KORTUC (KRC-01) Plus Radiotherapy for Organ Preservation in Rectal Cancer

Inclusion Criteria:

1. Males and females ≥ 18 years of age.
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
3. Histopathologically confirmed locally advanced rectal adenocarcinoma, stage III (high risk)
4. No evidence of metastatic disease on computed tomography (chest and abdomen), including resectable metastases. (M0, and no oligometastases)
5. At least one of the following criteria: cT4a, cT4b, presence of extramural invasion (EMVI+), cN2, involvement of the mesorectal fascia (MFI+), involvement of lateral lymph nodes (lat LN+)
6. Adenocarcinoma located with a lower border less than 15 cm from the anal margin
7. Primary resection without chemoradiotherapy is unlikely to achieve clear margins.
8. Tumor lesion must be mesurable by endoscopic visual assessment
9. Target tumor is accessible for intratumoral injections.
10. Intention to undergo treatment including 5 Fu based chemoradiotherapy and CAPOX (6 cycles) or FOLFOX (9 cycles)
11. Life expectancy \> 6 months
12. Acceptable organ functions, as evidenced by the following laboratory data:

    1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0×upper limit of normal (ULN).
    2. Total serum bilirubin ≤ 1.5×ULN.
    3. Absolute neutrophil count (ANC): ≥ 1500 cells/mm³.
    4. Platelet count: ≥ 100,000 cells/mm³.
    5. Hemoglobin: ≥ 9.0 g/dL.
    6. Serum creatinine levels ≤ 1.5×ULN, or calculated (by Cockcroft-Gault formula or other accepted formula) and measured creatinine clearance ≥50 mL/min.
    7. Amylase and lipase ≤ 1.5xULN.
    8. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ≤ 1.5.
13. Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior to the administration of the first study treatment and/or urine pregnancy 12 hours prior to the administration of the first study treatment.

    1. Female subjects of childbearing potential should be willing to use a highly effective method of contraception or be surgically sterile or abstain from heterosexual activity during the study treatment and for at least 15 months after the last dose of oxaliplatin and 6 months after the last dose of capecitabine or 5-fluorouracil, whichever period is longer.. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year. cf. section 7.8 "Pregnancy and contraception") Note: A woman is considered of childbearing potential following menarche and until becoming post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral oophorectomy, and bilateral salpingectomy. A "highly effective" birth control method is one which can achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include: combined (estrogen and progestogen containing) hormonal contraception; progestogen-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner (on the understanding that this is the only partner during the whole study duration), and sexual abstinence during the entire period of risk associated with study treatment. To prevent the risk of interaction between the study drug and hormonal contraceptives, hormonal contraceptives should be supplemented with a barrier method (preferably male condom). Following methods are considered as unacceptable methods (non-exhaustive list): periodic abstinence (calendar, symptothermal, post-ovulation methods) and withdrawal (coitus interruptus).
    2. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy until at least 12 months after the last dose of oxaliplatin and 3 months after the last dose of capecitabine or 5-fluorouracil, whichever period is longer.

    Also, it is recommended that women of childbearing potential partner use a highly effective method of contraception.
14. Patients who either do not consent to a tumor biopsy or do not have accessible lesions will not be eligible.
15. Patients should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.
16. Patient should be able and willing to comply with study visits and procedures as per protocol.
17. Patient must be affiliated to a social security system or beneficiary of the same.

Exclusion Criteria:

1. Patients not deemed fit for radiotherapy or preexisting condition which would deter radiotherapy, e.g., fistulas, severe ulcerative colitis (including subjects currently taking sulphasalazine), active Crohn's disease, prior adhesions.
2. Patients with hypokalemia below the lower limit of normal, hypomagnesemia, hypocalcemia, or QT/QTc interval \>450 msec in males or \>470 msec in females at inclusion are not eligible.
3. Any Previous radiotherapy in the pelvic region.
4. Contraindications to MRI (e.g., subjects with pacemakers, claustrophobia, excessive weight, etc.).
5. Participation in another clinical study with an investigational product during the last 3 months.
6. Prior rectal surgery.
7. Prior investigational treatment for rectal cancer.
8. Patients with known high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) tumors are not eligible, as these patients may benefit from standard-of-care immunotherapy.
9. High medical risk because of systemic diseases (e.g., uncontrolled infections, uncontrolled diabetes) in addition to the qualifying disease under study. Patients must not have any uncontrolled concurrent illness including, but not limited to, severe active or uncontrolled infection, symptomatic congestive heart failure, unstable, angina pectoris, cardiac arrhythmia, uncontrolled diabetes mellitus or psychiatric illness/social situations that would limit compliance with study requirements.
10. Patients receiving therapeutic anticoagulation are not eligible. Prophylactic anticoagulation at low dose (e.g., thromboprophylaxis) may be allowed at the investigator's discretion, provided that the bleeding risk is considered minimal.
11. Patients receiving concomitant treatment with brivudine or who have received brivudine within the previous 4 weeks.
12. Peripheral sensory neuropathy grade ≥2 (for the future administration of oxaliplatin)
13. Dihydropyrimidine deshydrogenase (DPD) deficiency. DPD status must be assessed prior to inclusion, and uracilemia testing is mandatory before initiation of fluorouracil-based treatment. Patients with unknown DPD status are not eligible.
14. Concomitant medications/comorbidities that may prevent the patient from receiving study treatments,
15. Contraindication to fluoropyrimidines or oxaliplatin and capecitabin as mentioned in the SMPC of investigational medicinal products: FOLFOX is contraindicated in patients with known hypersensitivity to 5-fluorouracil, oxaliplatin, leucovorin, or other platinum compounds; in those with severe renal impairment (CrCl \<30 mL/min), significant bone marrow suppression, uncontrolled infections, or pre-existing grade ≥2 peripheral neuropathy. It is also contraindicated in individuals with complete or partial dihydropyrimidine dehydrogenase (DPD) deficiency due to the risk of severe 5-FU toxicity, as well as in cases of severe hepatic dysfunction, pregnancy, and breastfeeding. Caution is advised in patients with poor performance status (ECOG ≥3).
16. Yellow fever vaccine and live attenuated vaccines are contraindicated due to the risk of severe vaccine-induced infection. Note: The currently authorized COVID-19 vaccines are not live vaccines and therefore can be safely administered.
17. Known history of human immunodeficiency virus (HIV) infection or seropositive results consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
18. Pregnant or breastfeeding women or intending to become pregnant during the clinical investigation.
19. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.