A Phase II Randomized Therapeutic Optimization Trial for Subjects With Refractory Metastatic Colorectal Cancer Using ctDNA: Rapid 1 Trial

This randomized, phase 2 study will investigate the use of the Signatera ctDNA assay versus the standard scan-based approach to guide treatment in patients with metastatic colorectal cancer. The aim of this study will be to measure and compare the overall survival, progression-free survival, and best overall response while on study of patients whose treatment has been guided by these two approaches.

Study Overview

• Status: Terminated
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Device: Signatera ctDNA assay; Drug: pre-specified sequence of FDA-approved drugs and drug combinations

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• A histologic confirmed adenocarcinoma of the colon or rectum with RECIST measurable metastatic disease measurable and not currently a candidate for oligometastatic definitive management
• Must have at least received first-line oxaliplatin-based therapy for metastatic disease, or a clinically acceptable and documented reason they did not, and progressed or were intolerant to the therapy. Individuals who recurred within 6 months of completion of oxaliplatin based adjuvant chemotherapy are also eligible. Subjects may enroll at any line of therapy past this first line so long as the patient's next clinically reasonable prescribed treatment would be Folfiri + Bevacizumab/biosimilar, Anti-EGFR therapy (with or without irinotecan), OR Lonsurf.
• Subjects must have tissue from either the primary and/or metastatic deposit available for submission at enrollment. Tissue can be from either a biopsy or resection surgery, whichever is most recent, but must be from the past five years.
• Subjects must have tissue and blood shipped to Natera no fewer than 10 days prior to starting treatment.
• Subjects must have had molecular profiling to determine tumor RAS, BRAF and MMR/MSI status
• Subjects with known or suspected Gilbert's disease must be formally tested for UGT1A1*28 with results available to study team prior to treatment initiation
• Any clinically relevant (as deemed by the PI) adverse events related to prior therapies must have resolved to Grade 1 or less (CTCAE 5.0) at study enrollment
• Age ≥18 years
• ECOG performance status of 0-2
• Life expectancy of at least 6 months

• Adequate organ function, as defined as:

  • Absolute neutrophil count (ANC) ≥ 1,500/µL
  • Hemoglobin ≥ 9g/dL
  • Platelets ≥ 100,000/µL
  • Total bilirubin ≤ 1.5 ULN or direct bilirubin ≤ 1 x ULN
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN; if liver metastases present, then AST and ALT must be ≤ 5 x ULN
  • Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 59 mL/min/1.73m using Cockcroft-Gault equation
• Subjects must not have more than one active malignancy at the time of enrollment (Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen [as determined by the treating physician and approved by the PI] may be included).
• Women of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 12 weeks after the end of protocol-specified treatment to minimize the risk of pregnancy.
• Males with female partners of child-bearing potential must agree to use physician-approved contraceptive methods throughout the study and should avoid conceiving children for 12 weeks following the last dose of the protocol-specified treatment.
• Written informed consent obtained from the subject and the subject agrees to comply with all the study related procedures

Exclusion Criteria:

• Colorectal cancer known to be Microsatellite High (MSI-H), deficient in DNA mismatch repair genes (dMMR), or BRAF (V600E) mutated
• Females or males of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 12 weeks after the last dose of the protocol-specified treatment
• Females who are pregnant or breastfeeding
• History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician
• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness
• Prior radiation therapy must have been completed 14 days prior to study entry
• Prior chemotherapy or biologic therapy must have been completed 21 days prior to study entry
• Known Dihydropyrimidine Dehydrogenase (DPD) deficiency

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: ctDNA assay-guided intervention; Subjects on this arm will be tested with the Signatera ctDNA assay while receiving treatment on a pre-specified sequence of FDA-approved drugs and drug combinations. Subjects will move through this sequence based on the results of the ctDNA assay. Subjects will move to a new drug or drug combination in the sequence when the ctDNA assay indicates a significant increase in ctDNA level. Subjects will also have imaging scans every 12 weeks while on each drug or drug combination and subjects will move to a new drug or drug combination if these scans indicate disease progression.	Device: Signatera ctDNA assay; Subjects will be tested with the Signatera ctDNA assay every 2 weeks.; Drug: pre-specified sequence of FDA-approved drugs and drug combinations; Subjects will receive treatment with a pre-specified sequence of FDA-approved drugs and drug combinations
Active Comparator: Scan-guided Intervention; Subjects on this arm will be treated with the same pre-specified sequence of FDA-approved drugs and drug combinations as those on the ctDNA assay- guided intervention arm. Subjects will move through the sequence based on the results of imaging scans, moving to a new drug or drug combination if imaging shows progressive disease.	Drug: pre-specified sequence of FDA-approved drugs and drug combinations; Subjects will receive treatment with a pre-specified sequence of FDA-approved drugs and drug combinations

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Determine the overall survival	580 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Treatment Response	Compare the proportion of subjects who receive ctDNA-guided treatment and scan-guided treatment that achieve each RECIST v1.1 response category (complete response, partial response, stable disease, and progressive disease) as their best response while on study treatment. Complete response is defined as the disappearance of all target lesions (any pathological lymph nodes must have reduction in short axis to <10 mm). Partial response is defined as least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of 1 or more new lesions is also considered progression. Stable disease is defined as either sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.	1 year
Progression-free Survival	Determine progression-free survival	6 months

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Natera, Inc.
• Investigators: Principal Investigator: Sherise Rogers, MD, University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2022
• Primary Completion (Actual): March 19, 2024
• Study Completion (Actual): March 19, 2024

Study Registration Dates

• First Submitted: March 4, 2021
• First Submitted That Met QC Criteria: March 4, 2021
• First Posted (Actual): March 8, 2021

Study Record Updates

• Last Update Posted (Estimated): July 1, 2025
• Last Update Submitted That Met QC Criteria: June 26, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: metastatic colorectal cancer; ctDNA; personalized medicine; precision oncology
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms
• Other Study ID Numbers: UF-STO-GI-012 (Other Identifier: University of Florida); IRB202100341 (Other Identifier: University of Florida); OCR40199 (Other Identifier: University of Florida)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No