Olaptesed (NOX-A12) Alone and in Combination With Pembrolizumab in Colorectal and Pancreatic Cancer

Inclusion Criteria:

1. Written informed consent

2. Age ≥18 years

3. a) Male or female patient with a history of treated metastatic stage IV colorectalcancer with liver metastases of the primary colorectal cancer after two or more linesof prior treatment OR b) Male or female patient with a history of treated metastaticstage IV pancreatic ductal adenocarcinoma with liver metastases of the primarypancreatic cancer after one or more lines of prior treatment

4. Histologically or cytologically confirmed diagnosis of colorectal or pancreatic ductalcancer with liver metastasis

5. Measurable disease based on RECIST 1.1 as determined by the site study team

6. Expected survival of at least three months

7. Patient with liver metastasi(e)s amenable to repeated biopsies

8. Patient agreeing to repeated biopsies of metastases

9. Karnofsky performance status ≥80 %

10. a) Colorectal cancer patients that have received current standard treatment options (progression or intolerance to oxaliplatin, irinotecan, 5-fluorouracil andtrifluridine/tipiracil with or without treatment combinations of cetuximab and/orbevacizumab, or ramucirumab or panitumumab, or regorafenib, including monotherapieswith any of these options) OR b) Pancreatic cancer patients that have received currenttreatment options (progression or intolerance to combination therapies withoxaliplatinum, irinotecan, 5-fluorouracil, gemcitabine, nab-paclitaxel or erlotinib,including monotherapies with any of these options)

11. No chemotherapy treatment within the last three weeks prior to study MT Day 1

12. Resolution of toxic effect(s) of the most recent prior chemotherapy to levels deemedappropriate by the investigator; if patients have received major surgery, they musthave recovered from the toxicity and/or complications from the intervention

13. The following laboratory parameters should be within the ranges specified:

• Hemoglobin (Hb) ≥ 8.0 g/dL

• Absolute neutrophil count (ANC) ≥ 1,000/mm³ (≥ 1.0 x 10^9/L)

• Platelets ≥ 100,000/mm³ (≥ 100 x 10^9/L)

• Creatinine ≤ 1.5 x ULN or glomerular filtration rate ≥ 60 mL/min/1.73m²

• Total bilirubin ≤ 1.5 x ULN (upper limit normal)

• ALT (alanine transaminase) ≤ 5 x ULN

• AST (aspartate transaminase) ≤ 5 x ULN

• INR (International Normalized Ratio) or PT (Prothrombin Time) ≤ 1.5 x ULN unlesspatient is receiving anticoagulant therapy as long as PT or PTT is withintherapeutic range of intended use of anticoagulants

• aPTT (Activated Partial Thromboplastin Time) ≤ 1.5 x ULN unless patient isreceiving anticoagulant therapy as long as PT or PTT is within therapeutic rangeof intended use of anticoagulants

14. Female patients of child-bearing potential must have a negative urine or serumpregnancy test within 28 days prior to randomization. If the urine test is positive orcannot be confirmed as negative, a serum pregnancy test will be required. Patientsmust agree to use an effective method of contraception or be abstinent during and for 120 days following last dose of drug (more frequent pregnancy tests may be conductedif required per local regulations)

15. Male patients must use an effective barrier method of contraception during study andfor 120 days following the last dose if sexually active with a FCBP

Exclusion Criteria:

1. Inability to personally provide written informed consent or to understand andcollaborate throughout the study

2. Inability or unwillingness to comply with study requirements

3. Patients with metastatic lesions suitable for resection

4. Patients with metastatic cancer that have a drastic clinical progression (e.g. fromKarnofsky performance 100% to 70%) within the last six weeks before screening

5. Participation in any clinical research study with administration of an investigationaldrug or therapy within 30 days prior to enrolment in the study

6. Use of any investigational or non-registered product (drug or vaccine) other than thestudy treatment

7. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if the patient haspreviously participated in pembrolizumab clinical studies

8. Prior radiation therapy of tumor/metastases

9. Diagnosis of immunodeficiency or requiring concomitant chronic treatment with systemiccorticosteroids or any other immunosuppressive agents within 7 days prior to the firstdose of study treatment; the use of physiologic doses of corticosteroids may beapproved after consultation with the Sponsor

10. Intake of immunomodulatory medication (Type 1 interferons)

11. Prior anti-cancer monoclonal antibody (mAb) within 2 weeks prior to study MT Day 1 orwho has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to suchagents administered more than 2 weeks earlier

12. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2weeks prior to study MT Day 1 or no recovery (i.e., ≤ Grade 1 or at baseline) fromadverse events due to a previously administered agent

13. Prior transfusion of blood products (including platelets or red blood cells) oradministration of colony stimulating factors (including G-CSF, GM-CSF or recombinanterythropoietin) within 4 weeks prior to study MT Day 1

14. Live vaccine within 30 days prior to the first dose of study treatment

15. Active autoimmune disease that has required systemic treatment in past 2 years (i.e.with use of disease modifying agents, corticosteroids or immunosuppressive drugs).Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is not considered aform of systemic treatment

16. History of interstitial lung disease

17. History of (non-infectious) pneumonitis that required steroids or current pneumonitis

18. History of anaphylaxis or severe drug hypersensitivity reactions

19. Active infection requiring systemic therapy

20. Known to be positive for Human Immunodeficiency Virus (HIV) or other chronicinfections (HBV, HCV) or with another confirmed or suspected immunosuppressive orimmunodeficient condition

21. Concurrent chronic severe medical problems (heart failure, uncontrolled diabetes,bleeding disorder etc.), unrelated to the malignancy, that would significantly limitfull compliance with the study or expose the patient to unacceptable risk

22. Known additional malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of theskin that has undergone potentially curative therapy or in situ cervical cancer

23. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis

24. History or current evidence of any condition, therapy, or laboratory abnormality thatmight confound the results of the study, interfere with the patient's participationfor the full duration of the study, or is not in the best interest of the patient toparticipate, in the opinion of the treating investigator, is pregnant orbreastfeeding, or expecting to conceive or father children within the projectedduration of the study, starting with the screening visit through 120 days after thelast dose of study treatment

25. Women of childbearing potential: refusal or inability to use effective means ofcontraception

26. Contra-indication or known hypersensitivity to olaptesed pegol, polyethylene glycol,pembrolizumab or further ingredients to the investigational medicinal products

27. Known psychiatric or substance abuse disorders that would interfere with cooperationwith the requirements of the study

28. Previous enrolment in this clinical study