Use of circulating tumor dna test to intensify post-operative treatment of patients with resected colon cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Gruppo Oncologico Del Nord Ovest

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Mar 2023 → ongoing

Decision date (initial)

2024-11-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-515152-20-00

EudraCT number

2021-002169-16

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective of the part 1 of this trial is to assess the rate of ct-DNA clearance at the end of the adjuvant treatment with FOLFOXIRI versus FOLFOX/CAPOX in stage III or high-risk stage II colon cancer patients with positive ct-DNA after surgery.
The primary objective of the target-driven part 1 of this trial is to assess the rate of ct- DNA clearance at the end of the adjuvant treatment with FOLFOX plus Trastuzumab and Tucatinib in stage III or high-risk stage II HER2+/RAS wt colon cancer patients with positive ct-DNA after surgery.
The primary objective of the part 2 of this trial is to assess the rate of ct-DNA clearance at the end of post-adjuvant treatment with trifluridine/tipiracil versus observation in stage III or high-risk stage II colon cancer patients with positive ct-DNA after the end of a fluoropyrimidine and oxaliplatin-based adjuvant therapy.

Secondary objectives 2

1. Secondary objectives of the part 1 and the target-driven part 1 of this study are to assess:  Safety profiles of study treatments;  Duration of Disease-free Survival (DFS);  Duration of Overall Survival (OS);  Prognostic impact of the post-surgery detection of ct-DNA  Prognostic impact of the clearance of ct-DNA at the end of the adjuvant therapy;  ct-DNA clearance during the adjuvant treatment as a surrogate marker of the efficacy of the adjuvant therapy, and therefore as a potentially useful and time-sparing endpoint for clinical trials;  Quality of life as measured by PROs questionnaires (EORTC QLQ-C30 EORTC QLQ-CR29 and EuroQol EQ-5D).
2. Secondary objectives of the part 2 of this study are to assess:  Safety profile;  Duration of Disease-free Survival (DFS);  Duration of Overall Survival (OS);  Prognostic impact of the post-adjuvant detection of ct-DNA;  Prognostic impact of the clearance of ct-DNA at the end of the post-adjuvant therapy;  ct-DNA clearance during the post-adjuvant treatment as a surrogate marker of efficacy;  Quality of life as measured by PROs questionnaires (EORTC QLQ-C30 EORTC QLQCR29 and EuroQol EQ-5D).

Conditions and MedDRA coding

Stage III and high-risk stage II resected colon cancer patients.

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 33

1. Part 1 and target-driven part 1, adjuvant phase II study: Written informed consent to study procedures;
2. 18 – 70 years of age ECOG PS ≤ 1 or 71-75 years of age with ECOG PS 0;
3. 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.
4. For target-driven Part 1 only: HER2+ and RAS wt disease as determined by a tissue-based assay (central laboratory assessment)
5. 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)
6. 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.
7. 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.
8. Positive ct-DNA after surgery (central assessment). The blood sample should be collected 2-6 weeks after the surgery.
9. Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥ 9 g/dl.
10. 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 .
11. Creatinine clearance ≥50 mL/min or serum creatinine ≤1.5 x UNL.
12. For target-driven Part 1 only: Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.
13. For patients eligible for protocol treatment, availability of formalin-fixed, paraffinembedded (FFPE) tumor tissue from the surgical specimen for translational analysis.
14. 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;
15. 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;
16. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;
17. Will and ability to comply with the protocol.
18. Part 2, post-adjuvant phase II study: Written informed consent to study procedures;
19. ≥ 18 years of age;
20. 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.
21. 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).
22. 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.
23. Availability of FFPE tumor tissue from the surgical specimen and blood sample for ct- DNA analysis within 28 days prior to randomization ((only for patients who received adjuvant as per clinical practice and not in the Part 1 of the study).
24. Positive ct-DNA after the end of adjuvant treatment (centrally laboratory assessment).
25. ECOG PS ≤ 1.
26. Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥9 g/dl.
27. 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.
28. Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL.
29. Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue from the surgical specimen for translational analyses (only for patients who received adjuvant as per clinical practice and not in the Part 1 of the study).
30. 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
31. 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;
32. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;
33. Will and ability to comply with the protocol.

Exclusion criteria 19

1. Part 1, adjuvant phase II study and Part 2, post-adjuvant phase II study: Any evidence of metastatic disease (radiological or pathological metastasis);
2. Macroscopic or microscopic evidence of residual tumor (R1 or R2 resections) after surgery;
3. 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;
4. For Part 1 and target-driven Part 1 only: patient with complete dihydropyrimidine dehydrogenase (DPYD) deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT);
5. History or evidence upon physical examination of CNS disease unless adequately treated.
6. Clinical signs of malnutrition.
7. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.
8. Evidence of bleeding diathesis or coagulopathy
9. 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
10. Significant vascular disease (i.e. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
11. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
12. Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer);
13. Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
14. Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
15. 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.
16. For Target-driven Part 1 population only:Has ongoing ≥ Grade 2 diarrhea of any etiology at screening;
17. Presence of known chronic liver disease;
18. 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.
19. 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 for subjects on study treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. The primary endpoint is the ct-DNA clearance rate.
2. Part 1 of the study ct-DNA clearance rate after the end of the adjuvant treatment is defined as the 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.
3. Target-driven part 1 of the study ct-DNA clearance rate after the end of the adjuvant treatment is defined as the 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.
4. Part 2 of the study ct-DNA clearance rate after the end of post-adjuvant treatment is defined as the 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 endpoints 15

1. Part 1 of the study Overall Toxicity Rate 1 is defined as the 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.
2. Toxicity Rate 1 is defined as the percentage of patients, relative to the total of enrolled subjects in the 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.
3. Disease Free Survival 1 (DFS1) is defined as the time from randomization of the part 1 of the study to the first documentation of disease relapse or death due to any cause, whichever occurs first.
4. Overall survival 1 (OS1) is defined as the 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.
5. The analysis of PROs endpoints (assessed using the EORTC QLQ-C30, the EORTC QLQCR29 and the EuroQol EQ-5D questionnaires) will be assessed according to the EORTC Scoring and Reference Values Manual. All scores and subscales will be compared between the treatment arms.
6. Target-driven Part 1 of the study Overall Toxicity Rate TD1 is defined as the 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.
7. Toxicity Rate TD1 is defined as the 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.
8. Disease Free Survival TD1 (DFS-TD1) is defined as the 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.
9. Overall survival TD1 (OS-TD1) is defined as the time from enrollment of the targetdriven 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.
10. The analysis of PROs endpoints (assessed using the EORTC QLQ-C30, the EORTC QLQCR29 and the EuroQol EQ-5D questionnaires) will be assessed according to the EORTC Scoring and Reference Values Manual. All scores and subscales will be compared between the treatment arms.
11. Part 2 of the study Overall Toxicity Rate 2 is defined as the 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.
12. Toxicity Rate 2 is defined as the 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, according to National Cancer Institute Common Toxicity Criteria (version 5.0), during post-adjuvant treatment and follow-up.
13. Disease Free Survival 2 (DFS2) is defined as the time from randomization of the part 2 of the study to the first documentation of disease relapse or death due to any cause, whichever occurs first.
14. Overall survival 2 (OS2) is defined as the 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.
15. The analysis of PROs endpoints (assessed using the EORTC QLQ-C30, the EORTC QLQCR29 and the EuroQol EQ-5D questionnaires) will be assessed according to the EORTC Scoring and Reference Values Manual. All scores and subscales will be compared between the treatment arms.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Gruppo Oncologico Del Nord Ovest

Sponsor organisation

Gruppo Oncologico Del Nord Ovest

Address

Via Goffredo Mameli 3/1

City

Genoa

Postcode

16122

Country

Italy

Scientific contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Public contact point

Organisation

Gruppo Oncologico Del Nord Ovest

Contact name

Laura Delliponti

Third parties 8

Locations

1 EU/EEA country · 52 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 19 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications