Previously treated metastatic colorectal cancer MedDRA version: 19.0 Level: PT Classification code 10010030 Term: Colorectal cancer recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: SGI-110
Pharmaceutical Form: Lyophilisate and solvent for solution for injection
INN or Proposed INN: SGI-110
Current Sponsor code: SGI-110
Concentration unit: mg milligram(s)
Concentrat
Sponsors
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1 Participants must have histologically or cytologically confirmed adenocarcinoma of the colon or rectum 1.1 Patients in the phase I cohort must have biopsiable disease and be amenable to having two research biopsies 1.2 Archival tissue must be procured if available 2 Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan. See section 10 for the evaluation of measureable disease. 3 3.1.6 Patients in the phase II cohort must have progressed while receiving irinotecan therapy in the metastatic setting. There are no limitations on number of prior therapies in the metastatic setting. 4 Age minimum of 18 years. Because no dosing or adverse event data are currently available on the use of SGI-110 in participants 3,000/mcL • Absolute neutrophil count > 1,500/mcL • Platelets > 100,000/mcL • total bilirubin 50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal 8 The effects of SGI-110 on the developing human fetus are unknown. For this reason and because oncological agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. 9 Ability to understand and the willingness to sign a written informed consent document. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 9 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 9
Exclusion criteria
Exclusion criteria: 1 Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. 2 Participants may not be receiving any other study agents. 3 Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. 4 History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, decitabine or SGI-110. 5 Subjects who have received prior therapy with any hypomethylating agents. 6 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. 7 Pregnant women are excluded from this study because SGI-110 is a/an hypomethylating agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with SGI-110, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. 8 Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years; or individuals with another malignancy that are deemed by the investigator to be at low risk for clinically meaningful recurrence (ex cervical cancer in situ, definitively treated early stage prostate cancer (confined to prostate with Gleason 6 or below), efinitely treted breast ductal or lobular carcinoma in situ, basal cell or squamous cell carcinoma of the skin.) 9 HIV-positive individuals on combination antiretroviral therapy are ineligible, as these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated. 10 Previous treatment with regorafenib AND TAS-102 (This applies to phase II only. If patients have previously received either regorafenib OR TAS-102, they must b able to receive the alternate regimen if randomized to the standard of care arm) 11. Hospitalization for an acute medical issue within 4 weeks prior to screening visit that would otherwise not be managed in an infusion center or outpatient clinic setting (e.g., a patient admitted to complete a transfusion would not be ineligible.). 12 Symptomatic bowel obstruction within 6 months prior to enrollment. Patinets who undergo surgical correction of obstructing lesion will be eligible within 6 months.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I Component: Stage I --To assess safety and tolerability of combination SGI-110 + irinotecan in colon cancer patients --To determine the phase II dose of the combination of SGI-110 + irinotecan Phase II Component: Stage II --To improve median progression-free survival from that reported with regorafenib and TAS-102 to 4 months for SGI-110+irinotecan in previously treated metastatic colon cancer patients who have progressed on irinotecan.;Secondary Objective: Phase I Component: Stage I --To assess changes in global methylation and expression at the tumor level with SGI-110 and irinotecan treatment --To assess for pharmacokinetic interactions of SGI-110 and irinotecan--To assess for correlation between disease response and drug exposure Phase II Component: Stage II --To evaluate response rate as determined by RECIST criteria 1.1 --To evaluate concurrent SGI-110+irinotecan treatment versus regorafenib alone --To improve median overall survival from historical rate of 6.4 months --To assess for potential predictive biomarkers of response and survival using baseline tissue ;Primary end point(s): Stage I: Determination of the preferred dose of SGI-110, 30 mg/m2, 45 mg/m2 or 60 mg/m2, in combination with Irinotecan. The number of dose-limiting toxicities at each dose level will be reported. Additional toxicity frequencies by type and grade will be summarized by dose level for all doses. Stage II: Evaluate the progression free survival (PFS) in patients receiving combination SGI-110 plus Irinotecan compared to standard of care treatment with regorafenib. Events are defined as disease progression or death from any cause. All patients treated on protocol will be included in the determination of PFS, regardless of treatment modification or discontinuation.;Timepoint(s) of evaluation of this end point: Stage I: After treatment of up to 12 patients Stage II: After 12 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Stage I 1) The design of this study will allow assessment of global and candidate gene methylation differences at the tumor level. We hypothesize that Irinotecan resistance may be reversed with the use of the demethylating SGI-110 therapy. Changes in global methylation by LINE-1 will be assessed in post-treatment biopsy specimens in the dose escalation cohort for proof of the effect of SGI-110. Changes will be plotted by dose level and overall using boxplots of the log transformed raw data. A paired t-test, or the nonparametric Wilcoxon signed rank test, will be used to test if the changes are significantly different from zero. Similar analyses will be used to assess gene expression changes in WRN, DR1, TPAF2E, DEXI, BNIP3, and MED1. 2) Pharmacokinetic (PK) sampling studies are proposed for all participating patients who undergo pharmacodynamic endpoints. Single dose PK samples will be collected on Cycle1, Day 1, at the following time points: pre-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hr. The following PK parameters describing the concentration time profile of SGI-110 will be calculated: total exposure will be calculated as area under the plasma concentration-time curve (AUC) using the linear trapezoidal rule by using noncompartmental methods (Winonlin, version 5.3) and/or compartmental modeling (Adapt II, release 4.0). Other parameters such as maximum concentration (Cmax), time to maximal concentration (Tmax) and half life (T1/2) will also be calculated. Cmax and Tmax will be obtained from the data, while the half-life will be calculated as 0.693/k, where k is the slope of terminal elimination phase. Associations between SGI-110 exposure parameters (Cmax and AUC) and pharmacodynamic endpoints (i.e., global methylation changes and toxicity) will be assessed using appropriate non-parametric statistical tests. Stage II 1. The 4-month PFS will be compared between arms of the study using a one-sided, 0.05 alpha level, log-rank | — |
Countries
Netherlands, United States
Contacts
Public ContactTrial Office Medical Oncology VUMC
VU University Medical Centre
Outcome results
None listed