Study of CHS-388 (Formerly Known as SRF388) in Patients With Advanced Solid Tumors

Part A and Part B Abbreviated Inclusion Criteria:

• ≥ 18 years of age

• Locally advanced or metastatic (Stage IV) solid tumor that has progressed during orafter standard therapy, and for whom no available therapies are appropriate (basedon investigator judgment)

• Patients in Part B with advanced or metastatic ccRCC, HCC, or NSCLC must have atleast 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

• Patients with HCC in Part B must have at least 1 measurable target lesion accordingto modified RECIST (mRECIST)

• Patients with HCC must have unresectable disease, Barcelona Clinic Liver Cancer (BCLC1) Stage B (not eligible for transcatheter arterial chemoembolization [TACE])or Stage C

• For patients in Part B with ccRCC, demonstrated progressive disease (PD) during orafter the most recent treatment regimen. Prior treatment history must includeprogression during or after treatment with regimen(s) that have included a vascularendothelial growth factor (VEGF)-targeted agent and an immune checkpoint inhibitor.Patients who did not progress on but discontinued the VEGF-targeted agent fortoxicity or intolerability are permitted.

• For patients in Part B with HCC, demonstrated PD during or after the most recenttreatment regimen. Prior treatment history must include progression during or aftertreatment with a VEGF-targeted agent. Patients who did not progress on butdiscontinued the VEGF-targeted agent for toxicity or intolerability are permitted.

• For Part B patients in the tumor biopsy subsets only, must have tumor tissue that isaccessible for pretreatment and on-treatment tumor biopsy in the opinion of theInvestigator and be willing to undergo pretreatment and on-treatment biopsies perprotocol

• Serum creatinine clearance ≥ 30 mL/min per Cockcroft-Gault formula or serumcreatinine ≤ 2.0 x the upper limit of normal (ULN)

• Total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN if elevated because of Gilbert's syndrome and ≤ 2 x ULN for patients with HCC or patients with known liver metastases)

• Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase/serum glutamicpyruvic transaminase (ALT/SGPT) < 2.5 x ULN (< 5 x ULN if liver metastasis or forpatients with HCC)

• For patients with HCC, Child-Pugh class A or B7 with a serum albumin ≥ 2.8 g/dL (≥ 28 g/L)

• Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1.0 x 109/L, hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100 x 109/L. For patients withHCC, platelet count ≥ 75 x 109/L without transfusion

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Patients with NSCLC must have histologically confirmed locally advanced and/ormetastatic Stage IV NSCLC

• Patients with NSCLC must have demonstrated progressive disease during or after themost recent treatment regimen

Part C Abbreviated Inclusion Criteria:

• ≥ 18 years of age

• Advanced RCC of any histology or advanced HCC previously treated with at least onesystemic anticancer therapy OR histologically or cytologically confirmed metastaticor unresectable adenocarcinoma or squamous cell NSCLC

• Patients with HCC must have unresectable disease, Barcelona Clinic Liver Cancer (BCLC) Stage B (not eligible for transcatheter arterial chemoembolization) or StageC

• At least 1 measurable lesion per RECIST 1.1

• Patients with HCC must have at least 1 measurable target lesion according tomodified RECIST (mRECIST)

• ECOG performance status of 0-1

• ANC ≥1500/µL (1.5 x 109/L)

• Platelets ≥100 000/µL (≥ 100 x 109/L)

• Hemoglobin for participants with RCC: ≥9.0 g/dL; for participants with HCC: ≥8.5g/dL

• Creatinine OR measured or calculated creatinine clearance (GFR can also be used inplace of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant withcreatinine levels >1.5 × institutional ULN

• Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for participants with totalbilirubin levels >1.5 × ULN

• AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with livermetastases)

• International normalized ratio (INR) OR prothrombin time (PT) Activated partialthromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulanttherapy as long as PT or aPTT is within therapeutic range of intended use ofanticoagulants

• For patients with HCC, Child-Pugh Class A or B7 with a serum albumin ≥ 2.8 g/dL (≥ 28 g/L)

• Willingness of male and female patients who are not surgically sterile orpostmenopausal to use medically acceptable methods of birth control for the durationof the study drug period (or beginning 14 days before the initiation ofpembrolizumab for oral contraception), including 75 days after the last dose ofCHS-388 or 120 days after the last dose of pembrolizumab; male patients must refrainfrom donating sperm during this period. Sexually active men, and women using oralcontraceptive pills, should also use barrier contraception with spermicide.Azoospermic male patients and WCBP who are continuously not heterosexually activeare exempt from contraceptive requirements. However, female patients must stillundergo pregnancy testing as described in this section.

Part C Abbreviated Inclusion Criteria Specific to Patients with RCC or HCC from Part A or Part B:

• Progressed on CHS-388 by RECIST 1.1

• Did not experience prior Grade ≥ 3 toxicity related to CHS-388

• Willingness to undergo pretreatment core or excisional biopsy if deemed safe andtumor is accessible, in the opinion of the Investigator

• Has received no systemic anticancer therapies between CHS-388 doses

Part C Abbreviated Inclusion Criteria specific to NSCLC Patients:

• No more than 3 prior lines of systemic therapy for unresectable or metastaticdisease with prior radiologic progression on or following platinum-basedchemotherapy and prior anti-PD-(L)1 therapy whether given alone or in combination

Part A and Part B Abbreviated Exclusion Criteria:

• Previously received an anti-IL-27 antibody or anti-IL-27 targeted therapy

• For patients in Part B with renal cell carcinoma (RCC), non-clear cell RCC histology

• For patients with HCC, known fibrolamellar or mixed hepatocellularcholangiocarcinoma

• History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibodytherapy or any excipient in the study drugs

• Major surgery within 4 weeks prior to Screening

• Unstable or severe uncontrolled medical condition (eg, unstable cardiac function,unstable pulmonary condition including pneumonitis and/or interstitial lung disease,uncontrolled diabetes) or any important medical illness or abnormal laboratoryfinding that would, in the Investigator's judgment, increase the risk to the patientassociated with his or her participation in the study

Part C Abbreviated Exclusion Criteria:

• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study drug

• Previously received an anti-IL 27 antibody or anti-IL 27 targeted therapy (exceptionto patients who received CHS-388 in Part A or Part B)

• No prior systemic therapy for unresectable or metastatic disease

• Received > 4 prior systemic regimens for unresectable or metastatic disease (priorPD-(L)1 inhibitors are allowed if the patient did not discontinue therapy due to ≥Grade 3 drug-related toxicity)

• For patients with HCC, fibrolamellar histology or mixed hepatocellularcholangiocarcinoma

• For patients with HCC, moderate or severe ascites

• For patients with HCC, inability to undergo disease evaluation with triphasiccomputed tomography or magnetic resonance imaging because of contrast allergy orother contraindication

• For patients with HCC, imaging findings consistent with ≥ 50% liver occupation byHCC tumors

• History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibodytherapy or any excipient in the study drugs

• Surgeries that required general anesthesia must be completed at least 2 weeks beforefirst study drug administration

• Prior autologous stem cell transplant ≤ 3 months before the first dose

• Prior allogeneic hematopoietic cell transplant within 6 months of the first dose orwith a history of or current clinical Graft-Versus-Host Disease

• Has had an allogenic tissue/solid organ transplant

• Other unstable or severe uncontrolled medical condition (eg, unstable cardiacfunction, unstable pulmonary condition, uncontrolled diabetes) or any importantmedical illness or abnormal laboratory finding that would, in the Investigator'sjudgment, increase the risk to the patient associated with his or her participationin the study

Part D Abbreviated Inclusion Criteria

• ≥ 18 years of age

• Histologically or cytologically confirmed metastatic or unresectable adenocarcinomaor squamous cell NSCLC

• No more than 3 prior lines of systemic therapy for unresectable or metastaticdisease with prior radiologic progression on or following platinum-basedchemotherapy and prior anti-PD-(L)1 therapy whether given alone or in combination

• At least 1 measurable lesion per RECIST 1.1

• ECOG performance status of 0-1

• ANC ≥1500/µL (1.5 x 109/L)

• Platelets ≥100 000/µL (≥ 100 x 109/L)

• Hemoglobin for participants with RCC: ≥9.0 g/dL

• Creatinine OR measured or calculated creatinine clearance (GFR can also be used inplace of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant withcreatinine levels >1.5 × institutional ULN

• Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for participants with totalbilirubin levels >1.5 × ULN

• AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with livermetastases)

• International normalized ratio (INR) OR prothrombin time (PT) Activated partialthromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulanttherapy as long as PT or aPTT is within therapeutic range of intended use ofanticoagulants

• Willingness of male and female patients who are not surgically sterile orpostmenopausal to use medically acceptable methods of birth control for the durationof the study drug period (or beginning 14 days before the initiation ofpembrolizumab for oral contraception), including 75 days after the last dose ofCHS-388 or 180 days after the last dose of toripalimab; male patients must refrainfrom donating sperm during this period. Sexually active men, and women using oralcontraceptive pills, should also use barrier contraception with spermicide.Azoospermic male patients and WCBP who are continuously not heterosexually activeare exempt from contraceptive requirements. However, female patients must stillundergo pregnancy testing as described in this section.

Part D Abbreviated Exclusion Criteria:

• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study drug

• Previously received an anti-IL 27 antibody or anti-IL 27 targeted therapy (exceptionto patients who received CHS-388 in Part A or Part B)

• No prior systemic therapy for unresectable or metastatic disease

• Received > 4 prior systemic regimens for unresectable or metastatic disease (priorPD-(L)1 inhibitors are allowed if the patient did not discontinue therapy due to ≥Grade 3 drug-related toxicity)

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent orwith an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a ≥Grade 3 irAE.

because of contrast allergy or other contraindication

• History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibodytherapy or any excipient in the study drugs

• Surgeries that required general anesthesia must be completed at least 2 weeks beforefirst study drug administration

• Prior autologous stem cell transplant ≤ 3 months before the first dose

• Prior allogeneic hematopoietic cell transplant within 6 months of the first dose orwith a history of or current clinical Graft-Versus-Host Disease

• Has had an allogenic tissue/solid organ transplant

• Other unstable or severe uncontrolled medical condition (eg, unstable cardiacfunction, unstable pulmonary condition, uncontrolled diabetes) or any importantmedical illness or abnormal laboratory finding that would, in the Investigator'sjudgment, increase the risk to the patient associated with his or her participationin the study