A Phase 1 Open-label, Multi-center Study of the Safety, Pharmacokinetics (PK), and Anti-tumor Activity of LYT-200 in Patients with Relapsed/refractory Acute Myeloid Leukemia (AML), or with Relapsed/Refractory, High/Very High Risk Myelodysplastic Syndrome (MDS).

Inclusion Criteria

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

Exclusion Criteria

1. Patient unwilling or unable to follow protocol requirements

2. Patient diagnosed with metastatic cancer of an unknown primary

3. Current illicit drug addiction (medical and recreational marijuana/cannabidiol [CBD]/

tetrahydrocannabinol [THC] would not be considered "illicit")

4. 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.

5. Pregnant and/or lactating females

6. Receiving any other investigational agents or participating in any other clinical

trial involving another investigational agent for treatment of solid tumors within 3

weeks or 5 half-lives of the administered drug (whichever is shorter) prior to the

first dose of study drug, or major surgery or planned surgery within 4 weeks of the

first dose of study drug (this includes dental surgery).

7. 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).

8. Patients with fungating tumor masses

9. History or current evidence of any condition, therapy, any active infections, or

laboratory abnormality that might confound the results of the trial, interfere with

the patient's participation for the full duration of the trial, or is not in the best

interest of the patient to participate, in the opinion of the treating Investigator

10. 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.

11. History of other prior or other concomitant malignancy that requires other active

treatment.

12. Active parenchymal brain metastases, patients with carcinomatous meningitis 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

13. 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

14. 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

15. Serious non-healing wound, active ulcer, or untreated bone fracture unless for e.g., a

rib fracture for (which does not elicit treatment)

16. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent

drainage procedures. For the purposes of this study, "recurrent" is defined as ³ 3

drains in the last 30 days

17. History of severe allergic, anaphylactic, or other hypersensitivity reactions to

chimeric or humanized antibodies or fusion proteins

18. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or

recent arterial thrombosis) within 6 months of Cycle 1, Day 1

19. History of pulmonary embolism, stroke or transient ischemic attack within 3 months

prior to Cycle 1, Day 1

20. Active autoimmune disorder (except type I/II diabetes, hypothyroidism requiring only

hormone replacement, vitiligo, psoriasis, or alopecia areata).

21. 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.

22. Severe tumor-related pain (Grade 3, CTCAE v.5.0) unresponsive to broad analgesic

interventions (oral and/or patches)

23. Hypercalcemia (defined as ³ Grade 3, per CTCAE v 5.0) despite use of bisphosphonates

24. 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

25. Received organ transplant(s)

26. Patients undergoing dialysis

27. For Part 1, hormonal androgen deprivation therapy is allowed to continue for patients

with metastatic castration-resistant prostate cancer

28. Any ablative therapy (Radio Frequency Ablation or Percutaneous Ethanol Injection) for

HCC < 6 weeks prior trial entry

29. Hepatic encephalopathy or severe liver adenoma

30. Child-Pugh score ≥ 7