Clinical trial NCT05062889: Exploiting Circulating Tumour DNA to Intensify the Postoperative Treatment Resected Colon Cancer Patients
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Stage II Colon Cancer
Stage III Colon Cancer
HER2-positive Colon Cancer
RAS Wild-type Colon Cancer
Keywords: Circulating tumor DNA
FOLFOX
CAPOX
FOLFOXIRI
Trifluridine/Tipiracil
Trastuzumab
Tucatinib
Lead sponsor: Gruppo Oncologico del Nord-Ovest
Sponsor class: OTHER
Collaborators: name: Servier
name: Foundation Medicine
name: Seagen Inc.
First posted: 2021-09-30
Enrollment: 477
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.
Primary purpose: TREATMENT

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

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: ct-DNA clearance rate after the end of the adjuvant treatment (ERASE-CRC part 1)
timeFrame: 6 months from the enrollment of the last patient in the adjuvant treatment
measure: ct-DNA clearance rate after the end of post-adjuvant treatment (ERASE-CRC part 2)
timeFrame: 6 months from the enrollment of the last patient in post-adjuvant treatment
measure: ct-DNA clearance rate after the end of target-driven adjuvant treatment (ERASE-CRC part 1 target-driven)
timeFrame: 6 months from the enrollment of the last patient in the target-driven adjuvant treatment
Secondary outcomes:
measure: Overall Toxicity Rate 1
timeFrame: 30 days from the last dose of the last patient in adjuvant treatment
measure: Toxicity Rate 1
timeFrame: 30 days from the last dose of the last patient in adjuvant treatment
measure: Disease Free Survival 1 (DFS1)
timeFrame: 60 months after the randomization of first patient in adjuvant treatment
measure: Overall Survival 1 (OS1)
timeFrame: 60 months after the randomization of first patient in adjuvant treatment
measure: Overall Toxicity Rate 2
timeFrame: 30 days from the last dose of TRIFLURIDINE/TIPIRACIL
measure: Toxicity Rate 2
timeFrame: 30 days from the last dose of TRIFLURIDINE/TIPIRACIL
measure: Disease Free Survival 2 (DFS2)
timeFrame: 60 months after the randomization of first patient in post-adjuvant treatment
measure: Overall Survival 2 (OS2)
timeFrame: 60 months after the randomization of first patient in post-adjuvant treatment
measure: Overall Toxicity Rate TD1
timeFrame: 30 days from the last dose of the last patient in target-driven adjuvant treatment
measure: Toxicity Rate TD1
timeFrame: 30 days from the last dose of the last patient in target-driven adjuvant treatment
measure: Disease Free Survival TD1 (DFS-TD1)
timeFrame: 60 months after the randomization of first patient in adjuvant treatment
measure: Overall survival TD1 (OS-TD1)
timeFrame: 60 months after the randomization of first patient in adjuvant treatment
Other outcomes:
Locations:
city: San Giovanni Rotondo
country: Italy
facility: Fondazione Casa Sollievo della Sofferenza
state: Foggia
city: Tricase
country: Italy
facility: Azienda Ospedaliera Cardinale Giovanni Panico
state: Lecce
city: Arezzo
country: Italy
facility: Ospedale San Donato di Arezzo
city: Brescia
country: Italy
facility: Spedali Civili di Brescia
city: Brescia
country: Italy
facility: Fondazione POLIAMBULANZA ISTITUTO OSPEDALIERO
city: Cagliari
country: Italy
facility: AOU Cagliari PO Policlinico Universitario Duilio Casula Presidio Policlinico Universitario "Duilio Casula"
city: Ferrara
country: Italy
facility: A.O.U. di Ferrara Arcispedale Sant'Anna
city: Firenze
country: Italy
facility: A.O.U Careggi
city: Genova
country: Italy
facility: E.O. Ospedali Galliera di Genova
city: Grosseto
country: Italy
facility: Ospedale Misericordia di Grosseto
city: Livorno
country: Italy
facility: Azienda USL Toscana Nord Ovest di Livorno
city: Lucca
country: Italy
facility: Ospedale San Luca di Lucca
city: Meldola
country: Italy
facility: Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"
city: Milano
country: Italy
facility: Ospedale San Raffaele
city: Milan
country: Italy
facility: Fondazione IRCCS INT - Milano
city: Novara
country: Italy
facility: Azienda Ospedaliero Universitaria Maggiore della Carita
city: Padua
country: Italy
facility: Istituto Oncologico Veneto IOV - IRCCS
city: Piacenza
country: Italy
facility: Azienda USL di Piacenza
city: Prato
country: Italy
facility: Nuovo Ospedale di Prato
city: Ravenna
country: Italy
facility: AUSL Romagna
city: Reggio Emilia
country: Italy
facility: Azienda USL IRCCS di Reggio Emilia (centro principale Reggio Emilia e centro satellite Guastalla).
city: Roma
country: Italy
facility: Policlinico Tor Vergata Roma
city: Roma
country: Italy
facility: Istituto per la ricerca sui tumori Regina Elena
city: Roma
country: Italy
facility: Policlinico Fondazione Agostino Gemelli
city: Roma
country: Italy
facility: Ospedale Fatebenefratelli Isola Tiberina
city: Siena
country: Italy
facility: Ospedale Campostaggia Poggiponsi
city: Torino
country: Italy
facility: IRCCS di Candiolo
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Friuli Centrale
Study officials:
affiliation: Azienda Ospedaliero, Universitaria Pisana
name: Roberto Moretto, MD
role: PRINCIPAL_INVESTIGATOR
References: