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

Primary Purpose

Previously Treated Metastatic Colorectal Cancer

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
SGI-110 Dose Escalation
Regorafenib
TAS-102
SGI-110
Irinotecan
Sponsored by
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Previously Treated Metastatic Colorectal Cancer focused on measuring SGI-110, irinotecan, regorafenib, methylation, colorectal, metastatic, TAS-102, lonsurf

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • USC / Norris Comprehensive Cancer Center
  • Sidney Kimmel Comprehensive Cancer Center
  • Memorial Sloan Kettering Cancer Center
  • VU Medisch Centrum

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Phase 1: Dose Escalation

Phase 2: Arm A SGI-110 + irinotecan

Phase 2: Arm B regorafenib or TAS-102

Arm Description

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.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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

Full Information

First Posted
July 8, 2013
Last Updated
September 14, 2020
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
Van Andel Research Institute, Astex Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01896856
Brief Title
Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
October 23, 2013 (Actual)
Primary Completion Date
August 26, 2019 (Actual)
Study Completion Date
August 26, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
Van Andel Research Institute, Astex Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Previously Treated Metastatic Colorectal Cancer
Keywords
SGI-110, irinotecan, regorafenib, methylation, colorectal, metastatic, TAS-102, lonsurf

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
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)
Allocation
Randomized
Enrollment
118 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Phase 1: Dose Escalation
Arm Type
Experimental
Arm Description
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 Title
Phase 2: Arm A SGI-110 + irinotecan
Arm Type
Experimental
Arm Description
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 Title
Phase 2: Arm B regorafenib or TAS-102
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
SGI-110 Dose Escalation
Other Intervention Name(s)
Guadecitabine
Intervention Description
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 Type
Drug
Intervention Name(s)
Regorafenib
Other Intervention Name(s)
Stivarga
Intervention Description
160 mg taken orally
Intervention Type
Drug
Intervention Name(s)
TAS-102
Other Intervention Name(s)
Lonsurf, trifluridine and tipiracil
Intervention Description
35 mg/m^2 taken orally
Intervention Type
Drug
Intervention Name(s)
SGI-110
Other Intervention Name(s)
Guadecitabine
Intervention Description
45 mg/m^2 administered as a subcutaneous injection
Intervention Type
Drug
Intervention Name(s)
Irinotecan
Other Intervention Name(s)
Camptosar
Intervention Description
125 mg/m^2 administered IV
Primary Outcome Measure Information:
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
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
Secondary Outcome Measure Information:
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nilo Azad, MD
Organizational Affiliation
SKCCC at JHMI
Official's Role
Principal Investigator
Facility Information:
Facility Name
USC / Norris Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Sidney Kimmel Comprehensive Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
VU Medisch Centrum
City
Amsterdam
ZIP/Postal Code
1081 HV
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28445481
Citation
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.
Results Reference
derived

Learn more about this trial

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

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