Metastatic Colorectal Cancer
Conditions
Keywords
metastatic colorectal cancer, precision oncology, personalized medicine, ctDNA
Brief summary
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.
Interventions
DEVICESignatera ctDNA assay
Subjects will be tested with the Signatera ctDNA assay every 2 weeks.
DRUGpre-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
Sponsors
Natera, Inc.
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 580 days | Determine the overall survival |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Treatment Response | 1 year | 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. |
| Progression-free Survival | 6 months | Determine progression-free survival |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 1 |
| 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. | 3 |
| Arm Not Assigned Subjects in this group were not assigned to an arm due to going on study, but were not randomized to either protocol arm due to withdrawal from the study prior to randomization. | 2 |
| Total | 6 |
Baseline characteristics
| Characteristic | Scan-guided Intervention | Arm Not Assigned | Total | ctDNA Assay-guided Intervention |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 5 Participants | 1 Participants |
| Age, Continuous | 63 years | 55.5 years | 57.83 years | 47 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 1 Participants | 3 Participants | 0 Participants |
| Region of Enrollment United States | 3 participants | 2 participants | 6 participants | 1 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 4 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 3 / 3 |
| other Total, other adverse events | 1 / 1 | 3 / 3 |
| serious Total, serious adverse events | 1 / 1 | 2 / 3 |
Outcome results
Primary
Overall Survival
Determine the overall survival
Time frame: 580 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ctDNA Assay-guided Intervention | Overall Survival | 0 Participants |
| Scan-guided Intervention | Overall Survival | 0 Participants |
Secondary
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.
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ctDNA Assay-guided Intervention | Best Overall Treatment Response | Progressive disease | 1 Participants |
| ctDNA Assay-guided Intervention | Best Overall Treatment Response | Stable disease | 0 Participants |
| ctDNA Assay-guided Intervention | Best Overall Treatment Response | Partial response | 0 Participants |
| ctDNA Assay-guided Intervention | Best Overall Treatment Response | Complete response | 0 Participants |
| Scan-guided Intervention | Best Overall Treatment Response | Complete response | 0 Participants |
| Scan-guided Intervention | Best Overall Treatment Response | Progressive disease | 3 Participants |
| Scan-guided Intervention | Best Overall Treatment Response | Partial response | 0 Participants |
| Scan-guided Intervention | Best Overall Treatment Response | Stable disease | 0 Participants |
Secondary
Progression-free Survival
Determine progression-free survival
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ctDNA Assay-guided Intervention | Progression-free Survival | 0 Participants |
| Scan-guided Intervention | Progression-free Survival | 0 Participants |