ERASE-CRC: Exploiting Circulating Tumour DNA to Intensify the Postoperative Treatment Resected Colon Cancer Patients

Sponsor

Gruppo Oncologico del Nord-Ovest (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05062889

Collaborator

Servier (Industry), Foundation Medicine (Industry)

300

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Stage II Colon Cancer Stage III Colon Cancer	Drug: 5-Fluorouracil continuous infusion FOLFOXIRI schedule 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 Drug: Irinotecan Drug: Trifluridine/Tipiracil	Phase 2

Detailed Description

Study Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

This is a prospective, open-label, multicentre study, including two phase II randomized trials. 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 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.This is a prospective, open-label, multicentre study, including two phase II randomized trials. 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 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.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Exploiting Circulating Tumour DNA to Intensify the Postoperative Treatment of Stage III and High-risk Stage II Resected Colon Cancer Patients With Adjuvant FOLFOXIRI and/or Post-adjuvant Trifluridine/Tipiracil

Anticipated Study Start Date :

Dec 1, 2022

Anticipated Primary Completion Date :

Oct 1, 2025

Anticipated Study Completion Date :

Dec 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm B FOLFOXIRI, part 1 (adjuvant) 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 3200 mg/sqm 48 h-continuous infusion, starting on day 1. To be repeated every two weeks for a maximum of 12 cycles. Other Names: 5FU Drug: Oxaliplatin FOLFOX and FOLFOXIRI schedule 85 mg/sqm iv over 2 hours, day 1. To be repeated every two weeks for a maximum of 12 cycles. Other Names: Oxa Drug: L-Leucovorin 200 mg/sqm iv over 2 hours, day 1. To be repeated every two weeks for a maximum of 12 cycles. Other Names: Lederfolin Drug: Irinotecan 165 mg/sqm iv over 60 minutes, day 1. To be repeated every two weeks for a maximum of 12 cycles.
Active Comparator: Arm A mFOLFOX6 or CAPOX (at investigator's choice), part 1 (adjuvant) 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 400 mg/sqm iv bolus, day 1. To be repeated every two weeks for a maximum of 12 cycles. Other Names: 5FU Drug: 5-Fluorouracil continuous infusion FOLFOX schedule 2400 mg/sqm 48 h-continuous infusion, starting on day 1. To be repeated every two weeks for a maximum of 12 cycles. Other Names: 5FU Drug: Oxaliplatin FOLFOX and FOLFOXIRI schedule 85 mg/sqm iv over 2 hours, day 1. To be repeated every two weeks for a maximum of 12 cycles. Other Names: Oxa Drug: Oxaliplatin CAPOX schedule 130 mg/sqm iv over 2 hours, day 1. To be repeated every three weeks for a maximum of 8 cycles. Other Names: Oxa Drug: Capecitabine 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.
Experimental: Arm B Trifluridine/Tipiracil, part 2 (post-adjuvant) 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 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. Other Names: FTD/TPI
No Intervention: Arm A Observation, part 2 (post-adjuvant) Follow-up

Outcome Measures

Primary Outcome Measures

ct-DNA clearance rate after the end of the adjuvant treatment [30 months from the enrollment of the first patient in adjuvant phase]
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.
ct-DNA clearance rate after the end of post-adjuvant treatment [6 months from the enrollment of the last patient in post-adjuvant treatment]
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.

Secondary Outcome Measures

Overall Toxicity Rate 1 [30 days from the last dose of the last patient in adjuvant treatment]
Percentage of patients, relative to the total of enrolled subjects in the Part 1 of the study, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 5.0), during adjuvant treatment and follow-up.
Toxicity Rate 1 [30 days from the last dose of the last patient in adjuvant treatment]
Percentage of patients, relative to the total of enrolled subjects in the Part 1 of the study, experiencing a specific adverse event of grade ≥ 3, according to National Cancer Institute Common Toxicity Criteria (version 5.0), during adjuvant treatment and follow-up.
Disease Free Survival 1 (DFS1) [60 months after the randomization of first patient in adjuvant treatment]
Time from randomization of the part 1 of the study to the first documentation of radiological disease relapse or death due to any cause, whichever occurs first. Secondary colorectal cancers are regarded as DFS events, whereas non-colorectal tumors are not. DFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of relapse for patients who are alive, on study and disease free at the time of the analysis. Alive patients having no tumor assessments after randomization will have time to event censored on the date of randomization.
Overall Survival 1 (OS1) [60 months after the randomization of first patient in adjuvant treatment]
Time from randomization of the Part 1 of the study to the date of death due to any cause. For patients still alive at the time of the analysis, the OS time will be censored on the last date the patients were known to be alive.
Overall Toxicity Rate 2 [30 days from the last dose of TRIFLURIDINE/TIPIRACIL]
Percentage of patients in the Part 2 of the study, relative to the total of enrolled subjects, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 5.0), during post-adjuvant treatment and follow-up.
Toxicity Rate 2 [30 days from the last dose of TRIFLURIDINE/TIPIRACIL]
Percentage of patients, relative to the total of enrolled subjects in the Part 2 of the study, experiencing a specific adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 5.0), during postadjuvant treatment and follow-up.
Disease Free Survival 2 (DFS2) [60 months after the randomization of first patient in post-adjuvant treatment]
Time from randomization of the part 2 of the study to the first radiological documentation of disease relapse or death due to any cause, whichever occurs first. Secondary colorectal cancers are regarded as DFS events, whereas non-colorectal tumors are not. DFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of relapse for patients who are alive, on study and disease free at the time of the analysis. Alive patients having no tumor assessments after randomization will have time to event censored on the date of randomization.
Overall Survival 2 (OS2) [60 months after the randomization of first patient in post-adjuvant treatment]
Time from randomization of the part 2 of the study to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria, Part I, adjuvant phase:

Written informed consent to study procedures;
18 - 70 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.

Inclusion Criteria, Part II, post-adjuvant phase:

Written informed consent to study procedures;
≥ 18 years of age;
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;
Fluoropyrimidine and oxaliplatin-containing adjuvant treatment for at least 3 months (6 cycles of 5-fluorouracil and oxaliplatin-based therapy or 4 cycles of capecitabine and oxaliplatin-based-therapy) and no more than 6 months (12 cycles of 5-fluorouracil and oxaliplatin-based therapy or 8 cycles of capecitabine and oxaliplatin-based-therapy);
Contrast-enhanced chest and abdominal CT scan (or abdomen MRI and chest CT if contrast-enhanced CT scan is contraindicated) performed within 4 weeks from the end of adjuvant therapy and 28 days prior to randomization;
Availability of FFPE tumor tissue from the surgical specimen and blood sample for ct-DNA analysis within 28 days prior to randomization;
Positive ct-DNA after the end of adjuvant treatment (centrally laboratory assessment);
ECOG Performance Status ≤ 1;
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.

Will and ability to comply with the protocol.

Exclusion Criteria:

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;
Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at screening. Sexually active males and females (of childbearing potential) unwilling to practice contraception (as defined in section 5.5) during the study and until 180 days after the last trial treatment.