Inclusion criteria
tumor, toxicities, cirrhosis, ≥3 neurologic toxicity, HCV-associated HCC, HCC, Extensive-stage SCLC, immune-related endocrinopathies, upper esophageal or salivary gland tumors, SCLC, ascites, intrahepatic cholangiocarcinoma, HBV infection, cancer, tumors, HCV infection, ocular adverse, active co-infection, extrahepatic cholangiocarcinoma, NSCLC, HDV, Gilbert’s syndrome, SCCHN, TNBC, gallbladder carcinoma, anaplastic lymphoma, hepatic encephalopathy, T790M-mutated NSCLC, GEJ cancer, colitis, pneumonitis, renal toxicity, pain, DLBCL, PD, alcohol abuse, HDV infection, primary CNS lymphoma
TUMOR, METASTATIC CERVICAL CANCER, MALIGNANT NEOPLASM, CIRRHOSIS, ONCOLOGY, MSI-LOW, ASCITES, SCLC, CANCER, METASTATIC CHOLANGIOCARCINOMA, MICROSATELLITE INSTABILITY, HEPATIC METASTASES, ADVERSE EVENTS, BRAIN METASTASES, GALLBLADDER CARCINOMA, HEPATIC ENCEPHALOPATHY, BONE METASTASES, COLITIS, BRAIN METASTASIS, EXTRAHEPATIC CHOLANGIOCARCINOMA, PNEUMONITIS, DISEASE, RECURRENT DISEASE, SOLID TUMORS, METASTATIC DISEASE, SECONDARY, INTRAHEPATIC CHOLANGIOCARCINOMA, NSCLC, TUMORS, PRIMARY CNS LYMPHOMA

Ability to provide informed consent and documentation of informed consent before initiation of any study-related tests or procedures that are not part of standard of care for the patient’s disease. Patients must also be willing and able to comply with study procedures, including the acquisition of specified research specimens.Age ≥18 years.Criterion for disease state.Dose-escalation phase: patients with histologically proven, unresectable, locally advanced or metastatic solid tumors of any histology for whom no approved therapy with demonstrated clinical benefit is available or patients who are intolerant to or have declined standard therapy.Cohort-expansion phase: patients with histologically proven, unresectable, locally advanced or metastatic malignant neoplasms for whom no approved therapy with demonstrated clinical benefit is available or patients who are intolerant to or have declined standard therapy as listed below:NSCLC that has progressed during or after treatment with platinum-based chemotherapy for unresectable, locally advanced or metastatic disease. NSCLC harboring an activating EGFR mutation or anaplastic lymphoma kinase (ALK) rearrangement must have progressed after available EGFR- or ALK-targeted therapy (including osimertinib for EGFR T790M-mutated NSCLC). Within this population, separate cohorts will enroll patients with the following requirements:CPI-naive NSCLC.NSCLC that has progressed during or after treatment with an anti-PD-1/PD-L1-based therapy.SCCHN that has progressed after treatment with platinum-based chemotherapy for metastatic or recurrent disease or progression of disease within 6 months of completing prior platinum therapy used as part of neoadjuvant, concurrent chemoradiation or adjuvant therapy. Within this population, separate cohorts will enroll patients with the following requirements:CPI-naive SCCHN.SCCHN that has progressed during or after treatment with an anti-PD-1/PD-L1-based therapy.Additional requirements applying to the SCCHN cohorts include:Patients with upper esophageal or salivary gland tumors will not be considered as SCCHN.Patients who refuse radical resection for recurrent disease are eligible.Patients must be willing to provide consent for a baseline and on-treatment tumor biopsy during the screening period and on day 56 (±7 d) in cycle 1, respectively. Exceptions may be made based on a medical contraindication at the discretion of the sponsor’s medical monitor.Patients with advanced, metastatic EOC for whom there is no available therapy likely to confer clinical benefit.Extensive-stage SCLC with radiologically confirmed PD after platinum-based chemotherapy. Presence of brain metastases is permitted if patient has completed treatment with surgery and/or radiation more than 4 weeks before date of first dose of study drug.Localized irradiation for SCLC is permitted as long as it was a minimum of 4 weeks before entering the study; however, single-dose palliative radiation of bone metastases for pain control may be allowed during the 4-week screening period.R/R DLBCL for which no treatment options expected to result in clinical benefit are available.R/R DLBCL treated with at least one combination chemotherapy regimen, including therapeutic anti-CD20 antibody (for example, rituximab and ofatumumab) and autologous stem cell transplant if indicated. Patients who are ineligible for or decline stem cell transplantation may be enrolled if eligibility criteria are otherwise met.Patients with primary CNS lymphoma or uncontrolled brain metastasis are not eligible.Patients must be willing to provide consent for a baseline and on-treatment tumor biopsy during the screening period and on day 56 (±7 d) in cycle 1, respectively. Exceptions may be made based on a medical contraindication at the discretion of the sponsor’s medical monitor.A minimum of 10 patients enrolled in this cohort must have previously received prior CD19-directed CAR-T cell therapy.Locally advanced or metastatic cholangiocarcinoma that has progressed during or after at least one systemic therapy. Patients with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma or gallbladder carcinoma are eligible for enrollment.Locally advanced or metastatic uninfected or HBV-associated or HCV-associated HCC and Child–Pugh A cirrhosis that has progressed during or after an approved and available anti-VEGF inhibitor therapy. The following are additional requirements for these patients: Patients with active HBV infection are required to be receiving effective antiviral therapy and have a viral load less than 100 IU mlAntiviral therapy is not required for patients with HCV infection.Patients with active co-infection with HBV and HCV are not eligible.Patients with HDV infection or active co-infection with HDV are not eligible.Patients with history of hepatic encephalopathy are not eligible.Patients with any prior or current clinically important ascites as measured by physical examination and that requires active paracentesis for control are not eligible. Patients with ascites only on radiographic imaging are eligible.Patients with active drug or alcohol abuse are not eligible.Locally advanced or metastatic cervical cancer that has progressed during or after at least one systemic therapy.Locally advanced or metastatic TNBC that has progressed during or after at least one systemic therapy.Locally advanced or metastatic GC or gastroesophageal junction (GEJ) cancer with known microsatellite instability (MSI) status that has progressed during or after at least one systemic therapy.HER2The initial dose-escalation step will enroll patients with HER2For all patients, the cancer must have progressed after standard therapy or have progressed during or after HER2-directed therapy if approved and available for patients with HER2For all patients (excluding patients with GC enrolled at the MTD or MAD), history of HER2 positivity is defined as:3+ by IHC or 2+ by IHC in combination with in situ hybridization (ISH) positivity (as per College of American Pathologists/American Society of Clinical Oncology 2016 guidelines) orHER2 amplification by next-generation sequencing in most recent tumor biopsy.For patients with HER2Patients must have received only one prior line of therapy for metastatic GC or GEJ cancer (that is, second-line patients).HER2 positivity must be demonstrated specifically per the HercepTest as 3+ by IHC or 2+ by IHC in combination with ISH positivity in most recent tumor biopsy.Known MSI status.Of the up to 30 paients with GC to be enrolled, a minimum of 26 must have MSI-low or microsatellite stable tumors.All patients in the HER2There is no restriction on the number of experimental therapies that the patient may have received in phase 1 trials.ECOG PS of 0 or 1.Life expectancy ≥12 weeks.Measurable disease as per RECIST version 1.1 criteria for the purpose of response assessment must either (1) not reside in a field that has been subjected to prior radiotherapy or (2) have demonstrated clear evidence of radiographic progression since the completion of prior radiotherapy and before study enrollment. Patients with DLBCL must have ≥1 measurable lesion >1.5 cm as defined by Revised International Working Group criteria (that is, the Lugano classification) for response assessmentPatients enrolled in this study must have an identified FFPE tumor specimen to enable determination of PD-1, PD-L1, LAG-3, MHC-II and Fcγ receptor genotyping (HER2Acceptable laboratory parameters for all patients, except for patients with HCC, are as follows:Platelet count ≥75 × 10Absolute neutrophil count ≥1.5 × 10ALT/AST ≤3.0× the upper limit of normal (ULN); for patients with hepatic metastases, ALT and AST ≤5× ULN.Total bilirubin ≤1.5× ULN, except patients with Gilbert’s syndrome, who may enroll if the conjugated bilirubin is within normal limits.Creatinine <2 mg dlAcceptable laboratory parameters for patients with HCC are as follows:Platelet count ≥60 × 10Absolute neutrophil count ≥1.0 × 10Hemoglobin ≥9.0 g dlALT and AST ≤5× ULN.Total bilirubin ≤3 mg dlInternational normalized ratio (INR) ≤2.3 or prothrombin time (PT) ≤6 s above control.Albumin ≥2.8 g dlCreatinine <2 mg dlFemale patients of childbearing potential (not surgically sterilized and between menarche and 1 year after menopause) must have a negative urine or serum pregnancy test performed within 72 h before the initiation of study drug administration. If a patient is sexually abstinent but capable of becoming pregnant, she must agree to remain abstinent from the time of consent through 120 d after discontinuation of study drug administration. Should sexual activity commence, the patient must agree to use highly effective contraceptive measures from the time of consent through 120 d after discontinuation of study drug administration.Highly effective methods of contraception include hormonal contraceptives, intrauterine device or system, vasectomy or tubal ligation. If a highly effective method is not achievable, then a ‘double-barrier’ method is an effective alternative in which the male partner must use a condom with spermicide and the female partner must use a diaphragm or cervical cap concurrently.HER2Male patients with partners of childbearing potential must use barrier contraception (that is, condom). In addition, male patients should also have their partners use another method of contraception from the time of consent through 120 d after discontinuation of study drug administration.HER2Is not pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the prescreening or screening visit through 120 d after the last dose of study drug.In patients who have previously received an immune CPI (for example, anti-PD-L1, anti-PD-1 and anti-CTLA-4) before enrollment, to be eligible to participate in the study, toxicities related to the CPI must have resolved to grade ≤1 or baseline. Patients with immune-related endocrinopathies that are secondary to checkpoint therapies, and that are well controlled on replacement therapy, are eligible. Regardless of resolution, patients who sustained the following immune CPI-related adverse events are ineligible:Grade ≥3 ocular adverse event.Changes in liver function tests that met the criteria for Hy’s law (>3× ULN of either ALT/AST with concurrent >2× ULN of total bilirubin and without alternate etiology).Grade ≥3 neurologic toxicity.Grade ≥3 colitis.Grade ≥3 renal toxicity.Grade ≥3 pneumonitis.