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Micronutrients

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Bevacizumab

Leucovorin

Fluorouracil

Irinotecan

Levoleucovorin

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Immunosuppressive Agents

Immunologic Factors

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Antidotes

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Vitamin B Complex

Trace Elements

Folinic Acid

Folate

Vitamin B9

Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 8\~12 hours. For patients who have failed bevacizumab with irinotecan-based chemotherapies, bevacizumab may be administered with FOLFIRI. FOLFIRI infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks, starting on C1D1. If bevacizumab is added to FOLFIRI, bevacizumab infusion should start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion. 5-FU 400 mg/ m\^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/ m\^2/day continuous infusion. For patients who could not tolerate FOLFIRI at the full dose previously, FOLFIRI should be started at the same dose level the patient tolerated FOLFIRI previously.

Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 8\~12 hours.

Napabucasin

Fluorouracil 400 mg/m\^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by Fluorouracil 1200 mg/m\^2/day (total 2400 mg/m\^2) continuous infusion.

Irinotecan 180 mg/m\^2 followed by or concurrent with leucovorin 400 mg/m\^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively.

Liu Wang

This is a randomized, open-label, multi-center, phase III study of Napabucasin plus bi-weekly FOLFIRI (Arm 1) vs. Napabucasin (Arm 2) for adult patients with metastatic CRC who have failed standard chemotherapy regimens. For patients who have failed bevacizumab with irinotecan-based chemotherapies (treatment failure is defined as radiologic progression of disease during or within 3 months following the last dose), bevacizumab maybe administered in combination with FOLFIRI to patients randomized to Arm 1.

A Phase III Clinical Study of Napabucasin (GB201) Plus FOLFIRI in Adult Patients With Metastatic Colorectal Cancer

A Phase III, Randomized, Open-Label Clinical Study of Napabucasin (GB201) in Combination With FOLFIRI Versus Napabucasin in Adult Patients With Previously Treated Metastatic Colorectal Cancer (CRC)

To assess the effect of Napabucasin plus biweekly FOLFIRI versus Napabucasin on the Overall Survival of patients with previously treated metastatic colorectal cancer.

Defined as the time from randomization to the first objective documentation of disease progression or death due to any cause.

Defined as the proportion of patients with a documented complete response or partial response (CR + PR) based on RECIST 1.1.

Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.

All patients who have received at least one dose of Napabucasin will be included in the safety analysis according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.0. The incidence of adverse events will be summarized by type of adverse event and severity.

QoL will be measured using the European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC-QLQ-C30) in patients with pretreated metastatic CRC treated with Napabucasin plus biweekly FOLFIRI versus Napabucasin.

To assess the effect of Napabucasin plus FOLFIRI versus Napabucasin on the Overall Survival of patients with metastatic colorectal cancer in biomarker positive patients. This biomarker-positive sub-population is defined as those patients with phospho-STAT3/nuclear β-catenin positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) archival tissue.

Defined as the time from randomization to the first objective documentation of disease progression or death due to any cause. This biomarker-positive sub-population is defined as those patients with nuclear β-catenin and/or phospho-STAT3 positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) archival tissue.

Defined as the proportion of patients with a documented complete response or partial response (CR + PR) based on RECIST 1.1. This biomarker-positive sub-population is defined as those patients with nuclear β-catenin and/or phospho-STAT3 positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) archival tissue.Defined as the proportion of patients with a documented complete response or partial response (CR + PR) based on RECIST 1.1. This biomarker-positive sub-population is defined as those patients with nuclear β-catenin and/or phospho-STAT3 positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) archival tissue.

Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1. This biomarker-positive sub-population is defined as those patients with nuclear β-catenin and/or phospho-STAT3 positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) archival tissue.

1Globe Health Institute LLC

Anti-Infective Agents

Lenograstim

Trifluridine

Mitogens

Guadecitabine

Azacitidine

Antiviral Agents

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.

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.

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.

* 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

SGI-110 Dose Escalation

Regorafenib

TAS-102

45 mg/m\^2 administered as a subcutaneous injection

SGI-110

Nilo Azad, MD

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).

In Phase 2, Arm B patients who have disease progression will be given the option to receive Arm A study drugs.

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

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

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:

1. grade 4 thrombocytopenia lasting \>7days
2. any grade 3-4 febrile neutropenia
3. grade 3 or higher non-hematologic toxicity unless it could be managed by supportive treatment
4. any other clinically significant adverse event which would place subjects at undue safety risk, or results in discontinuation of treatment.

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

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

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.

Van Andel Research Institute

Astex Pharmaceuticals, Inc.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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.

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.

Phase 1: Dose Level 1

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.

Phase 1: Dose Level -1

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.

Phase 1: Dose Level -1G

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.

Phase 1: Dose Level 1G

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.

Phase 2: Arm A SGI-110 + Irinotecan

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.

Phase 2: "Crossover" to Arm A From Arm B

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.

Phase 2: Arm B Regorafenib or TAS-102

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.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Dr. Nilofer Azad

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.

Dose Level 1

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.

Dose Level -1

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.

Dose Level -1G

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.

Dose Level 1G

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.

Number of Participants Experiencing a Dose Limiting Toxicity

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.

Progression Free Survival (PFS)

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.

Overall Survival

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.

Objective Response Rate

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase III Clinical Study of Napabucasin (GB201) Plus FOLFIRI in Adult Patients With Metastatic Colorectal Cancer	NCT03522649	Previously Trea...	Napabucasin Fluorouracil Leucovorin Irinotecan	18 Years -	1Globe Biomedical Co., Ltd.
A Phase III Clinical Study of Napabucasin (GB201) Plus FOLFIRI in Adult Patients With Metastatic Colorectal Cancer	NCT03522649	Previously Trea...	Napabucasin Fluorouracil Leucovorin Irinotecan	18 Years -	1Globe Biomedical Co., Ltd.
Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer	NCT01896856	Previously Trea...	SGI-110 Dose Es... Regorafenib TAS-102 SGI-110 Irinotecan	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Spots Global Cancer Trial Database for previously treated metastatic colorectal cancer