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

Stage III Colon Cancer Clinical Trial

— ERASE-CRC  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05062889
• Other study ID #: ERASE-CRC
• Status: Recruiting
• Phase: Phase 2
• Start date: May 17, 2023
• Est. completion date: December 2027

Study information

• Verified date: December 2023
• Source: Gruppo Oncologico del Nord-Ovest
• Contact: Roberto Moretto, MD
• Phone: +39050992069
• Email: robertomoretto8468[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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 1 target-driven resected stage III and high-risk stage II HER2+ and 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 477
• Est. completion date: December 2027
• Est. primary completion date: October 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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 1 and target-driven part 1, adjuvant phase II study

• Written informed consent to study procedures;

• 18 - 70 years of age ECOG PS = 1 or 71-75 years of age with ECOG PS 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;

• For target-driven Part 1 only: HER2+ and RAS wt disease as determined by a tissue-based assay (central laboratory assessment);

• 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, alkaline phosphatase =2.5 x UNL;

• Creatinine clearance =50 mL/min or serum creatinine =1.5 x UNL;

• For target-driven Part 1 only: Left ventricular ejection fraction (LVEF) =50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.

• Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue from the surgical specimen for translational analysis (only for patients eligible for protocol treatment);

• 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 they 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.

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.

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.

• Part 1, target-driven, adjuvant phase:

• Ongoing = Grade 2 diarrhea of any etiology at screening;

• Presence of known chronic liver disease;

• Known to be positive for hepatitis C infection (positive by polymerase chain reaction [PCR]). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of at least 12 weeks.

• Known to be positive for hepatitis B (HBV) by surface antigen (HBsAg) expression. Subjects who are positive for either hepatitis B surface antibody (HBsAB) or antibodies to the hepatitis B core antigen (HBcAB) should be screened using PCR measurement of hepatitis B DNA levels. Subjects with hepatitis B DNA levels by PCR that require nucleoside analogue therapy are not eligible for the trial. The latest local guidelines should be followed regarding the monitoring of hepatitis B DNA levels by PCR subjects on study treatment.

Related Conditions & MeSH terms

• Colonic Neoplasms
• Stage II Colon Cancer
• Stage III Colon Cancer

Intervention

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.
• 5-Fluorouracil bolus FOLFOX schedule
400 mg/sqm iv bolus, day 1. To be repeated every two weeks for a maximum of 12 cycles.
• 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.
• 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.
• Oxaliplatin CAPOX schedule
130 mg/sqm iv over 2 hours, day 1. To be repeated every three weeks for a maximum of 8 cycles.
• L-Leucovorin
200 mg/sqm iv over 2 hours, day 1. To be repeated every two weeks for a maximum of 12 cycles.
• 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.
• Irinotecan
165 mg/sqm iv over 60 minutes, day 1. To be repeated every two weeks for a maximum of 12 cycles.
• 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.
• Trastuzumab
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.
• Tucatinib
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.

Locations

Country	Name	City	State
Italy	Ospedale San Donato di Arezzo	Arezzo
Italy	Fondazione POLIAMBULANZA ISTITUTO OSPEDALIERO	Brescia
Italy	Spedali Civili di Brescia	Brescia
Italy	AOU Cagliari PO Policlinico Universitario Duilio Casula Presidio Policlinico Universitario "Duilio Casula"	Cagliari
Italy	A.O.U. di Ferrara Arcispedale Sant'Anna	Ferrara
Italy	A.O.U Careggi	Firenze
Italy	E.O. Ospedali Galliera di Genova	Genova
Italy	Ospedale Misericordia di Grosseto	Grosseto
Italy	Azienda USL Toscana Nord Ovest di Livorno	Livorno
Italy	Ospedale San Luca di Lucca	Lucca
Italy	Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"	Meldola
Italy	Fondazione IRCCS INT - Milano	Milan
Italy	Ospedale San Raffaele	Milano
Italy	Azienda Ospedaliero Universitaria Maggiore della Carita	Novara
Italy	Istituto Oncologico Veneto IOV - IRCCS	Padua
Italy	Azienda USL di Piacenza	Piacenza
Italy	Nuovo Ospedale di Prato	Prato
Italy	AUSL Romagna	Ravenna
Italy	Azienda USL IRCCS di Reggio Emilia (centro principale Reggio Emilia e centro satellite Guastalla).	Reggio Emilia
Italy	Istituto per la ricerca sui tumori Regina Elena	Roma
Italy	Ospedale Fatebenefratelli Isola Tiberina	Roma
Italy	Policlinico Fondazione Agostino Gemelli	Roma
Italy	Policlinico Tor Vergata Roma	Roma
Italy	Fondazione Casa Sollievo della Sofferenza	San Giovanni Rotondo	Foggia
Italy	Ospedale Campostaggia Poggiponsi	Siena
Italy	IRCCS di Candiolo	Torino
Italy	Azienda Ospedaliera Cardinale Giovanni Panico	Tricase	Lecce
Italy	Azienda Sanitaria Universitaria Friuli Centrale	Udine

Sponsors (4)

Lead Sponsor	Collaborator
Gruppo Oncologico del Nord-Ovest	Foundation Medicine, Seagen Inc., Servier

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	Overall Toxicity Rate 1	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.	30 days from the last dose of the last patient in adjuvant treatment
Secondary	Toxicity Rate 1	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.	30 days from the last dose of the last patient in adjuvant treatment
Secondary	Disease Free Survival 1 (DFS1)	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.	60 months after the randomization of first patient in adjuvant treatment
Secondary	Overall Survival 1 (OS1)	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.	60 months after the randomization of first patient in adjuvant treatment
Secondary	Overall Toxicity Rate 2	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.	30 days from the last dose of TRIFLURIDINE/TIPIRACIL
Secondary	Toxicity Rate 2	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.	30 days from the last dose of TRIFLURIDINE/TIPIRACIL
Secondary	Disease Free Survival 2 (DFS2)	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.	60 months after the randomization of first patient in post-adjuvant treatment
Secondary	Overall Survival 2 (OS2)	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.	60 months after the randomization of first patient in post-adjuvant treatment
Secondary	Overall Toxicity Rate TD1	Percentage of patients, relative to the total of enrolled subjects in the target-driven 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.	30 days from the last dose of the last patient in target-driven adjuvant treatment
Secondary	Toxicity Rate TD1	percentage of patients, relative to the total of enrolled subjects in the target-driven part 1 of the study, experiencing a specific adverse event = grade 3, according to National Cancer Institute Common Toxicity Criteria (version 5.0), during adjuvant treatment and follow-up.	30 days from the last dose of the last patient in target-driven adjuvant treatment
Secondary	Disease Free Survival TD1 (DFS-TD1)	time from enrollment of the target-driven part 1 of the study to the first 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 enrollment will have time to event censored on the date of enrollment.	60 months after the randomization of first patient in adjuvant treatment
Secondary	Overall survival TD1 (OS-TD1)	Time from enrollment of the target-driven 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.	60 months after the randomization of first patient in adjuvant treatment