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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01896856
Recruitment Status : Completed
First Posted : July 11, 2013
Results First Posted : September 14, 2020
Last Update Posted : October 6, 2020
Sponsor:
Collaborators:
Van Andel Research Institute
Astex Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
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.
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 : October 23, 2013
Actual Primary Completion Date : August 26, 2019
Actual Study Completion Date : August 26, 2019

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: 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 Name: Guadecitabine

Drug: Irinotecan
125 mg/m^2 administered IV
Other Name: 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 Name: 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 Name: Guadecitabine

Drug: Irinotecan
125 mg/m^2 administered IV
Other Name: Camptosar


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants Experiencing a Dose Limiting Toxicity [ Time Frame: 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:

    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.

  2. Progression Free Survival (PFS) [ Time Frame: 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 [ Time Frame: Up to 3 years ]
    Overall Survival is defined as the time (in months) between the start of treatment and death.

  2. Objective Response Rate [ Time Frame: 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
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01896856


Locations
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United States, California
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center
Baltimore, Maryland, United States, 21231
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Netherlands
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
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Principal Investigator: Nilo Azad, MD SKCCC at JHMI
  Study Documents (Full-Text)

Documents provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
Study Protocol and Statistical Analysis Plan  [PDF] February 5, 2020

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT01896856    
Other Study ID Numbers: J1369
NA_00085870 ( Other Identifier: JHMIRB )
First Posted: July 11, 2013    Key Record Dates
Results First Posted: September 14, 2020
Last Update Posted: October 6, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
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:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Trifluridine
 Irinotecan
Guadecitabine
Azacitidine
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Antimetabolites, Antineoplastic