Multicenter randomized Phase III trial evaluating contact X-ray brachytherapy for rectal preservation in intermediate substage rectal adenocarcinoma (TRESOR)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Digestive System Diseases [C06]

Trial duration

26 Mar 2024 → ongoing

Decision date (initial)

2023-10-27

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

PHRC-K22-2013

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Therapy

To assess efficacy of contact X-ray brachytherapy (CXB) in addition to TNT in order to increase survival with organ preservation (OP), in selected intermediate risk group of rectal adenocarcinomas (size from 3.1 to 6 cm, cT2N1 or T3N0-1, M0).

Secondary objectives 4

1. To assess impact of CXB and OP on anorectal function (LARS score) and quality of life (QLQ CR-29 and C-30 (see appendix 4)).
2. To assess toxicity (NCI-CTC v5.0) and surgical morbidity (Clavien-Dindo classification (see appendix 3) of the addition of CXB to total neoadjuvant therapy (TNT).
3. To assess the efficacy of CXB on clinical complete response (cCR) rate at 7 weeks after the end of neoadjuvant chemo radiotherapy (nCRT), and on local recurrence rates (LR).
4. To determine overall survival (OS), disease-free survival (DFS), and metastasis-free survival (MFS) in both arms.

Conditions and MedDRA coding

Adult patients with intermediate low or mid rectal adenocarcinoma to be treated with total neoadjuvant therapy (TNT) potentially eligible for rectal preservation.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Patient with histologically proven rectal adenocarcinoma
2. Biological values within the following limits: Total Bilirubin ≤ 1.5 times the upper limit of normal (ULN); ASAT and ALAT ≤ 5 N; Creatinine ≤ 1.5 N and creatinine clearance> 60 ml/min; Neutrophils ≥ 1.5. 109 / L; Platelets ≥ 150. 109 / L; Hemoglobin ≥ 9 g / dL (patients can be included even if they have been transfused); Albuminemia≥30g / L before starting mFOLFIRINOX chimotherapy;
3. Women of childbearing potential must have a negative serum β-HCG pregnancy test within 15 days prior to the administration of the first study treatment or urine pregnancy 72 hours prior to the administration of the first study treatment.
4. Sexually active women of childbearing potential must agree to use a highly effective method of contraception, or to abstain from sexual activity during the study and for at least 6 months after the last study treatment administration (and at least 15 months after the last oxaliplatin infusion). A woman is considered of childbearing potential following menarche and until becoming post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) unless permanently sterile. [...] Following methods are considered as unacceptable methods (non-exhaustive list): periodic abstinence (calendar, symptothermal, post-ovulation methods) and withdrawal (coitus interruptus).
5. 5. Patient eligible for treatment with mFOLFIRINOX chemotherapy. Inclusion is possible before, during or at the end of a minimum of 4 cycles of mFOLFIRINOX chemotherapy (in case of toxicity) or up to a maximum of 6 cycles.
6. Sexually actives males patients must agree to use condom during the study and for at least 6 months after the last study treatment administration (and at least 12 months after the last oxaliplatin infusion).Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception for the same duration.
7. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
8. Patients must be affiliated to a social security system or beneficiary of the same
9. Intermediate risk factors: size ≥ 3.1 cm and ≤ 6 cm, < 66% circumference, cT2N1 or T3N0-1, M0 at diagnostic.
10. Accessible by digital rectal exam, distal or middle rectum (<11 cm from anal verge), not significantly involving the anal canal (external sphincter not involved) at diagnostic.
11. Operable patient
12. Age ≥ 18 years.
13. WHO status 0 or 1 at diagnostic
14. 3. If patients have lymph node involvement, this should be defined as : any lymph node with short axis ≥ 9 mm ; Lymph nodes 5 to 8 mm in short axis with at least two morphologic criteria ; Lymph nodes <5 mm and all three morphologic criteria The suspicious morphologic criteria include round shape, irregular borders, and heterogeneous signal intensity.

Exclusion criteria 19

1. Other cancer in the 5 years prior to start m Folfirinox chimiotherapy into the trial or concomitant (except in situ cancer of the cervix, or basal cell carcinoma of the skin).
2. Given the oxaliplatin-related risk of prolongation of QT, patient with hypokalemia less than normal, hypomagnesemia, hypocalcemia, and QT/QTc interval longer than 450 msec for men and longer than 470 msec for women on the inclusion ECG should not be allowed at diagnostic.
3. Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia).
4. Unbalanced serious illness, underlying infection likely to prevent the patient from receiving treatment current pregnancy (obligatory pregnancy test at baseline) or breastfeeding.
5. Psychiatric illness compromising the understanding of information or the conduct of the study.
6. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
7. Known history of hypersensitivity to, fluorouracil, capecitabine, oxaliplatin, irinotecan, folinic acid, or to any of their excipients, according to the SmPCs of these products
8. Recent or concomitant treatment with brivudine, according to the SmPC of fluorouracile and of capecitabine before starting mFOLFIRINOX chimotherapy.
9. Chronic inflammatory bowel disease and/or bowel obstruction and in case of concomitant use with St John's Wort, according to the SmPC of irinotecan before starting mFOLFIRINOX chimotherapy.
10. Peripheral sensory neuropathy with functional impairment prior to first treatment, according to the SmPC of oxaliplatin before starting mFOLFIRINOX chimotherapy.
11. Inability to sign informed consent or to undergo medical follow-up of the test for geographical, social or psychological reasons.
12. Pregnant or breastfeeding women
13. No other anti-tumour prior treatments (chemotherapy, hormone therapy, biologic response inhibitors, targeted therapy) may be used for rectal adenocarcinoma. All live or attenuated vaccines are prohibited before starting mFOLFIRINOX chemotherapy, during chemotherapy treatment and for up to 6 months afterwards.
14. The combination of warfarin (Coumadine®) with an mFOLFIRINOX regimen, FOLFOX or capecitabine is not recommended. It is preferable to use heparin or LMWH. If warfarin cannot be avoided, more frequent monitoring of prothrombin ratio and INR is necessary before starting mFOLFIRINOX chimotherapy.
15. Pimozide (Orap®), and cisapride (Prepulsid®) are formally contraindicated: increased risk of ventricular arrhythmias, especially torsades de pointes before starting mFOLFIRINOX chimotherapy.
16. History of pelvic irradiation or pelvis surgery
17. Early tumor (T1-2N0, size < 3.1 cm) or advanced tumor (T3 > 6cm ᴓ, T4, N2, M1) at dignostic
18. Dihydropyrimidine dehydrogenase (DPD) deficiency. The blood uracil level must be measured at screening. The uracilemia dosing result is mandatory prior the inclusion of patient. In patients with moderate to severe renal impairment, results should be interpreted with caution, and additional testing (e.g., DPYD gene genotyping) may be considered if the interpretation is uncertain.
19. Patient who stopped mFolfirinox after 3 cycles or less

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Survival with organ preservation, defined as a rectum intact, owing to: - no radical TME, - no locoregional regrowth unless amenable to limited curative (R0) salvage surgery by local excision (LE), and no permanent stoma (including a never reversed protective stoma, or a stoma owing to toxicities and/or poor functional outcomes).

Secondary endpoints 7

1. - Anorectal function: low anterior resection syndrome score (LARS score, appendix 2)
2. - Quality of life : EORTC questionnaires QLQ CR-29 and C-30 (appendix 2)
3. - Safety : toxicity grading of the National Cancer Institute (NCI-CTC v5.0)
4. - Surgical complications: Clavien-Dindo Classification of surgical complications (appendix 3).
5. - Clinical complete response rates at 7 weeks after nCRT
6. - Local recurrence rate
7. Efficacy: overall survival (OS), disease-free survival (DFS), and metastasis-free survival (MFS) rates.

Investigational products

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

Test 1

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Locations

1 EU/EEA country · 15 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 16 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