Phase Ib of L-NMMA and Pembrolizumab

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 histologically confirmed advanced, PD-L1-positive cervical cancer with disease progression on or after chemotherapy that is not eligible for platinum-containing chemotherapy or that has relapsed after or is refractory to platinum-containing chemotherapy OR histologically confirmed recurrent, locally advanced, or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score \[CPS\] ≥10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy. OR histologically confirmed recurrent, locally advanced, or metastatic Gastric Cancer, with disease progression on or after two or more systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy, and whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test. OR histologically confirmed hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease OR histologically confirmed recurrent, locally advanced or metastatic Merkel Cell Carcinoma (MCC) who had not received prior systemic therapy for their advanced disease OR histologically confirmed advanced renal cell carcinoma (RCC) first-line treatment. OR histologically confirmed metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. OR histologically confirmed refractory primary mediastinal large B-cell lymphoma (PMBCL), who have relapsed after two or more prior lines of therapy. OR MSI-H or dMMR unresectable or metastatic cancer that has relapsed after prior treatment and has no satisfactory alternative treatment options. OR adult patients with unresectable or metastatic tumor mutational burden-high (TMB-H) \[≥10 mutations/megabase (mut/Mb)\] solid tumors; * 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.