Preoperative Radiotherapy And ASTX660 in Rectum Cancer

Inclusion Criteria: Locally advanced rectum cancer where primary resection without chemoradiotherapy isunlikely to achieve clear margins as defined by:

• a distance between the tumor or its lymph node and the mesorectal fascia ≤ 2 mm on thepelvic MRI at diagnosis.
• *and/or N2
• No evidence of metastatic disease on CT-scan (chest and abdomen), including resectablemetastases
• Age : ≥ 18 years old at the time of informed consent
• Successfully received at least 4 cycles and up to 6 cycles of mFOLFIRINOX (LCRT armonly)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0 or 1
• Acceptable organ functions, as evidenced by the following laboratory data:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0×upperlimit of normal (ULN)
• Total serum bilirubin ≤1.5×ULN
• Absolute neutrophil count (ANC): ≥2,000 cells/mm^3
• Platelet count: ≥100,000 cells/mm^3
• Hemoglobin: ≥ 9.0 g/dL
• Serum creatinine levels ≤1.5×ULN, or calculated (by Cockcroft-Gault formula orother accepted formula) or measured creatinine clearance ≥50 mL/min
• Amylase and lipase ≤1.5xULN
• Adequate blood coagulation function as evidenced by an International NormalizedRatio (INR) ≤ 1.5.
• Women of childbearing potential must have a negative serum β-HCG pregnancy test within 3 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.
• Female subjects of childbearing potential should be willing to use a highly effectivemethod of contraception or be surgically sterile, or abstain from heterosexualactivity for the course of the study through 6 months after the last dose of studymedication. Subjects of childbearing potential are those who have not been surgicallysterilized or have not been free from menses for > 1 year.
• Male subjects should agree to use an adequate method of contraception startingwith the first dose of study therapy through 6 months after the last dose ofstudy therapy.
• Also, it is recommended that women of childbearing potential partner use a highlyeffective method of contraception.
• Patient should understand, sign, and date the written informed consent form prior toany protocol-specific procedures performed. Patient must be able and willing to complywith study visits and procedures as per protocol.
• Patient must be affiliated to a social security system or beneficiary of the same.

Exclusion Criteria:

• Any contraindications to MRI (e.g. subjects with pacemakers, claustrophobia, excessiveweight, etc).
• Participation in another clinical study with an investigational product during thelast 3 months.
• No other anticancer therapy during study participation. (however, informed consent canbe signed during mFOLFIRINOX for patients willing to enter the LCRT arm).
• Hypersensitivity to tolinapant (ASTX660) or excipients of the drug product, or to anyother component of the study treatment regimen, including:
• 5-FU, capecitabine and known dihydropyrimidine dehydrogenase (DPD) deficiency, or
• Oxaliplatin, or
• Irinotecan and known Gilbert disease or genotype UGT1A1 (LCRT arm only)
• Previous radiotherapy in the pelvic region
• Preexisting condition that would deter radiotherapy, e.g. fistulas, severe ulcerativecolitis (including subjects currently taking sulphasalazine), active Crohn's disease,prior adhesions
• Preexisting condition that would deter chemotherapy, e.g. pneumonitis, pulmonaryfibrosis, pernicious anemia or other anemias caused by vitamin B12 deficiency
• Prior rectal surgery
• Prior investigational treatment for rectal cancer
• Poor medical risk because of systemic diseases (e.g., uncontrolled infections,uncontrolled diabetes) in addition to the qualifying disease under study
• Life-threatening illness, significant organ system dysfunction, or other conditionthat, in the investigator's opinion, could compromise subject safety or the integrityof the study outcomes, or interfere with the absorption or metabolism of tolinapant (ASTX660)
• A history of, or at risk for, cardiac disease, as evidenced by 1 or more of thefollowing conditions:
• Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO)or multiple-gated acquisition scan (MUGA)
• Congestive cardiac failure of ≥ Grade 3 severity according to New York HeartAssociation (NYHA) functional classification defined as subjects with markedlimitation of activity and who are comfortable only at rest
• Unstable cardiac disease including unstable angina or hypertension as defined bythe need for overnight hospital admission within the last 3 months (90 days)
• History or presence of complete left bundle branch block, third-degree heartblock, cardiac pacemaker, or clinically significant arrhythmia
• Concurrent treatment with any medication that prolongs QT interval and may inducetorsades de pointes and which cannot be discontinued at least 2 weeks beforetreatment with tolinapant (ASTX660)
• Personal history of long QTc syndrome or ventricular arrhythmias includingventricular bigeminy
• Screening 12-lead ECG with measurable QTc interval (according to eitherFridericia's or Bazett's correction) of ≥470 msec)
• Any other condition that, in the opinion of the investigator, could put thesubject at increased cardiac risk
• Refractory nausea and vomiting, chronic gastrointestinal diseases (eg, inflammatorybowel disease and/or bowel obstruction), or significant bowel resection that mayimpair adequate absorption and bioavailability of study drug. Major disturbance ofbowel function (e.g. gross fecal incontinence or requiring > 6 mg loperamide eachday).
• Known history of human immunodeficiency virus (HIV) infection; or seropositive resultsconsistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV)infection.
• Peripheral sensory neuropathy grade >2
• Pregnancy or ongoing breastfeeding
• Patient under guardianship or deprived of his liberty by a judicial or administrativedecision or incapable of giving its consent. Yellow fever vaccine and live attenuated vaccines are contraindicated due to risk of severevaccine-induced infection. NB :
• The currently authorized COVID-19 vaccines are not live vaccines and therefore can besafely administered.
• For patients registered in LCRT, all eligibility criteria will be fulfilled duringmFOLFIRINOX (until 2 weeks after the end of mFOLFIRINOX).
• For patients registered in SCRT, all eligibility criteria will be fulfilled before anytreatment.