Study of ctDNA Guided Change in Tx for Refractory Minimal Residual Disease in Colon Adenocarcinomas

Study Overview
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Brief Summary
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This is a phase 1b, prospective, single arm, non-randomized, open-label clinical trial determining the efficacy of adjuvant trifluridine and tipiracil (TAS-102) in combination with irinotecan in patients with ctDNA positive colon adenocarcinoma.

Detailed Description
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Treatment on study will be administered in 14 day cycles.

Official Title
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Proof of Concept Study of ctDNA Guided Change in Treatment for Refractory Minimal Residual Disease in Colon Adenocarcinomas

Conditions
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Colon Adenocarcinoma, Colorectal Cancer

Intervention / Treatment
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* Drug: TAS-102
* Drug: Irinotecan
* Combination Product: Standard Treatment
* Diagnostic Test: Signatera MRD ctDNA Assay


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed adenocarcinoma of the colon (high rectal cancer is eligible if resected and no radiation needed). Other histologies which are treated per NCCN guidelines for adjuvant colon cancer are eligible. Must have Stage II, Stage III, or Stage IV colorectal cancer after curative intent resection eligible for adjuvant doublet chemotherapy for at least 3 months. Must have ctDNA positive assay (tested by Signatera MRD assay) after at least 3 months of perioperative chemotherapy Age ≥ 18 years Performance status: ECOG performance status ≤2 Life expectancy of greater than 3 months Adequate organ and marrow function as defined below: leukocytesL ≥ 3,000/mcL absolute neutrophil count: ≥ 1,500/mcL platelets: ≥ 80,000/mcl total bilirubin: within normal institutional limits AST(SGOT)/ALT(SPGT): ≤ 3 X institutional upper limit of normal or ≤ 5 X if liver metastases are present creatinine: <1.5 X ULN The effects of TAS-102 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because topoisomerase inhibitors 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, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. a. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Ability to swallow tablets Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria: Patients who have had major surgery within 4 weeks, or chemotherapy or radiotherapy within 2 weeks prior to Cycle 1 Day 1 All toxicities attributed to prior anti-cancer therapy other than alopecia must have resolved to grade 1 or baseline Patients may not be receiving any other investigational agents. Patients with known metastases. History of allergic reactions attributed to compounds of similar chemical or biologic composition to TAS-102, irinotecan or other agents used in study. 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. Prior treatment with irinotecan or TAS-102. History of another primary cancer within the last 3 years with the exception of non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical carcinoma in-situ. Inability to comply with study and follow-up procedures as judged by the Investigator Patients who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants. -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TASIRI<br>Patients randomized to the experimental arm (TASIRI) will be treated with TAS-102 25mg/m2 p.o. on days 1-5 and irinotecan 180mg/m2 i.v. on day 1 every 14 days. If ANC <1500/uL on day 1 of a cycle, then G-CSF will be added on day 6 for three days. | Drug: TAS-102<br>* Given PO<br>* Other names: trifluoridine and tipiracil;Drug: Irinotecan<br>* Given IV<br>* Other names: CPT-11;Combination Product: Standard Treatment<br>* 6 cycles for a 2-week regimen (infusional 5FU based) and up to 4 cycles for a 3-week regimen (oral capecitabine based) after randomization<br>Diagnostic Test: Signatera MRD ctDNA Assay<br>* To be performed within 6-8 weeks of Cycle 1 Day 1. A Mid-treatment ctDNA is to be completed within 6 - 8 weeks of starting treatment. ctDNA is to also be completed within four weeks after completion of study treatment (+/- two weeks)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of ctDNA positivity in treatment cohort after 6 cycles or at least 3 months of adjuvant treatment | Percent of patients positive for ctDNA after 6 cycles or at least 3 months months after starting adjuvant treatment will be used to estimate the efficacy of adjuvant trifluridine and tipiracil (TAS102) in combination with irinotecan in patients with ctDNA positive colon adenocarcinoma. The Signatera MRD ctDNA Assay will be used to measure ctDNA positivity. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Grade 3-5 Adverse Events | To evaluate the tolerability of drug-related grade 3-5 adverse events in patients with ctDNA positive colon adenocarcinoma. Toxicity and adverse events are based on the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0. | 8 weeks |