PRODIGE 90 - FFCD 22024 - PREDIR-NEOREC - Neoadjuvant dostarlimab with short course radiotherapy in a watch-and-wait strategy for microsatellite unstable or mismatch repair-deficient locally advanced rectal cancer patients: a randomized phase II trial

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

6 Feb 2025 → ongoing

Decision date (initial)

2024-07-31

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Fédération Francophone de Cancérologie Digestive

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

Treatment strategy failure (TSF) rate at 24 months.
Failure being defined as the absence of clinical complete response (cCR, Digital Rectal Examination, MRI and Endoscopy) and/or local or distant disease progression.
Absence of clinical complete response is defined as failure in 1 or more of the measurement parameters such DRE, MRI, Endoscopy.

Secondary objectives 11

1. Tolerability (NCI-CTCAE v5.0 assessed treatment and nontreatment related adverse events (dosta
2. Rate of organ preservation at 2 years
3. Rate of local excision, TME (total mesorectal excision) surgery or creation of a permanent colostomy/ileostomy at 2 years
4. Quality (R0, completeness of the mesorectum) and morbidity (according to Clavien Dindo and Quirke classification) of local excision or TME or permanent colostomy/ileostomy if needed
5. Disease Free Survival (DFS) at 6, 12, 24 and 36 months
6. Overall survival (OS) at 6, 12, 24 and 36 months
7. Quality of life score changes in EORTC QLQ-C30 and QLQ-CR29 scales (at baseline, 3, 6, 12 and 24 months)
8. Low Anterior Resection Syndrome score LARS (at baseline, 3, 6, 12 and 24 months)
9. Incontinence score WEXNER (at baseline, 3, 6, 12 and 24 months)
10. Sexual function scales IIEF5/ FDFI (at baseline, 3, 6, 12 and 24 months)
11. Objective response rate (ORR)

Conditions and MedDRA coding

Rectal cancer locally advanced with microsatellite unstable or mismatch repair-deficient

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Age ≥18 years
2. Histologically proven rectal adenocarcinoma with Mismatch-repair Deficient (dMMR)/ microsatellite instability-high (MSI-H). Tumour status (dMMR/MSI-H) should be determined using both IHC (Immunohistochemistry) and PCR (polymerase chain reaction) or NGS (Next-Generation sequencing).
3. T2-T4 Nany and Tany N+ disease
4. WHO performance status 0 or 1
5. Adequate liver function: AST and ALT ≤ 5 x ULN (upper normal limit), total bilirubin ≤ 35 µM/L, albumin ≥ 28 g/L and Child-Pugh A score (if cirrhosis associated)
6. Adequate hematological and renal function (hemoglobin > 9 g/dl, platelets > 100 G/L, ANC ≥ 1.5 G/L) and renal function (creatinine clearance ≥ 40ml/min according to MDRD formula)
7. Negative pregnancy test done 72 hours prior to registration, for women of childbearing potential only. Women of childbearing potential must agree to use contraception during the trial treatment and for at least 4 months after discontinuation of the experimental treatments. Men who have sex with women of childbearing potential must agree to use contraception during treatment and for at least 4 months after discontinuation of the experimental treatments
8. Ability of patient to understand, sign and date the informed consent form before any study specific screening procedures
9. Patient affiliated to a social security scheme
10. Middle and lower third rectal adenocarcinoma (diagnosed on the basis of standard clinical and MRI criteria)
11. • Participant receiving corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy.

Exclusion criteria 23

1. Upper third rectal adenocarcinoma (above 10 cm from the anal verge or sus-peritoneal on standard clinical and MRI criteria)
2. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
3. Tumor is causing symptomatic bowel obstruction (diverting stoma (ileostomy or colostomy) is allowed in case of obstructive rectal cancer. Bowel obstruction should not be an exclusion criteria as the obstruction has been relieved by a diverting stoma. It should be reminded that a stent is not recommended but not excluded in mid and low rectal cancer)
4. Known HIV infection
5. Vaccinations (live vaccine) within 14 days prior to start of treatment
6. Immunosuppression, including subjects with conditions requiring systemic corticosteroid treatment (>10 mg/day prednisone equivalent)
7. Active autoimmune disease requiring systemic treatment within the past 2 years or documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents at non-physiologic doses
8. History of organ transplantation
9. Pregnant or breastfeeding women
10. Patients who have already received immunotherapy, chemotherapy or radiotherapy for rectal cancer
11. Any progressive disease that has not been balanced over the last 6 months: hepatic insufficiency, renal insufficiency, respiratory insufficiency, etc
12. Other cancer treated within the last 5 years except in situ cervical carcinoma or basocellular/ spinocellular carcinoma or a cancer of the lynch syndrome spectrum considered cured at the time of inclusion.
13. Persons deprived of liberty or under guardianship or incapable of giving consent
14. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol or followup schedule
15. Participant has an active infection requiring systemic therapy within 1 week prior to the anticipated first dose of study treatment.
16. Contraindication to pelvic radiotherapy
17. Hypersensitivity to dostarlimab or any of its excipients
18. Allergy to any component of Chinese hamster ovary cells.
19. History of severe active life-threatening autoimmune disease
20. Interstitial lung disease
21. Uncontrolled central nervous system metastases or carcinomatous meningitis
22. Reccurent rectal cancer
23. • Patient has experienced any of the following with prior immunotherapy: any immune‑related AE (irAE) of Grade 3 or higher, immune-related severe neurologic events of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain‑Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms [DRESS] syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary objective is to evaluate the treatment strategy failure (TSF) rate at 24 months from the date of randomization.

Secondary endpoints 6

1. Adverse events (AEs) assessed according to NCI-CTCAE v5.0 will be presented by the number of patients with at least one AE by maximum grade and by causality to treatment (dostarlimab).
2. Disease Free Survival (DFS): DFS is defined by the time between the date of randomization and the date of disease recurrence including local, locoregional or metastatic relapse, second colorectal cancer, death whatever the cause of death. Patients alive without recurrence or second cancer will be censored at date of last news. The rate of alive patients without recurrence or second cancer will be done at 6, 12, 24 and 36 months.
3. Overall survival (OS): OS is defined by the time between the date of randomization and the date of death (regardless of the cause). Alive patients will be censored at date of last news. The rate of alive patients will be done at 6, 12, 24 and 36 months
4. The rate of organ preservation at 2 years is defined at the rate of patients without resection of primary tumor (local excision, TME surgery, permanent colostomy/ileostomy) at 2 years. The rate of local excision, TME (total mesorectal excision) surgery or creation of a permanent colostomy/ileostomy at 2 years is defined as the rate of patients with surgery at 2 years.
5. Quality of life: Quality of life will be assessed according to the questionnaire of EORTC QLQ-C30 and QLQ-CR29 scales (at baseline, 3, 6, 12 and 24 months). Scores will be described at inclusion by treatment arm. The time to final deterioration of the global health score will be calculated: it is defined as the time from the date of randomisation to the date of deterioration of more than 10 points compared to the inclusion score (without any improvement later) or death. Alive patients without d
6. Objective response rate (ORR): Objective Response rate is defined by patients with partial or complete response. The best tumor response will be evaluated throughout the treatment. The response is evaluated according to the various categories: complete, partial, stability, progression or non-evaluable response.

Investigational products

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

Test 1

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

Mehdi KAROUI

Public contact point

Organisation

Centre Hospitalier Universitaire De Dijon

Contact name

Mehdi KAROUI

Third parties 1

Locations

1 EU/EEA country · 66 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 31 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