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OPTIMISE: Optimization of treatment selection and follow-up in oligometastatic colorectal cancer – a ctDNA-guided phase II randomized approach with a run-in feasibility part
Background
Patients with detectable circulating tumor DNA (ctDNA) after surgery for colorectal cancer are considered to have microscopic residual disease and consequently a high risk of recurrence. The same applies to patients after local ablative treatment (LAT) for metastatic colorectal cancer (mCRC). We observed a temporal clearance of ctDNA during adjuvant chemotherapy, but ctDNA recurrence after therapy termination. This indicate that patients with ctDNA positive status may need more intensified adjuvant chemotherapy than standard of care (SOC). In OPTIMISE we investigate the use of ctDNA for treatment decisions on adjuvant chemotherapy after LAT for mCRC. We hypothesis that recurrence can be prevented with intensified adjuvant chemotherapy in patients with ctDNA positive blood samples post ablations, and that patients without detectable ctDNA have undergone successful radical treatment and will not need adjuvant chemotherapy.
Trial design
OPTIMISE is an open label 1:1 randomized multicentre, phase II study, comparing ctDNA guided adjuvant chemotherapy against standard of care (SOC) approach, with a run-in phase investigating feasibility measures. Eligibility criteria comprise, Radical intended treatment for metastatic spread from CRC (resection, radiofrequency ablation, stereotactic body radiation therapy, or other experimental local treatment), No evidence of further disease according to SOC, Age ≥ 18 years, ECOG performance status 0-2, Clinically eligible for adjuvant triple chemotherapy at investigators decision, Adequate bone marrow function allowing systemic chemotherapy, Anticonception for fertile women and for the male patients with a fertile partner, Written and verbally informed consent. Exclusion criteria are, Neuropathy CTCAE grade > 1, Other malignant tumour within 5 year except non-melanoma skin cancer or carcinoma in situ cervicis uteri, Pregnant or breastfeeding women, Intolerance or allergy to 5-FU, leucovorin, oxaliplatin, irinotecan or capecitabin Before randomization participants undergo a PET-CT scan to exclude metabolically detectable lesions. In ARM A patients are treated according to SOC, and blood samples collected for later retrospective ctDNA analysis. In ARM B, patients follow a ctDNA-guided strategy; ctDNA positivity lead to escalation strategy with 4 months of FOLFOXIRI followed by 2 months of 5-FU, ctDNA negative status to de-escalation strategy by shared decision-making. Endpoints Primary endpoint; fraction of patients alive without recurrence 2 years after inclusion. Secondary endpoints; CTCAE grade 3-5 toxicity, ctDNA negativity (6 months + 1 year), Time to molecular -biological and radiological recurrence, Rate of local and distant relapse, Overall survival, QoL and Cost-effectiveness. Laboratory methods. Blood samples are collected in streck-tubes and analysed for tumor specific mutations and methylations by multiplex ddPCRs in two Danish laboratories (with tumor-agnostic approach). Sample size is 350 but will be revised based on findings in the run-in phase. Feasibility measures for the run-in phase are: Inclusion of 30 patients over 12 months in two Danish Hospitals, Compliance with randomization > 80%, Rate of unexpected PET-CT positive cases 20%, Eligibility for triple chemotherapy > 80%. The study is including.
Clinical trial identification
NCT04680260.
Legal entity responsible for the study
Sponsors.
Funding
OPTIMISE is a researcher-initiated study and administered trial. The study is supported by The Danish Comprehensive Cancer Center Danish Research Center for Circulating Tumour DNA-guided Cancer Management, Danish Cancer Society (grant no. R257-A14700), Danish Cancer Society (grant no. R269-A15652) and foundation of Central Denmark Region (grant no. A1602). The investigators have no financial relation to the grant provider nor any financial interest in the project.
Disclosures
L. Jensen: Research grant / Funding (institution): Clinical trial, MSD, Clinical trial, BMS, Clinical trial, INCYTE. All other authors have declared no conflicts of interest.
