Inclusion Criteria: Part 1 and Part 2:

• Written Informed Consent (mentally competent patient, able to understand and willing to sign the informed consent form).
• Male or non-pregnant female, age ≥ 18 years.
• Histologically confirmed unresectable metastatic cancer (adenocarcinomas and squamous cell carcinomas allowed).
• Able to comply with the study protocol, as per Investigator’s judgment.
• Life expectancy > 3 months according to Investigator’s judgement.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Coronavirus SARS-CoV-2 (COVID-19) negative patients (by real time quantitative polymerase chain reaction [RT-qPCR]) at the time of enrollment (test done within 72 h prior to enrollment).
• Patient able and willing to undergo pre- and on/post-treatment biopsies. According to the Investigator’s judgement, the planned biopsies should not expose the patient to substantially increased risk of complications. Every effort will be made that the same lesion is biopsied on repeat biopsies. If the patient is eligible according to all other criteria but declines to consent to a biopsy or there are other medical reasons precluding biopsy, this will be discussed with the sponsor.
• Measurable disease, according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Note that lesions intended to be biopsied should not be target lesions.
• Vaccination for COVID-19 and common flu is allowed before or during the study period. Information on timing and type of vaccine must be recorded.
• Adequate hematologic and end organ function, defined by the following laboratory results obtained prior to first dose of study drug treatment, provided no anti-cancer treatment was administered within the last 7 days:
  • neutrophil count ≥ 1 x 10^9/L;
  • platelet count ≥ 100 x 10^9/L; for hepatocellular carcinoma (HCC) in Part 1 ≥ 50 x 10^9/L;
• • hemoglobin ≥ 8.5 g/dL without transfusion in the previous week;
  • creatinine ≤ 1.5 x upper limit of normal (ULN);
  • aspartate aminotransferase AST (SGOT) ≤ 3 x ULN (≤ 5 x ULN when HCC or hepatic metastases are present);
  • alanine aminotransferase (ALT [SGPT]) ≤ 3 x ULN (≤ 5 x ULN when HCC or hepatic metastases present);
  • bilirubin ≤ 1.5 x ULN (patients with known Gilbert’s disease may have a bilirubin ≤ 3.0 x ULN);
  • albumin ≥ 3.0 g/dL;
  • international normalized ratio (INR) and partial thromboplastin time (PTT);
  • ≤ 1.5 x ULN;
  • amylase and lipase ≤ 1.5 x ULN.
• No evidence of active infection or infections requiring parenteral antibiotics, and no serious infection within 4 weeks before study start.
• Women of child-bearing potential must have a negative pregnancy test within 72 h prior to start of treatment. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or to use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 180 days after the last study treatment.
• A woman is of childbearing potential if she is post-menarche, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
• Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptom-thermal, or post ovulation methods) and withdrawal are not acceptable methods of contraception. Fertile men must practice effective contraceptive methods during the study, unless documentation of infertility exists.
• Four (4) weeks or 5 half-lives (whichever is shorter) since the last dose of anti-cancer therapy before the first LYT-200 administration.
• Continuation of bisphosphonate treatment (e.g., zoledronic acid) or denosumab for bone metastases, which have been stable for at least 6 months before C1D1, is allowed...
• Biliary or gastric outlet obstruction allowed, provided it is effectively drained by endoscopic, operative, or interventional means.
• Pancreatic, biliary, or enteric fistulae allowed, provided they are controlled with an appropriate non-infected and patent drain (if any drains or stents are in situ, patency needs to be confirmed before study start).

• Additionally, for Part 1 only:

Patients:

• for whom there are no available standard of care options; or 
•  
• who have declined available and indicated standard of care therapy; or
• who are not eligible for available and indicated standard of care therapy.

Additionally, for Part 2 only:

• PDAC expansion cohort: 1st line metastatic patients who are either gemcitabine-containing regimen naïve or at least 3 months out of having been treated using a gemcitabine-containing regimen previously in a neoadjuvant or adjuvant/locally advanced setting.
• CRC and CCA expansion cohorts – patients who have received at least one prior line of therapy in the metastatic setting.

Exclusion Criteria:

• Patient unwilling or unable to follow protocol requirements.
• Patient diagnosed with metastatic cancer of an unknown primary.
• Prior or current illicit drug addiction (medical and recreational marijuana/cannabidiol [CBD]/ tetrahydrocannabinol [THC] would not be considered "illicit").
• Clinically significant, active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease). Prophylactic or therapeutic use of anticoagulants is allowed.
• Pregnant and/or lactating females.
• Receiving any other investigational agents or participating in any other clinical trial involving another investigational agent for treatment of solid tumors within 4 weeks or 5 half-lives of the administered drug.(whichever is shorter) prior to Cycle 1, Day 1 of the study, or other investigational therapy or major surgery within 4 weeks of the date of consent, or planned surgery within 4 weeks of envisaged study start (this includes dental surgery).
• Radiation therapy within 4 weeks of the first dose of study drug, except for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass, and which does not jeopardize required measurable lesions for response assessment (RECIST v1.1).
• Patients with fungating tumor masses.
• Patients with locally advanced PDAC without distant organ metastatic deposits.
• Grade 4 immune-mediated toxicities with a prior checkpoint inhibitor. Grade 2 or Grade 3 pneumonitis or any other Grade 3 checkpoint inhibitor-related toxicity that led to immunotherapy treatment discontinuation. Low-grade (< Grade 3) toxicities, such as neuropathy from prior treatments, manageable electrolyte abnormalities and lymphopenia, alopecia and vitiligo are allowed.
• History of second malignancy, except those treated with curative intent more than five years previously without relapse or low likelihood of recurrence (for example, non-melanotic skin cancer, cervical carcinoma in situ, early (or localized) prostate cancer, or superficial bladder cancer).
• Active brain or leptomeningeal metastases. Patients with brain metastases are eligible provided they have shown clinically and radiographically stable disease for at least 4 weeks after definitive therapy and have not used steroids (> 10 mg/day of prednisone or equivalent) for at least 4 weeks prior to the first dose of study drug.
• Evidence of severe or uncontrolled systemic diseases, congestive heart failure > New York Heart Association (NYHA) class 2, myocardial infarction (MI) within 6 months, or laboratory finding that in the view of the Investigator makes it undesirable for the patient to participate in the trial.
• Any medical condition that the Investigator considers significant to compromise the safety of the patient or that impairs the interpretation of LYT-200 toxicity assessment.
• Serious non-healing wound, active ulcer, or untreated bone fracture.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of Cycle 1, Day 1.
• History of pulmonary embolism, stroke or transient ischemic attack within 3 months prior to Cycle 1, Day 1.
• History of abdominal fistula or gastrointestinal perforation within 6 months prior to Cycle 1, Day 1.
• Active auto-immune disorder (except type I/II diabetes, hypothyroidism requiring only hormone replacement, vitiligo, psoriasis, or alopecia areata).
• Requires systemic immunosuppressive treatment, including, but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents. Patients who have received or are receiving acute, low dose systemic immunosuppressant medications (e.g., ≤ 10 mg/day of prednisone or equivalent) may be enrolled. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy [e.g., ≤ 10 mg/day of prednisone equivalent] for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone), topical steroids, intranasal steroids, intra-articular, and ophthalmic steroids is allowed.
• Severe tumor-related pain (Grade 3, Common Terminology Criteria for Adverse Events [CTCAE] v.5.0) unresponsive to broad analgesic interventions (oral and/or patches).
• Uncontrolled hypercalcemia, despite use of bisphosphonates.
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk of treatment complications.
• Received organ transplant(s).
• Patients undergoing dialysis.
• For patients enrolled into anti-PD-1 mAb combination cohorts, no prior exposure to any anti-PD-1 agent in any prior lines of therapy.
• For Part 1, hormonal androgen deprivation therapy is allowed to continue for patients with metastatic castration-resistant prostate cancer.
• Any ablative therapy (Radio Frequency Ablation or Percutaneous Ethanol Injection) for HCC < 6 weeks prior trial entry.
• Hepatic encephalopathy or severe liver adenoma.
• Child-Pugh score ≥ 7.