MNK Inhibitor AUM001 in Combination With Either Pembrolizumab or Irinotecan to Treat Metastatic Colorectal Cancer

• Drug: Tinodasertib
• Drug: Pembrolizumab
• Drug: Irinotecan

Main Inclusion criteria:

1. The participant provides written informed consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment. for the trial.
2. Subjects are at least 18 years of age at the time of signing the Informed Consent Form
3. Subjects with histologically or cytologically confirmed diagnosisthe process of identifying a disease based on signs and symptoms, patient history and medical test results of locally advancedat a late stage, far along or metastatic CRC.
   1. Locally determined histological diagnosis is acceptable for study entry in Module 1.
   2. Subjects can be enrolled in module 1 regardless of microsatellite stability status.
   3. Only subjects with CRC MSS will be enrolled in module 2, arm B’.
4. Subjects who have had >2 lines of prior therapy for their CRC.
   1. Prior use of irinotecan or irinotecan containing regimens is permitted
   2. CRC MSI-H patients should have been treated with a checkpoint inhibitor and have progressed on such therapy or found to be resistant, refractory or intolerant to the checkpoint inhibitor
   3. Patients with an available molecularly targeted therapymedication that targets specific molecular features of cancer cells such as antibodies targeting VEGF/R, EGFR, encorafenib/cetuximab, prior to study entry. Additionally, patients with driver mutations for which an FDA approved therapy is available such as BRAF V600E, HER2 or NTRK should have been offered such therapy prior to study entry.
   4. CRC subjects will be eligible to enrol in Arm C’ if they have failed an established 5-fluorouracil containing regimen and have progressed after oxaliplatin based or irinotecan-based combination therapy and do not have a driver mutation for which there is an approved targeted therapy.
5. Subject must have provided archival tumor tissuea group of cells that work together to perform a function sample or newly obtained core or excisional or punch needle biopsyremoval of a section of tissue to analyse for cancer cells of a tumor lesion not previously irradiated.
6. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiologist.
7. Eastern Cooperative Oncologythe study, diagnosis and treatment of cancer Group (ECOG) performance status of 0 to 1.
8. Have a predicted life expectancy of greater or equal to 3 months.
9. Have adequate organ function
10. HIV infected participants must be on anti-retroviral therapy (ART) and have a well-controlled HIV infectiona condition where harmful pathogens, such as bacteria, viruses or parasites, have entered the body/disease
11. Women of childbearing potential must not be breastfeeding and must have a negative serum or urine pregnancy test. Must be willing to use an adequate method of contraception.
12. Women of non-childbearing potential: Evidence of post-menopausal status is required.
13. Male subjects: Non-sterilized male subjects who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom plus spermicide. Male subjects should refrain from sperm donation throughout this period.