Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT01896856
• Collaborator: Van Andel Research Institute (Other), Astex Pharmaceuticals, Inc. (Industry)
• Enrollment: 118
• Locations: 4
• Arms: 3
• Actual Duration (Months): 70.1
• Patients Per Site: 29.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Previously Treated Metastatic Colorectal Cancer	Drug: SGI-110 Dose Escalation; Drug: Regorafenib; Drug: TAS-102; Drug: SGI-110; Drug: Irinotecan	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 118 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: In Phase 2, Arm B patients who have disease progression will be given the option to receive Arm A study drugs.In Phase 2, Arm B patients who have disease progression will be given the option to receive Arm A study drugs.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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 in Previously Treated Metastatic Colorectal Cancer Patients
• Actual Study Start Date: Oct 23, 2013
• Actual Primary Completion Date: Aug 26, 2019
• Actual Study Completion Date: Aug 26, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1: Dose Escalation 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.	Drug: SGI-110 Dose Escalation; 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; Other Names: Guadecitabine
Experimental: Phase 2: Arm A SGI-110 + irinotecan 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.	Drug: SGI-110; 45 mg/m^2 administered as a subcutaneous injection; Other Names: Guadecitabine ; Drug: Irinotecan; 125 mg/m^2 administered IV; Other Names: Camptosar
Active Comparator: Phase 2: Arm B regorafenib or TAS-102 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.	Drug: Regorafenib; 160 mg taken orally; Other Names: Stivarga ; Drug: TAS-102; 35 mg/m^2 taken orally; Other Names: Lonsurf trifluridine and tipiracil ; Drug: SGI-110; 45 mg/m^2 administered as a subcutaneous injection; Other Names: Guadecitabine ; Drug: Irinotecan; 125 mg/m^2 administered IV; Other Names: Camptosar

Outcome Measures

Primary Outcome Measures

1. Number of Participants Experiencing a Dose Limiting Toxicity [28 days]

   Number of participants experiencing a Dose Limiting Toxicity (DLT) in each dose level. DLT is defined as any of the following study drug-related toxicities occurring during the first cycle of study drug on study: grade 4 thrombocytopenia lasting >7days any grade 3-4 febrile neutropenia grade 3 or higher non-hematologic toxicity unless it could be managed by supportive treatment any other clinically significant adverse event which would place subjects at undue safety risk, or results in discontinuation of treatment.

2. Progression Free Survival (PFS) [Up to 12 months]

   Progression Free Survival is the time (in months) from start of treatment to progression, clinical deterioration attributed to disease, or death.

Secondary Outcome Measures

1. Overall Survival [Up to 3 years]

   Overall Survival is defined as the time (in months) between the start of treatment and death.

2. Objective Response Rate [Assessed until disease progression, up to 3 years]

   Objective Response Rate (ORR) is defined as the number of subjects achieving a Complete Response (CR) or Partial Response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. CR = disappearance of all target lesions, PR = at least 30% decrease in the sum of diameters of target lesions.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum

• Phase I only: patients with biopsiable disease amenable to having two research biopsies.

• Have measurable disease

• Phase II only: progressed while receiving irinotecan therapy in the metastatic setting. There are no limitations on number of prior therapies in the metastatic setting.

• Life expectancy of greater than 12 weeks.

• Eastern Cooperative Oncology Group (ECOG) performance status <1

• Normal organ and marrow function as defined by study-specified laboratory tests

• Must use adequate contraception through the study and for 3 months after last dose of study drug.

Exclusion Criteria:

• Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) of first dose of study drug or who have not recovered from treatment-related adverse events

• Receiving any other investigational agents

• Participants with known brain metastases

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, decitabine or SGI-110.

• Received prior therapy with any hypomethylating agents.

• 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.

• Pregnant or nursing women

• History of a different malignancy are ineligible with exceptions (disease-free for at least 5 years with low risk for recurrence, cervical cancer in situ, definitively treated early stage prostate cancer, definitively treated breast ductal or lobular carcinoma in situ, and basal cell or squamous cell carcinoma of the skin).

• HIV-positive individuals on combination antiretroviral therapy

• Phase II only: previous treatment with regorafenib and TAS-102. If patients have previously received either regorafenib OR TAS-102, they must be able to receive the alternate regimen if randomized to standard of care (Arm B).

• Hospitalization for an acute medical issue within 4 weeks prior to screening visit

• Symptomatic bowel obstruction within 6 months prior to enrollment, Patients who undergo surgical correction of obstructing lesion will be eligible within 6 months.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
2	Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21231
3	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
4	VU Medisch Centrum	Amsterdam		Netherlands	1081 HV

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Van Andel Research Institute
• Astex Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Nilo Azad, MD, SKCCC at JHMI

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 5, 2020

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT01896856
• Other Study ID Numbers: J1369; NA_00085870
• First Posted: Jul 11, 2013
• Last Update Posted: Oct 6, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: SGI-110; irinotecan; regorafenib; methylation; colorectal; metastatic; TAS-102; lonsurf
• Additional relevant MeSH terms: Colorectal Neoplasms; Trifluridine; Irinotecan; Guadecitabine; Azacitidine

Study Results

Participant Flow

Arm/Group Title	Phase 1: Dose Level 1	Phase 1: Dose Level -1	Phase 1: Dose Level -1G	Phase 1: Dose Level 1G	Phase 2: Arm A SGI-110 + Irinotecan	Phase 2: Arm B Regorafenib or TAS-102
Arm/Group Description	Guadecitabine (SGI-110) 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle.	Guadecitabine (SGI-110) 30 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle.	Guadecitabine (SGI-110) 30 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) mandatory during cycle 1, and given per clinician judgement cycle 2 and beyond.	Guadecitabine (SGI-110) 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) mandatory during cycle 1, and given per clinician judgement cycle 2 and beyond.	SGI-110 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) was given during cycle 1 with option to give additional growth factor support at subsequent cycles per clinician judgement.	Subjects received either regorafenib or Lonsurf (TAS-102). Regorafenib 160 mg was taken orally daily from days 1-21 of each 28-day cycle or TAS-102 35 mg/m^2 was taken orally twice daily on days 1-5 and 8-12 of each 28-day cycle. Subjects that had previously received one of these standard of care drugs (regorafenib or TAS-102) received the other on study. For subjects that had never received either regorafenib or TAS-102, the choice of therapy was deferred to the treating physician and patient.
Period Title: Overall Study
STARTED	6	3	7	6	62	34
COMPLETED	6	3	6	6	62	34
NOT COMPLETED	0	0	1	0	0	0

Baseline Characteristics

Arm/Group Title	Phase 1: Dose Level 1	Phase 1: Dose Level -1	Phase 1: Dose Level -1G	Phase 1: Dose Level 1G	Phase 2: Arm A SGI-110 + Irinotecan	Phase 2: Arm B Regorafenib or TAS-102	Total
Arm/Group Description	Guadecitabine (SGI-110) 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle.	Guadecitabine (SGI-110) 30 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle.	Guadecitabine (SGI-110) 30 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) mandatory during cycle 1, and given per clinician judgement cycle 2 and beyond.	Guadecitabine (SGI-110) 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) mandatory during cycle 1, and given per clinician judgement cycle 2 and beyond.	SGI-110 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) was given during cycle 1 with option to give additional growth factor support at subsequent cycles per clinician judgement.	Subjects received either regorafenib or TAS-102. Regorafenib 160 mg was taken orally daily from days 1-21 of each 28-day cycle or TAS-102 35 mg/m^2 was taken orally twice daily on days 1-5 and 8-12 of each 28-day cycle. Subjects that had previously received one of these standard of care drugs (regorafenib or TAS-102) received the other on study. For subjects that had never received either regorafenib or TAS-102, the choice of therapy was deferred to the treating physician and patient.	Total of all reporting groups
Overall Participants	6	3	7	6	62	34	118
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54.5	64	52	54.5	55.0	59.5	57.0
Sex: Female, Male (Count of Participants)
Female	2 33.3%	2 66.7%	2 28.6%	4 66.7%	21 33.9%	18 52.9%	49 41.5%
Male	4 66.7%	1 33.3%	5 71.4%	2 33.3%	41 66.1%	16 47.1%	69 58.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	5 8.1%	1 2.9%	6 5.1%
Not Hispanic or Latino	6 100%	3 100%	7 100%	6 100%	57 91.9%	33 97.1%	112 94.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	1 16.7%	9 14.5%	4 11.8%	14 11.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	5 71.4%	0 0%	3 4.8%	8 23.5%	16 13.6%
White	6 100%	3 100%	2 28.6%	5 83.3%	47 75.8%	22 64.7%	85 72%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	3 4.8%	0 0%	3 2.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Experiencing a Dose Limiting Toxicity
Description	Number of participants experiencing a Dose Limiting Toxicity (DLT) in each dose level. DLT is defined as any of the following study drug-related toxicities occurring during the first cycle of study drug on study: grade 4 thrombocytopenia lasting >7days any grade 3-4 febrile neutropenia grade 3 or higher non-hematologic toxicity unless it could be managed by supportive treatment any other clinically significant adverse event which would place subjects at undue safety risk, or results in discontinuation of treatment.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Per protocol, Dose Limiting Toxicities were only assessed in Phase 1 subjects in order to determine the Phase 2 dose of SGI-110. 1 Patient in Dose Level -1G was taken off study for non-compliance due to transportation issues before completion of Cycle 1 and was not considered evaluable for DLT analysis.

Arm/Group Title	Dose Level 1	Dose Level -1	Dose Level -1G	Dose Level 1G
Arm/Group Description	SGI-110 45 mg/m^2 subcutaneously on days 1-5 of each 28-day cycle Irinotecan 125 mg/m^2 IV on days 8 and 15 of each 28-day cycle.	SGI-110 30 mg/m^2 subcutaneously on days 1-5 of each 28-day cycle Irinotecan 125 mg/m^2 IV on days 8 and 15 of each 28-day cycle.	SGI-110 30 mg/m^2 subcutaneously on days 1-5 of each 28-day cycle Irinotecan 125 mg/m^2 IV on days 8 and 15 of each 28-day cycle. Growth Factor Support with Filgrastim and/or Pegfilgrastim given during Cycle 1 and in subsequent cycles per clinician judgement.	SGI-110 45 mg/m^2 subcutaneously on days 1-5 of each 28-day cycle Irinotecan 125 mg/m^2 IV on days 8 and 15 of each 28-day cycle. Growth Factor Support with Filgrastim and/or Pegfilgrastim given during Cycle 1 and in subsequent cycles per clinician judgement.
Measure Participants	6	3	6	6
Count of Participants [Participants]	1 16.7%	2 66.7%	1 14.3%	1 16.7%

2. Primary Outcome

Title	Progression Free Survival (PFS)
Description	Progression Free Survival is the time (in months) from start of treatment to progression, clinical deterioration attributed to disease, or death.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Per protocol, the progression-free survival objective was only assessed in Phase 2 subjects. 18 subjects who received Arm B treatment were eligible to "crossover" to receive Arm A treatment. These participants were not included in the number analyzed in Arm A because they were not assessed for progression free survival after Arm A treatment.

Arm/Group Title	Phase 2: Arm A SGI-110 + Irinotecan	Phase 2: Arm B Regorafenib or TAS-102
Arm/Group Description	SGI-110 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) was given during cycle 1 with option to give additional growth factor support at subsequent cycles per clinician judgement.	Subjects received either regorafenib or TAS-102. Regorafenib 160 mg was taken orally daily from days 1-21 of each 28-day cycle or TAS-102 35 mg/m^2 was taken orally twice daily on days 1-5 and 8-12 of each 28-day cycle. Subjects that had previously received one of these standard of care drugs (regorafenib or TAS-102) received the other on study. For subjects that had never received either regorafenib or TAS-102, the choice of therapy was deferred to the treating physician and patient.
Measure Participants	62	34
Median (95% Confidence Interval) [months]	2.37	2.09

3. Secondary Outcome

Title	Overall Survival
Description	Overall Survival is defined as the time (in months) between the start of treatment and death.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Per protocol, the overall survival objective was only assessed in Phase 2 subjects. 18 subjects who received Arm B treatment and were eligible to "crossover" to receive Arm A treatment were not included in the number analyzed in Arm A because they were not assessed for overall survival after receiving Arm A treatment.

Arm/Group Title	Phase 2: Arm A SGI-110 + Irinotecan	Phase 2: Arm B Regorafenib or TAS-102
Arm/Group Description	SGI-110 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) was given during cycle 1 with option to give additional growth factor support at subsequent cycles per clinician judgement.	Subjects received either regorafenib or TAS-102. Regorafenib 160 mg was taken orally daily from days 1-21 of each 28-day cycle or TAS-102 35 mg/m^2 was taken orally twice daily on days 1-5 and 8-12 of each 28-day cycle. Subjects that had previously received one of these standard of care drugs (regorafenib or TAS-102) received the other on study. For subjects that had never received either regorafenib or TAS-102, the choice of therapy was deferred to the treating physician and patient.
Measure Participants	62	34
Median (95% Confidence Interval) [months]	7.15	7.66

4. Secondary Outcome

Title	Objective Response Rate
Description	Objective Response Rate (ORR) is defined as the number of subjects achieving a Complete Response (CR) or Partial Response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. CR = disappearance of all target lesions, PR = at least 30% decrease in the sum of diameters of target lesions.
Time Frame	Assessed until disease progression, up to 3 years

Outcome Measure Data

Analysis Population Description

ORR only assessed for Phase 2. 5 from Arm A and 2 from Arm B were excluded from response rate analysis as they didn't get a follow-up scan. 18 subjects in Arm B were eligible to "crossover" to receive Arm A treatment. They were not included in the number analyzed in Arm A because they were not assessed for objective response after Arm A treatment.

Arm/Group Title	Phase 2: Arm A SGI-110 + Irinotecan	Phase 2: Arm B Regorafenib or TAS-102
Arm/Group Description	SGI-110 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) was given during cycle 1 with option to give additional growth factor support at subsequent cycles per clinician judgement.	Subjects received either regorafenib or TAS-102. Regorafenib 160 mg was taken orally daily from days 1-21 of each 28-day cycle or TAS-102 35 mg/m^2 was taken orally twice daily on days 1-5 and 8-12 of each 28-day cycle. Subjects that had previously received one of these standard of care drugs (regorafenib or TAS-102) received the other on study. For subjects that had never received either regorafenib or TAS-102, the choice of therapy was deferred to the treating physician and patient.
Measure Participants	57	32
Count of Participants [Participants]	1 16.7%	0 0%

Adverse Events

Time Frame	Adverse Events (AEs) were collected from the first dose of study drug through 30 days after the last dose of study drug, up to 13 months
Adverse Event Reporting Description	18 patients from Arm B were eligible to "crossover" to receive Arm A study treatment after they had progression with Arm B treatment. They were assessed for adverse events after receiving Arm A treatment. Their adverse events are reported here in a separate arm.
Arm/Group Title	Phase 1: Dose Level 1		Phase 1: Dose Level -1		Phase 1: Dose Level -1G		Phase 1: Dose Level 1G		Phase 2: Arm A SGI-110 + Irinotecan		Phase 2: "Crossover" to Arm A From Arm B		Phase 2: Arm B Regorafenib or TAS-102
Arm/Group Description	Guadecitabine (SGI-110) 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle.		Guadecitabine (SGI-110) 30 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle.		Guadecitabine (SGI-110) 30 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) mandatory during cycle 1, and given per clinician judgement cycle 2 and beyond.		Guadecitabine (SGI-110) 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) mandatory during cycle 1, and given per clinician judgement cycle 2 and beyond.		SGI-110 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) was given during cycle 1 with option to give additional growth factor support at subsequent cycles per clinician judgement.		Per protocol, Arm B subjects were given the option to "crossover" and receive Arm A study drugs after disease progression on Arm B. 18 Arm B subjects received Arm A study drugs after initial progression. SGI-110 45 mg/m^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) was given during cycle 1 with option to give additional growth factor support at subsequent cycles per clinician judgement.		Subjects received either regorafenib or TAS-102. Regorafenib 160 mg was taken orally daily from days 1-21 of each 28-day cycle or TAS-102 35 mg/m^2 was taken orally twice daily on days 1-5 and 8-12 of each 28-day cycle. Subjects that had previously received one of these standard of care drugs (regorafenib or TAS-102) received the other on study. For subjects that had never received either regorafenib or TAS-102, the choice of therapy was deferred to the treating physician and patient.
All Cause Mortality
	Phase 1: Dose Level 1		Phase 1: Dose Level -1		Phase 1: Dose Level -1G		Phase 1: Dose Level 1G		Phase 2: Arm A SGI-110 + Irinotecan		Phase 2: "Crossover" to Arm A From Arm B		Phase 2: Arm B Regorafenib or TAS-102
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/3 (0%)		0/7 (0%)		1/6 (16.7%)		3/62 (4.8%)		0/18 (0%)		4/34 (11.8%)
Serious Adverse Events
	Phase 1: Dose Level 1		Phase 1: Dose Level -1		Phase 1: Dose Level -1G		Phase 1: Dose Level 1G		Phase 2: Arm A SGI-110 + Irinotecan		Phase 2: "Crossover" to Arm A From Arm B		Phase 2: Arm B Regorafenib or TAS-102
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		1/3 (33.3%)		2/7 (28.6%)		1/6 (16.7%)		15/62 (24.2%)		8/18 (44.4%)		1/34 (2.9%)
Blood and lymphatic system disorders
Anemia	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Febrile neutropenia	1/6 (16.7%)		0/3 (0%)		2/7 (28.6%)		0/6 (0%)		4/62 (6.5%)		2/18 (11.1%)		0/34 (0%)
Neutropenia	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Gastrointestinal disorders
Abdominal pain	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Colitis	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Diarrhea	0/6 (0%)		1/3 (33.3%)		1/7 (14.3%)		0/6 (0%)		2/62 (3.2%)		1/18 (5.6%)		0/34 (0%)
Nausea	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Upper gastrointestinal hemorrhage	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		0/18 (0%)		1/34 (2.9%)
Vomiting	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
General disorders
Fatigue or Malaise	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		1/18 (5.6%)		0/34 (0%)
Fever	1/6 (16.7%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		0/18 (0%)		0/34 (0%)
Infections and infestations
Bacteremia	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		1/18 (5.6%)		0/34 (0%)
Sepsis	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		4/62 (6.5%)		3/18 (16.7%)		0/34 (0%)
Skin infection	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Upper respiratory tract infection	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Urinary tract infection	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		1/18 (5.6%)		0/34 (0%)
Wound infection	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Investigations
Blood bilirubin increased	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Metabolism and nutrition disorders
Dehydration	0/6 (0%)		0/3 (0%)		0/7 (0%)		1/6 (16.7%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/6 (16.7%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		0/18 (0%)		0/34 (0%)
Renal and urinary disorders
Acute kidney injury	0/6 (0%)		0/3 (0%)		0/7 (0%)		1/6 (16.7%)		0/62 (0%)		0/18 (0%)		0/34 (0%)
Vascular disorders
Hypotension	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Other (Not Including Serious) Adverse Events
	Phase 1: Dose Level 1		Phase 1: Dose Level -1		Phase 1: Dose Level -1G		Phase 1: Dose Level 1G		Phase 2: Arm A SGI-110 + Irinotecan		Phase 2: "Crossover" to Arm A From Arm B		Phase 2: Arm B Regorafenib or TAS-102
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		3/3 (100%)		6/7 (85.7%)		6/6 (100%)		58/62 (93.5%)		18/18 (100%)		30/34 (88.2%)
Blood and lymphatic system disorders
Anemia	4/6 (66.7%)		2/3 (66.7%)		5/7 (71.4%)		2/6 (33.3%)		37/62 (59.7%)		8/18 (44.4%)		15/34 (44.1%)
Febrile neutropenia	0/6 (0%)		2/3 (66.7%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		3/18 (16.7%)		0/34 (0%)
Lymphopenia	5/6 (83.3%)		1/3 (33.3%)		4/7 (57.1%)		3/6 (50%)		7/62 (11.3%)		3/18 (16.7%)		5/34 (14.7%)
Neutropenia	6/6 (100%)		3/3 (100%)		5/7 (71.4%)		4/6 (66.7%)		27/62 (43.5%)		10/18 (55.6%)		12/34 (35.3%)
Thrombocytopenia	3/6 (50%)		1/3 (33.3%)		3/7 (42.9%)		2/6 (33.3%)		20/62 (32.3%)		6/18 (33.3%)		3/34 (8.8%)
Leukopenia	6/6 (100%)		1/3 (33.3%)		5/7 (71.4%)		4/6 (66.7%)		28/62 (45.2%)		6/18 (33.3%)		11/34 (32.4%)
Cardiac disorders
Sinus tachycardia	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		1/18 (5.6%)		1/34 (2.9%)
Endocrine disorders
Glucose intolerance	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		1/18 (5.6%)		0/34 (0%)
Gastrointestinal disorders
Abdominal pain	2/6 (33.3%)		0/3 (0%)		2/7 (28.6%)		2/6 (33.3%)		5/62 (8.1%)		3/18 (16.7%)		6/34 (17.6%)
Constipation	3/6 (50%)		0/3 (0%)		0/7 (0%)		1/6 (16.7%)		4/62 (6.5%)		1/18 (5.6%)		3/34 (8.8%)
Diarrhea	2/6 (33.3%)		2/3 (66.7%)		3/7 (42.9%)		3/6 (50%)		24/62 (38.7%)		6/18 (33.3%)		7/34 (20.6%)
Dry mouth	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		0/18 (0%)		3/34 (8.8%)
Dyspepsia	0/6 (0%)		1/3 (33.3%)		0/7 (0%)		1/6 (16.7%)		0/62 (0%)		0/18 (0%)		0/34 (0%)
Mucositis oral	2/6 (33.3%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		2/18 (11.1%)		1/34 (2.9%)
Nausea	5/6 (83.3%)		1/3 (33.3%)		6/7 (85.7%)		4/6 (66.7%)		28/62 (45.2%)		5/18 (27.8%)		11/34 (32.4%)
Vomiting	0/6 (0%)		3/3 (100%)		4/7 (57.1%)		2/6 (33.3%)		9/62 (14.5%)		4/18 (22.2%)		5/34 (14.7%)
General disorders
Chills	0/6 (0%)		0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		0/62 (0%)		0/18 (0%)		0/34 (0%)
Edema limbs	1/6 (16.7%)		0/3 (0%)		4/7 (57.1%)		1/6 (16.7%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Fatigue or malaise	3/6 (50%)		2/3 (66.7%)		4/7 (57.1%)		5/6 (83.3%)		37/62 (59.7%)		10/18 (55.6%)		14/34 (41.2%)
Fever	4/6 (66.7%)		1/3 (33.3%)		2/7 (28.6%)		0/6 (0%)		8/62 (12.9%)		0/18 (0%)		1/34 (2.9%)
Injection site reaction	4/6 (66.7%)		1/3 (33.3%)		5/7 (71.4%)		4/6 (66.7%)		12/62 (19.4%)		5/18 (27.8%)		0/34 (0%)
Infections and infestations
Abscess or skin infection	1/6 (16.7%)		0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/62 (0%)		0/18 (0%)		0/34 (0%)
Injury, poisoning and procedural complications
Bruising	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		1/18 (5.6%)		0/34 (0%)
Infusion related reaction	0/6 (0%)		0/3 (0%)		1/7 (14.3%)		1/6 (16.7%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Investigations
Alkaline phosphatase increased	3/6 (50%)		1/3 (33.3%)		5/7 (71.4%)		2/6 (33.3%)		8/62 (12.9%)		0/18 (0%)		0/34 (0%)
ALT increased	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		2/62 (3.2%)		0/18 (0%)		3/34 (8.8%)
AST increased	2/6 (33.3%)		0/3 (0%)		4/7 (57.1%)		1/6 (16.7%)		2/62 (3.2%)		2/18 (11.1%)		2/34 (5.9%)
Blood bilirubin increased	1/6 (16.7%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		5/62 (8.1%)		1/18 (5.6%)		2/34 (5.9%)
Weight loss	1/6 (16.7%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		5/62 (8.1%)		1/18 (5.6%)		1/34 (2.9%)
Hyperglycemia	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		2/62 (3.2%)		1/18 (5.6%)		0/34 (0%)
Hypocalcemia	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		0/18 (0%)		2/34 (5.9%)
Hypophosphatemia	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		2/34 (5.9%)
Metabolism and nutrition disorders
Anorexia	4/6 (66.7%)		0/3 (0%)		3/7 (42.9%)		3/6 (50%)		14/62 (22.6%)		2/18 (11.1%)		11/34 (32.4%)
Dehydration	0/6 (0%)		1/3 (33.3%)		2/7 (28.6%)		0/6 (0%)		0/62 (0%)		0/18 (0%)		1/34 (2.9%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	0/6 (0%)		0/3 (0%)		1/7 (14.3%)		0/6 (0%)		0/62 (0%)		1/18 (5.6%)		1/34 (2.9%)
Myalgia	1/6 (16.7%)		0/3 (0%)		2/7 (28.6%)		0/6 (0%)		3/62 (4.8%)		0/18 (0%)		0/34 (0%)
Nervous system disorders
Dizziness	1/6 (16.7%)		1/3 (33.3%)		2/7 (28.6%)		0/6 (0%)		3/62 (4.8%)		0/18 (0%)		0/34 (0%)
Dysgeusia	3/6 (50%)		0/3 (0%)		1/7 (14.3%)		0/6 (0%)		3/62 (4.8%)		0/18 (0%)		2/34 (5.9%)
Headache	3/6 (50%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		1/62 (1.6%)		0/18 (0%)		0/34 (0%)
Skin and subcutaneous tissue disorders
Alopecia	3/6 (50%)		1/3 (33.3%)		2/7 (28.6%)		2/6 (33.3%)		11/62 (17.7%)		1/18 (5.6%)		1/34 (2.9%)
Palmar-plantar erythrodysesthesia	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		0/18 (0%)		2/34 (5.9%)
Vascular disorders
Hypertension	0/6 (0%)		0/3 (0%)		0/7 (0%)		0/6 (0%)		0/62 (0%)		0/18 (0%)		2/34 (5.9%)
Hypotension	0/6 (0%)		1/3 (33.3%)		1/7 (14.3%)		0/6 (0%)		1/62 (1.6%)		1/18 (5.6%)		0/34 (0%)

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

The Principal Investigators (PIs) from participating sites must provide the Johns Hopkins PI with a copy of any proposed publication for review and comment at least 30 days prior to submission.