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

NCT01896856 | Completed Phase 1 Results DMC

• 2 other identifiers: J1369NA_00085870
• Study Type: interventional
• Target: 118
• Locations: 2 countries
• Sites: 4

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).

Conditions

Previously Treated Metastatic Colorectal Cancer

Keywords

SGI-110; irinotecan; regorafenib; methylation; colorectal; metastatic; TAS-102; lonsurf

Outcome Measures

Primary Outcomes (2)

• 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: 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.

  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 Outcomes (2)

• Overall Survival

  Up to 3 years

• Objective Response Rate

  Assessed until disease progression, up to 3 years

Study Arms (3)

Phase 1: Dose Escalation

EXPERIMENTAL

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

Phase 2: Arm A SGI-110 + irinotecan

EXPERIMENTAL

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; Drug: Irinotecan

Phase 2: Arm B regorafenib or TAS-102

ACTIVE COMPARATOR

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; Drug: TAS-102; Drug: SGI-110; Drug: Irinotecan

Interventions

SGI-110 Dose Escalation DRUG

* 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

Also known as: Guadecitabine

Phase 1: Dose Escalation

Regorafenib DRUG

160 mg taken orally

Also known as: Stivarga

Phase 2: Arm B regorafenib or TAS-102

TAS-102 DRUG

35 mg/m\^2 taken orally

Also known as: Lonsurf, trifluridine and tipiracil

Phase 2: Arm B regorafenib or TAS-102

SGI-110 DRUG

45 mg/m\^2 administered as a subcutaneous injection

Also known as: Guadecitabine

Phase 2: Arm A SGI-110 + irinotecan; Phase 2: Arm B regorafenib or TAS-102

Irinotecan DRUG

125 mg/m\^2 administered IV

Also known as: Camptosar

Phase 2: Arm A SGI-110 + irinotecan; Phase 2: Arm B regorafenib or TAS-102

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• Van Andel Research Institute: collaborator
• Astex Pharmaceuticals, Inc.: collaborator

Study Sites (4)

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Sidney Kimmel Comprehensive Cancer Center

Baltimore, Maryland, 21231, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

VU Medisch Centrum

Amsterdam, 1081 HV, Netherlands

Location

Related Publications (2)

• Lee V, Parkinson R, Zahurak M, Cope L, Cercek A, Verheul H, Gootjes E, Lenz HJ, Iqbal S, Jones P, Baylin S, Rami V, Ahuja N, El Khoueiry A, Azad NS. A phase II study of guadecitabine combined with irinotecan vs regorafenib or TAS-102 in irinotecan-refractory metastatic colorectal cancer patients. Int J Cancer. 2024 May 15;154(10):1794-1801. doi: 10.1002/ijc.34845. Epub 2024 Feb 5.

  PMID: 38312102 DERIVED

• 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.

  PMID: 28445481 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

guadecitabine; regorafenib; trifluridine tipiracil drug combination; Irinotecan

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Nilofer Azad
• Organization: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

nazad2@jhmi.edu

410-614-9169

Study Officials

• Nilo Azad, MD

  SKCCC at JHMI

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: In Phase 2, Arm B patients who have disease progression will be given the option to receive Arm A study drugs.

Study Record Dates

• First Submitted: July 8, 2013
• First Posted: July 11, 2013
• Study Start: October 23, 2013
• Primary Completion: August 26, 2019
• Study Completion: August 26, 2019
• Last Updated: October 6, 2020
• Results First Posted: September 14, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (3); NL (1)