An Open-Label Multicenter Phase 1b Study of Tolinapant (ASTX660) in Combination With Radiotherapy/Chemoradiotherapy (RT/CRT) in Preoperative Treatment of Patients With Rectum Cancer (PRAAR 1: Preoperative Radiotherapy And ASTX660 in Rectum Cancer)
Compare two arms: * Chemotherapy followed by tolinapant (ASTX660) in combination with Long-Course Radio Chemotherapy (LCRT), and * Tolinapant (ASTX660) in combination with Short-Course Radiotherapy (SCRT) followed by chemotherapy For each patient, the treatment arm will be allocated on the following basis: patients will be allocated to the chemotherapy followed by LCRT arm unless they present at least one of the following criteria: contraindication to receive mFOLFIRINOX (including intolerance to irinotecan and UGT1A1\*28 polymorphism), age \> 75, general condition incompatible with the radiotherapy schedule of LCRT. In such case, patients will be allocated to the SCRT arm. Tolinapant (ASTX660) will be administered orally once a day for 7 consecutive days every other week during 10 weeks (One week On / One week Off during 10 weeks). Both treatment arms will have a dose escalation part to determine the MTD and/or RP2D, followed by an expansion part where up to 21 subjects will be dosed at the RP2D. Both arms will enroll simultaneously.
∙ Locally advanced rectum cancer where primary resection without chemoradiotherapy is unlikely to achieve clear margins as defined by:
• a distance between the tumor or its lymph node and the mesorectal fascia ≤ 2 mm on the pelvic MRI at diagnosis.
‣ \*and/or N2
• No evidence of metastatic disease on CT-scan (chest and abdomen), including resectable metastases
• Age : ≥ 18 years old at the time of informed consent
• Successfully received at least 4 cycles and up to 6 cycles of mFOLFIRINOX (LCRT arm only)
• 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×upper limit 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 or other accepted formula) or measured creatinine clearance ≥50 mL/min
⁃ Amylase and lipase ≤1.5xULN
⁃ Adequate blood coagulation function as evidenced by an International Normalized Ratio (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 effective method of contraception or be surgically sterile, or abstain from heterosexual activity for the course of the study through 6 months after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.
‣ Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy.
⁃ Also, it is recommended that women of childbearing potential partner use a highly effective method of contraception.
• Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. Patient must be able and willing to comply with study visits and procedures as per protocol.
• Patient must be affiliated to a social security system or beneficiary of the same.