Phase Ib of L-NMMA and Pembrolizumab

The purpose of this Phase Ib study is to test the safety of NG-monomethyl-L-arginine (L-NMMA)
and pembrolizumab when used together in participants with melanoma, non-small cell lung
cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma
(cHL), urothelial carcinoma, or microsatellite instability-high (MSI-H)/mismatch repair
deficient (dMMR) cancer. Pembrolizumab is a type of treatment that stimulates the immune
system to attack cancer cells. The immune system is normally the body's first defense against
threats like cancer. However, sometimes cancer cells produce signals like PD-L1 that prevent
the immune system from detecting and killing them. Pembrolizumab blocks programmed death-1
(PD-1) so your immune system can detect and attack cancer cells. To help further boost the
cancer-fighting ability of your immune system, L-NMMA will be used along with pembrolizumab.
L-NMMA is a nitric oxide synthase inhibitor. The presence of nitric oxide synthase in the
area around the cancer cells blocks the cancer-fighting ability of the immune system. Thus,
the use of L-NMMA and pembrolizumab together may make the immune system work harder to attack
and destroy the cancer cells.

In this study, up to 3 different doses of L-NMMA will be studied (12.5, 15, and 20 mg/kg).
Participants will only receive one of the three L-NMMA doses. The first several study
participants will receive the 15 mg/kg dose. If the 15 mg/kg dose of L-NMMA causes serious
side effects, L-NMMA will be given to other study participants at the lower dose of 12.5
mg/kg. If the 15 mg/kg dose of L-NMMA does not cause serious side effects, L-NMMA will be
given to other study participants at the higher dose of 20 mg/kg. All study participants will
be given the same dose of pembrolizumab (200 mg). This study will allow us to see the highest
dose of L-NMMA that can be used safely with pembrolizumab in participants with melanoma,
NSCLC, HNSCC, cHL, urothelial carcinoma, or MSI-H/dMMR cancer.

Inclusion Criteria:

- Female or male aged ≥ 18 years on the day of informed consent signing;

- Has histologically confirmed metastatic melanoma that is treatment naïve or has
relapsed after or is refractory to ipilimumab or BRAF inhibitor (if BRAF mutation
positive), OR histologically confirmed metastatic NSCLC that has high programmed
death-ligand 1 (PD-L1) expression (tumor proportion score [TPS] ≥50%) with no
epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic
tumor aberrations or histologically confirmed metastatic NSCLC that is PD-L1 positive
(TPS ≥1%) and has progressed on or after platinum containing therapy (subjects with
NSCLC harboring EGFR/ALK genomic aberrations must have received an FDA-approved
targeted therapy for these aberrations) OR histologically confirmed HNSCC that has
relapsed after or is refractory to platinum-containing chemotherapy, OR histologically
confirmed cHL that has relapsed after three or more lines of therapy or is refractory
to treatment OR histologically confirmed locally advanced or metastatic urothelial
carcinoma that is not eligible for platinum-containing chemotherapy or that has
relapsed after or is refractory to platinum-containing chemotherapy OR MSI-H or dMMR
unresectable or metastatic cancer that has relapsed after prior treatment and has no
satisfactory alternative treatment options;

- Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1;

- Eastern Cooperative Oncology Group performance status of 0−2;

- Life expectancy ≥ 6 months;

- Adequate organ function:

Absolute neutrophil count ≥1,500/mm3, platelets ≥100,000/mm3, hemoglobin ≥9 g/dL
(transfusion permitted), serum creatinine OR measured or calculated creatinine clearance
≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X
institutional ULN, serum total bilirubin ≤ 1.5 X ULN OR direct bilirubin ≤ ULN for subjects
with total bilirubin levels > 1.5 ULN, alanine transaminase and aspartate transaminase ≤
2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases, albumin >2.5 mg/dL,
International normalized ratio or prothrombin time ≤1.5 X ULN, and activated partial
thromboplastin time ≤1.5 X ULN;

- Cardiac ejection fraction of ≥ 45%;

- Female subjects of childbearing potential should have a negative serum pregnancy
(beta-human chorionic gonadotropin) within 7 days prior to receiving the first dose of
trial treatment and should not be lactating;

- Female subjects of childbearing potential must be willing to use an adequate method of
contraception for the course of the trial through 120 days after the last dose of
trial treatment;

- Male subjects of childbearing potential must be willing to use an adequate method of
contraception for the course of the trial through 120 days after the last dose of
trial treatment;

- Willing and able to provide written informed consent/assent for the trial.

Exclusion Criteria:

- History of poorly controlled hypertension (defined as systolic blood pressure >150
mmHg);

- History of New York Heart Association class III or greater cardiac disease;

- History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic
conduction abnormality within the past 12 months;

- History of congenital QT prolongation;

- Absolute corrected QT interval of >480 milliseconds in the presence of potassium >4.0
milliequivalent/L and magnesium >1.8 mg/dL;

- Currently participating and receiving study therapy or has participated in a study of
an investigational agent and received study therapy or used an investigational device
within 4 weeks of the first dose of the trial treatment;

- Concurrent use of medications that interact with nitrate/nitrites;

- Concurrent use of any complementary or alternative medicines;

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment;

- Known history of active tuberculosis (Bacillus Tuberculosis);

- Hypersensitivity to L-NMMA, pembrolizumab, or any of their excipients;

- Has had a prior anticancer monoclonal antibody within 4 weeks prior to study Day 1 or
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to
agents administered more than 4 weeks earlier;

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent;

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

- Has known active central nervous system metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging for at least 4 weeks prior to the
first dose of trial treatment and any neurologic symptoms have returned to baseline),
have no evidence of new or enlarging brain metastases, and are not using steroids for
at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability;

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e., with use of disease-modifying agents, corticosteroids or immunosuppressive
drugs);

- History of non-infectious pneumonitis that required steroids or current pneumonitis;

- Has an active infection requiring systemic therapy;

- History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the trial, interfere with the subject's participation
for the full duration of the trial, or is not in the best interest of the subject to
participate, in the opinion of the treating investigator;

- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial;

- Is pregnant or breastfeeding, or expecting to conceive a child within the projected
duration of the trial, starting with the prescreening or screening visit through 120
days after the last dose of trial treatment;

- Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent;

- Known history of human immunodeficiency virus;

- Has known active hepatitis B or hepatitis C;

- Received a live vaccine within 30 days of planned start of the trial treatment;

- Unwilling or unable to comply with the trial protocol.