LYT-200 Alone and in Combination With Chemotherapy or Tislelizumab in Patients With Locally Advanced or Metastatic Solid Tumors

Part 1

1. Written Informed Consent (mentally competent patient, able to understand and willing to sign the informed consent form)

2. Age ≥ 18 years, male or non-pregnant female

3. Able to comply with the study protocol, as per Investigator's judgment

4. Histologically confirmed, unresectable locally advanced or metastatic cancer. There are no limits to prior lines of therapies received for the treatment of the cancer condition for which the patient is being enrolled into this study.

1. For the Part 1 combination urothelial carcinoma Cohorts 13 and 14: histologically or cytologically confirmed diagnosis of unresectable, locally advanced or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra (i.e., transitional cell carcinoma).

2. For the Part 1 combination H/N cancer Cohorts 11 and 12: histologically confirmed, locally advanced or metastatic squamous cell carcinoma of head and neck (SCCHN; oral cavity, oropharynx, hypopharynx, or larynx).

5. For urothelial and H/N combination cancer cohorts, prior exposure to immunotherapy is allowed, with standard of care treatment options and/or within a clinical trial context. If the patient received an anti-PD-1 and/or an anti-PD-L1 containing regimen at any point, they must have demonstrated at least stable disease, as per RECIST 1.1 or iRECIST criteria to one of these treatment regimens, if these measurements are available. If RECIST or iRECIST measurements are not available, then clinical PFS of at least 4 months is required to have been achieved on any of the prior anti-PD-1 and/or anti-PD-L1 containing regimens.

6. There is no PD-L1 expression requirement for the Part 1 combination urothelial and H/N cohorts; however, fresh biopsy or archival tissue is required for assessment of PD-L1 by IHC, or a historical PD-L1 expression by IHC must be available. If PD-L1 expression data are already available, this does not override the protocol preference for obtaining a fresh biopsy whenever feasible.

7. For Part 1 combination cohort H/N cancer patients of oropharynx origin: human papilloma virus (HPV) status needs to be established in the screening period or at any point while patient is on study drug, unless it is historically known. p16+ as a surrogate for HPV+, HPV RNA ISH or DNA PCR are all acceptable. The study accepts both HPV+ and HPV- patients.

8. Life expectancy \> 3 months according to Investigator's judgment

9. ECOG performance status 0-1

10. Patient able and willing to undergo pre- and on/post treatment biopsies. According to the Investigator's judgment, 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.

11. Measurable disease, according to RECIST v1.1. Note that lesions intended to be biopsied should not be target lesions.

12. Adequate hematologic and end organ function, defined by the following laboratory results obtained prior to first dose of study drug treatment, provided no anticancer treatment was administered within the last 7 days:

1. neutrophil count ≥ 1 x 109/L

2. platelet count ≥ 100 x 109/L; for hepatocellular carcinoma (HCC) in Part 1 ≥ 50 x 109/L

3. hemoglobin ≥ 9.0 g/dL without transfusion in the previous week

4. creatinine ≤ 1.5 x the upper limit of normal (ULN); or eGFR \> 50 mg/mmol

5. aspartate aminotransferase AST (SGOT) ≤ 3 x ULN (≤ 5 x ULN when HCC or hepatic metastases are present)

6. alanine aminotransferase (ALT \[SGPT\]) ≤ 3 x ULN (≤ 5 x ULN when HCC or hepatic metastases present)

7. bilirubin ≤ 1.5 x ULN (patients with known Gilbert's disease may have a bilirubin ≤ 3.0 x ULN)

8. albumin ≥ 3.0 g/dL

9. international normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN, unless patient receiving anticoagulant therapy

13. No evidence of active serious infection or infections requiring parenteral antibiotics.

14. Women of childbearing 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 (e.g., 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.

15. Four (4) weeks or 5 half-lives (whichever is shorter) since the last dose of anticancer therapy before the first LYT-200 administration

16. Bisphosphonate treatment (e.g., zoledronic acid) or denosumab are allowed if previously used prior to commencement of clinical trial.

17. Patients:

1. who have already received at least one prior line of systemic therapy for metastatic or locally advanced disease, and/or

2. who have a tumor type for which there are no available standard of care options

18. Patients who have not previously received a gemcitabine-containing regimen

What this study is about