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Post-surgical Liquid Biopsy-guided Treatment of Stage III and High-risk Stage II Colon Cancer Patients: the PEGASUS Trial

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ClinicalTrials.gov Identifier: NCT04259944
Recruitment Status : Recruiting
First Posted : February 7, 2020
Last Update Posted : October 6, 2020
Sponsor:
Collaborator:
Guardant Health, Inc.
Information provided by (Responsible Party):
IFOM, The FIRC Institute of Molecular Oncology

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.

Condition or disease Intervention/treatment Phase
Colon Cancer Drug: CAPOX Drug: Capecitabine Drug: FOLFIRI Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Post-surgical Liquid Biopsy-guided Treatment of Stage III and High-risk Stage II Colon Cancer Patients
Actual Study Start Date : June 16, 2020
Estimated Primary Completion Date : September 30, 2023
Estimated Study Completion Date : December 15, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Biopsy

Arm Intervention/treatment
Experimental: Liquid Biopsy-Guided Adjuvant Treatment

A post-surgical LB executed 2-4 weeks after surgery will guide a "Molecular Adjuvant" treatment:

  • ctDNA+ patients: CAPOX for 3 months
  • ctDNA- patients: capecitabine (CAPE) for 6 months. LB after 1 cycle and if found ctDNA+ will be switched to CAPOX.

A post-Molecular Adjuvant treatment LB will be performed and instruct subsequent treatment:

  • ctDNA+/+ patients: up-scale to a "Molecular Metastatic" treatment with FOLFIRI for 6 months or until radiological progression or toxicity;
  • ctDNA-/+ patients: up-scale to a "Molecular Metastatic" treatment with CAPOX for 6 months or until radiological progression or toxicity. LB after 3 months at the end of treatment and in case of positivity switch to FOLFIRI.
  • ctDNA+/- patients: de-escalate treatment to CAPE for 3 months. 3 LB performed within 3 months and in case of positivity switch to FOLFIRI.
  • ctDNA-/- patients: interventional follow-up comprising 2 further LB and in case of positivity switch to CAPOX treatment.
Drug: CAPOX

DAY 1

  • OXA 130 mg/m2 administered as intravenous infusion over 2 hours in 250 mL dextrose 5%
  • CAPE 1000 mg/m2 administrated per os twice daily

DAY 2-14

• CAPE 1000 mg/m2 os twice daily

Cycle length is 3 weeks comprising 2 hours of oxaliplatin infusion every 21 days, 14 days of oral capecitabine and 7 days of resting.


Drug: Capecitabine

DAY 1-14

• CAPE 1250 mg/m2 os twice daily

Cycle length is 3 weeks comprising 14 days of oral capecitabine and 7 days of resting.


Drug: FOLFIRI

Day 1:

  • IRI, 180 mg/m2 administered as iv infusion over 30-90 minutes in 250 mL dextrose 5%, concurrently (via a Y-connector) with
  • LV, 400 mg/m2 administered as an iv infusion over 2 hours, in 250 mL dextrose 5%, followed by
  • 5-FU, 400 mg/m2 administered as a bolus injection (iv push administered by hand) and then at 2400 mg/m2 administered as a iv infusion over 46 hours.

Cycle length is 2 weeks comprising approximately 48 hours of infusion and 12 days of rest.





Primary Outcome Measures :
  1. Number of post-surgery and post-adjuvant false negative cases after a double ctDNA-negative detection [ Time Frame: 2 years ]
    Cases that become positive at subsequent interventional LB or that experience radiological relapse


Secondary Outcome Measures :
  1. Disease-Free Survival (DFS) [ Time Frame: 2 & 3 years ]
  2. Overall Survival (OS) [ Time Frame: 5 years ]
  3. Safety and tolerability according to CTCAE version 5.0 [ Time Frame: 2 years ]
  4. Assessment of QLQ-C30 and CR-29 EORTC questionnaires [ Time Frame: 2 years ]
  5. Number of patients experiencing ctDNA seroconversion (i.e. ctDNA+ that become ctDNA-) after any chemotherapy regimen remaining disease free [ Time Frame: 2 & 3 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04259944


Contacts
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Contact: Silvia Marsoni, MD +3902574303862 silvia.marsoni@ifom.eu
Contact: Paolo Luraghi, PhD clinical.trials@ifom.eu

Locations
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Italy
ASST Papa Giovanni XXIII Not yet recruiting
Bergamo, Italy
Principal Investigator: Stefania Mosconi, MD         
Ospedale Policlinico San Martino IRCCS Recruiting
Genova, Italy
Principal Investigator: Stefania Sciallero, MD         
Fondazione IRCCS Istituto Nazionale dei Tumori Recruiting
Milan, Italy
Principal Investigator: Filippo Pietrantonio, MD         
Istituto Europeo di Oncologia IRCCS Not yet recruiting
Milan, Italy
Principal Investigator: Maria Giulia Zampino, MD         
Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda Recruiting
Milan, Italy
Principal Investigator: Andrea Sartore-Bianchi, MD         
Istituto Oncologico Veneto IRCCS Recruiting
Padova, Italy
Principal Investigator: Sara Lonardi, MD         
Spain
University Hospital del Mar Recruiting
Barcelona, Spain
Principal Investigator: Clara Montagut, MD         
Vall d'Hebron Institute of Oncology Recruiting
Barcelona, Spain
Principal Investigator: Josep Tabernero, MD         
Principal Investigator: Elena Elez, MD         
INCLIVA Biomedical Research Institute Recruiting
Valencia, Spain
Principal Investigator: Andres Cervantes, MD         
Sponsors and Collaborators
IFOM, The FIRC Institute of Molecular Oncology
Guardant Health, Inc.
Investigators
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Study Chair: Sara Lonardi, MD Istituto Oncologico Veneto IRCCS
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Responsible Party: IFOM, The FIRC Institute of Molecular Oncology
ClinicalTrials.gov Identifier: NCT04259944    
Other Study ID Numbers: IFOM-CPT005/2019/PO004
2019-002074-32 ( EudraCT Number )
First Posted: February 7, 2020    Key Record Dates
Last Update Posted: October 6, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by IFOM, The FIRC Institute of Molecular Oncology:
liquid biopsy
colon cancer
adjuvant treatment
ctDNA
Additional relevant MeSH terms:
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Colonic Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Capecitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents