Circulating Cell-Free Tumor DNA Testing in Guiding Treatment for Patients With Advanced or Metastatic Colorectal Cancer

A Randomized Study Evaluating Tailoring of Advanced/Metastatic Colorectal Cancer (CRC) Therapy Using Circulating Cell-Free Tumor DNA (ctDNA) (TACT-D)

This phase II trial studies circulating cell-free tumor DNA testing to guide treatment with regorafenib or TAS-102 in patients with colorectal cancer that has spread to other areas of the body. Studying samples of blood from patients with colorectal cancer may help doctors understand how well patients respond to treatment. Regorafenib and TAS-102 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known how well ctDNA testing works in guiding treatment with regorafenib and TAS-102 for patients with advanced or metastatic colorectal cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Stage IV Colorectal Cancer AJCC v8; Stage IVA Colorectal Cancer AJCC v8; Stage IVB Colorectal Cancer AJCC v8; Stage IVC Colorectal Cancer AJCC v8; Stage III Colorectal Cancer AJCC v8; Stage IIIA Colorectal Cancer AJCC v8; Stage IIIB Colorectal Cancer AJCC v8; Stage IIIC Colorectal Cancer AJCC v8; Refractory Colorectal Carcinoma
• Intervention / Treatment: Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Other: Laboratory Procedure; Drug: Regorafenib; Drug: Trifluridine and Tipiracil Hydrochloride; Other: Best Practice

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the ability of early change in circulating tumor-derived deoxyribonucleic acid (ctDNA) (ctDNA-early dynamic changes [EDC] or A ctDNA) during systemic therapy in metastatic colorectal cancer (mCRC) to predict radiographic progression (only standard of care [SOC] arm).

II. To evaluate differences in clinically significant treatment-related adverse events (TRAEs) of interest (grade 3/4 toxicity per National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, intolerable grade 2 toxicity or any toxicity requiring dose reduction) between SOC and ctDNA arm.

SECONDARY OBJECTIVES:

I. To evaluate differences in patient-reported outcomes (PROs) between SOC and ctDNA arm.

II. To compare Response Evaluation Criteria in Solid Tumors (RECIST) duration of complete response (DCR) (partial response [PR] and stable disease [SD]) between SOC and ctDNA arm.

III. To evaluate differences in overall survival (OS) between SOC and ctDNA arm.

IV. To evaluate differences between SOC and ctDNA arm with regards to emergency severity indices (ESIs): Hospitalizations/emergency room visits.

V. To evaluate differences between SOC and ctDNA arm with regards to ESIs: Need for medical interventions (blood transfusions and intravenous [IV] hydration).

VI. To evaluate cost-effectiveness associated with both strategies, i.e. SOC strategy and ctDNA strategy in treatment of mCRC.

VII. To compare time to deterioration of Eastern Cooperative Oncology Group (ECOG) performance status (PS) between SOC and ctDNA arms.

VIII. To compare time to deterioration of PROs between SOC and ctDNA arms. IX. To evaluate differences in proportion of patients referred to clinical trial after completion of therapy between SOC and ctDNA arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo ctDNA testing and depending on the results receive either regorafenib orally (PO) on days 1-21, trifluridine and tipiracil hydrochloride (TAS-102) PO twice daily (BID) on days 1-5 and 8-12, or regorafenib PO on days 1-21 and TAS-102 PO BID on days 1-5 and 8-12. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive regorafenib or TAS-102 per standard of care. Treatment continues in the event of disease stability or regression as per discretion of treating physician or absence of disease progression.

After completion of study treatment, patients are followed up at 2 weeks and then monthly for up to 18 months.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kanwal Raghav; Phone Number: 713-792-2828; Email: kpraghav@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed colorectal cancer.
• Patients must have advanced or metastatic disease with no curative options.
• Patients must have radiographically evaluable disease.
• Patients must have had at least 2 prior therapies for mCRC (including fluorouracil [5-FU], oxaliplatin, irinotecan, bevacizumab; cetuximab/panitumumab [for RAS wild type (WT) patients]) and have either progressed on or intolerant to these agents or use of these agents is contraindicated.
• Patients must be clinically eligible for either regorafenib or TAS-102 as per their treating physician.
• Patients must have a negative serum pregnancy test done less than are equal to 14 days prior to randomization for women of childbearing potential only. 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.
• Patients must have ability to complete questionnaire(s) by themselves or with assistance.
• Patients must have ability to provide informed written consent.
• Patients must be willing to return to enrolling institution for follow-up as per study schedule.
• Patients must be willing to provide blood samples for correlative studies.
• Any of the following: Pregnant or nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.

Exclusion Criteria:

• Patient who have received prior TAS-102 are eligible to enroll on the study if they can receive regorafenib and vice-versa. Otherwise these patients will be excluded from the study.
• Congestive heart failure > New York Heart Association (NYHA) class 2, unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months) or myocardial infarction less than 3 months prior to randomization.
• Ongoing infection > grade 2 CTCAE version 4.0.
• Symptomatic metastatic brain or meningeal tumors unless the patient is > 3 months from definitive therapy, has a negative imaging study within 4 weeks of randomization and is clinically stable with respect to brain lesions at the time of randomization (Note: patient must not be undergoing acute steroid therapy or taper [chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies]).
• Renal failure requiring hematological or peritoneal dialysis.
• Patients unable to swallow oral medications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (ctDNA testing, regorafenib, TAS-102); Patients will receive either regorafenib by mouth on days 1-21 every 28 day cycle or TAS-102 by mouth twice daily on days 1-5 and 8-12 every 28 day cycle. Patients in this arm will get ctDNA testing and will continue treatment beyond 1st cycle depending on ctDNA results. Beyond that patients will continue treatment in the absence of disease progression or unacceptable toxicity.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies; Other: Laboratory Procedure; Undergo ctDNA testing; Other Names: Test; Lab Test; Lab Tests; Laboratory Test; Tests; Drug: Regorafenib; Given by mouth; Other Names: BAY 73-4506; Stivarga; Drug: Trifluridine and Tipiracil Hydrochloride; Given by mouth; Other Names: Lonsurf; TAS-102; TAS 102; Tipiracil Hydrochloride Mixture with Trifluridine; Trifluridine/Tipiracil; Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102
Active Comparator: Arm II (SOC); Patients will receive either regorafenib by mouth on days 1-21 every 28 day cycle or TAS-102 by mouth twice daily on days 1-5 and 8-12 every 28 day cycle as per standard of care. Patients in this arm will continue treatment in the absence of disease progression or unacceptable toxicity.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies; Drug: Regorafenib; Given by mouth; Other Names: BAY 73-4506; Stivarga; Drug: Trifluridine and Tipiracil Hydrochloride; Given by mouth; Other Names: Lonsurf; TAS-102; TAS 102; Tipiracil Hydrochloride Mixture with Trifluridine; Trifluridine/Tipiracil; Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102; Other: Best Practice; Receive SOC; Other Names: standard of care; standard therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early change in circulating tumor-derived deoxyribonucleic acid (DNA) (ctDNA) as a predictor of radiographic progression (Arm II-SOC)	Number of patients with rise in ctDNA level will be compared to Number of patients with progression of disease on scans.	First 4 months after treatment initiation
Treatment-related adverse events (TRAEs) of interest (grade 3/4 toxicity, intolerable grade 2 toxicity, or any toxicity requiring dose reduction) between arms	Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. To compare the proportions of patients who have experienced TRAEs of interest within the first 4 months between the two treatment arms, Fisher's exact test will be used.	First 4 months after treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean patient-reported outcomes (PROs) score as per MD Anderson Symptom Inventory (MDASI-GI)	Mean PROs scores measured by MDASI-GI scales will be compared between arms	Up to 18 months
Mean patient-reported outcomes (PROs) score as per PRO-CTCAE	Mean PROs scores measured by PRO-CTCAE scales will be compared between arms	Up to 18 months
Percentage of patients with partial response (PR)	Percentage of patients with PR will be compared between arms	Up to 18 months
Percentage of patients with stable disease (SD)	Percentage of patients with SD will be compared between arms	Up to 18 months
Overall survival (OS)	OS will be compared between arms.	Up to 18 months
Percentage of patients who present with events of special interest (ESIs)	Percentage of patients who present with ESIs [described as either Hospitalizations/emergency room visits or need for medical interventions (blood transfusions and IV hydration)] will be compared between arms	Up to 18 months
Cost measured in US dollars	Cost measured in US dollars will be compared between arms	Up to 18 months
Median time to performance status deterioration	Will be compared between arms.	Up to 18 months
Median time to PRO deterioration	Will be compared between arms.	Up to 18 months
Proportion of patients referred to clinical trial	Will be compared in both arms.	Up to 18 months

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Kanwal Raghav, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• M D Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2019
• Primary Completion (Estimated): August 31, 2024
• Study Completion (Estimated): August 31, 2024

Study Registration Dates

• First Submitted: February 1, 2019
• First Submitted That Met QC Criteria: February 15, 2019
• First Posted (Actual): February 18, 2019

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 17, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Trifluridine
• Other Study ID Numbers: 2018-0233 (Other Identifier: M D Anderson Cancer Center); NCI-2019-00246 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No