| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously treated metastatic colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Previously treated metastatic colorectal cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10010030 |
| E.1.2 | Term | Colorectal cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 <18 years of age, children are excluded from this study but will be eligible for future pediatric trials.
5 Life expectancy of greater than 12 weeks.
6 ECOG performance status <1
7 Participants must have normal organ and marrow function as defined below:
• Leukocytes > 3,000/mcL
• Absolute neutrophil count > 1,500/mcL
• Platelets > 100,000/mcL
• total bilirubin < 1.5X institutional upper limit of normal
• AST (SGOT)/ALT (SGPT) </= 3.0 X institutional upper limit of normal
• creatinine < 1.5X institutional upper limit of normal or creatinine clearance > 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.
|
|
| E.4 | Principal 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. |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage I:
After treatment of up to 12 patients
Stage II:
After 12 months |
|
| E.5.2 | 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 test.
2. All patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data).
All subjects in the study will be included in the main analysis of the response rate. Patients in response categories 4-9 should be considered to have a treatment failure (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. Response rate will be estimated overall and by treatment arm. A Fisher’s Exact or chi square test will be use to compare response rates across treatment arms.
3. Standard life table methods will be used to analyze OS. Four month, 1-year and median survival will be reported, overall and by treatment arm. We acknowledge that OS assessment will be compromised with the cross-over design and will report as such.
4. Baseline global methylation will be categorized as high or low and OS Kaplan Meier curves plotted by category. The change in global methylation will be categorized as positive or negative and OS Kaplan Meier curves plotted by category. Similar analyses will be used for individual expression markers.
5. 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 and Irinotecan 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 changestoxicity and toxicity) will be assessed using appropriate non-parametric statistical tests.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Stage I:
Methylation:
Post treatment (21 days)
PK:
pre-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hr
Stage II:
PFS:
After 4 months
Response rate:
After 4 months and 12 months
Overall survival:
After 4 months and 12 months
Methylation:
Post treatment (21 days)
PK:
pre-dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hr |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
Print
