Study to Investigate Outcome of Individualized Treatment in Patients With Metastatic Colorectal Cancer

Pre-screening:

Inclusion Criteria:

* Has a histologically-proven locally advanced or metastatic adenocarcinoma from colon or rectum
* Has received or is receiving systemic treatment for mCRC
* Has non-resectable metastases and eligible to undergo a radiological-guided core biopsy from at least one metastasis
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Has measurable or evaluable disease (per RECIST v1.1)
* Is capable of giving signed informed consent, as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

Exclusion Criteria:

* Has other clinically significant medical conditions which, in the opinion of the treating physician, makes it undesirable for the patient to participate in the study or which could jeopardize compliance with study requirements.

MAIN STUDY:

Inclusion Criteria:

1. Has a histologically-proven locally advanced or metastatic adenocarcinoma from colon or rectum (mCRC)
2. Has received at least two lines of SOC chemotherapy for mCRC Note: 1) For patients who develop a metastatic relapse \< 6 months after completed total neo-adjuvant treatment in conjunction with a metastasectomy, this treatment will be considered as one line (e.g. first-line) chemotherapy. 2) Patients with the gene RAS wild-type tumors should have received or have been offered and refused prior treatment with antibodies against epidermal growth factor receptor (EGFR) (e.g. in combination with prior lines of chemotherapy) unless it was contraindicated due to underlying conditions or the tumor contains molecular alterations suggested to provide primary resistance to EGFR-targeted therapy.
3. Has full combined pharmacogenomic profile (genomic and transcriptomic profile of the patients tumor and ex vivo drug sensitivity testing of PDOs from the patient's own tumors cells) from which the MTB suggests a treatment with one of the defined targeted anti-cancer therapies provided this study
4. Has measurable or evaluable disease (per RECIST v1.1)
5. ECOG performance status 0 or 1
6. For orally administered drugs, the participant must be able to swallow and tolerate oral medication and must have no known malabsorption syndrome.
7. Because of the risks of drug treatment to a developing fetus, women of child-bearing potential and men must agree to use adequate contraception in accordance with the respective SmPC and as listed in Appendix 4 for the duration of study participation, and up to 7 months following completion of study therapy. Male study patients, even if surgically sterilized, (i.e. post-vasectomy) must agree to one of the following: practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, or completely abstain from sexual intercourse.
8. Has acceptable organ function as defined below. However, as noted below (exclusion criterion 16), drug-specific inclusion/exclusion criteria specified in the Appendix 16/respective SmPC for each agent will take precedence for this and all inclusion criteria:

   1. Absolute neutrophil count ≥ 1.5/nL (nL = nano Litre)
   2. Hemoglobin \> 10 g/dL
   3. Platelets \> 100/nL
   4. Total bilirubin \< 1.5 x institutional upper limit of normal (ULN)
   5. Aspartate aminotransferase AST (SGOT) and alanine aminotransferase ALT(SGPT) \< 2.5 x institutional upper limit of normal (ULN) (or \< 5 x ULN in patients with known hepatic metastases)
   6. Calculated or measured creatinine clearance ≥ 50 mL/min/1.73 m2

Exclusion Criteria:

1. Has ongoing toxicity \> CTCAE grade 2, other than peripheral neuropathy and alopecia, related to anti-tumor treatment that was completed within 4 weeks prior to registration. Patients with ongoing peripheral neuropathy of ≥ CTCAE grade 3 will be excluded.
2. Has received previous treatment with the selected study drug for the same malignancy.
3. Has a tumor with a genomic variant known to confer resistance to an anti-cancer agent available in this study, the patient will not be eligible to receive that agent but will be eligible to receive other drugs available in this study if all inclusion and exclusion criteria are met for that drug.
4. Is receiving any other anti-cancer therapies (cytotoxic, biologic, radiation, or hormonal other than for replacement). Participants may be on warfarin, low molecular weight heparin or direct factor Xa inhibitors, unless such therapies are prohibited by drug-specific exclusion criteria (please consult the corresponding SmPC and Appendix 16 for prohibited medication and contraindication/precautions).
5. Is pregnant or breastfeeding or refusing any type of required contraception methods.
6. Has known Central Nervous System (CNS) metastases.
7. Has preexisting cardiac conditions, including uncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias, or symptomatic congestive heart failure.
8. Has left ventricular ejection fraction (LVEF) known to be \< 40%.
9. Has had a stroke (including TIA) or an acute myocardial infarction within 6 months before the first dose of study treatment.
10. Has had acute gastrointestinal bleeding within 1 month of start of treatment
11. Has other clinically significant medical conditions which, in the opinion of the treating physician, makes it undesirable for the patient to participate in the study or which could jeopardize compliance with study requirements.
12. Meets any of the assigned drug contraindications or other drug-specific exclusion criteria as described in the respective SmPC and in Appendix 16