A Study of ILB2109 and Toripalimab in Patients With Advanced Solid Malignancies

This is a multicenter, open-label, phase Ib/IIa study. The first part of the study will evaluate the safety, tolerability and preliminary efficacy of ILB2109 and Toripalimab in patients with locally advanced or metastatic solid malignancies. The second part of the study will evaluate the efficacy of ILB2109 and Toripalimab in patients with selected advanced solid malignancies.

This is a two-part study consists of dose escalation and expansion in selected indications. The dose escalation part adopts a 3+3 protocol design and consists of 2 cohorts. Based on the data obtained from the escalation study, selected dose cohort will be expanded in 10 tumor types to further investigate the efficacy of the combination therapy. Subjects will be assessed for safety and efficacy outcomes at pre-specified time points.

Eligibility Criteria:
Inclusion Criteria:

1. Adult patients between the ages of 18 and 80 years.
2. Patients with histologically or cytologically confirmed solid tumours that are advanced, metastatic and or progressive, for whom there is no effective standard therapy available.
3. Eastern Collaborative Oncology Group (ECOG) Performance Status of ≤2.
4. Expected life expectancy ≥3 months.
5. Evaluable disease, either measurable on imaging, or with informative tumour marker(s), as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Eisenhauer, et al. 2009).
6. Laboratory values at Screening:

   Absolute neutrophil count ≥1.5 x 109/L; Platelets ≥75 x 109/L; Hemoglobin ≥ 90g/L; Total bilirubin \<1.5 times the upper limit of normal; Aspartate aminotransferase (AST) ≤3 times the upper limit of normal, ≤ 5 times the upper limit of normal if subject has hepatic malignancies; Alanine aminotransferase (ALT) ≤2.5 times the upper limit of normal, ≤ 5 times the upper limit of normal if subject has hepatic malignancies; Estimated glomerular filtration rate (GFR) of \>50 mL/min (based on the Cockcroft-Gault formula; International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT) ≤1.5 times the upper limit of normal; Left Ventricular Ejection Fraction (LVEF) ≥ 50%; Corrected QT Interval by Fridericia Method: male\<450ms, female\<470ms; and
7. Negative human chorionic gonadotropin (hCG) test in women of childbearing potential.
8. Sexually active male and female patients of childbearing potential must agree to use an effective method of birth control (e.g. barrier methods with spermicides, oral or parenteral contraceptives and/or intrauterine devices) during the entire duration of the study and for 90 days after final administration of ILB-2109, or the patient must be surgically sterile .
9. Ability to give written, informed consent prior to any study-specific Screening procedures.

Exclusion Criteria:

1. In the past 3 weeks: received systemic anti-tumor therapy, including chemotherapy, radiation, biologics, androgen, targeted therapy and immunotherapy with the following exceptions: i. received treatment containing nitrosoureas or mitomycin C in the past 6 weeks; ii. received oral fluorouracil or small molecule targeted therapy or Chinese Traditional Medicine (CTM) with anti-neoplasm indication in the past 2 weeks ;
2. In the past 4 weeks: received any other investigational treatment;
3. Gastrointestinal disease (e.g. Crohn's disease, ulcerative colitis, or short gut syndrome) that would impact on drug absorption;
4. Uncontrollable third-spacing of fluids;
5. Known CNS metastasis with clinical symptoms or the need of steroid treatment or CNS lesion ≥ 1.5cm or with the evidence of lesion enlargement in the past 4 weeks;
6. Severe cardiovascular diseases including symptomatic heart failure (NYHA Class II and above), unstable angina, arrythmia, myocardial infarction within the past 6 months, embolism or pulmonary embolism within the past 3 months;
7. Having any risk factors of QT prolongation, including present or family history of long QT syndrome or using any medication with known QT prolongation effect;
8. Poor controlled chronic diseases, including poorly controlled diabetes mellitus (defined as HbA1c ≥ 8.5%), poorly controlled hypertension, has a history of hypertensive emergency or hypertensive encephalopathy, endocrine diseases that require systemic therapy;
9. Current diagnosis of interstitial pneumonia or a history of chronic emphysema, COPD, or TB infection;
10. Autoimmune diseases that required systemic therapy within the past 2 years, with the exception of vitiligo, asthma, atopic diseases and autoimmune thyroid diseases that are stable on thyroid replacement therapy;
11. Active infection with the need if IV antibiotic treatment;
12. Known HIV infection;
13. Active HBV infection (defined as positive HBsAg and HBV-DNA\>500 IU/ml), active HCV infection (positive HCV antibody but HCV-RNA \< lower limit of detection is allowed to participate);
14. Known syphilis infection;
15. Received systemic steroid at a dose greater or equivalent to 10mg of prednisone per day or other immune modulating treatments in the past 14 days;
16. Plan to receive live vaccine during the study period (4 weeks prior to the 1st dose till 6 months after the last dose);
17. Major surgery within the past 4 weeks;
18. Previous allogeneic bone marrow transplant or solid organ transplant;
19. Known history of psychiatric disease/alcohol or drug abuse that would affect subject's compliance to trial protocol;
20. Any unresolved toxicities from prior therapies higher than CTCAE grade 1 with the following exceptions: i. alopecia; ii. peripheral neuropathy; iii. thyroid function abnormalities that can be treated with replacement therapy;
21. Known history of CTCAE grade 3 and above irAE in previous immunotherapies;
22. Known allergy to ILB-2109 or Toripalimab;
23. Subjects who are currently pregnant or breastfeeding;
24. Other conditions that in the opinion of the investigator will make the subject unfit to participate in this trial;