Inclusion Criteria:

• Voluntarily signed informed consent form (ICF).
• Ability and willingness to adhere to all study procedures.
• Male or female patients ≥ 18 years of age at the time of signing the ICF.
• BMI ≥ 18 kg/m^2 .
• Locally advanced unresectable or metastatic solid tumor confirmed by histology or cytology, and:
  • For Part A: Available SOC therapies have been exhausted, or SOC therapies are not available in this setting (relapsed/refractory disease).
  • Note that prior therapy may have included an immune checkpoint inhibitor (ICI), such as an anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) treatment.
  • For Part B: Suitable for anti-PD-1/L1 monotherapy and no prior anti-PD-1/L1 therapy in the advanced/metastatic setting.
  • Note that prior anti-PD-1/L1 therapy in the adjuvant setting is acceptable.
  • For Part A: On tumor imaging, as assessed by RECIST v1.1 and iRECIST, with measurable or unmeasurable disease.
  • For Part B: On tumor imaging, as assessed by RECIST v1.1 and iRECIST, with at least one measurable disease.
• Life expectancy ≥ 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0-1 for Part A and Part B.
• Adequate end-organ and hematopoietic function, defined based on the following laboratory results obtained within 7 days prior to the first dose of study treatment [Day 1]):
  • Absolute neutrophil count (ANC) ≥ 1.5×10^9 /L (1500/µL), without granulocyte colonystimulating factor (G-CSF) support.
  • Note that G-CSF may be administered until 14 days prior to C1D1.
  • Platelet count ≥ 90×10^9 /L (90,000/µL) without transfusion within 14 days prior to C1D1. c. Hemoglobin ≥ 90 g/L (9 g/dL).
  • Note that patients may be transfused or receive erythropoietic treatment to meet this criterion until 14 days prior to C1D1.
  • Creatinine clearance ≥ 60 mL/min;
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x the upper limit of normal (ULN) with or without primary or metastatic liver tumor lesions;
  • Total bilirubin (TBIL) ≤ 1.5 x ULN;
  • For patients not receiving therapeutic anticoagulation: International Normalized Ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT) ≤ 1.5 x ULN;
  • For patients receiving warfarin: INR ≤ 3.0 x ULN and no bleeding within 14 days prior to Day 1. Patients receiving therapeutic anticoagulation must be on a stable dose for a minimum of 14 days prior to Day 1. Patients on low molecular weight heparin will be allowed.
• For women of childbearing potential (WOCBP, Appendix 6): agreement to remain either totally abstinent or to use of at least one (1) methods of acceptable contraception from screening until three (3) months after the last dose of study drug. Acceptable methods of contraception are defined as those that result, alone or in combination, in a low failure rate (i.e., < 1% per year) when used consistently or correctly, such as an intra-uterine device, hormone contraception, barrier methods (e.g., condom with spermicidal foam/gel/film/ suppository). Females must refrain from donating eggs.
• For males who are sexually active with a female partner of childbearing potential: agreement to remain totally abstinent or to use a barrier contraception (e.g., condom with spermicidal foam/gel/film/suppository) from screening until three (3) months following the last dose of study drug. Males must refrain from donating sperm during this same period. This criterion may be waived for male patients who had a vasectomy > 6 months prior to Day 1.

Exclusion Criteria:

• Patients with leptomeningeal (LMD) metastases or patients with new and/or progressive brain metastases at the time of study entry. Patients with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after central nervous system (CNS)-directed treatment (radiotherapy and/or surgery), as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period.
• History of primary malignancy other than the diseases under study, not in remission greater than three (3) years prior to Day 1. Exceptions that do not require a 3-year remission include: adequately treated non-melanoma skin cancer, cervical carcinoma in situ on biopsy or squamous intraepithelial lesion on Papanicolaou (PAP) smear, in situ prostate cancer (with no evidence of active disease for two [2] years prior to Day 1), or resected melanoma in situ and radically resected papillary thyroid carcinoma.
• Persistence of AEs from prior anti-cancer therapy that have not resolved to Grade 1 (except for alopecia and hypothyroidism), or any history of Grade ≥ 3 immune-related adverse events (irAEs), Grade ≥ 2 pneumonitis, hypophysitis or encephalitis related to immunotherapy, or other Grade ≥ 3 drug-related CNS toxicity.
• Active systemic autoimmune disease or a history of autoimmune disorder that may relapse (e.g., systemic lupus erythematosus [SLE], rheumatoid arthritis, inflammatory bowel disease [IBD], autoimmune thyroid disorder*, multiple sclerosis, vasculitis, glomerulitis, eczema, psoriasis, etc.). • *Note that primary or secondary hypothyroidism, well controlled with hormone replacement therapy is permitted.
• Major trauma or major surgery within 4 weeks prior to Day 1 or anticipated major surgery during study participation.
• Serious unhealing wound, ulcer, or bone fracture.
• History of and/or presence of any of the following cardiovascular and cerebrovascular events or conditions:
  • History of myocardial infarction, unstable or severe angina, or arterial thrombotic event (such as cerebrovascular attack [CVA] or transient ischemic attack [TIA]) within 12 months prior to Day 1;
  • Significant abnormalities on the screening of ECG, including QTc interval > 470 msec (average of triplicate measurements, corrected for heart rate using Fridericia’s formula), second degree (Mobitz type II) or third degree atrioventricular (AV) block, or other clinically significant (in the Investigator’s opinion) arrhythmia;
  • Current New York Heart Association (NYHA) stage II-IV congestive heart failure (CHF);
  • Left ventricular ejection fraction (LVEF) < 50%;
  • Note that LVEF assessment by echocardiogram (ECHO) scan performed as part of the patient’s regular care within 4 weeks prior to the screening visit may be used for confirmation of eligibility.
  • Other clinically significant (in the Investigator’s opinion) cardiac diseases (e.g., valvular disease, cardiomegaly, ventricular hypertrophy, cardiomyopathy, myocarditis, etc.);
  • Uncontrolled hypertension (defined as a systolic blood pressure [SBP] ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg at screening), despite appropriate antihypertensive therapy, or poor compliance with an antihypertensive regimen.
• Clinically significant third space effusion (e.g., ascites, pleural effusion, pericardial effusion) within two (2) months prior to Day 1.
• Active or recent (past 6 months) bleeding disorder, including gastrointestinal (GI) bleeding, as evidenced by hematemesis, significant hemoptysis, or melena within 6 months prior to Day 1.
• Active thrombophlebitis, thromboembolism, or hypercoagulability state. a. Patients with a history of deep venous thrombosis (DVT) may participate if completely resolved, with the last treatment given ≥ 6 months prior to Day 1.
• Uncontrolled diabetes.
• Chronic severe liver disease or Child-Pugh B or C liver cirrhosis.
• Current active lung infection requiring treatment (e.g., pneumonia, pulmonary tuberculosis), evidence of active pneumonitis on screening CT scan, or history of interstitial lung disease (e.g., hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, etc.). Note that a history of radiation therapy-induced locoregional interstitial pneumonitis > 6 months prior to Day 1 is permitted.
• Any active or symptomatic bacterial, viral, or fungal infection requiring systemic therapy within 14 days prior to Day 1. Prophylactic anti-microbial therapy according to institutional protocols is acceptable.
• Positive tests on screening for the following: a. Human immunodeficiency virus (HIV) b. Hepatitis B surface antigen (HBsAg). c. Hepatitis B core antibody (HBcAb) unless the follow-on hepatitis B virus (HBV) DNA test is negative. d. Hepatitis C virus (HCV) antibody test, unless the follow-on HCV ribonucleic acid (RNA) test is performed and shows HCV viral load < 15 IU/mL.
• History of alcoholism or drug abuse within the past year.
• Patients with active peptic ulceration.
• Patients with a history or evidence of esophago-gastric fundal varices.
• Any psychiatric illness (e.g., dementia, altered mental status) or social situation that would prevent study participation or limit compliance with study requirements.
• Any other significant co-morbidity, disease, clinical laboratory, or physical examination finding that contraindicates the use of the study treatment, or may represent an unacceptable risk from treatment complications, or may affect adherence to the study procedures or the interpretation of the study results. Prohibited prior and ongoing treatments:
• Treatment with commercially available or investigational large molecule cancer therapies, including monoclonal antibodies (mAbs), bispecific antibodies, antibody-drug conjugates, fusion protein, bispecific T-cell engager, peptide, tumor-infiltrating cells (TIL)within 28 days prior to the first dose of study treatment (Day 1).
• Treatment with small molecule inhibitor/chemotherapeutic drugs within 14 days or 5 halflives, whichever is longer (6 weeks for nitrosoureas or mitomycin) prior to Day 1.
• Autologous stem cell transplant (ASCT) or chimeric antigen receptor T cell (CAR-T), chimeric antigen receptor natural killer (CAR-NK), T cell receptor-engineered T cell (TCRT) therapy within 3 months prior to Day 1.
• Prohibited prior radiotherapy:
  • Radiation therapy > 30 Gy to the lung within 6 months prior to Day 1;
  • Other radiation therapy within 28 days prior to Day 1;
  • Palliative radiotherapy for bone metastases or other non-target lesions: within 14 days prior to Day 1.
  • Note that the patient must have recovered from the adverse effects of radiation therapy before Day 1;
• Any prior organ transplant, including allogeneic peripheral blood stem cell (PBSC) or bone marrow transplant.
• Systemic corticosteroid or other immunosuppressive therapy for any indication within 14 days prior to Day 1. Exceptions: a. Patients receiving topical or inhaled corticosteroids or local (e.g., intra-articular) steroid injections may participate.
• Patients who are on treatment with drugs known to prolong the QT/QTc interval and cannot be transitioned to other medications.
• Patients who are on treatment with labetalol or any other agents the Investigator and the Sponsor consider will impact bioanalysis.
• Live, attenuated vaccine within 28 days prior to Day 1. Coronavirus disease (COVID)-19 vaccination is acceptable. 
• Known hypersensitivity to the study drug(s) or any component(s) of the study drug(s).
• History of any drug-induced anaphylactic or other severe hypersensitivity reactions.
• History of any of the following: drug-induced severe cutaneous adverse reaction (SCAR; including, but not limited to Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN], or drug reaction with eosinophilia and systemic symptoms [DRESS]), or doselimiting immune- mediated reactions.
• Any condition that would prevent or otherwise adversely affect the oral administration (including absorption following oral administration) of PTT-936.
• For patients enrolled in Part B: Presence of a contraindication for the selected ICIs combination agent, as per the applicable U.S. Prescribing Information.
• Pregnancy and breast-feeding.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 10/26/23. Questions regarding updates should be directed to the study team contact.