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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Previously Treated Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: SGI-110 Dose Escalation
* Drug: Regorafenib
* Drug: TAS-102
* Drug: SGI-110
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing a Dose Limiting Toxicity | 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. | 28 days | 
| Progression Free Survival (PFS) | Progression Free Survival is the time (in months) from start of treatment to progression, clinical deterioration attributed to disease, or death. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival is defined as the time (in months) between the start of treatment and death. | Up to 3 years | 
| Objective Response Rate | 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. | Assessed until disease progression, up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SGI-110, irinotecan, regorafenib, methylation, colorectal, metastatic, TAS-102, lonsurf