PRODIGE 88-CIRCULATE PAC: Phase III multicentric, open-label, randomized study to investigate the efficacy of chemotherapy in patients with positive ctDNA after surgery and adjuvant chemotherapy for a high-risk stage II and stage III Colorectal Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Dijon

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

7 May 2026 → ongoing

Decision date (initial)

2023-09-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

PHRC K 2022 · NATERA Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

show a longer TTR in circulating tumor DNA positive (ctDNA+) patients treated in arm A with FOLFIRI + Bevacizumab (Bev) or in arm B with Trifluridine Tipiracil (TT) + Bev vs. those in the clinical and ctDNA surveillance/control arm (arm C).

Secondary objectives 10

1. TTR in ctDNA+ patients (A + B) vs. arm C patients who would not have received additional therapy
2. Overall survival (OS) in ctDNA+ patients: A vs. C and B vs. C and (A+B) vs. C
3. Disease Free Survival (DFS) in ctDNA+ patients: A vs. C and B vs. C and (A+B) vs. C
4. ctDNA clearance in ctDNA+ patients (timing and rate)
5. The predictive value of baseline and early ctDNA clearance for long term oncological outcomes
6. Secondary surgery/ablation for disease recurrence and rate of potentially curable recurrences
7. Tolerability of experimental treatments
8. Quality of life using the QLQ-C30 and EQ5D questionnaires
9. 36-month recurrence rate in ctDNA+ and ctDNA- patients
10. Analyzing these different primary and secondary objectives with a ctDNA tumor-agnostic test

Conditions and MedDRA coding

Colon carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Fully resected R0 stage III or high-risk stage II† colon or upper rectal adenocarcinoma treated with standard (neo)adjuvant chemotherapy-ACT (FOLFOX/ CAPOX) for 3 to 6 months based on local multidisciplinary meeting
2. Patients ≥ 18 years (provided the score of the G8 geriatric questionnaire is >14 for patients 70 years or older)
3. WHO performance status < 2
4. No residual disease on TAP CT-scanner and/or liver MRI + thoracic CT-scan in the case of contra-indication to dye contrast and PET-scan (if available), within 3 weeks of the screening visit.
5. Adequate hematological, renal and liver functions: neutrophils ≥ 1,5 G/L, platelet count ≥ 100 G/L, hemoglobin ≥ 9 g/dL (5,6 mmol/l); Total bilirubin ≤ 1.5 x ULN (upper limit of normal); AST and ALT ≤ 2.5 x ULN; Alkaline phosphatase ≤ 2.5 x ULN; Creatinine clearance ≥50 ml/min according to CKD EPI formula
6. Available tumor sample and pathological report
7. Negative pregnancy test in woman with childbearing potential
8. Women of childbearing potential must agree to use a highly effective method of contraception during the trial and for at least 6 months after discontinuation of the experimental treatments. Men who have sexual relations with women of childbearing potential must agree to use contraception during treatment and for at least 6 months after discontinuation of the experimental treatments
9. Signed written informed consent obtained prior to any study specific procedures
10. Patient affiliated to a social security scheme

Exclusion criteria 18

1. Patients already treated with trifluridine tipiracil or irinotecan or Bevacizumab in the past 3 years
2. Known Uridine Diphosphate Glucuronyltransferase (UGT1A1) deficiency or Known Gilbert’s disease
3. Continuous intake of strong inducers of CYP3A4 (posaconazole, voriconazole, itraconazole, isavuconazole, ritonavir, verapamil, diltiazem, grapefruit juice (equivalent to one half a day)
4. Continuous intake of strong inhibitors of CYP3A4 (St John’s Wort, Hypericum perforatum, rifampicin, phenobarbital, primidone, phenytoin and carbamazepin)
5. Bowel obstruction
6. Recent concomitant treatment with brivudine (related to fluorouracil)
7. Participation in another interventional study for postoperative therapy
8. Persons deprived of liberty or under guardianship or incapable of giving consent
9. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol or follow-up schedule.
10. Uncontrolled intercurrent illness
11. dMMR/MSI-H colon cancer
12. Previous malignancies other than adequately treated in situ carcinoma of the uterine cervix or basal or squamous cell carcinoma of the skin, unless there has been a disease-free interval of at least 3 years
13. Pregnant or breastfeeding women
14. Deep arterial thromboembolic events including cerebrovascular accident or myocardial infarction within the last 6 months prior to randomization. Uncontrolled hypertension or symptomatic arrhythmia
15. Therapy should not be initiated for at least 28 days following major surgery (the surgical incision should be fully healed prior to study drug administration)
16. Any known specific contraindication or allergy to the treatments used in the study
17. Total or partial dihydropyrimidine dehydrogenase (DPD) deficiency (uracilemia > 16ng/ml)
18. Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanized antibodies (related to Bevacizumab).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to recurrence (TTR), defined as time from randomization to disease recurrence, which includes locoregional or metastatic relapse, death with evidence of recurrence and death from colorectal cancer (CRC) cause

Secondary endpoints 9

1. TTR (primary endpoint): will be defined as the time from randomization to disease recurrence including locoregional or metastatic relapse, death with evidence of recurrence and death from CRC cause. Patients alive without relapse or who had died from a cause other than CRC, will be censored at the date of last news.
2. OS: will be defined as the time from randomization to death whatever the cause of death. Patients who are alive will be censored at the to date of last news.
3. DFS: will be defined as the time from randomization to all causes of death, second primary colorectal cancers (CRCs), locoregional and metastatic relapse, but not second primary non-CRCs. Patients alive without relapse or second CR cancer or who died for other cause than CRC will be censored at date of last news
4. CtDNA clearance rate: will be defined as the percentage of patients with a clearance of ctDNA
5. The predictive value of baseline and early ctDNA clearance for long term oncological outcomes
6. Rate of secondary surgery/ablation for disease recurrence: will be defined as the percentage of patients with a secondary surgery/ablation after disease recurrence
7. Tolerability: Toxicities will be graded according to the NCI-CTCAE v 5.0 criteria before each cycle
8. Quality of life: Quality of life will be assessed according to the questionnaire of EORTC QLQ-C30 and EQ5D questionnaires. Survival without QoL deterioration is defined as the time between randomization and the occurrence of a deterioration
9. Recurrence rate: will be defined as the percentage of patients with a disease recurrence (including locoregional or metastatic relapse), and the rate of potentially curable recurrences will be defined as the percentage of patients with a potentially curable recurrence (i.e oligometastatic disease)

Investigational products

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

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Dijon

Sponsor organisation

Centre Hospitalier Universitaire De Dijon

Address

1 Boulevard Jeanne D Arc, Bp 77908 Bp 77908

City

Dijon

Postcode

21000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Dijon

Contact name

Coordinator

Public contact point

Organisation

Centre Hospitalier Universitaire De Dijon

Contact name

Coordinator

Third parties 4

Locations

1 EU/EEA country · 101 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

Corrective measures 1 · Art. 77 CTR

Results and documents

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

Documents 15 files

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

Application history

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