treatment but may be continued on SGI-110 
alone.  If both drugs cannot be restarted, the subject should be withdrawn from the study and enter 
the 30-day follow up period.   
Table 4 below provides suggested guidelines for the Investigator to use along with his/her best 
judgment for SGI-110 and irinotecan dose delay and/or reduction based on the AEs observed. If 
SGI-110 dosing is delayed due to SGI-110-related toxicities for > 28 consecutive days despite 
supportive treatment per standard clinical practice and/or more than 1 dose reduction of SGI-110 
and 2 dose reductions of irinotecan are required, stop SGI-110 and irinotecan therapy, discontinue 
the subject from the study, and complete the follow-up visit within 30 days of the last 
administration of SGI-110 or irinotecan, whichever is discontinued last. 


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Table 4: 
Dose Modification Guidance for SGI-110 and Irinotecan for Selected 
Study Drug-Related Toxicities (Phase I) 
 
 
Neutropenia or febrile neutropenia or anemia 
Occurrence 
Grade 
Dosing Guideline After Recovery to Grade ≤ 1 or baseline 
1st 
G 4 
Treat anemia with transfusion; Start GCSF prophylactically in Cycle 2. No change in 
SGI-110 dose or irinotecan dose.  
2nd 
 G 4 
Despite GSCF prophylaxis at ≥ Cycle 2, decrease SGI-110 dose to 45 mg/m2 if previous 
SGI-110 dose was 60 mg/m2 or to 30 mg/m2 if previous dose was at 45 mg/m2.  
3rd 
 G 4 
 Continue SGI-110 at 30 mg/m2 but reduce irinotecan dose to 75% of previous dose. 
and continue GCSF prophylaxis 
4th 
 G 4 
Discontinue subject from study 
Thrombocytopenia 
Occurrence 
Grade 
Suggested Action 
1st 
G 3 
G 4 
No change in SGI-110 or irinotecan dose  
Reduce SGI-110 by one dose  level 
2nd 
 G 4 
Despite SGI-110 dose reduction, decrease irinotecan dose to 75%  
3rd 
 G 4 
Despite SGI-110 dose reduction, decrease irinotecan dose to 50% 
4th  
 G 4  
Discontinue subject   
Transaminitis or Increased Creatinine 
Occurrence 
Grade 
Suggested Action 
1st 
≥ G 3 
No change in SGI-110 dose; reduce irinotecan by 25% 
2nd     
≥ G 3 
Reduce irinotecan to 50% 
3rd 
> G 3 
Discontinue patient from study treatment 
 
Table 5: 
Dose Modification Guidance for SGI-110 and Irinotecan with mandatory 
growth factor support for Selected Study Drug-Related Toxicities (Phase 
II) 
 
 
SGI-110 Dose Level 1G = 45mg/m2 D1-5, Irinotecan 125mg/m2 D8 and 15,  filgrastim 5mcg/kg 
C1D9-14 and peg-filgrastim 6mg C1D16 (further growth factor support in subsequent cycles at 
physician discretion) 
 
 
Neutropenia or febrile neutropenia or anemia 
Occurrence 
Grade 
Dosing Guideline After Recovery to Grade ≤ 1 or baseline 
1st 
G 4 
Treat anemia with transfusion;  
Decrease SGI-110 dose to 30mg/m2, or if already reduced*, decrease irinotecan to 75%
2nd 
 G 4 
Decrease irinotecan dose to 75%, or to 50% (if previously reduced to 75%) 
3rd 
 G 4 
Decrease irinotecan dose to 50% from 75% or discontinue if already reduced to 50% 
4th 
 G 4 
Discontinue subject from study 
Thrombocytopenia 
Occurrence 
Grade 
Suggested Action 


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1st 
G 3 
G 4 
No change in SGI-110 or irinotecan dose  
Decrease irinotecan dose to 75% 
2nd 
 G 4 
Despite irinotecan dose reduction, decrease SGI-110 to 30mg/m2 
3rd 
 G 4 
Despite SGI-110 dose reduction, decrease irinotecan dose to 50% 
4th  
 G 4  
Discontinue subject   
Transaminitis or Increased Creatinine 
Occurrence 
Grade 
Suggested Action 
1st 
≥ G 3 
No change in SGI-110 dose; decrease irinotecan to 75% 
2nd     
≥ G 3 
Decrease irinotecan dose to 50% 
3rd 
> G 3 
Discontinue patient from study treatment 
*SGI-110 cannot be dose reduced beyond 30mg/m2 
 
6.3.3 Dose modification for regorafenib or TAS-102 toxicities 
Patients randomized to regorafenib or TAS-102 treatment in phase II of the study will have dose 
modifications at the Investigator’s discretion and judgment per standard clinical practice and per 
most current FDA-approved package insert.  
 
 
7 DRUG FORMULATION AND ADMINISTRATION  
 
7.1 SGI-110 
 
7.1.1 Description 
 
Sodium (2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazin-1(2H)-yl)-2 (hydroxymethyl) 
tetrahydrofuran-3-yl ((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-
hydroxytetrahydrofuran-2-yl)methyl phosphate 
 
7.1.2 Form 
 
SGI-110 product is supplied in a two-vial configuration. 
SGI-110 for Injection, 100 mg is a 5 mL glass vial containing lyophilized SGI-110 
drug powder for reconstitution and subcutaneous injection using the custom diluent 
supplied in a separate vial. Each vial is stoppered with fluoropolymer coated butyl 
rubber closure and sealed with a blue flip-off cap. SGI-110 for Injection, 100 mg 
vial is individually packaged in a heat-sealed aluminum foil pouch with a single 
desiccant bag to protect from moisture. 
SGI-110 Diluent for Reconstitution, 3 mL or 1.2mL is a 5 mL glass vial with 3 mL 
or 1.2mL of custom diluent. Each vial is stoppered with fluoropolymer coated 
butyl rubber closure and sealed with a white flip-off cap. 


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7.1.3 Storage and Stability 
 
SGI-110 for Injection, 100 mg vial is stored at refrigerated condition of 2–8ºC in 
the original packaging until use. SGI-110 Diluent for Reconstitution, 3 mL can be 
stored at 2–30°C, and 1.2mL can be stored at is stored at 2–8°C in upright position 
until use. Both vials are preservative-free and for single use only. SGI-110 must be 
stored in a secure, locked facility accessible only to authorized study personnel. 
OSHA Guidelines for handling cytotoxic drugs outlined in the American Journal 
of Hospital Pharmacy must be followed.26 As with other potentially toxic anti-
cancer agents, care should be exercised in the handling and preparation of SGI-110. 
The use of gloves and protective garments is recommended. Preparation should 
occur in a vertical laminar flow biological hood using proper aseptic technique. If 
SGI-110 contacts the skin, it should be immediately be treated with borax buffer 
solution pH 10 followed by washing immediately and thoroughly with soap and 
water. If SGI-110 contacts the mucous membranes, flush thoroughly with water. 
Drug spilling can be inactivated by 2 N sodium hydroxide solution.  
7.1.4 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and 
safe disposal of the chemotherapeutic agent in a self-contained and protective 
environment. 
 
7.1.5 Availability 
 
SGI-110 is an investigational agent and will be supplied free-of-charge from 
Astex Pharmaceuticals. 
 
7.1.6 Ordering and accountability 
 
An initial supply of SGI-110 will be shipped to each study center’s pharmacy when 
all the initiation documents, including IRB approvals and IRB approved ICF, have 
been received and reviewed by Astex Pharmaceuticals and upon activation of the 
study center by the Coordinating Center JH SKCCC. Thereafter, it is the 
responsibility of the trial pharmacist to order a resupply. 
SGI-110 must be kept in a locked limited access room. The study drug must not be 
used outside the context of the protocol. Under no circumstances should the 
Investigator or other study center personnel supply SGI-110 to other Investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this 
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An accurate accounting of the study drugs and investigational devices must be 
maintained. These records must show dates, lot numbers, quantities received, and 
dispensed. SGI-110 accountability records must be maintained and readily 
available for inspection by regulatory authorities at any time. 
7.1.7 Destruction and Return 
 
At the end of the study, unused supplies of SGI-110 should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. 
 
7.2 Irinotecan 
 
7.2.1 Description 
 
This is an FDA approved chemotherapy drug for the treatment of metastatic colon 
cancer.  It is also active in other diseases, namely other GI cancers, lung and 
gynecologic malignancies.  Irinotecan (125 mg/m2/w) will be administered IV.  It 
is commercially available. 
 
7.2.2 Form 
 
Irinotecan is commercially available. Vials contained 100 mg of irinotecan as a 
pale yellow transparent solution in 5 mL total volume per vial. Each milliliter of 
solution contains 20 mg of irinotecan hydrochloride (on the basis of the trihydrate 
salt), 45 mg of sorbitol NF powder, and 0.9 mg of lactic acid, USP. The pH of the 
solution has been adjusted to 3.5 (range, =3.0 to 3.8) with sodium hydroxide or 
hydrochloric acid. 
  
7.2.3 Storage and Stability 
 
Intact vials are to be stored at controlled room temperature, protected from light until 
use.  Once diluted, the solution is physically and chemically stable for up to 24 
hours at room temperature (approximately 25C) and in ambient fluorescent 
lighting.  Solutions diluted in 5% Dextrose Injection, USP, and stored at 
refrigerated temperatures (approximately 2 to 8C), and protected from light are 
physically and chemically stable for 48 hours. Refrigeration of admixture using 
0.9% Sodium Chloride Injection, USP, is not recommended due to a low and 
sporadic incidence of visible particulates. 
7.2.4 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and 
safe disposal of the chemotherapeutic agent in a self-contained and protective 
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7.2.5 Availability 
 
Irinotecan is a standard of care, commercially available agent that is FDA –
approved for metastatic colorectal cancer. It is readily available in oncology 
pharmacies at SKCCC and USC Cancer Center and will be billed as standard of 
care. 
7.3 Regorafenib 
 
7.3.1 Description 
The chemical name for regorafenib is 4-[4-({[4-chloro-3-(trifluoromethyl) 
phenyl] carbamoyl} amino)-3fluorophenoxy]-N-methylpyridine-2-carboxamide 
monohydrate. 
 
Following a 160 mg dose of regorafenib in patients with advanced solid tumors, 
regorafenib reaches a mean peak plasma level (Cmax) of 2.5 μg/mL at a median 
time of 4 hours and a mean area under the plasma concentration vs. time curve 
(AUC) of 70.4 μg*h/mL. The AUC of regorafenib at steady-state increases less 
than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib 
reaches a mean Cmax of 3.9 μg/mL and mean AUC of 58.3 μg*h/mL. The mean 
relative bioavailability of tablets compared to an oral solution is 69% to 83%. 
 
Regorafenib is highly protein bound (99.5%) and is metabolized by CYP3A4 and 
UGT1A9. The mean (range) elimination half-lives for a single 160 mg dose of 
regorafenib and the  M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 
25 hours (14 to 32 hours), respectively. The M-5 metabolite has a longer 
mean (range) elimination half-life of 51 hours (32 to 70 hours). Approximately 
71% of a radiolabeled dose was excreted in feces and 19% of the dose was 
excreted in urine (17% as glucuronides) within 12 days after administration of a 
radiolabeled oral solution at a dose of 120 mg. 
 
In vitro studies with human hepatic microsomes or recombinant enzymes showed 
that regorafenib and its metabolites competitively inhibit CYP2C8, CYP2C9, 
CYP2B6, CYP3A4, CYP2D6, CYP2C19, UGT1A1, UGT1A9, BCRP, and P-
glycoprotein. 
 
Regorafenib is a substrate of CYP3A4 and UGT1A9. In pharmacokinetic studies 
conducted in humans, mean regorafenib AUC concentrations were increased and 
decreased in the setting of concomitant administration with strong CYP3A4 
inhibitors and inducers, respectively. 
  
7.3.2 Form 
 
Regorafenib 40 mg tablet is the only commercially available formulation. It is pink 
and oval in appearance. 


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7.3.3 Storage and Stability 
 
Regorafenib tablets are supplied in packages containing three bottles, with each 
bottle containing 28 tablets for a total of 84 tablets per package. Tablets must be 
stored in their original bottle. The desiccant should not be removed. Unused 
tablets should be discarded 28 days after opening the bottle in accordance our 
chemotherapy waste policies. 
 
Regorafenib should be stored at 25°C (77°F) with excursions permitted from 15 
to 30°C (59 to 86°F). 
  
7.3.4 Availability 
 
Regorafenib is a FDA-approved, standard of care agent for metastatic, pretreated 
colorectal cancer.  It will be provided through standard Special Order Pharmacies 
and billed as standard of care.    
 
7.3.5 Ordering 
 
Regorafenib will be ordered through standard of care prescription and Specialty 
Order Pharmacies. 
7.4 TAS-102 (Lonsurf) 
 
 
7.4.1 Description 
TAS-102 (Lonsurf) is an antitumor nucleoside drug that combines FTD and 
TPI at a molar ratio of 1:0.5.  The chemical name for TAS-102 (Lonsurf) is 
trifluridine (α,α,α-trifluorothymidine) and tipiracil hydrochloride (5-chloro-6-[(2-
iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione monohydrochloride 
 
As per the manufacturer’s guide: “After twice daily dosing of LONSURF, 
systemic exposure AUC of trifluridine increased more than dose-proportionally 
over the dose range of 15 to 35 mg/m2. After administration of LONSURF 35 
mg/m2 twice daily, the mean elimination half-life (t1/2) of trifluridine was 1.4 
hours and of tipiracil was 2.1 hours after a single dose. The mean elimination 
half-life at steady state of trifluridine was 2.1 hours and of tipiracil was 2.4 hours. 
The accumulation of trifluridine was 3-fold for AUC0-last and 2-fold for peak 
plasma concentration (Cmax) at steady state while no accumulation was observed 
for tipiracil. Administration of a single dose of LONSURF containing tipiracil and 
trifluridine 35 mg/m2 increased the mean AUC0-last of trifluridine by 37-fold and 
Cmax by 22-fold with reduced variability compared to trifluridine 35 mg/m2 
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Following a single oral administration of LONSURF at 35 mg/m2 in patients with 
cancer, the mean time to peak plasma concentration (Tmax) of trifluridine was 
around 2 hours.  
 
A standardized high-fat, high-calorie meal decreased trifluridine Cmax, tipiracil 
Cmax and AUC by approximately 40%, but did not change trifluridine AUC 
compared to those in a fasting state in patients with cancer following 
administration of a single dose of LONSURF 35 mg/m2. It is recommended to 
take LONSURF within 1 hour after completion of the morning and evening meals 
based on the observed correlation between the increase in the Cmaxof trifluridine 
and the decrease in neutrophil counts.  
 
Trifluridine mainly binds to human serum albumin. The in vitro protein binding 
of trifluridine in human plasma is greater than 96%, independent of drug 
concentration and presence of tipiracil. Plasma protein binding of tipiracil is 
below 8% 
 
Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP) 
enzymes. Trifluridine is mainly eliminated by metabolism via thymidine 
phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY). 
No other major metabolites were detected in plasma or urine. 
 
Following a single dose of LONSURF at 60 mg, the mean 48-hour cumulative 
urinary excretion was 1.5% for unchanged trifluridine, 19.2% for FTY, and 29.3% 
for unchanged tipiracil.” 
 
7.4.2 Form 
 
TAS-102 is formulated as an immediate-release film-coated tablet, which is 
supplied in strengths (expressed as FTD content): 
• 
The 15-mg white, round tablet contains 15 mg FTD and 7.065 mg TPI as 
active ingredients. 
• 
The 20-mg pale-red, round tablet contains 20 mg FTD and 9.42 mg TPI as 
activeingredients. 
 
Both tablet strengths contain lactose monohydrate, pregelatinized starch, stearic 
acid,hypromellose, titanium dioxide, polyethylene glycol, and magnesium 
stearate. The 20-mg tablet for TAS-102 also contains red ferric oxide. 
 
i. Storage and Stability 
 
TAS-102 cards must be stored at room temperature between 59°F and 86°F (15°C 
and 30°C). 
  
ii. Availability 
 


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TAS-102 is a FDA-approved, standard of care agent for metastatic, pretreated 
colorectal cancer.  It will be provided through standard Special Order Pharmacies 
and billed as standard of care.    
 
iii. Ordering 
 
TAS-102 will be ordered through standard of care prescription and Specialty 
Order Pharmacies. 
8 CORRELATIVE/SPECIAL STUDIES  
 
A unique patient identifier will be assigned to each patient by the coordinating center.  The 
same unique patient identifier linked to the tumor biopsies will be used to shield the 
archived blood samples. The protocol scientific investigator(s) handling the samples will be 
blinded as to the patient identification, patient data and outcome. 
Research bloods and biopsies will be batched and sent to Dr. Ahuja’s laboratory at the 
conclusion on enrollment for the study as described in this section. 
 
After shipping, samples and associated data will be stored at Johns Hopkins unless the 
patient withdraws consent. 
 
Up to two sources of tumor DNA (blood and tumor biopsies) will be evaluated for DNA 
methylation status in each patient.  Blood will be drawn from all patients in the study prior 
to starting treatment, as well as on days 8, 15, and 22 of the study for Cycle 1.  For the 
subsequent cycles, blood will be collected prior to reconvening treatment on Day 1 and 15 
(as well as on day 8 of cycle 2), for patients on Arm A. On Arm B, cycles 1 and 2, samples 
will be collected on days 1 and 15. Subsequent cycles (Cycle 3 and beyond) correlative 
samples will be collected on day 1 of a cycle.  The blood samples will be used to assess the 
methylation status of free tumor DNA circulating in the blood. Tumor biopsies will be 
performed on all patients prior to starting treatment and post-treatment biopsies will be 
obtained prior to treatment (Cycle 1 Day1), and on ~ Cycle 1 Day 8 in Phase I and cycle 2 
Day 8-15 for patients selected for biopsy in Phase II, and at the conclusion of the trial 
(optional).Methylation status will be assessed pre- and post-treatment.  In those patients who 
have evidence of methylation changes comparing pre and post treatment analyses, further 
confirmatory studies will be done to assess if these changes in methylation correlate with 
gene re-expression.  
 
Methylation-specific PCR (MSP) will be used to detect the presence of methylated alleles 
for specific genes described below.30-34 Genes found to be methylated in pre-treatment 
specimens will be monitored for post-treatment changes in methylation using MSP. 
Methylation analysis may then be performed by using a nested MSP approach. The nested 
MSP approach has a sensitivity of 1 in 50,000 methylated allele to determine the genes that 
are methylated amongst the panel for each patient. A non-nested real-time MSP approach 
will then be used to follow the biologic response across various time points in the study for 
the genes of interest. This strategy of nested MSP followed by non-nested MSP has been 
validated in the ongoing study in the MDS/AML patients using bone marrow specimens as a 


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useful monitoring tool for biologic response. 
 
Patients will have plasma samples analyzed for DNA methylation patterns pre-treatment as 
well as on Days 8, and 15 and 22 for Cycle 1. For the subsequent cycles, blood will be 
collected prior to reconvening treatment on Day 1 and 15 (as well as on day 8 of cycle 2), 
for patients on Arm A. On Arm B, cycles 1 and 2, samples will be collected on days 1 and 
15. Subsequent cycle (Cycle 3 and beyond) correlative samples will be collected on day 1 of 
a cycle.  Candidate genes that will be analyzed for promoter methylation include potentially 
(but not limited to): p16, SFRP 1, TFPI-2, IGFBP3, O6-MGMT, APC, CHFR, RASSF1A, 
WRN, DR1, and hMLH1. Genes found to be methylated in pre-treatment specimens will be 
monitored for post-treatment changes in methylation using quantitative MSP. DNA will first 
be extracted from plasma using the Methylation-On-Beads (MOB) technology, a novel 
nano-based methodology designed to capture extremely low quantities of blood found in 
blood.34-35  Serum-based methylation analysis has been performed and reported previously 
using a variety of approaches.36-38 In previous studies, this nano-enabled assay demonstrated 
high sensitivity for screening of common cancers such as lung and colorectal and points to 
the enormous potential of using this platform for surveillance of responses to epigenetic 
therapy.  The utility of the nano-enabled platform will be explored in the ongoing 
correlative studies to develop a sensitive assay for detection of response to epigenetic 
therapy. Methylation analysis will then be performed by using a quantitative MSP approach. 
8.1 Archival tissue 
 
We will consent patients to obtain paraffin-embedded blocks of prior tissues including 
their primary cancer, if possible. This will allow us to perform methylation analysis on 
primary tumors, and determine if the primary and metastatic lesions have a similar 
profile.  DNA will be extracted and analyzed similar to the treatment for tumor biopsies 
above. Expression analysis will also be performed in selected cases, as feasible. 
 
Archival tissues will be requested for each patient from all prior surgeries. Paraffin 
blocks containing tumor sections will be requested. Paraffin blocks must be 
confirmed by the pathologist to contain primary tumor. These blocks must be sectioned 
to generate a total of 10 curls of 10 micron thickness. These curls should be placed in 
two 2ml eppendorf tubes with 5 curls in each. The eppedorf tubes must be clearly 
labeled with the Patient ID, date from which the primary tumor was collected (date of 
surgery), and appropriate pathology report for the block will be requested. Additionally, 
one stained hematoxylin and eosin slide (H&E) and two unstained plus slides should be 
created from the same blocks.  These slides must be labeled with the Patient ID, and the 
date of surgery as above. 
 
8.2 Pharmacokinetic Studies 
 
Pharmacokinetic evaluation will be conducted during Phase 1 only, in all subjects in order to 
evaluate exposures of SGI-110 and decitabine in the disease population. SGI-110 does not inhibit 
nor induce CYP3A4, which is the major contributing enzyme to irinotecan metabolism. As such, 


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irinotecan pharmacokinetics will not be evaluated in this study as its exposures are not expected 
to be affected by SGI-110. 
 
Pharmacokinetics of SGI-110 and decitabine will be assessed from plasma concentrations.  
Plasma samples will be prepared from blood drawn at the following time-points: 
Cycle 1, Day 1: pre-dose, 15 min, 30 min, 60 min, 90 min, 2 hr, 4 hr, 6 hr and 8 hr post-dose. 
Sampling windows are up to 10% of protocol specified time point but no more than 1 hour.  
Details for procedure for PK sample collection are included below. 
Plasma samples will be appropriately labeled and shipped for analysis to: 
 
Nabeela Aleem, Sample Coordinator 
Frontage Laboratories, Inc. 
700 Pennsylvania Drive  
Exton, PA 19341 
P: 484-348-4790 
Email : <naleem@frontagelab.com> 
 
Procedures: 
A. Preparation of K2EDTA Vacutainer tubes containing THU (tetrahydrouridine) 
Materials— 
THU: Calbiochem 584222, EMD Chemicals, Inc. 
 
Notes and Preparation of THU: 
1. The BioVision, Inc datasheets indicate that the 10 mg vial of THU must be stored frozen 
and protected from light at –20°C. The material is hygroscopic and difficult to weigh, and 
reconstitution of the entire contents at the intended concentration is strongly suggested. 
2. Following reconstitution in water (do not use methanol), aliquots can be purged with 
nitrogen and frozen at –20°C. The datasheets indicate that these aliquots are stable for up 
to 3 months at –20°C. 
3. Prepare a 0.4 mg/mL solution of THU. Since the datasheet purity of THU is listed as 
>80% (by TLC), assume that there are 8 mg of THU per vial of THU. Diluting this to a 
volume of 20 mL in a graduated cylinder or graduated centrifuge tube gives a 0.4 mg/mL 
(400 ug/mL) solution of THU. Keep this solution on ice. 
 Measure a volume of 10 ml of sterile water into a graduated cylinder or a 50 mL 
graduated  centrifuge tube 
 Use a serological pipette to add approximately 1 ml of water to the vial of THU. 
 Mix/shake the THU vial as best as possible, until the powder seems to be 
dissolved in the water. 
 Transfer the liquid from the THU vial into the graduated cylinder or graduated 
centrifuge tube 
 Bring the total volume of the container to 20 ml. 
 
Preparation of Vacutainer tubes: 
1. Pop the top of the vacutainer tube to break the vacuum seal. 
2. Using a pipettor, immediately deliver at least 20 uL (20-30 uL) of the THU solution into 
each of the labeled K2EDTA 6 mL Vacutainer tubes. 


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3. When all K2EDTA Vacutainer tubes have been prepared with the THU and labeled, store 
the tubes refrigerated for up to 30 days. 
4. Toss the THU aliquot remainder when done. 
 
B. Plasma Sample Collection: 
Note: Blood samples for PK studies need to be processed immediately. It is imperative that the 
following procedures be followed after collection of the sample to stabilize the drug and its 
various metabolites. 
1. Using a syringe, collect a 6 mL peripheral blood sample and transfer to the 6 mL 
K2EDTA tube preloaded with THU and stored at 4°C. 
2. Immediately upon collection, mix the blood sample by gently inverting the tube 8-10 
times and then immediately place the tube in a container of wet ice. Samples must be 
kept on the wet ice until centrifuged. Use wet ice to avoid sample hemolysis. 
3. Centrifuge the EDTA tube, pre-loaded with THU, at either 1800 g x 10 min at 4°C or 
1500 g x15 min at 4°C. The tube should be centrifuged within 1- 2 hours of collection. 
4. Immediately after centrifugation, use the pipettes provided to transfer at least 1.0 mL of 
plasma into each of 2 labeled screw top tubes and store in a –20°C freezer until shipment. 
5. Store the samples for a minimum of 8 hours at –20°C until packaging for shipment to 
Frontage Labs. Samples should be shipped to Frontage for analysis within 90 days of 
collection, if possible. 
6. Samples should be packaged for shipment in triple packaging, sealed and cushioned and 
containing sufficient amount of crushed dry ice to last the duration of transport. 
 
 
PK Specimen Collection guide 
 
 
 
8.3 Pharmacodynamic Studies 
8.3.1 Tumor Biopsies 
Mandatory tumor biopsies will be required at baseline and on Cycle 1 Day 8 in the 
phase I cohort. Tumor biopsies at baseline and during Cycle 2 (between C2D8 and 
C2D15)   will also be collected from the first 36 patients enrolled in the phase II 
cohort with biopsiable disease randomized to SGI-110 + Irinotecan (Arm A) 
approximately evenly spread between the following study sites: SKCCC, VUMC, 
MSKCCC, and USC-Norris. Core biopsies are required;  4-6  passes must be 
obtained. Fine needle aspiration biopsies may be allowed only after PI approval. 
Pre- and post- biopsy should be performed from same organ site. For example: if 


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pre- biopsy is liver, then post- biopsy should also be liver and preferably the same 
lesion. Biopsy sites (liver, colon, intra-abdominal implants) in metastatic colorectal 
cancer are generally amenable to biopsy, and pre- and post-treatment tissue 
sampling is an important strength of this study. Post-treatment biopsies will be done 
~cycle 1 day 8 (and between C2D8 and C2D15 during the phase II portion of the 
study).The timing of the post-treatment biopsy will be performed based on prior 
experience in the leukemic patients where the majority of demethylation events 
have been seen at between 8-15 days of each cycle.  Patients with baseline biopsies 
who remain on the trial beyond 6 cycles will be asked to participate in another 
research biopsy between cycles 6-9.   
There was no comparable data in solid tumors. All biopsy specimens will be stored 
as fresh tissue at least -70°C for extraction of DNA and RNA. Biopsy specimens 
will be studied for tumor methylation profiles, as described below. Evaluation of 
expression of genes that become demethylated post-treatment will be performed 
using quantitative real-time PCR and/or expression arrays. If an attempt at biopsy is 
unsuccessful, the patient will still be eligible for treatment and the subsequent 
biopsies will be foregone. Tumor biopsies and plasma from the phase I portion of 
the trial will be analyzed prior to moving onto phase II for demethylation and the 
timing of the biopsies in the phase II component of the trial may be adjusted based 
on these results.  As of December 2015, our Phase I data showed no clear pattern in 
demethylation at C1D8, while serum demethylation appeared to have a delayed and 
dose-dependent nadir in the middle of cycle 2, therefore timing of the second 
biopsy was moved to C2D8-15. 
 
Tumor Biopsy Processing 
 
Prior to initiation of therapy, tumor samples will be collected by direct or 
ultrasound-guided core biopsy from accessible tumor tissue. A maximum of 6 
core tissue samples will be obtained from each patient. Core biopsy is preferred 
and FNAs are only to be done when core biopsy is not safe (such as with lung 
lesions). There are 4 parts to the procedure: preparation, slide creation, dry 
protocol, and RNAlater protocol. Biopsies must be flash frozen within minutes 
of biopsy collection, and immediately stored at -70C or below. Biopsies may 
be batched and shipped at the end of this study to Dr. Nita Ahuja’s 
laboratory as detailed in this protocol. DO NOT ship biopsies out on 
Thursday or Friday to prevent weekend arrival; shipment should occur the 
following Monday. All samples, blood and biopsies MUST BE OVERNIGHT 
EXPRESSED to ensure next day delivery. When preparing for shipment, fill 
an insulated styrofoam box with DRY ICE (NOT ICE), enough to fill at least 
¾ of the box. This will ensure that plenty of dry ice remains during the 
duration of the delivery process to protect the quality of the specimens.  Fill 
half the box with DRY ICE, place the specimens in the middle, and fill up to 
top with DRY ICE. 
 
a. CORE BIOPSY PROTOCOL 
i. Preparation: 


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1.Prepare a 50:50 mixture of dry ice and isopropanol mixture in a 
styrofoam bucket to a depth of 1 inch.  A liquid nitrogen bath is also 
acceptable. 
2. Label 5 cryovials with Patient ID, Cycle/ Day, Specimen Type (biopsy, 
location), and Date of collection.  
3.Fill one of the vials with 1mL RNAlater and add RNAlater designation 
on the tube. 
 
ii. Slide creation: 
1. The first biopsy passage should be used for the creation of an H&E or 
cryoslide which an onsite pathologist will use to confirm the biopsy is 
tumor tissue. 
a. If it is not possible to obtain an onsite pathologist, please create an 
H&E slide and send to Dr. Nita Ahuja’s laboratory for analysis 
b. After the pathologist’s confirmation, keep and store slides at room 
temperature and send to Dr. Nita Ahuja’s laboratory. 
 
iii. Dry protocol: 
1.During each of the subsequent passes, transfer each biopsy to an 
enclosed empty 1.8mL cryovial (Use sterile techniques) 
2.Flash freeze each vial immediately by adding the cryovial to the 50:50 
mixture in the bucket or in the liquid nitrogen. 
 
iv. RNAlater protocol: 
1. On the last passage, add a core biopsy to the cryovial filled with 
RNAlater and flash freeze by immersing the tube in the 50:50 
mixture or liquid nitrogen. 
a. NOTE: RNAlater is NOT sterile and needle dipped in this 
solution should not be reused on the patient 
2. Samples will be stored at or below -70C until shipped to Dr. Nita 
Ahuja via overnight express in DRY ICE. ADD ENOUGH DRY ICE 
TO FILL AT LEAST ¾ OF THE INSULATED SHIPPING BOX. 
Biopsies may be batched and shipped at the end of this study to Dr. 
Nita Ahuja’s laboratory. Avoid shipping on Thursdays and Fridays to 
prevent weekend arrival. Store in -70C or below until following 
Monday to ship for Tuesday arrival. 
 
 
b. FNA PROTOCOL 
There are 3 steps to this protocol: preparation, slide creation, and saline 
protocol. 
 
i.Preparation 
1.Prepare a 50:50 mixture of dry ice and isopropanol mixture in a 
Styrofoam bucket to a depth of 1 inch. A liquid nitrogen bath is also 
acceptable. 


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2.Label 5 cryovials with patient identification, date of collection, 
Cycle/Day, and specimen type (biopsy location.) 
3.Add 1mL of saline to each tube. 
 
ii. Slide Creation 
1.Perform the first FNA biopsy pass 
2.Create an H&E slide or Cryoslide 
3.Have an onsite pathologist confirm the sample is of tumor. 
a. If an onsite pathologist is not available, please send the slides to 
Hopkins for analysis 
b. Keep the slides at room temperature 
 
iii. Saline protocol: 
1. Transfer subsequent FNA aspirate to separate cryovials  filled with 
saline. 
a. Inject and swish the cells into the saline 
2.Flash freeze the cells immediately by immersing cryovials to the 50:50 
mixture in the bucket. 
3.Samples are to be stored at -70C. 
4.When shipped, the samples should be shipped overnight express in 
enough DRY ICE to fill at least ¾ of the box. 
 
8.3.1.1 Methylation analysis 
 
Genome-wide methylation analysis will be performed using the Infinium Illumina 
based assay that allows methylation analysis of >450,000 CpG sites covering 
greater than 14,000 genes. Beta values indicating methylated CpG islands will be 
isolated.  Pre- and post-treatment biopsies will be compared to determine genes 
that demethylated following treatment. Cannonical tumor suppressor genes will 
be closely scrutinized for CpG island methylation.  These results will then be 
correlated with expression values. 
 
Methylation patterns in the promoter regions of selected tumor suppressor genes 
will be determined using quantitative real time nested Methylation Specific PCR 
(MSP). This technology is ideally suited for increasing the throughput of PCR 
analysis and gaining a level of quantification not possible with the standard MSP 
analysis. DNA will be isolated from blood, and tumor biopsies and treated with 
sodium bisulfite under denaturing conditions (123). Bisulfite modified DNA from 
each post treatment specimen will be analyzed for changes in DNA methylation at 
specific gene promoters (to include p16, SFRP1, IGFBP3, TFPI2, RASSF1A, and 
mlh1). PCR primers for these have been described and are in frequent use in the 
Ahuja lab.  
 
For each gene, separate PCR reactions will be performed with methylated-specific 
primers and unmethylated specific primers (as used in conventional gel based 
MSP analysis).  Each reaction will be run in triplicate. A separate PCR reaction 


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will utilize primers specific for the unmethylated promoter region of the beta-
actin gene, a gene necessary for normal cell structure and function, which has 
never been observed to be methylated in any cancer. Real-time curves for the 
MSP reaction will be compared to the unmethylated reaction and to the beta-actin 
control. Mixing experiments utilizing DNA from cell lines methylated at a given 
locus and a completely unmethylated DNA source (normal DNA) will be 
performed to determine accuracy of quantification. Assays will be performed on 
the Bio-Rad I-cycle. Two methods of detection will be compared: non-specific 
quantification of PCR products using Syber Green, and specific detection using 
molecular beacons. A ratio of the inverse of the cycle threshold for the methylated 
gene of interest over the inverse of the cycle threshold for beta-actin will be 
calculated. This ‘methylation index’ will be compared pre- and post-treatment.   
 
If changes in methylation pattern are observed by MSP, this result will be further 
validated by bisulfite sequencing of selected genes 
 
8.3.1.2   Expression analysis  
 
The goal of DNA methyltransferase inhibition is reversal of transcriptional 
inhibition due to repressive chromatin conformation related to hypermethylation 
and changes in histone tails along with changes in miRNA. Given the 
heterogeneity of metastatic colorectal cancer the selection of specific genes to be 
studied across patient samples is challenging. Evaluation of expression of genes 
that become demethylated post-treatment will be performed using quantitative 
real-time PCR, whenever possible. Gene re-expression will be studied also using 
genome wide strategies using quantitative PCR using the Ampliflour if additional 
funds are available. Universal amplification and detection system (Intergen). This 
system has the advantage of the use of multiple fluorophores for each gene (up to 
four fluorophores can currently be analyzed). RT-PCR used semi-quantitatively 
will be combined with real-time quantification using the ABI 7700 system within 
the Johns Hopkins Oncology Center. Beta-actin will be used as a control.  
Expression will be reported as a ratio of gene specific to control gene expression 
levels.    
8.3.2 Research Blood  
 
Blood samples for methylation analysis will be collected from all participants into the 
enclosed purple top tubes (10 mL EDTA BD Vacutainer cell preparation tubes, Becton 
Dickinson, Franklin Lakes, NJ).  These tubes are designed to separate plasma and 
mononuclear cells from whole blood.  For each collection day, total of 50 mL of blood 
will be drawn from the patient (5 tubes of 10 mL each).  Each purple tube holds 
approximately 10 of blood, yielding close to 5ml of plasma.   
 
 Blood tubes must be kept in ice, and processed within 30 minutes of collection. If 
collected at the Johns Hopkins Hospital, the blood samples will be processed in Dr. 
Ahuja’s laboratory. For other participating sites, blood must be kept on ice, processed 
within 30 minutes, and the plasmas and WBC collected must be stored at or below -70C 


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44 
until they can be shipped to Dr. Ahuja’s laboratory. Overnight express shipping and use 
of adequate amount of dry ice will be practiced to preserve the quality of specimen in the 
shipping process. All collected specimens will be stored at or below -70C in Dr. Ahuja’s 
laboratory. 
Processing of Blood: (For Plasma and White blood cells) 
1. 
Take 1 empty 15 mL conical tube for each K2-EDTA tube collected 
2. 
First add 3 mL of Ficoll-Paque PLUS buffer to each conical tube.  
(NOTE:  Ficoll-Paque PLUS buffer MUST BE KEPT AT 4ºC and out of light for 
storage.) 
3. 
Using one conical tube for each purple top blood tube, Carefully layer the blood on to Ficoll-
Paque PLUS buffer conical tubes by tilting the conical tube at an angle close to horizontal and 
letting the blood from the purple-top tube run very slowly down the side of the conical tube.  
THIS IS IMPORTANT. If done correctly, the blood should sit right on top of the buffer as 
shown below (Figure A).  Repeat this step for each of the tubes.  
4. 
Next, centrifuge tubes for 10 minutes at 3000 rpm at 4ºC. Be sure that the centrifuge is 
balanced. The layers will now separate as shown below (Figure B). 
5. 
Carefully pipet the plasma layer (the clear yellow layer on top) from each conical tube into a 
new 15 mL conical tube (1 tube for each).   
Pay careful attention to not draw from the white buffy coat (the second layer below 
plasma in Figure B).  To ensure this, stop pipetting plasma at a level 3.5 mL above the RBC 
layer (Red layer at the bottom). For example, if the top of the RBC is at 3mL, then pipet plasma 
out down to 6.5 mL and stop. 
6. 
Pipet the buffy coat (WBCs) from each conical tube pooling them into a single new 15 mL 
conical tube.   
NOTE:  Gently navigate your pipette tip to collect clumps of WBC around the buffy coat.  Be 
careful not to draw the Ficoll-Buffer sitting below the white buffy coat (the third layer). 
7. 
Once plasma and the white buffy coats are collected from each conical tube you should have, 
depending on the patient sample,  5 conical tubes filled with 4-5 mL plasma each and one, 
conical tube filled with 2-4 mL WBCs.  You may now discard the conical tubes filled with 
ficoll and RBCs.   
8. 
Take the single conical tube filled with WBCs and add an equal volume of 1x PBS to the 
volume of WBCs present, mix by inverting 5 times. 
9. 
Take the single tube with pooled WBCs from step 11 and the 5 tubes with plasma from step 8. 
Spin all five sample tubes in the centrifuge for 5 minutes at 1500 rpm at 4ºC. Be sure that the 
centrifuge is balanced. 
10. After centrifugation you may have a small white pellet at the bottom of each of the plasma 
tubes (5 tubes) and you will have a larger white pellet in the single WBC tube.   
Be careful not to disturb the pellets in the plasma tubes or the WBC tubes (Although you 
will not be collecting the pellets from the 4 tubes with plasma you do not want them to 
contaminate the plasma) 
11. Take the plasma from the 5 conical plasma tubes.  Into 6 Eppendorf (1.5 mL) tubes Add 0.5 
mL plasma. 
Do not disturb any pellet that may have formed.   
12. Add the remaining plasma in 1.0 mL aliquots into additional 1.5 mL Eppendorf tubes (between 
12 and 16 tubes).   
Do not disturb any pellet that may have formed.   


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45 
13. Now take the conical tube with the WBCs.  There should be a white pellet at the bottom You 
want this pellet.     
14. Being careful not to disturb the pellet Remove by pipetting (Do not decant) and discard any 
liquid from the conical tube (leave a little liquid ~200 uL behind to make sure the pellet is 
not disturbed).   
15. Add 3 mL 1x PBS to the pellet and mix by flicking the tube gently to re-suspend the cells.    
(If the cells do not re-suspend by flicking the tube you may carefully pipet the cells up 
and down to re-suspend them in the PBS) 
16. Once the cells have been re-suspended add 6 aliquots of 0.5 mL of the WBCs in step 18 into 
1.5 mL Eppendorf tubes.   
17. When finished you should have 6 tubes with 0.5 mL of plasma from step 14; 16-20 tubes with 
1.0 mL of plasma from step 15; and 6 tubes with 0.5 mL of WBCs from step 19.  
18. Label samples as PLASMA OR WBC, as applicable, including study number (J1369), unique 
patient ID (assigned by the consortium), date of collection, and time point in treatment cycle. 
19. Freeze plasma and WBC samples in their Eppendorf tubes at or below -70ºC until shipment or 
transfer to Dr. Nita Ahuja’s Laboratory. 
 
 
 
 
CRITICAL POINT: At time of shipping, fill an insulated styrofoam box 
with DRY ICE (NOT ICE), enough to fill at least ¾ of the box. This will 
ensure that plenty of dry ice remains during the duration of the delivery 
process to protect the quality of the specimens.  Fill half the box with 
DRY ICE, place the specimens in the middle, and fill up to top with DRY 
ICE. 
 
Figure B: 
Figure A : 


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46 
a. Shipping of processed Plasma/WBC can be bundled and sent at 
the end of the trial. They must be sent via overnight express. Please 
avoid shipping out on Fridays to prevent arrival of items over the 
weekend. 
b.  Shipping of the biopsies may be sent to Dr. Nita Ahuja’s 
laboratory as a batched collection as long as they were prepared and 
stored according to the instructions outlined above (must be stored 
at or below -70C until shipment).  To avoid weekend arrivals, 
biopsies must not be shipped out on a Thursday or Friday.  
 
All tubes must be clearly labeled with the unique patient ID (assigned by the consortium), 
Cycle and Day, specimen type (Plasma, WBC, or biopsy) and Date of collection. 
 
During the course of the study, blood and tumor biopsies will be shipped from the centers 
to the coordinating center lab at Johns Hopkins University School of Medicine.  After 
conclusion of the study, samples will be sent for analysis to Dr. Nita Ahuja’s laboratory 
at the Yale School of Medicine.   
 
 
 
 
 
 
 
9  STUDY CALENDARS 
 
Baseline evaluations are to be conducted within 2-week prior to start of protocol 
therapy. Scans must be done <4 weeks prior to the start of therapy. In the event that the 
participant's condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy 
All assessments must be performed prior to administration of any study 
medication. All study assessments and medications should be administered within 
+ 3 days of the protocol-specified date, unless otherwise noted.  
 
 


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47 
Phase I Portion – Dose levels -1G, -1, 1, 1G, and 2 
 
 
 
Pre- 
Study 
C1  
d1 
C1   
d8 
C1 
d9-14 
C1 
d15 
C1 
d22 
C2 
d1 
C2 
d8 
  C2    
d15 
C2 
d22 
C3 
d1a 
C3 
d8 a 
C3 
d15 a 
C3 
d22 a 
Off  
Studyc  
SGI-110 Days 1-5 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Irinotecan 
 
 
X 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Growth Factor Support 
 
 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Physical exam (Ht, Wt, 
BSA, VS)e 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance Status 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff, plts 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Serum chemistryb 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
CEA 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
X------------------------------------------------------------------------------------------------------------------X 
X 
 
Tumor measurements 
 
X 
 
Repeated every 8 weeks. Documentation (radiologic) must be provided for subjects 
removed from study for progressive disease. 
X c 
Radiologic evaluation 
X 
 
Radiologic measurements should be performed every 8 weeks 
Xc 
B-HCG 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Bloods 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
PK Study 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: All study calendar evaluations for cycle 3 are representative of cycle 3 and beyond. 
b: Albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, glucose, phosphorus, potassium, total  protein, SGOT   
[AST], SGPT [ALT], sodium. 
c: Off-study evaluation should be performed within 30 days of last dose. 
d: Serum pregnancy test (women of childbearing potential). 
e: Baseline height will be measured and recorded once during pre-study, and this value for height will be used through the patient’s 
duration of study.  
f: Growth factor support will be initiated with filgrastim 5mcg/kg/day on cycle 1 day 9-14 for patients enrolled on Dose levels -1G 
and 1G. Additional growth factor support during Cycle 1 and on subsequent cycles will be provided per clinician judgment. 
 
 
 


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48 
Phase I Portion – Dose level 3 
 
 
Pre- 
Study 
C1  
d1 
C1   
d8 
C1 
d9-14 
C1 
d15
C1 
d22 
C2 
d1 
C2 d8  C2     
d15 
C2 
d22 
C3 
d1a 
C3 
d8 a 
C3 
d15 a 
C3 
d22 a 
Off  
Studyc 
SGI-110 Days 1-5 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Irinotecan 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Physical exam (Ht, Wt, 
BSA, VS)e 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance Status 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff, plts 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Serum chemistryb 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
CEA 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
X---------------------------------------------------------------------------------------------------------------X 
X 
 
Tumor measurements 
 
X 
 
Repeated every 8 weeks. Documentation (radiologic) must be provided for subjects 
removed from study for progressive disease. 
X c 
Radiologic evaluation 
X 
 
Radiologic measurements should be performed every 8 weeks 
Xc 
B-HCG 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Bloods 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
PK Study 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: All study calendar evaluations for cycle 3 are representative of cycle 3 and beyond. 
b: Albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, glucose, phosphorus, potassium, total  protein, SGOT   
[AST], SGPT [ALT], sodium. 
c: Off-study evaluation should be performed within 30 days of last dose. 
d: Serum pregnancy test (women of childbearing potential). 
e: Baseline height will be measured and recorded once pre-study, and this value for height will be used through the patient’s duration
of study.  
 
 
 
 
 
 
 


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49 
Phase II Portion 
Arm A – SGI-110 + Irinotecan 
 
 
 
Pre- 
Stud
y
C1  d1 C1   
d8 
C1 
d9-
14
C1 
d15 
C1 
d22 
C2 
d1 
C2 
d8 
  C2    
d15 
C2 
d22 
C3 
d1b 
C3 
d8 b 
C3 
d15 b 
C3 
d22 b 
Off  
Studyc  
SGI-110 Days 1-5a 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Irinotecana 
 
 
X 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Growth factor support 
 
 
 
X--- a 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QoL questionnaire 
 
X 
 
 
 
 
 
 
 
 
Xi 
 
 
 
X 
Concurrent meds 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Physical exam (Ht, Wt, 
BSA, VS)g 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance Status 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff, plts 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Serum chemistryd 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
CEA 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 
X------------------------------------------------------------------------------------------------------
-------X
X 
 
Tumor measurements 
 
X 
 
Repeated every 8 weeks. Documentation (radiologic) must be provided for subjects 
removed from study for progressive disease. 
X e 
Radiologic evaluation 
X 
 
Radiologic measurements should be performed every 8 weeks 
Xe 
Archival Tissue 
X 
 
 
 
B-HCG 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsy 
Xh 
 
 
 
 
 
 
 
Xh -------Xh
 
 
 
 
 
 
Research Bloods 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 


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50 
 
 
 
 
a: Arm A -Dose Level 1G from Phase I, SGI-110 45mg/m2 D1-5, Irinotecan 125mg/m2 D8 and 15. Treatment cycle is 28 days. Growth factor support of 
filgrastim (or institutional equivalent) 5mcg/kg/day on days 9-14 and peg-filgrastim 6mg on day 16 of cycle 1 is mandatory. Additional growth factor 
support during Cycle 1 and on subsequent cycles will be provided per clinician judgment. 
b: All study calendar evaluations for cycle 3 are representative of cycle 3 and beyond. 
c: Off-study evaluation should be performed within 30 days of last dose. 
d: Albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, glucose, phosphorus, potassium, total  protein, SGOT   [AST], SGPT [ALT], 
sodium. 
f: Serum pregnancy test (women of childbearing potential). g: Baseline height will be measured and recorded once pre-study, and this value for height 
will be used through the patient’s duration of study 
h: SKCCC, VUMC, MSKCCC, and USC-Norris, will obtain biopsies on a total of 36 patients (distributed roughly evenly between the sites) for the first 
patients enrolled to the phase 2 if they have both biopsiable disease and are randomized to SGI-110 + Irinotecan.  Additional optional biopsy will be 
requested of patients with baseline research biopsy who remain on trial through Cycle 6-9. 
i: QoL surveys will be done on C3D1 and every other cycle subsequently (i.e. Cycle 5 Day 1, Cycle 7 Day 1, etc) 
 
 
 


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51 
Arm B - Regorafenib 
 
 
 
 
 
 
Pre- 
Study 
C1  d1 C1   
d8 
C1 
d15 
C1 
d22 
C2 
d1 
C2 
d8 
  C2    
d15 
C2 
d22 
C3 
d1a
C3 
d8  a 
C3 
d15  a 
C3 
d22  a 
Off  
Studyb  
Regorafenibc 
 
X  - - - - - - - - - - - 
- 
 
X  - - - - - - - - - - - 
-
 
X  - - - - - - - - - - - - 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
QoL questionnaire 
 
X 
 
 
 
 
 
 
 
Xd 
 
 
 
X 
Concurrent meds 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Physical exam (Ht, Wt, 
BSA, VS)e 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance Status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Blood Pressuref 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
CBC w/diff, plts 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Serum chemistryg 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Lipase 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CEA 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X----------------------------------------------------------------------------------------------------X 
X 
 
Tumor measurements 
 
X 
Repeated every 8 weeks. Documentation (radiologic) must be provided for subjects 
removed from study for progressive disease. 
X b 
Radiologic evaluation 
X 
Radiologic measurements should be performed every 8 weeks 
Xb 
Archival Tissue 
X 
 
 
B-HCG 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Bloods 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
a: All study calendar evaluations for cycle 3 are representative of cycle 3 and beyond. 
b: Off-study evaluation should be performed within 30 days of last dose. 
c: Arm B (regorafenib 160 mg/day days 1-21). Treatment cycle is 28 days 
d: QoL surveys will be done on C3D1 and every other cycle subsequently (i.e. Cycle 5 Day 1, Cycle 7 Day 1, etc) 
e: Baseline height will be measured and recorded once pre-study, and this value for height will be used through the patient’s duration of study 
f: Weekly blood pressures for first 6 weeks (can be checked with primary care physician or at patient’s home), further blood pressure monitoring as 
determined by history of abnormality 
g: Albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, glucose, phosphorus, potassium, total  protein, SGOT   [AST], SGPT [ALT], 
sodium. 
h: Serum pregnancy test (women of childbearing potential). 
 


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52 
Arm B – TAS-102 
 
 
 
 
Pre- 
Stud
C1  d1 C1   
d8 
C1 
d15 
C1 
d22 
C2 
d1 
C2 
d8 
  C2    
d15 
C2 
d22 
C3 
d1a
C3 
d8  a 
C3 
d15  a 
C3 
d22  a 
Off  
Studyb  
TAS-102c 
 
X-------------
 
 
X-------------
 
 
X------------- 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
QoL questionnaire 
 
X 
 
 
 
 
 
 
 
Xd 
 
 
 
X 
Concurrent meds 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Physical exam (Ht, Wt, 
BSA, VS)e 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance Status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff, plts 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Serum chemistryf 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
CEA 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X----------------------------------------------------------------------------------------------------X 
X 
 
Tumor measurements 
 
X 
Repeated every 8 weeks. Documentation (radiologic) must be provided for subjects 
removed from study for progressive disease. 
X b 
Radiologic evaluation 
X 
Radiologic measurements should be performed every 8 weeks 
Xb 
Archival Tissue 
X 
 
 
B-HCG 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Bloods 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
a: All study calendar evaluations for cycle 3 are representative of cycle 3 and beyond. 
b: Off-study evaluation should be performed within 30 days of last dose. 
c: Arm B (TAS-102 35mg/m2 twice a day on Days 1-5 and 8-12). Treatment cycle is 28 days 
d: QoL surveys will be done on C3D1 and every other cycle subsequently (i.e. Cycle 5 Day 1, Cycle 7 Day 1, etc) 
e: Baseline height will be measured and recorded once pre-study, and this value for height will be used through the patient’s duration of study 
f: Albumin, alkaline phosphatase, total bilirubin, BUN, calcium, chloride, glucose, phosphorus, potassium, total  protein, SGOT   [AST], SGPT [ALT], 
sodium. 
g: Serum pregnancy test (women of childbearing potential). 
 


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53 
10 MEASUREMENT OF EFFECT  
 
As epigenetic agents may take many months to show their benefit as seen in MDS/AML 
studies,25 in both Phase 1 and Phase 2, subjects receiving SGI-110 + irinotecan may continue 
receiving their assigned treatment if their disease progresses based on RECIST 1.1 criteria if 1) 
the patient is clinically stable, 2) the patient is informed of their scan results and agrees to 
continue therapy, and 3) the patient’s provider agrees that remaining on study would be 
appropriate for the patient.39  
 
Although response is not the primary endpoint of this trial, participants with measurable 
and/or non-measurable disease will be assessed by RECIST 1.1 criteria.39 For the 
purposes of this study, participants should be reevaluated approximately every 8 weeks. 
In addition to a baseline scan, confirmatory scans should also be obtained at least 4 
weeks following initial documentation of an objective response. 
10.1 Antitumor Effect– Solid Tumors 
For the purposes of this study, participants should be re-evaluated for response every 8 
weeks. In addition to a baseline scan, confirmatory scans should also be obtained not less 
than 4 weeks following initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
guideline.39 Changes in the diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria. 
10.1.1 Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study 
treatment will be evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response. Only those participants who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable 
for response. These participants will have their response classified according 
to the definitions stated below. (Note: Participants who exhibit objective 
disease progression or die prior to the end of cycle 1 will also be considered 
evaluable). 
10.1.2 Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one 
(1) lesion that can be accurately measured in at least one dimension with 
longest diameter  >20 millimeters (mm) using conventional techniques (CT, 
MRI, x-ray) or  >10 mm with spiral CT scan. Measurable lesions must be at 


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54 
least 2 times the slice thickness in mm. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Reminder: A lesion in a previously irradiated area is not eligible for 
measurable disease unless there is objective evidence of progression of the 
lesion prior to study enrollment. Lesions in previously irradiated areas 
must be clearly identified as such. 
  
Malignant lymph nodes. To be considered pathologically enlarged and 
measurable, a lymph node must be > 15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  
 
All other lesions (or sites of disease), including small lesions (longest diameter 
<10 mm or pathological lymph nodes with > 10 to < 15mm short axis, are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, abdominal masses identified by physical exam that are not 
measurable by reproducible imaging techniques, and cystic lesions are all 
considered non-measurable. 
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. Lesions must be accurately 
measured in 1 dimension with a minimum size of 10 mm by CT or MRI (slice 
thickness no greater than 5 mm), 20 mm by chest x-ray. Nodes must have a 
short axis > 15 mm. The short axis should be included in the sum of the 
lesions in the calculation of response. Nodes that shrink to < 10 mm are 
considered normal. Target lesions should be selected on the basis of their size, 
be representative of all the involved organs, and should be lesions that can be 
followed with reproducible repeated measurements.  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered target lesions if the soft tissue component meets 
the definition of measurability as defined above. Cystic lesions thought to 
represent cystic metastases can be considered as target lesions. However, if non-
cystic lesions are present, these are preferred for selection as target lesions. 
Lesions in previously irradiated areas or areas subject to other loco-regional 
therapy are usually not considered measurable unless there has been 
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Non-target lesions.  
All other lesions, including small lesions < 10 mm or pathological lymph 
nodes measuring > 10 mm to < 15 mm in short axis, as well as truly non-
measurable lesions, which include leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, abdominal masses identified by physical exam that are not 
measurable by reproducible imaging techniques.  
10.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, 
calipers, or digital measurement tool. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used to assess the anti-tumor effect of a 
treatment. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). For the case of 
skin lesions, documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended. 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung; however, CT is 
preferable. 
Conventional CT and MRI. These techniques should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the 
chest, abdomen, and pelvis. Head and neck tumors and those of extremities 
usually require specific protocols. 
Ultrasound (US). When the primary endpoint of the study is objective 
response evaluation, US should not be used to measure tumor lesions. It is, 
however, a possible alternative to clinical measurements of superficial palpable 
lymph nodes, subcutaneous lesions, and thyroid nodules. US might also be useful 
to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
FDG PET and PET/CT. FDG PET will not be used for response assessment 


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Endoscopy, Laparoscopy. The utilization of these techniques for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this 
specific context require sophisticated equipment and a high level of expertise 
that may only be available in some centers. Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation 
purposes in reference centers. However, such techniques may be useful to 
confirm complete pathological response when biopsies are obtained. 
Tumor markers. Tumor markers alone cannot be used to assess response. If 
markers are initially above the upper normal limit, they must normalize for 
a subject to be considered in complete clinical response.  
10.1.4 Response Criteria  
10.1.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  
Disappearance of all target lesions. Any pathological lymph node must 
have reduction in short axis to < 10 mm. 
Partial Response (PR):  
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  
 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study with at least a 5 
mm absolute increase in the sum of all lesions. The 
appearance of one or more new lesions* denotes disease 
progression.  
 
Stable Disease (SD):  
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study. 
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must 
be given. 


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Note: If tumor response data is missing for target lesions, the overall 
assessment must be UN unless there is new disease that would result in 
an overall assessment of PD. However, if there is missing or 
unevaluable data for non-target lesions, but data is available for all 
target lesions, the overall response for that time point will be assigned 
based on the sum LD of all target lesions. Additionally, the assessment 
of CR cannot be made if there is missing or unevaluable data for non-
target lesions. In this case, the overall assessment would be PR. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal 
(i.e. not due to difference in scanning technique, imaging modality, or findings 
thought to represent something other than tumor (ex: new bone lesions may be 
healing or flare of pre-existing lesions). However, a lesion identified on a 
follow-up scan in an anatomical location that was not scanned at baseline is 
considered new and will indicate PD. If a new lesion is equivocal (because of 
small size, etc.), follow-up evaluation will clarify if it truly represents new 
disease and if PD is confirmed, progression should be declared using the date of 
the initial scan on which the lesion was discovered.  
10.1.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size ( < 10 mm short axis).  
Note: If tumor markers are initially above the upper normal limit, 
they must normalize for a subject to be considered in complete 
clinical response. 
Incomplete Response/Stable Disease (SD): Persistence of one or 
more non-target lesions and/or maintenance of tumor marker level 
above the normal limits. 
Progressive Disease (PD): Appearance of one or more new 
lesions* (new lesions must be > slice thickness) and/or 
unequivocal progression of existing non-target lesions. 
Overall level of substantial worsening that merits discontinuation 
of therapy. A useful test that can be applied when assessing non-
targets for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease. 


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Unknown (UN): Assessment of non-target lesions cannot be made due 
to insufficient or unevaluable data. In this case, a concise explanation 
must be given. 
10.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The participant's best response assignment will 
depend on the achievement of both measurement and confirmation 
criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for 
when Confirmation is 
Required: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD
No 
PR 
>4 wks confirmation 
CR 
Not evaluated
No
PR
PR 
Non-CR/Non-
PD/Not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/Not 
evaluated
No 
SD 
Documented at least once 
>4 wks from baseline 
PD 
Any
Yes or No
PD
No prior SD, PR or CR 
Any 
PD*
Yes or No
PD
Any 
Any
Yes
PD
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:   Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as "symptomatic deterioration". Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New 
Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
NonCR/non-PD 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Non-CR/non-PD is preferred over stable disease for non-target disease since SD is 
increasingly used an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised.  
10.1.5 Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrence or PD is objectively documented, taking as 
reference for PD the smallest measurements recorded since the treatment started. 
Duration of overall complete response: The duration of overall CR is 
measured from the time measurement criteria are first met for CR until the 
first date that recurrent disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started. 
10.1.6 Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of 
treatment to time to progression event, including objective disease progression, 
clinical deterioration attributed to disease, or death. 
10.2 Other Response Parameters 
 
CEA will be followed on study monthly for exploratory purposes but will not be used for 
response assessment. 
 
Additionally in the phase II portion of the study, all subjects will be asked to complete a 
quality of life assessment using the Functional Assessment of Cancer Therapy (FACT-C) 
questionnaire at the start of study Cycle 1 Day 1, Cycle 3 Day 1, every other cycle 


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subsequently (i.e. Cycle 5 Day 1, Cycle 7 Day 1, etc), and at end of study/study withdrawal 
(optional).  
11 ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 Definitions 
11.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
 
 
11.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
 Results in death 
 Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
 Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
 Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
 Is a congenital anomaly or birth defect; or 
 Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 


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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. 
 
Events not considered to be serious adverse events are hospitalizations for: 
 routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
 emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
 respite care 
 
 
11.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
11.1.3.1 Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk.   
 
Refer to Section 6 for a listing of expected adverse events associated 
with the study agent(s). 
11.1.3.2 Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   
11.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows:  
 
 Related – There is reasonable evidence that the AE is related to the study 
treatment. 
 Unrelated - The AE is clearly NOT related to the study treatment. 


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11.2 Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
11.3 Reporting Requirements 
 
Each participating investigator is required to abide by the reporting requirements. The 
study must be conducted in compliance with FDA regulations, local safety reporting 
requirements, and reporting requirements of the principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that institution 
to their respective IRB. It is the responsibility of each participating investigator to 
report serious adverse events to the PI of this study, Dr. Azad, and/or others as 
described below.  
11.4 Reporting to the Study Sponsor 
11.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment must be reported 
to the Principal Investigator, Dr. Azad, on the local institutional SAE form. This 
includes events meeting the criteria outlined in Section 11.1.2, as well as the 
following: 
 
 Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and related with the intervention. 
 
 All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 


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 All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time 
of continuing review.  
 
Participating investigators must report each serious adverse event to the Principal 
Investigator Dr. Azad within 24 hours of learning of the occurrence. In the event 
that the participating investigator does not become aware of the serious adverse 
event immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 24 hours after learning of it and 
document the time of his or her first awareness of the adverse event. Report 
serious adverse events by, email to: 
 
 
 
 
 
 
Email: GISafetyReporting@jhmi.edu 
 
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information should 
describe whether the event has resolved or continues, if and how the event was 
treated, and whether the participant will continue or discontinue study 
participation. 
 
Coordinating center will fax or email serious adverse events (initial and follow-up 
reports) to Astex Drug Safety within 24 hours of receiving SAE report to:  
  
Astex Drug Safety 
North America Local Fax:  925.551.3226 
North America Toll-Free Fax:  1.800.576.6568 
Email: drugsafety@astx.com 
 
Astex Pharmaceuticals will provide a quarterly listing of all SAEs received to 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins for comparison 
with the Sponsor’s listing.  Any missing SAEs or any discrepancies will be 
reported at that time. 
11.4.2 Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the Principal Investigator Dr. Azad 
on the toxicity Case Report Forms.   
11.5 Reporting to the Institutional Review Board (IRB) 
 


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Other investigative sites should report serious adverse events to their respective IRB 
according to the local IRB’s policies and procedures in reporting adverse events. A 
copy of the submitted institutional SAE form should be forwarded to: 
 
 
 
Dr. Nilofer Azad 
 
 
  
 
 
Email: GISafetyreporting@jhmi.edu 
 
The Principal Investigator Dr. Azad will submit SAE reports from outside institutions to 
the SKCCC IRB per their policies and procedures in reporting adverse events.  
11.6 Reporting to the Food and Drug Administration (FDA) 
 
The Principal Investigator Dr. Azad, as holder of the IND, will be responsible for all 
communication with the FDA. Dr. Azad will report to the FDA, regardless of the site of 
occurrence, any adverse event that is serious, unexpected and related  to the study 
treatment (Suspected Unexpected Serious Adverse Reactions or SUSARs) according 
the regulatory-defined timelines (7-day or 15-day reports). Dr. Azad will copy Astex 
pharmaceuticals (SGI-110 manufacturer) on any such reports. 
 
  
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of the 
adverse events and progress of the investigation. All IND annual reports will be 
submitted to the FDA by the IND Sponsor. 
 
Events will be reported to the FDA using Form FDA 3500A (Mandatory Reporting 
Form for investigational agents) or FDA Form 3500 (Voluntary Reporting Form for 
commercial agents). Forms are available at 
http://www.fda.gov/medwatch/getforms.htm.  
 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the 
investigational agent.  Such reports are to be telephoned or faxed (301-796-9845) to the 
FDA within 7 calendar days of first learning of the event.   
 
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any serious adverse event that is 
unexpected and possibly related to the investigational agent in a written IND Safety 
Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND 
concerning similar events should be analyzed.  The new report should contain comments 
on the significance of the new event in light of the previous, similar reports.  Written IND 
safety reports with Analysis of Similar Events are to be submitted to the FDA within 15 
calendar days of first learning of the event.  


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11.7 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
11.8 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case 
report form and recorded in the participant’s medical record to facilitate source data 
verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the Overall Principal Investigator and their respective IRB of any unanticipated 
death or adverse event occurring after a participant has discontinued or terminated 
study participation that may reasonably be related to the study.   
 
12 DATA AND SAFETY MONITORING 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 11.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
 
12.1.1 
This is a Level II study under the SKCCC Data Safety Monitoring Plan. Data 
monitoring of this protocol will occur on a regular basis with the frequency dependent on the rate 
of subject accrual and the progress of the study. The protocol will be monitored internally at 
SKCCC by Dr. Nilofer Azad and externally by the SKCCC CRO QA Office and the 
Coordinating Center in accordance with the JHU SKCCC Data Safety Monitoring Plan.  Outside 
sites, USC, VUmc, and MSKCCC will use their internal clinical research offices to monitor their 
study patients and regulatory documents. Outside sites will provide copies of monitoring reports 
to the coordinating center. Eligibility for both sites will be monitored by the SKCCC CRO as 
well. 
 
All trial monitoring and reporting will be done through the Safety Monitoring Committee (SMC) 
at SKCCC.  


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Authorized representatives of the Coordinating Center may visit any satellite sites connected to 
the outside sites to perform audits or inspections, including source data verification. The purpose 
of these audits or inspections is to systematically and independently examine all trial-related 
activities and documents to determine whether these activities were conducted and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), and any applicable regulatory requirements. 
 
 
12.1.2 
Dr. Azad will be holding the IND for this study.  She will comply with all 
regulated reporting requirements to the FDA. 
 
13 REGULATORY CONSIDERATIONS 
 
13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 
any other necessary documents must be submitted, reviewed and approved by a 
properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The Overall Principal Investigator (or Protocol Chair) will 
disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
13.2 Informed Consent 
 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  
13.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 


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 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
 
State laws 
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
13.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
13.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
13.6 Data Collection 
 


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Data will be collected and reported on either paper case report forms (CRF) or through 
an internal data monitoring system, which will be determined prior to the start of the 
study. 
13.7 Multi-center Guidelines 
This protocol will adhere to the policies and requirements of the SKCCC.  
 The Overall Principal Investigator/Coordinating Center is responsible for 
distributing all IND Action Letters or Safety Reports to all participating 
institutions for submission to their individual IRBs for action as required. 
 Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and adverse event reporting at each site.  
 Except in very unusual circumstances, each participating institution will order 
the agent(s) directly from the supplier. A participating site may order the 
agent(s) only after the initial IRB approval for the site has been forwarded to 
the Coordinating Center.  
 
Multicenter Guidelines 
 
 
Protocol Chair (Dr. Azad) 
 
The Protocol Chair is responsible for performing the following tasks: 
 Coordinating, developing, submitting, and obtaining approval for the protocol as well 
as its subsequent amendments. 
 Assuring that all participating institutions are using the correct version of the 
protocol. 
 Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
 Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
 Reviewing data from all sites. 
 
 
Coordinating Center 
 
The Coordinating Center is responsible for performing the following tasks: 
 Ensuring that IRB approval has been obtained at each participating site prior to the 
first patient registration at that site, and maintaining copies of IRB approvals from 
each site. 
 Managing central patient registration. 
 Collecting and compiling data from each site. 
 Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties. 
 Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
 
Participating Sites 


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Participating sites are responsible for performing the following tasks: 
 Following the protocol as written, and the guidelines of Good Clinical Practice 
(GCP). 
 Submitting data to the Coordinating Center. 
 Registering all patients with the Coordinating Center by submitting patient 
registration form, and signed informed consent promptly. 
 Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
 Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center. 
 
Collecting and submitting data according to the schedule specified by the protocol. 
 
 
14 STATISTICAL CONSIDERATIONS  
 
The hypothesis of this study is that SGI-110, a demethylating agent, can sensitize pretreated 
metastatic colorectal cancer patients to retreatment with irinotecan. 
14.1 Study Design/Endpoints 
 
This is a Phase I/II study of Irinotecan and SGI-110 in patients with locally advanced or metastatic 
colorectal cancer.  The dose escalation portion of the study will be used to determine the preferred 
dose of SGI-110, 30mg/m2, 45 mg/m2 or 60 mg/m2, in combination with Irinotecan.  The second 
portion of this study will be an open-label randomized phase II study with one arm receiving 
combination SGI-110 plus Irinotecan at the recommended dose from phase 1 (determined to be 
SGI-110 45mg/m2, Irinotecan 125mg/m2, with mandatory growth factor support) and the other 
arm receiving Regorafenib or TAS-102 at the standard commercial dose.  The primary objective 
of the study is based on a comparison of PFS in the SGI-110 arm to that in the Regorafenib or 
TAS-102 arm, the two approved standard of care drugs in this setting.  The primary endpoint for 
the Phase II study will be progression free survival (PFS).  The study will randomize patients to 
the SGI-110 versus Regorafenib or TAS-102 at a ratio of 2:1.  The randomized Regorafenib or 
TAS-102 group will provide information about PFS with the standard of care drugs to verify 
assumptions made in the design of the study.  
 
Phase I primary objective:  To assess safety and tolerability of Irinotecan in combination with 
SGI-110 in patients with advanced colon cancer. Determine the maximum tolerated dose (MTD) 
of Irinotecan in combination with SGI-110 and recommend a dose for phase II study. 
 
Phase I secondary objectives:   
1. To assess changes in global methylation and expression at the tumor level with SGI-110 
and Irinotecan treatment. 
2. To assess the pharmacokinetics of SGI-110 in metastatic colon cancer patients and 
correlate with changes in global methylation. 
 
Dose Escalation:  Three dose levels of SGI-110, 30mg/m2, 45 mg/m2 and 60 mg/m2, will be tested 
in combination with Irinotecan in this portion of the study.  Dose level 1 will be IRI 125 mg/m2 


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70 
days 8 and 15 and SGI-110 45 mg/m2 days 1-5 and dose level 2 will be IRI 125 mg/m2 days 8 and 
15 and SGI-110 60 mg/m2 days 1-5; dose level 3 would be SGI-110 at 60 mg/m2 days 1-5 with 
IRI at 125 mg/m2 days 1, 8, and 15. Starting with dose level 1, three patients will be treated in a 
standard 3+3 dose escalation design.  If none of the first three patients experiences a DLT then the 
next three will be treated using the next higher dose.  If one of the first three has a DLT, an 
additional three patients will be enrolled at that level.  If only one of six develops a DLT, then the 
dose will be escalated for the next three patients.  If two or more of the six have a DLT, then the 
dose will be de-escalated to the previous dose where an additional three patients will be treated.   
The MTD is defined as the highest dose at which 0 or 1 dose-limiting toxicities are observed in 
six patients.  A total of 6 patients will be treated at the MTD.  The target toxicity with this type of 
design is less than 30%.   
 
If there are two DLTs at the first dose level, a decreased dose schedule of SGI-110, which is less 
myelosupressive, will be considered with a similar 3+3 escalation of SGI-110.  The next dose level 
below dose level 1 (dose level -1) would consist of IRI 125 mg m2 days 8 and 15 and SGI-110 30 
mg/m2 days 1-5. If no DLTs are encountered with dose level -1, the next three patients will be 
entered at dose level 1G, or IRI 125mg/m2 days 8, and 15 and SGI-110 45mg/m2 days 1-5. If one 
of the three patients has a DLT at dose level -1, an additional three patients will be enrolled at that 
level. If only one of six develops a DLT, then the dose will be escalated for the next three patients 
to dose level 1G. If two or more DLTs out of 6 are encountered at Dose level -1, at least an 
additional 3 patients will be enrolled at the lower dose level, Dose level -1G. If 0/3 or 1/6 DLTs 
occur on Dose level -1G, the next 3 patients will be dose escalated to Dose level 1G. If 2 or more 
DLTs out of 6 are experienced at Dose level -1G, the MTD will have been exceeded. 
 
Figure 14.1.1. De-escalation Schema. 
 
 
1G


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Sample size/accrual rate for dose escalation:  The accrual rate for the dose escalation portion of 
this study is expected to be 3 patients per month.  The maximum sample size in the dose escalation 
portion of the study could be 12 patients.  If no patients experience a DLT, 9 patients will be 
enrolled.   
 
Analysis of primary objective in dose escalation cohort: 
The number of dose-limiting toxicities at each dose level will be reported.  Additional toxicity 
frequencies by type and grade will be summarized by dose level for all doses.     
 
Analysis of secondary objectives in dose escalation: 
 
1) The design of this study will allow assessment of global and candidate gene methylation 
differences at the tumor level.  We hypothesize that Irinotecan resistance may be reversed 
with the use of the demethylating SGI-110 therapy.  Changes in global methylation by 
LINE-1 will be assessed in post-treatment biopsy specimens in the dose escalation cohort 
for proof of the effect of SGI-110.  Changes will be plotted by dose level and overall using 
boxplots of the log transformed raw data.  A paired t-test, or the nonparametric Wilcoxon 
signed rank test, will be used to test if the changes are significantly different from zero.  
Similar analyses will be used to assess gene expression changes in WRN, DR1, TPAF2E, 
DEXI, BNIP3, and MED1.   
2) Pharmacokinetic (PK) sampling studies are proposed for all participating patients who 
undergo pharmacodynamic endpoints.  Single dose PK samples will be collected on 
Cycle1, Day 1, at the following time points: pre-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hr.  
The following PK parameters describing the concentration time profile of SGI-110 will be 
calculated: total exposure will be calculated as area under the plasma concentration-time 
curve (AUC) using the linear trapezoidal rule by using noncompartmental methods 
(Winonlin, version 5.3) and/or compartmental modeling (Adapt II, release 4.0).  Other 
parameters such as maximum concentration (Cmax), time to maximal concentration (Tmax) 
and half-life (T1/2) will also be calculated. Cmax and Tmax will be obtained from the data, 
while the half-life will be calculated as 0.693/k, where k is the slope of terminal elimination 
phase.  Associations between SGI-110 exposure parameters (Cmax and AUC) and 
pharmacodynamic endpoints (i.e., global methylation changes and toxicity) will be 
assessed using appropriate non-parametric statistical tests.   
 
Moving to Phase II Component: Our hypothesis is that SGI-110 treatment will sensitize colon 
cancer patients to retreatment with irinotecan.  Accordingly, it will be important to see that the 
dose of SGI-110 that is at the MTD does have pharmacodynamics effects at the tumor level.  
Patient tumor biopsies post-treatment will be analyzed by LINE assay for demethylation to assess 
for at least 10% demethylation from baseline in the tumor biopsies.  We aim to see this level of 
demethylation in at least 60% of post-treatment biopsies as previously described in phase O 
studies. 
 
Phase II primary objective:  Evaluate the progression free survival (PFS) in patients receiving 
combination SGI-110 plus Irinotecan compared to standard of care treatment with regorafenib or 
TAS-102.  Events are defined as disease progression or death from any cause. All patients treated 


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72 
on protocol will be included in the determination of PFS, regardless of treatment modification or 
discontinuation.  
 
Epigenetic therapy may take several cycles to exert its maximal benefit, and preclinical data has 
demonstrated initial tumor growth is possible prior to tumor shrinkage. Patients on treatment with 
SGI-110 and IRI will be allowed to remain on study if their tumor progresses on RECIST 1.1 
criteria if they are 1) clinically stable, 2) their provider feels it would be in their best interest, and 
3) the patient is informed of scan results and consents to remain on treatment.  In this circumstance, 
they will be reimaged on schedule after 2 further cycles.  If this subsequent imaging confirms 
progressive disease, the date of the progression even will be dated to the first (initial) scan date 
that progression was first documented. 
  
Phase II secondary objectives: 
1. Evaluate and compare response rates between arms of the study as determined by RECIST 
criteria 1.1. 
2. Evaluate and compare overall survival (OS) between arms of the study. 
3. Assess for potential predictive markers of survival using baseline tissue. 
4. To assess the pharmacokinetics of SGI-110 in metastatic colon cancer patients and 
correlate with changes in global methylation. 
 
Sample Size/Accrual Rate: The median PFS of patients on the phase III CORRECT trial of 
Regorafenib in metastatic colorectal cancer reported by Grothey and Van Cutsem was 1.9 
months.11 The median PFS of patients on the phase III RECOURSE trial of TAS-102 in metastatic 
colorectal adenocarcinoma reported by Mayer15 was 2.0 months.  The PFS curves of these two 
trials were superimposable and therefore hazard rates over four time intervals were estimated based 
on the published PFS curve (figure 3.) for Regorafenib from the CORRECT trial.  Simple linear 
regressions were used to fit the natural logarithm of the Kaplan-Meier product limit estimate of 
the PFS function as a function of time in four intervals: from 1 to 6 weeks, 6 to 12, 12 to 18, and 
18 to 56 weeks.  These estimated hazard rates: 0.0113, 0.0558, 0.3238, and 0.0748 per person 
week were used in simulations to evaluate power for this study.  We hypothesize that the SGI-110 
combination treatment will improve the 4 month PFS from 23% to 46.5%.  Patients will be 
randomized to the SGI-110 + irinotecan (Arm A) and the Regorafenib or TAS-102 arm (Arm B) 
in a 2:1 ratio.  Using a one sided 5% type I error allowance, accrual of 48 patients per year for 2 
years (Arm A and B target sample sizes of 64 and 32 respectively) with an additional 2 years of 
follow up, this study will provide sufficient events to have 83% power to detect an improvement 
of the median PFS from 1.9 months to 3.6 months, i.e. a hazard ratio of 0.526. 
 
Quality of Life Assessment: Quality of life will be assessed with the Functional Assessment of 
Cancer Therapy (FACT-C) quality of life tool.  An overall quality of life score for the domains: 
physical well-being, social/family well-being, emotional well-being, and functional well-being, as 
well as the colon cancer specific subscale score will be obtained at the start of the study (Cycle 1 
Day 1), at the beginning of cycle three (Cycle 3 Day 1), every other cycle subsequently (i.e. Cycle 
5 Day 1, Cycle 7 Day 1, etc), and at the off study visit for every patient.  Scoring will follow 
guidelines provided by FACIT administration guidelines manual.   The change in total score 
between pre-treatment and the start of cycle three will be compared between arms of the study 
with a t-test.  Two subscale sums of the total score: the sum of physical and functional well-being, 


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73 
and the sum of social/family and emotional well-being, will be similarly analyzed.  The change in 
the colon cancer specific domain will also be compared between arms of the study.  We anticipate 
that we will have minimal missing data at the start of cycle 3 as this is the first time a patient could 
come off study for progression.  At this time point, any missing data would be due to DLTs, SAE 
events, or voluntary withdrawal.  In these cases, documentation of the reason for missing data and 
the QoL at the time of withdrawal will be obtained with the off study evaluation. 
 
Futility monitoring plan:  We will monitor the study for futility using a non-parametric Bayesian 
predictive probability approach.40-42 This monitoring plan is based on calculations of the posterior 
distribution of the survival distribution and simulations to determine the probability that the PFS 
at 4 months on the treatment arm will be greater than that on the control arm at the end of the 
study.  When the trial is monitored, Gibbs sampling is used to generate samples from the posterior 
distribution of the survival distribution via Monte Carlo simulation, given the data and a Dirichlet 
process prior.  Censored observations are treated as random quantities and PFS event times are 
simulated for each censored observation.  This is repeated many times and ultimately converges 
to a realization of the parameters drawn from the posterior distribution.  The algorithm is that 
reported in Kuo and Smith.42  If the probability that the treatment 4 month PFS is greater than the 
control PFS at 4 months is very low, less than 33.3%, the study will be stopped for futility.   
 
The reference hazard rates were estimated based on the published PFS curve (figure 3.) for 
Regorafenib.11  Simple linear regressions were used to fit the natural logarithm of the Kaplan-
Meier product limit estimate of the survival function as a function of time in four intervals: from 
1 to 6 weeks, 6 to 12, 12 to 18, and 18 to 56 weeks.  Survival times were then generated using a 
piecewise exponential distribution with these estimated hazard rates: 0.0113, 0.0558, 0.3238, and 
0.0748 per person week.  For simulation purposes, the effect of treatment was assumed to 
multiply these hazard rates by factors of 1.0 (no difference), 0.80, 0.60, 0.526, 0.50, 0.40 and 
0.35.  The randomization ratio for these simulated studies was 2:1 and a single interim analysis, 
evaluating 4 month PFS, was performed after 50% of the patients were enrolled, i.e. n=32 in 
Arm A (SGI-110) and n=16 in Arm B (Regorafenib or TAS-102).  A one-sided 0.05 alpha level 
log-rank test was used for the final analysis.  Plots of the reference curve (black) and six 
scenarios of treatment effects (red) are shown in figure 1.  In scenario one, the reference and 
treatment hazard rates are equal.  Table 1 gives operating characteristics of this monitoring plan 
for these scenarios.  Column 4 in table 1 is the proportion of studies rejecting the null hypothesis 
out of the number of studies that did not stop for futility.  Column 5 is the overall proportion of 
studies with a positive result. 
 
 
Table 1.  Operating characteristics of monitoring rule from 500 simulated studies with interim 
analysis on 4 month PFS and final analysis based on the log-rank test. 
 
 
Scenario 
Control 
hazard 
rate (λ) 
multiplier 
Stop for 
Futility % 
Rejected at 
final 
analysis %* 
Overall 
studies 
rejecting Ho 
% 
1 
1.00 
26.4% 
5.4% 
4.0% 
2 
0.80 
12.8% 
22.0% 
19.2% 


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3 
0.60 
5.2% 
68.8% 
65.2% 
4 
0.526 
2.0% 
84.7% 
83.0% 
5 
0.50 
1.2% 
89.1% 
88.0% 
6 
0.40 
0.6% 
98.4% 
97.8% 
7 
0.35 
0.0% 
99.8% 
99.8% 
 
*Denominator is the number of simulations that do not stop early for futility. 
 
 
Analysis of primary objective: 
Standard life table methods will be used to analyze PFS.  We will report the 4-month, 1-year and 
median PFS with 95% confidence intervals for both arms of the study.   
 
Analysis of secondary objectives: 
 
1. The 4-month PFS will be compared between arms of the study using a one-sided, 0.05 
alpha level, log-rank test. 
2. All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations. Each patient will be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death 
because of other cause, or 9) unknown (not assessable, insufficient data).  
All subjects in the study will be included in the main analysis of the response rate. Patients 
in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result 
in exclusion from the analysis of the response rate.  Response rate will be estimated overall 
and by treatment arm.  A Fisher’s Exact or chi square test will be use to compare response 
rates across treatment arms.   
3. Standard life table methods will be used to analyze OS.  Four month, 1-year and median 
survival will be reported, overall and by treatment arm. We acknowledge that OS 
assessment will be compromised with the cross-over design and will report as such. 
4. Baseline global methylation will be categorized as high or low and OS Kaplan Meier 
curves plotted by category.  The change in global methylation will be categorized as 
positive or negative and OS Kaplan Meier curves plotted by category.  Similar analyses 
will be used for individual expression markers. 
5. Pharmacokinetic (PK) sampling studies are proposed for all participating patients who 
undergo pharmacodynamic endpoints.  Single dose PK samples will be collected on 
Cycle1, Day 1, at the following time points: pre-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hr.  
The following PK parameters describing the concentration time profile of SGI-110 and 
Irinotecan will be calculated: total exposure will be calculated as area under the plasma 
concentration-time curve (AUC) using the linear trapezoidal rule by using 
noncompartmental methods (Winonlin, version 5.3) and/or compartmental modeling 
(Adapt II, release 4.0).  Other parameters such as maximum concentration (Cmax), time to 
maximal concentration (Tmax) and half-life (T1/2) will also be calculated. Cmax and Tmax will 
be obtained from the data, while the half-life will be calculated as 0.693/k, where k is the 
slope of terminal elimination phase.  Associations between SGI-110 exposure parameters 


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75 
(Cmax and AUC) and pharmacodynamic endpoints (i.e., global methylation changes toxicity 
and toxicity) will be assessed using appropriate non-parametric statistical tests.   
Stratification Factors 
 
Patients will be stratified by two factors: assignment to Regorafenib or TAS-102, and time 
from last irinotecan treatment (>6 months or < 6 months) through an algorithm to maintain 
balance between the arms as much as possible. 
14.2 Reporting and Exclusions 
 
14.2.1 Evaluation of toxicity. All participants will be evaluable for toxicity 
from the time of their first treatment. 
14.2.2 Evaluation of response.  All participants included in the study must be 
assessed for response to treatment.  Each participant should be assigned 
one of the following categories: 1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because of 
other cause, or 9) unknown (not assessable, insufficient data). By 
arbitrary convention, category 9 usually designates the "unknown" status 
of any type of data in a clinical database. 
 
 


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Version 2.0 February 5, 2020 
 
 
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Version 1.3, April 21, 2014 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
80 
Appendix A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 
 
 


 
 
 
 
81
APPENDIX B:   PATIENT DIARY 
Today’s date: _________________________ 
Agent:  
Regorafenib _____ mg daily 
Patient instructions: Regorafenib should be taken with a low-fat meal once a day. 
 
 
 
____________________ 
 
Patient Signature 
 
 
____________________ 
 
Date 
 
Study 
Day 
Date 
Time of 
Dose 
# Tablets 
taken 
Blood Pressure
(Cycle 1, Days 
1, 8, 15, and 22 
& Cycle 2, Days 
1 and 8) 
Comments
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 


 
 
 
 
82
APPENDIX C:   PATIENT DIARY 
Today’s date _________________________ 
Agent:  TAS-102 ________ mg twice daily 
Patient instructions: TAS-102 should be taken twice daily within one hour after a meal. 
 
 
 
 
____________________ 
 
Patient Signature 
 
 
____________________ 
 
Date 
 
 
Study 
Day 
Date 
Time of 
AM Dose 
Time of 
PM Dose 
# Tablets 
taken 
AM / PM
Comments
 
1 
 
 
 
/ 
 
2 
 
 
 
/ 
 
3 
 
 
 
/ 
 
4 
 
 
 
/ 
 
5 
 
 
 
/ 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
/ 
 
9 
 
 
 
/ 
 
10 
 
 
 
/ 
 
11 
 
 
 
/ 
 
12 
 
 
 
/ 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 


 
 
 
 
83
APPENDIX D: FACT-C (Version 4) 
 
Study #: ________________________ 
Subject ID: _________________________ 
 
Subject initials: __________________ 
Subject date of birth: _________________ 
 
Today’s date: ____________________ 
 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of 
energy
 .......................................................................................... 
0 
1 
2 
3 
4 
GP2 
I have 
nausea
 .......................................................................................... 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my 
family
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have 
pain
 .......................................................................................... 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of 
treatment
 .......................................................................................... 
0 
1 
2 
3 
4 
GP6 
I feel 
ill
 .......................................................................................... 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in 
bed
 ..........................................................................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 


 
 
 
 
84
 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel 
sad
 .......................................................................................... 
0 
1 
2 
3 
4 
GS1 
I feel close to my 
friends
 .......................................................................................... 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my 
family
 .......................................................................................... 
0 
1 
2 
3 
4 
GS3 
I get support from my 
friends
 .......................................................................................... 
0 
1 
2 
3 
4 
GS4 
My family has accepted my 
illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support)
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex 
life
 .......................................................................................... 
0 
1 
2 
3 
4 


 
 
 
 
85
GE2 
I am satisfied with how I am coping with my 
illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my 
illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GE4 
I feel 
nervous
 .......................................................................................... 
0 
1 
2 
3 
4 
GE5 
I worry about 
dying
 .......................................................................................... 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get 
worse
 .......................................................................................... 
0 
1 
2 
3 
4 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at 
home)
 .......................................................................................... 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is 
fulfilling
 .......................................................................................... 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy 
life
 .......................................................................................... 
0 
1 
2 
3 
4 
GF4 
I have accepted my 
illness
 .......................................................................................... 
0 
1 
2 
3 
4 
GF5 
I am sleeping 
well
 .......................................................................................... 
0 
1 
2 
3 
4 


 
 
 
 
86
GF6 
I am enjoying the things I usually do for 
fun
 .......................................................................................... 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
now
 .......................................................................................... 
0 
1 
2 
3 
4 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
C1 
I have swelling or cramps in my stomach 
area
 .......................................................................................... 
0 
1 
2 
3 
4 
C2 
I am losing 
weight
 .......................................................................................... 
0 
1 
2 
3 
4 
C3 
I have control of my 
bowels
 .......................................................................................... 
0 
1 
2 
3 
4 
C4 
I can digest my food 
well
 .......................................................................................... 
0 
1 
2 
3 
4 
C5 
I have diarrhea 
(diarrhoea)
 .......................................................................................... 
0 
1 
2 
3 
4 
C6 
I have a good 
appetite
 .......................................................................................... 
0 
1 
2 
3 
4 
C7 
I like the appearance of my 
body
 .......................................................................................... 
0 
1 
2 
3 
4 
Q2 
Do you have an ostomy appliance?  (Mark one box) 
        No 
or 
        Yes 
 
If yes, please answer the next two items: 
 


 
 
 
 
87
C8 
I am embarrassed by my ostomy 
appliance
 .......................................................................................... 
0 
1 
2 
3 
4 
C9 
Caring for my ostomy appliance is 
difficult
 .......................................................................................... 
0 
1 
2 
3 
4