Exploiting Circulating Tumour DNA to Intensify the Postoperative Treatment Resected Colon Cancer Patients

NCT05062889 | Suspended Phase 2

• 1 other identifier: ERASE-CRC
• Study Type: interventional
• Target: 477
• Locations: 1 country
• Sites: 28

Brief Summary

The aims of this study are to evaluate if an intensified adjuvant treatment with FOLFOXIRI could increase the rate of cases with undetectable ct-DNA after chemotherapy and to evaluate if a further adjuvant treatment with Trifluridine/Tipiracil could increase the rate of cases with undetectable ct-DNA and therefore improve DFS in a population at high-risk of relapse. An additional target-driven cohort of HER2+ RAS wild-type colon cancer patients will be assessed for ct-DNA clearance after a tailored treatment with Trastuzumab and Tucatinib plus FOLFOX

Conditions

HER2-positive Colon Cancer; RAS Wild-type Colon Cancer; Stage II Colon Cancer; Stage III Colon Cancer

Keywords

Circulating tumor DNA; FOLFOX; CAPOX; FOLFOXIRI; Trifluridine/Tipiracil; Trastuzumab; Tucatinib

Outcome Measures

Primary Outcomes (3)

• ct-DNA clearance rate after the end of the adjuvant treatment (ERASE-CRC part 1)

  Percentage of patients, relative to the total of enrolled subjects in the Part 1 of the study with undetectable ct-DNA at the end of adjuvant treatment.

  6 months from the enrollment of the last patient in the adjuvant treatment

• ct-DNA clearance rate after the end of post-adjuvant treatment (ERASE-CRC part 2)

  Percentage of patients, relative to the total of enrolled subjects in the Part 2 of the study with undetectable ct-DNA at the end of post-adjuvant treatment.

  6 months from the enrollment of the last patient in post-adjuvant treatment

• ct-DNA clearance rate after the end of target-driven adjuvant treatment (ERASE-CRC part 1 target-driven)

  Percentage of patients, relative to the total of enrolled subjects in the target-driven part 1 of the study with undetectable ct-DNA at the end of adjuvant treatment.

  6 months from the enrollment of the last patient in the target-driven adjuvant treatment

Secondary Outcomes (12)

• Overall Toxicity Rate 1

  30 days from the last dose of the last patient in adjuvant treatment

• Toxicity Rate 1

  30 days from the last dose of the last patient in adjuvant treatment

• Disease Free Survival 1 (DFS1)

  60 months after the randomization of first patient in adjuvant treatment

• Overall Survival 1 (OS1)

  60 months after the randomization of first patient in adjuvant treatment

• Overall Toxicity Rate 2

  30 days from the last dose of TRIFLURIDINE/TIPIRACIL

Study Arms (5)

Arm B FOLFOXIRI, part 1 (adjuvant)

EXPERIMENTAL

FOLFOXIRI Irinotecan 165 mg/sqm iv over 60 minutes day 1, followed by Oxaliplatin 85 mg/sqm iv over 2 hours day 1, in two-way with L-Leucovorin 200 mg/sqm iv over 2 hours, day 1 followed by 5-fluoruracil 3200 mg/sqm 48 h-continuous infusion, starting on day 1; to be repeated every 2 weeks for a maximum of 12 cycles. In the case of oxaliplatin and/or irinotecan interruption because of adverse events, patient's refusal or investigator's choice, the continuation of the other drugs until 12 cycles is recommended.

Drug: 5-Fluorouracil continuous infusion FOLFOXIRI schedule; Drug: Oxaliplatin FOLFOX and FOLFOXIRI schedule; Drug: L-Leucovorin; Drug: Irinotecan

Arm A mFOLFOX6 or CAPOX (at investigator's choice), part 1 (adjuvant)

ACTIVE COMPARATOR

mFOLFOX6 Oxaliplatin 85 mg/sqm iv over 2 hours, day 1 in two-way with L-Leucovorin 200 mg/sqm iv over 2 hours, day 1 followed by 5-fluorouracil 400 mg/sqm iv bolus, day 1 followed by 5-fluoruracil 2400 mg/sqm 48 h-continuous infusion, starting on day 1; to be repeated every 2 weeks for a maximum of 12 cycles. The continuation of 5FU/leucovorin until 12 cycles is recommended also if oxaliplatin is interrupted because of adverse events, patient's refusal or investigator's choice. CAPOX Oxaliplatin 130 mg/sqm iv over 2 hours, day 1; Capecitabine 1000 mg/sqm/bid per os from day 1 to day 14; to be repeated every 3 weeks until 8 cycles. The continuation of Capecitabine until 8 cycles is recommended also if oxaliplatin is interrupted because of adverse events, patient's refusal or investigator's choice. Pending the results of ct-DNA analysis, up to 2 cycles of FOLFOX/CAPOX before randomization are allowed to start the adjuvant treatment within 8-10 weeks after surgery

Drug: 5-Fluorouracil bolus FOLFOX schedule; Drug: 5-Fluorouracil continuous infusion FOLFOX schedule; Drug: Oxaliplatin FOLFOX and FOLFOXIRI schedule; Drug: Oxaliplatin CAPOX schedule; Drug: L-Leucovorin; Drug: Capecitabine

Trastuzumab and Tucatinib plus mFOLFOX6, part 1 target-driven (adjuvant)

EXPERIMENTAL

Tucatinib 300 mg (two 150 mg tablets)/bid orally twice daily (approximately 8 to 12 hours between doses with or without a meal); Trastuzumab 4 mg/kg iv over 30 minutes, day 1 (loading dose: 6 mg/kg iv over 90 minutes), followed by mFOLFOX6 Oxaliplatin 85 mg/sqm iv over 2 hours, day 1 in two-way with L-Leucovorin 200 mg/sqm iv over 2 hours, day 1 followed by 5-fluorouracil 400 mg/sqm iv bolus, day 1 followed by 5-fluoruracil 2400 mg/sqm 48 h-continuous infusion, starting on day 1; to be repeated every 2 weeks for a maximum of 12 cycles. In the case of oxaliplatin and/or trastuzumab and/or tucatinib interruption because of adverse events, patient's refusal or investigator's choice, the prosecution of the other drugs until 12 cycles is recommended. Pending the results of ct-DNA analysis, up to 2 cycles of FOLFOX/CAPOX before randomization are allowed to start the adjuvant treatment within 8-10 weeks after surgery

Drug: 5-Fluorouracil bolus FOLFOX schedule; Drug: 5-Fluorouracil continuous infusion FOLFOX schedule; Drug: Oxaliplatin FOLFOX and FOLFOXIRI schedule; Drug: Oxaliplatin CAPOX schedule; Drug: L-Leucovorin; Drug: Trastuzumab; Drug: Tucatinib

Arm B Trifluridine/Tipiracil, part 2 (post-adjuvant)

EXPERIMENTAL

Trifluridine/Tipiracil: 35 mg/ m2/bid per os days 1-5 and 8-12 to be repeated every 4 weeks until 6 cycles.

Drug: Trifluridine/Tipiracil

Arm A Observation, part 2 (post-adjuvant)

NO INTERVENTION

Follow-up

Interventions

5-Fluorouracil continuous infusion FOLFOXIRI schedule DRUG

3200 mg/sqm 48 h-continuous infusion, starting on day 1. To be repeated every two weeks for a maximum of 12 cycles.

Also known as: 5FU

Arm B FOLFOXIRI, part 1 (adjuvant)

5-Fluorouracil continuous infusion FOLFOX schedule DRUG

2400 mg/sqm 48 h-continuous infusion, starting on day 1. To be repeated every two weeks for a maximum of 12 cycles.

Also known as: 5FU

Arm A mFOLFOX6 or CAPOX (at investigator's choice), part 1 (adjuvant); Trastuzumab and Tucatinib plus mFOLFOX6, part 1 target-driven (adjuvant)

Oxaliplatin CAPOX schedule DRUG

130 mg/sqm iv over 2 hours, day 1. To be repeated every three weeks for a maximum of 8 cycles.

Also known as: Oxa

Arm A mFOLFOX6 or CAPOX (at investigator's choice), part 1 (adjuvant); Trastuzumab and Tucatinib plus mFOLFOX6, part 1 target-driven (adjuvant)

5-Fluorouracil bolus FOLFOX schedule DRUG

400 mg/sqm iv bolus, day 1. To be repeated every two weeks for a maximum of 12 cycles.

Also known as: 5FU

Arm A mFOLFOX6 or CAPOX (at investigator's choice), part 1 (adjuvant); Trastuzumab and Tucatinib plus mFOLFOX6, part 1 target-driven (adjuvant)

Oxaliplatin FOLFOX and FOLFOXIRI schedule DRUG

85 mg/sqm iv over 2 hours, day 1. To be repeated every two weeks for a maximum of 12 cycles.

Also known as: Oxa

Arm A mFOLFOX6 or CAPOX (at investigator's choice), part 1 (adjuvant); Arm B FOLFOXIRI, part 1 (adjuvant); Trastuzumab and Tucatinib plus mFOLFOX6, part 1 target-driven (adjuvant)

L-Leucovorin DRUG

200 mg/sqm iv over 2 hours, day 1. To be repeated every two weeks for a maximum of 12 cycles.

Also known as: Lederfolin

Arm A mFOLFOX6 or CAPOX (at investigator's choice), part 1 (adjuvant); Arm B FOLFOXIRI, part 1 (adjuvant); Trastuzumab and Tucatinib plus mFOLFOX6, part 1 target-driven (adjuvant)

Capecitabine DRUG

Capecitabine 1000 mg/sqm/bid per os from day 1 to day 14. To be repeated every 3 weeks until 8 cycles. Available as 500 and 150 mg tablets.

Arm A mFOLFOX6 or CAPOX (at investigator's choice), part 1 (adjuvant)

Irinotecan DRUG

165 mg/sqm iv over 60 minutes, day 1. To be repeated every two weeks for a maximum of 12 cycles.

Arm B FOLFOXIRI, part 1 (adjuvant)

Trifluridine/Tipiracil DRUG

35 mg/m2/bid per os days 1-5 and 8-12. To be repeated every 4 weeks until 6 cycles. Available as 20 and 15 mg tablets.

Also known as: FTD/TPI

Arm B Trifluridine/Tipiracil, part 2 (post-adjuvant)

Trastuzumab DRUG

4 mg/kg iv over 30 minutes, day 1 (loading dose: 6 mg/kg iv over 90 minutes). To be repeated every two weeks for a maximum of 12 cycles.

Trastuzumab and Tucatinib plus mFOLFOX6, part 1 target-driven (adjuvant)

Tucatinib DRUG

300 mg (two 150 mg tablets)/bid orally twice daily (approximately 8 to 12 hours between doses with or without a meal) for a maximum of 12 biweekly cycles.

Trastuzumab and Tucatinib plus mFOLFOX6, part 1 target-driven (adjuvant)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent to study procedures;
• years of age ECOG Performance Status ≤ 1 or 71-75 years of age with ECOG Performance Status 0;
• Histologically confirmed stage III or high-risk stage II adenocarcinoma of colon including intraperitoneal rectal cancer. Stage II colon cancers are defined at high risk if at least one major prognostic factor (pT4, less than 12 nodes examined, clinical presentation with bowel perforation) or at least two minor prognostic factors (grade 3 or 4, clinical presentation with bowel obstruction, histological signs of vascular or lymphatic or perineural invasion, high preoperative CEA levels) are reported;
• Curative surgery performed no less than 4 and no more than 12 weeks prior to randomization (pending results of ct-DNA analysis, up to 2 cycles of FOLFOX/CAPOX are allowed to start the adjuvant treatment within 8-10 weeks after surgery);
• Contrast-enhanced chest and abdominal CT scan (or abdomen MRI and chest CT if contrast-enhanced CT scan is contraindicated) performed after the surgery and prior to randomization with no evidence of metastatic disease;
• Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue from the surgical specimen and blood sample for ct-DNA analysis within 28 days prior randomization;
• Positive ct-DNA after surgery (central assessment);
• Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥ 9 g/dl;
• Total bilirubin ≤1.5 fold the upper-normal limits (UNL), ASAT (SGOT) and/or ALAT (SGPT) ≤2.5 x UNL (or \<5 x UNL in the case of liver metastases), alkaline phosphatase ≤2.5 x UNL (or \<5 x UNL in case of liver metastases);
• Creatinine clearance ≥50 mL/min or serum creatinine ≤1.5 x UNL;
• Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For this trial, women of childbearing potential are defined as all women after puberty, unless the participants are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient;
• Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception.
• Contraception, starting during study screening visit throughout the study period up to 180 days after the last dose of chemotherapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;
• \- Will and ability to comply with the protocol.
• Written informed consent to study procedures;

You may not qualify if:

• Part 1, adjuvant phase and Part 2, post-adjuvant phase
• Any evidence of metastatic disease (radiological or pathological metastasis);
• Macroscopic or microscopic evidence of residual tumor (R1 or R2 resections) after surgery;
• Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ;
• For Part 1 only: patient with complete dihydropyrimidine dehydrogenase (DPYD) deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT);
• History or evidence upon physical examination of CNS disease unless adequately treated;
• Clinical signs of malnutrition;
• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration;
• Evidence of bleeding diathesis or coagulopathy;
• Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication;
• Significant vascular disease (i.e. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment;
• Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication;
• Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer);
• Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs;
• Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies;

Sponsors & Collaborators

• Foundation Medicine: collaborator
• Seagen Inc.: collaborator
• Gruppo Oncologico del Nord-Ovest: lead
• Servier: collaborator

Study Sites (28)

Fondazione Casa Sollievo della Sofferenza

San Giovanni Rotondo, Foggia, 71013, Italy

Location

Azienda Ospedaliera Cardinale Giovanni Panico

Tricase, Lecce, 73039, Italy

Location

Ospedale San Donato di Arezzo

Arezzo, 52100, Italy

Location

Spedali Civili di Brescia

Brescia, 25123, Italy

Location

Fondazione POLIAMBULANZA ISTITUTO OSPEDALIERO

Brescia, 25124, Italy

Location

AOU Cagliari PO Policlinico Universitario Duilio Casula Presidio Policlinico Universitario "Duilio Casula"

Cagliari, 09042, Italy

Location

A.O.U. di Ferrara Arcispedale Sant'Anna

Ferrara, 44100, Italy

Location

A.O.U Careggi

Florence, 50134, Italy

Location

E.O. Ospedali Galliera di Genova

Genova, 16128, Italy

Location

Ospedale Misericordia di Grosseto

Grosseto, 58100, Italy

Location

Azienda USL Toscana Nord Ovest di Livorno

Livorno, 57124, Italy

Location

Ospedale San Luca di Lucca

Lucca, 55100, Italy

Location

Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"

Meldola, 47014, Italy

Location

Fondazione IRCCS INT - Milano

Milan, 20133, Italy

Location

Ospedale San Raffaele

Milan, 20132, Italy

Location

Azienda Ospedaliero Universitaria Maggiore della Carita

Novara, 28100, Italy

Location

Istituto Oncologico Veneto IOV - IRCCS

Padua, 35128, Italy

Location

Azienda USL di Piacenza

Piacenza, 29121, Italy

Location

Nuovo Ospedale di Prato

Prato, 59100, Italy

Location

AUSL Romagna

Ravenna, 48121, Italy

Location

Azienda USL IRCCS di Reggio Emilia (centro principale Reggio Emilia e centro satellite Guastalla).

Reggio Emilia, 42123, Italy

Location

Policlinico Tor Vergata Roma

Roma, 00133, Italy

Location

Istituto per la ricerca sui tumori Regina Elena

Roma, 00144, Italy

Location

Policlinico Fondazione Agostino Gemelli

Roma, 00168, Italy

Location

Ospedale Fatebenefratelli Isola Tiberina

Roma, 00186, Italy

Location

Ospedale Campostaggia Poggiponsi

Siena, 53100, Italy

Location

IRCCS di Candiolo

Torino, 10060, Italy

Location

Azienda Sanitaria Universitaria Friuli Centrale

Udine, 33100, Italy

Location

MeSH Terms

Conditions

Colonic Neoplasms

Interventions

Fluorouracil; Leucovorin; Capecitabine; Irinotecan; trifluridine tipiracil drug combination; Trastuzumab; tucatinib

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Camptothecin; Alkaloids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Roberto Moretto, MD

  Azienda Ospedaliero, Universitaria Pisana

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a prospective, open-label, multicentre study, including two phase II randomized trials (Part 1 and Part 2) and a non-randomized cohort (Part 1 target-driven) In Part 1 resected stage III and high-risk stage II colon cancer patients with positive ct- DNA after surgery will be randomized to receive FOLFOX for 12 cycles or CAPOX for 8 cycles (at investigator choice) versus FOLFOXIRI for 12 cycles; In Part 1 target-driven resected stage III and high-risk stage II HER2+ RAS wild-type colon cancer patients with positive ct-DNA after surgery will receive Trastuzumab and Tucatinib plus FOLFOX for 12 cycles. In Part 2 resected stage III and high-risk stage II colon cancer patients with positive ct- DNA after the end of a fluoropyrimidine and oxaliplatin-based adjuvant therapy - either in the frame or outside of Part 1 - will be randomized to receive observation or Trifluridine/Tipiracil for 6 cycles.

Study Record Dates

• First Submitted: September 13, 2021
• First Posted: September 30, 2021
• Study Start: May 17, 2023
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): December 1, 2029
• Last Updated: February 3, 2026

Record last verified: 2026-01

Locations

IT (28)