IBI308 in Subjects With Advanced/Metastatic Solid Malignancies

An Open-label, Phase 1b Multicenter Study of IBI308 in Subjects With Advanced/Metastatic Solid Malignancies

The study is to evaluate preliminary anti-tumor activity (overall response rate, ORR) of IBI308 monotherapy in subjects with advanced/metastatic solid malignancies.

Patients will be recruited for 2 cohorts:

• Cohort 1: Advanced/metastatic cancers with TMB>10 mutations per megabase (mut/Mb). This enrollment of this cohort has been stopped per sponsor's communication with the sites. For patients who have already enrolled in this cohort, treatment and monitoring will be conducted as stipulated by the protocol. The patients will remain on study until disease progression or intolerable toxicity, death, withdrawal of consent, or end of study, whichever occurs first.

Cohort 2: Advanced/metastatic endometrial cancer (N=40)

Inclusion Criteria:

1. Subjects able to give voluntary informed consent, understand the study and are willing to follow and complete all the test procedures.

2. Subjects (males and females) of childbearing potential should be willing to use reliable contraception methods that are deemed effective by the investigator from visit 1 through 90 days following the last dose of study drug. Postmenopausal women must have been amenorrhea for at least 12 months to be considered of non-childbearing potential.

3. Male or female subjects ≥18 years

   1. At least one measurable lesion (per RECIST version 1.1)
   2. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1.
   3. Subjects with life expectancy of ≥ 3 month

4. If subject received anti-tumor therapy:

   1. Generalized radiation therapy must have been completed 3 weeks prior to enrollment, or local radiotherapy or radiation therapy for bone metastases for 2 weeks prior to enrollment. Treatment with radiopharmaceuticals must have been completed 8 weeks prior to enrollment.
   2. Previous chemotherapy, biotherapy (tumor vaccines, cytokines, or growth factors that control cancer), tyrosine kinase inhibitors, or approved targeting and other treatments should have completed at least 3 weeks prior to the first administered dose in this study;

5. Subjects must have adequate organ function (liver, kidney function and hematopoietic function tests) prior IBI308 administration

   1. Absolute neutrophil count (ANC) ≥1.5 x10^9/L
   2. Platelet count ≥ 100 x 10^9/L
   3. Hemoglobin ≥ 9 g / dL (whole blood or component transfusion within 7 days before 1st dose of study drug is prohibited)
   4. Renal function tests: serum creatinine ≤1.5 ×upper limit of normal range (ULN) or an estimated glomerular filtration rate (eGFR) ≥ 50 mL/min/1.73 m2
   5. Liver function tests alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN, for patients with known liver cancer or liver metastases, AST and ALT ≤ 5 x ULN
   6. Total bilirubin (TBil) ≤1.5 x ULN; If Gilbert's Syndrome may have Bilirubin> 1.5 x ULN
   7. Coagulation tests: aPTT ≤ 1.5 x ULN and INR ≤2.0

6. Cohort Specific Inclusion Criteria:

Cohort 1: Advanced/metastatic cancers with high TMB expression

i. Advanced/metastatic cancers with TMB level > 10 mut/Mb ii. Histologically or cytologically confirmed unresectable Stage III/IV NSCLC or other advanced/metastatic cancers (for example, melanoma, bladder cancer, SCLC, prostate cancer, colorectal cancer, gastric cancer) iiI. Separate informed consent is required for subjects who provide fresh biopsies for serial tumor biopsies for biomarker testing. TMB testing should be performed on the most recently obtained tumor sample.

v. Subjects must be tested for TMB level before entering the study, and pre-screen informed consent is required for TMB testing. Subjects who have existing FoundationOne TMB testing results from within 6 months of study entry do not need to have repeat testing.

vi. Refractory or intolerant to standard therapy or for whom no standard therapy exists. Subjects must have no available therapy likely to confer clinical benefit for their cancer. Subjects who experienced irAE grade ≥ 3, or grade 2 recurrent pneumonitis, or who had to discontinue prior anti-PD-1/PD-L1 treatment due to irAEs of any grade will not be eligible.

vi. NSCLC subjects with EGFR mutation and/or ALK rearrangement and/or ROS-1 positive, should have received appropriate targeted therapy and are refractory to targeted therapy prior to enrolling this trial.

Cohort 2: Advanced/metastatic endometrial Cancer i. Histologically confirmed advanced/metastatic endometrial cancer. ii. Refractory or intolerant to standard therapy, and no available therapy likely to confer clinical benefit for their cancer. Subjects who experienced irAE grade ≥ 3, or who had to discontinue prior anti-PD-1/PD-L1 treatment due to irAEs of any grade will not be eligible.

Exclusion Criteria:

1. Legal incapacity or limited legal capacity.

2. Pregnancy, lactation, breastfeeding.

3. Concurrent anticancer treatment (e.g., cytoreductive therapy or cytokine therapy except for erythropoietin) or use of other investigational product within 28 days before start of trial treatment; major surgery within 28 days before start of trial treatment (excluding prior diagnostic biopsy.

   Note: Small molecule or antibody targeted therapy < 3 weeks from start of trial treatment will be excluded.

4. Received a biologic (G-CSF, GM-CSF) within 14 days prior to the first dose of study drug.

5. Vaccination within 4 weeks of first dose of IBI308 and while on study except for administration of inactivated vaccines (e.g., inactivated influenza vaccines)

6. Failure to recover from adverse events from the most recent anti-tumor treatment to CTCAE ≤ grade 1 or baseline with the exception of alopecia;

7. Active autoimmune disease requiring systemic treatment within the past 1 year or a documented history of clinically severe autoimmune disease or a syndrome that requires systemic steroids or immunosuppressive agents during the conduct of this study. Exceptions: - Vitiligo, eczema, psoriasis (<10% of body surface area (BSA) of skin eruption or systemic involvement) or resolved childhood asthma/atopy, autoimmune hypothyroidism stable on hormone replacement.

8. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

9. Acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection.

10. History of primary immunodeficiency, stem cell or organ transplant, or previous clinical diagnosis of tuberculosis.

11. Subject who have had severe infection within 4 weeks or signs and symptoms of any active infection within 2 weeks prior to the first dose administration.

12. Known allergies, hypersensitivity, or intolerance to protein-based therapies or with a history of any significant drug allergy (e.g., anaphylaxis, hepatotoxicity, immune-mediated thrombocytopenia or anemia

13. Subjects who experienced (irAE) grade≥3 immunotherapy-related adverse events. Subjects with CNS metastasis unless they are asymptomatic or adequately treated with radiotherapy and/or surgery and subjects are neurologically stable with minimal residual symptoms/signs 14 days prior to dosing.

14. Patients who require high dose of systemic corticosteroids (>10 mg/day prednisone or equivalents) for at least 2 weeks prior to treatment are not eligible.

15. Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure (New York Heart Association) NYHA III or IV, unstable angina pectoris even if medically controlled, history of myocardial infarction during the last 3 months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia).

16. Any other serious underlying medical (e.g., uncontrolled hypertension, active uncontrolled infection, active gastric ulcer, uncontrolled seizures, cerebrovascular incidents, gastrointestinal bleeding, severe signs and symptoms of coagulation and clotting disorders, other serious cardiac conditions not listed in exclusion criteria), psychiatric, psychological, familial or geographical condition that, in the judgment of the investigator, may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.