Clinical trial NCT04259944: Post-surgical Liquid Biopsy-guided Treatment of Stage III and High-risk Stage II Colon Cancer Patients: the PEGASUS Trial
Official title: Post-surgical Liquid Biopsy-guided Treatment of Stage III and High-risk Stage II Colon Cancer Patients: the PEGASUS Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Colon Cancer
Keywords: liquid biopsy
colon cancer
adjuvant treatment
ctDNA
colorectal cancer
CAPOX
FOLFIRI
CAPE
Lead sponsor: IFOM ETS - The AIRC Institute of Molecular Oncology
Sponsor class: OTHER
Collaborators: name: Guardant Health, Inc.
First posted: 2020-02-07
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: PEGASUS is a prospective multi-centric study designed to prove the feasibility of using liquid biopsy to guide the post-surgical and post-adjuvant clinical management in 140 microsatellite stable Stage-III and T4N0 Stage-II colon cancer patients.

Detailed description: The LUNAR1 Test (Guardant Health, Redwood City, CA, USA) will be used for ctDNA determination. For the efficacy analysis, the PEGASUS cohort will be compared with a cohort of 420 patients from the TOSCA trial (NCT00646607) population matched 3:1 for all known prognostic phenotypes.

A post-surgical LB executed 2-4 weeks after surgery will guide a "Molecular Adjuvant" treatment as follows: i) ctDNA+ patients will receive CAPOX for 3 months; ii) ctDNA- patients will receive capecitabine (CAPE) for 6 months but will be retested after 1 cycle, and if found ctDNA+ will be switched to CAPOX treatment.

Immediately after the end of the "Molecular Adjuvant" treatment a further LB will be performed and instruct subsequent treatment. Positive patients (ctDNA+/+ and ctDNA-/+) will receive an up-scaled "Molecular Metastatic" systemic treatment for 6 months or until radiological progression or toxicity as follows: i) ctDNA+/+ patients will be treated with FOLFIRI; ii) ctDNA-/+ patients with CAPOX. These patients will be subjected to a LB after 3 months at the end of treatment and in case of positivity will be switched to FOLFIRI.

Patients experiencing ctDNA conversion to negative (ctDNA+/-) will receive a de-escalated treatment with CAPE for 3 months. 3 LB will be performed within 3 months and in case of positivity the patient will be switched to FOLFIRI. Patients with ctDNA-/- will be subjected to an interventional follow-up comprising 2 further LB and in case of positivity they will be switched to CAPOX treatment. PEGASUS is piggybacked to AlfaOmega (NCT04120935), a Master Observational Protocol that will follow patients from diagnosis to 5 years or recurrence/death (whichever comes first), collecting clinical data, radio-images and biological samples. AlfaOmega provides a clinical and logistic ecosystem for the seamless integration of PEGASUS clinical results with the biological underpinning of colon cancer.

Eligibility criteria: Inclusion Criteria:

* Pegasus trial written informed consent.
* Age ≥ 18 years.
* Histologically confirmed diagnosis of operable stage III or T4N0 stage II colon cancer located 12 cm from the anal verge by endoscopy and above the peritoneal reflection at surgery.
* Availability of plasma collected prior to surgery.
* Availability of the original FFPE tumor tissue.
* Acceptance to undergo at least all the interventional liquid biopsies.
* ECOG performance status 0-1.
* Normal organ functions. (as defined in section 9.3)
* Women with childbearing potential should complete a pregnancy test and be willing to use highly effective contraceptive methods.

Exclusion Criteria:- Patients having a MSI-H/MMRd tumor are excluded from the study (done according to standard clinical practice).

* History of another neoplastic disease, unless in remission for ≥ 5 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
* Had an incomplete diagnostic colonoscopy and/or polyps removal.
* Macroscopic or microscopic evidence of residual tumor (R1 or R2 resections). Patients should never have had any evidence of metastatic disease (including presence of tumor cells in the peritoneal lavage).
* Current or recent treatment with another investigational drug or participation in another investigational study
* Patient unable to comply with the study protocol owing to psychological, social or geographical reasons.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
* Inadequate contraception (male or female patients) if of childbearing or procreational potential.
* Clinically relevant cardiovascular disease.
* Acute or subacute intestinal occlusion or history of inflammatory bowel disease.
* Pre-existing neuropathy \> grade 1. Known grade 3 or 4 allergic reaction to any of the components of the treatment.
* Has a known DPD (DihydroPyrimidine Dehydrogenase) deficiency.
* Has a known Gilbert Syndrome or UGT1A1 homozygous \*28/\*28 germline variant.
* Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required.
* Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
* Has a known history of active TB (Bacillus Tuberculosis).

Primary outcomes:
measure: Number of post-surgery and post-adjuvant false negative cases after a double ctDNA-negative detection
timeFrame: 2 years
Secondary outcomes:
measure: Disease-Free Survival (DFS)
timeFrame: 2 & 3 years
measure: Overall Survival (OS)
timeFrame: 5 years
measure: Safety and tolerability according to CTCAE version 5.0
timeFrame: 2 years
measure: Assessment of QLQ-C30 and CR-29 EORTC questionnaires
timeFrame: 2 years
measure: Number of patients experiencing ctDNA seroconversion (i.e. ctDNA+ that become ctDNA-) after any chemotherapy regimen remaining disease free
timeFrame: 2 & 3 years
Other outcomes:
Locations:
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino IRCCS
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Milan
country: Italy
facility: Istituto Europeo di Oncologia IRCCS
city: Milan
country: Italy
facility: Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda
city: Padova
country: Italy
facility: Istituto Oncologico Veneto IRCCS
city: Perugia
country: Italy
facility: Ospedale Santa Maria della Misericordia
city: Ravenna
country: Italy
facility: AULS della Romagna
city: Sant Joan Despí
country: Spain
facility: Hospital Moises Broggi
state: Barcelona
city: Barcelona
country: Spain
facility: University Hospital del Mar
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology
city: Valencia
country: Spain
facility: INCLIVA Biomedical Research Institute
Study officials:
affiliation: Istituto Oncologico Veneto IRCCS
name: Sara Lonardi, MD
role: STUDY_CHAIR
References: