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

• 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: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Van Andel Research Institute; Astex Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information

• First Submitted Date: July 8, 2013
• First Posted Date: July 11, 2013
• Results First Submitted Date: August 24, 2020
• Results First Posted Date: September 14, 2020
• Last Update Posted Date: October 6, 2020
• Actual Study Start Date: October 23, 2013
• Actual Primary Completion Date: August 26, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 24, 2020)

• 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.
• 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.

Original Primary Outcome Measures (submitted: July 10, 2013)

• Phase 1/2: SGI-110 + irinotecan versus regorafenib adverse events [ Time Frame: 4 years ]
  In Phase 1, subjects will be assessed for adverse events attributable to SGI-110 and/or irinotecan. In Phase 2, subjects will be assessed for adverse events attributable to SGI-110 and/or irinotecan versus regorafenib.
• Phase 1/2: Response [ Time Frame: 4 ]
  Subjects will be monitored for response via RECIST 1.1 criteria.

Current Secondary Outcome Measures (submitted: August 24, 2020)

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

Original Secondary Outcome Measures (submitted: July 10, 2013)

Phase 1/2: survival [ Time Frame: 4 years ]

Subjects will be monitored for survival (overall survival versus progression free survival).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

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

• Condition: Previously Treated Metastatic Colorectal Cancer

Intervention

• 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
• 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

Study Arms

• 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.

  Intervention: Drug: SGI-110 Dose Escalation
• 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.

  Interventions:

  • Drug: SGI-110
  • Drug: Irinotecan
• 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.

  Interventions:

  • Drug: Regorafenib
  • Drug: TAS-102
  • Drug: SGI-110
  • Drug: Irinotecan

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 24, 2020): 118
• Original Estimated Enrollment (submitted: July 10, 2013): 108
• Actual Study Completion Date: August 26, 2019
• Actual Primary Completion Date: August 26, 2019 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands, United States

Administrative Information

• NCT Number: NCT01896856
• Other Study ID Numbers: J1369; NA_00085870 ( Other Identifier: JHMIRB )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Original Responsible Party: Same as current
• Current Study Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Original Study Sponsor: Same as current

Collaborators

• Van Andel Research Institute
• Astex Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Nilo Azad, MD; SKCCC at JHMI

• PRS Account: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Verification Date: August 2020