Overview

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

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.