A Phase 1 Study Evaluating the Safety, Tolerability, and Initial Efficacy of IBI188 in Advanced Malignancies

Phase Ia study is composed of two stages: Phase Ia Part A initial dose escalation and Phase Ia Part B maintenance dose escalation. Both parts will adopt the classical 3+3 dose escalation design. The starting dose for phase Ia part A is 0.1 mg/kg QW, followed by 2 dose cohorts (0.3 mg/kg QW and 1 mg/kg QW). Duration of dose limiting toxicity (DLT) observation is 14 days.

Phase Ia Part B will have 4 dose cohorts(3mg/kg QW#10mg/kg QW#20mg/kg QW #30mg/kg QW and 45mg/kg Q3W). DLT observation period is 28 days. The subject number for each cohort in Phase Ia Part B will be increased to 6 if the subject number enrolled in each cohort is less than 6

Inclusion criteria

• Advanced solid tumors and lymphomas defined by:

• Histologically/cytologically confirmed solid tumors and lymphomas
• Solid Tumors failed from standard therapy
• Lymphoma patients who have had at least two standard treatment failures
• Subject has at least 1 measurable disease per RECIST v1.1. Lymphomas have at least one measurable lesion and 18FDG-avid lesion according to the Lugano 2014 criteria.
• Male or female subject above 18 years
• ECOG Performance Status 0 to 1
• Must have adequate organ and bone marrow function, including the following:

• Blood routine: absolute neutrophil count (ANC) ≥ 1.5 x10^9/L; platelet count ≥ 75 x 10^9/L; hemoglobin ≥ 10 g/dL. (For subjects with AML, WBC < 25×10^9/L was required , and there is no restriction for the rest in blood routine test ).
• Hepatic: total bilirubin ≤ 1.5 times of the upper limit of normal (ULN), aspartate transaminase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 X ULN (≤5 X ULN if with liver involvement). total bilirubin ≤ 3×ULN if subjects were diagnosed with Gilbert syndrome.
• Renal: serum creatinine ≤ 1.5 X ULN or estimated creatinine clearance ≥50mL/min. Urinary protein < 2+. For subjects with urinary protein ≥2+ at baseline, a 24h urine collection should be performed with urine protein < 1g.
• Coagulation tests INR < 1.5, partial prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN
• Subjects with life expectancy of ≥ 12 weeks
• Female subjects of child-bearing potential or male subjects with female partners of child-bearing potential must be willing to use viable contraception method that is deemed effective by the investigator throughout the treatment period and for at least 6 months following the last dose of study drug.
• Be willing to sign the Informed Consent Form (ICF), and can follow the visit schedule and procedures defined in the protocol.

Exclusion criteria

• Previous exposure to any anti-CD47 monoclonal antibody or SIRPα antibody.
• Subjects participating in any other interventional clinical study
• Received blood transfusion, biologic G-CSF, GM-CSF, erythropoietin, thrombopoietin (TPO) or IL-11within 3 weeks prior to the first dose of study drug
• Receive the last dose of anti-tumor therapy (chemotherapy, endocrine therapy, targeted therapy, immunotherapy or tumor embolization, etc.) within 3 weeks before the first dose of the study.
• Immunosuppressive drugs were used within 7 days before the first dose of the study
• Plan to receive live attenuated vaccines within 4 weeks before the first dose treatment or during the study period.
• Has undergone major surgery (craniotomy, thoracotomy or laparotomy) or is expected to require major surgery during the first dose of the study.
• Any remaining AEs > grade 1 from prior anti-tumor treatment as per CTCAE v5.0, with exception of the residual hair loss nor fatigue
• Had received total pelvic radiotherapy before.
• Central nervous system metastases:
• Subjects with active or suspected autoimmune disease or a history of the disease in the past two years
• known history of primary immunodeficiency.
• known history of active pulmonary tuberculosis.
• known history of allograft transplantation and history of allogeneic hematopoietic stem cell transplantation.
• known to be allergic to any IBI188 preparations.
• Ascites of clinical significance, including any ascites that may be detected by physical examination, previously treated or still in need of treatment, may be enrolled if only a small amount of ascites is shown on imaging but asymptomatic.

• Subjects with moderate bilateral pleural effusion, or massive pleural effusion on one side, or respiratory dysfunction requiring drainage.

• Pregnant or nursing females.