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

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).

Study Overview

• Status: Completed
• Conditions: Previously Treated Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: SGI-110 Dose Escalation; Drug: SGI-110; Drug: Irinotecan; Drug: Regorafenib; Drug: TAS-102

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU Medisch Centrum
• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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: 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; Drug: Regorafenib; 160 mg taken orally; Other Names: Stivarga; Drug: TAS-102; 35 mg/m^2 taken orally; Other Names: Lonsurf; trifluridine and tipiracil

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Astex Pharmaceuticals, Inc.; Van Andel Research Institute
• Investigators: Principal Investigator: Nilo Azad, MD, SKCCC at JHMI

Publications and helpful links

General Publications

• Sharma A, Vatapalli R, Abdelfatah E, Wyatt McMahon K, Kerner Z, A Guzzetta A, Singh J, Zahnow C, B Baylin S, Yerram S, Hu Y, Azad N, Ahuja N. Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells. PLoS One. 2017 Apr 26;12(4):e0176139. doi: 10.1371/journal.pone.0176139. eCollection 2017. Erratum In: PLoS One. 2020 Nov 30;15(11):e0242750.

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2013
• Primary Completion (Actual): August 26, 2019
• Study Completion (Actual): August 26, 2019

Study Registration Dates

• First Submitted: July 8, 2013
• First Submitted That Met QC Criteria: July 10, 2013
• First Posted (Estimate): July 11, 2013

Study Record Updates

• Last Update Posted (Actual): October 6, 2020
• Last Update Submitted That Met QC Criteria: September 14, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: colorectal; irinotecan; metastatic; regorafenib; TAS-102; methylation; SGI-110; lonsurf
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Irinotecan; Azacitidine; Trifluridine; Guadecitabine
• Other Study ID Numbers: J1369; NA_00085870 (Other Identifier: JHMIRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No