Overview

This is a multicenter, open-label, dose escalation and expansion study. During the study, subjects will be evaluated for safety, toxicity, tolerability, PK/PD, immunogenicity, biomarkers, and antitumor activity of HB0025. The phase I study will enroll up to 154 subjects with advanced solid tumors who have progressed on or after standard of care therapy and for whom there is no further treatment available that in the judgement of the patient's physician would be beneficial. One cycle is defined as 28 days.

Eligibility

Inclusion Criteria:

1. Male or female. Age ≥ 18 years.
2. Willing and able to provide signed and dated informed consent prior to any study-related procedures and willing and able to comply with all study procedures.
3. 1) Dose escalation phase: Patients with histologically or cytologically confirmed advanced malignant solid tumor who have received or been intolerant of all standard therapies thought to confer clinical benefit. These solid tumors include but are not limited to hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), renal carcinoma (RCC), endometrial carcinoma, etc.
4. Dose expansion phase:
   1. Advanced HCC Cohort:
   2. Unresectable HCC with diagnosis confirmed by histology/cytology or clinical criteria.

        ii) Assessed by the investigator as likely to benefit from the study drug therapy; and
        should have progressed at least one prior systemic therapy regimen which could include but
        not limited to sorafenib, lenvatinib, donafenib, systematic chemotherapy,etc.
        iii)Child-Pugh Classification with score ≤ 6 points.(See Appendix13.6 for criteria)
        VI)HBsAg test is negative.Patients with active hepatitis B virus (HBV) infection must have
        a viral load < 500 IU/mL within 28 days prior to start of study treatment and be on
        suppressive therapy (per local standard of care) for a minimum of 14 days prior to start of
        study treatment and for the length of the study.
        b) Advanced Renal Cell Carcinoma Cohort and Advanced Endometrial Carcinoma Cohort:
        i) Histopathological and/or cytological diagnosis of patients with advanced clear cell
        renal carcinoma, advanced endometrial carcinoma, who are not suitable for radical treatment
        or have relapsed/metastatic disease; Advanced clear cell renal carcinoma should be assessed
        as medium-high risk by the International Metastatic Renal Cell Carcinoma Database Alliance
        (IMDC).
        ii) Assessed by the investigator as likely to benefit from the study drug therapy Patient
        with disease progression from at least one previous systemic treatment or who are
        intolerant to the current standard treatment as determined by the investigator.
        c) Other advanced solid tumor cohort: Patient with other advanced solid tumors that are not
        suitable for radical therapy or relapse /metastasis diagnosed histopathological and/or
        cytologically according to the type of tumor that responds well during the dose escalation
        phase.
        4. Accelerated escalation: Evaluable disease per RECIST v1.1 for solid tumors; Radiographic
        disease assessment at baseline can be performed up to 28 days prior to the first dose.
        5. 3+3 dose escalation and dose expansion cohort: At least one measurable tumor lesion as
        per RECIST criteria v1.1 defined as having at least one dimension with a minimum size of 10
        mm in the longest diameter by CT or MRI scan for non-nodal lesions or ≥15 mm in short axis
        for nodal lesions. Radiographic disease assessment at baseline can be performed up to 28
        days prior to the first dose.
        6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
        7. Life expectancy ≥3 months.
        8. Adequate hepatic function as evidenced by meeting all the following requirements:
          1. Total bilirubin ≤ 1.5 × upper limit of normal (ULN).
          2. AST and ALT ≤ 2.5 × ULN; AST or ALT ≤ 5 × ULN if liver metastases are present.
        9. Serum creatinine (Scr) < 1.5 × ULN and calculated creatinine clearance (CrCL) > 40
        mL/min (Cockroft-Gault Equation).
        10. Hematological function defined as:
          1. Absolute neutrophil count ≥1,500/µL without growth factor support within 2 weeks prior
             to the first dose of HB0025.
          2. Hemoglobin ≥ 9 g/dL without transfusion or erythropoietin within 2 weeks prior to the
             first dose of HB0025.
          3. Platelet count ≥ 75,000/µL without transfusion or recombinant human thrombopoietin
             within 2 weeks prior to the first dose of HB0025.
        11. Coagulation: International Normalized Ratio (INR)≤1.6 (unless receiving anticoagulation
        therapy). Subjects on full-dose oral anticoagulation must be on a stable dose (minimum
        duration 14 days). If receiving warfarin, the subject must have an INR≤3.0 and no active
        bleeding (ie, no bleeding within 14 days prior to first dose of study drug). Subjects on
        low molecular weight heparin will be allowed. Subjects must have no active bleeding or
        clinically significant bleeding within 14 days prior to first dose of study drug.
        12. Recovery, to Grade 0-1, from adverse events related to prior anticancer therapy except
        alopecia, < Grade 2 sensory neuropathy, lymphopenia, and endocrinopathies controlled with
        hormone replacement therapy.
        13. All patients will be required to provide (if available) archived paraffin blocks or at
        least 10 unstained slides prior to study entry. Patients who do not have available archival
        tissue will be asked (optional) to provide fresh tissue from core-needle or punch biopsy.
        Exclusion Criteria:
        Patients who meet any of the following criteria cannot be enrolled:
          1. Symptomatic central nervous system metastases; patients with asymptomatic CNS
             metastases who are radiologically and neurologically stable > 4 weeks following
             CNS-directed therapy, and are on a stable or decreasing dose of corticosteroids
             equivalent to < 10 mg prednisone/day for at least 2 weeks prior to study treatment are
             eligible for study entry.
          2. Active autoimmune disease or history of autoimmune disease requiring systemic therapy
             < 2 years prior to screening except hypothyroidism, vitiligo, Grave's disease,
             Hashimoto's disease, or Type I diabetes. Patients with childhood asthma or atopy that
             has not been active in the 2 years prior to study screening are eligible.
          3. History of Grade 3-4 immune-related adverse events (irAEs) or irAEs requiring
             discontinuation of prior therapies, (except for grade 3 endocrinopathy that is managed
             with hormone replacement therapy).
          4. Use of systemic corticosteroids in a dose equivalent to > 10 mg/day of prednisone or
             other immunosuppressive agent < 2 weeks prior to screening; the use of topical,
             intraocular, intra-articular, intranasal or inhaled corticosteroids (systemic
             absorption is low) will be allowed to prevent (e.g., allergy to contrast agents) or
             treat non-autoimmune condition (e.g. delayed hypersensitivity caused by exposure to
             allergens).
          5. Cerebrovascular accident (CVA), Transient ischemic attack (TIA), myocardial infarction
             (MI), unstable angina, or New York Heart Association (NYHA) class III or IV heart
             failure < 6 months of study entry; mean ECG QT-interval corrected according to
             Fridericia's formula (QTcF) > 470 milliseconds (ms) (males) or > 480 ms (females)
             obtained from three ECGs; uncontrolled arrhythmia < 3 months of study entry. Patients
             with rate-controlled arrhythmias may be eligible for study entry at discretion of the
             Investigator.
          6. Uncontrolled diabetes mellitus with hemoglobin A1c > 8%.
          7. Subjects who have received previous simultaneous therapy with a PD-1 pathway inhibitor
             and a macromolecule VEGF inhibitor (Bevacizumab, Ramucirumab, etc).
          8. Anticancer therapy or radiation < 5 half-lives or 4 weeks (whichever is shorter) prior
             to study entry; palliative radiotherapy to a single area < 2 weeks prior to study
             screening is permitted. Measurable lesions cannot be previously irradiated unless they
             have demonstrated growth after radiation therapy (RT).
          9. Prior stem cell, bone marrow or solid organ transplant.
         10. Concurrent malignancy < 5 years prior to entry other than adequately treated cervical
             carcinoma-in-situ, localized squamous cell cancer of the skin, basal cell carcinoma,
             localized prostate cancer, ductal carcinoma in situ of the breast, or < T1 urothelial
             carcinoma. Patients with prostate cancer that is under active surveillance are
             eligible.
         11. Any of the following infections. 1) Active infection requiring intravenous therapy < 2
             weeks prior to screening. 2) Active tuberculosis (via medical history). 3) Positive
             test for HIV antibody at screening. 4) Active hepatitis B or C. HBV carriers without
             active disease (HBV DNA titer < 1000 cps/mL or 200 IU/mL), or cured Hepatitis C
             (negative HCV RNA test) may be enrolled.
         12. Major surgery < 4 weeks or minor surgery < 2 weeks prior to screening; wound must be
             fully healed.
         13. History of severe allergic reactions, Grade 3-4 allergic reaction to treatment with
             another monoclonal antibody, or known to be allergic to protein drugs or recombinant
             proteins or excipients in HB0025 drug formulation.
         14. Live virus vaccines < 30 days prior to screening.
         15. Pregnant or breast-feeding females.
         16. Any investigational agents or study drugs from a previous clinical study within 30
             days of the first dose of study treatment.
         17. Any other serious underlying medical condition (e.g. active gastric ulcer,
             uncontrolled seizures, cerebrovascular incidents, gastrointestinal bleeding, severe
             signs and symptoms of coagulation and clotting disorders, cardiac conditions), or
             psychiatric, psychological, familial condition or geographical location 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.
         18. Women of childbearing potential who do not consent to use acceptable methods of birth
             control during treatment and for an additional 90 days after the last administration
             of HB0025.
         19. Men with a partner of childbearing potential who do not consent to use acceptable
             methods of birth control during treatment and for an additional 90 days after the last
             administration of HB0025.
        1) Single method i) Intrauterine device (IUD) ii) Vasectomy of a female subject's male
        partner iii) Contraceptive rod implanted into the skin 2) Combination method (requires use
        of two of the following) i) Diaphragm with spermicide (cannot be used in conjunction with
        cervical cap/spermicide) ii) Cervical cap with spermicide (nulliparous women only) iii)
        Contraceptive sponge (nulliparous women only) iv) Male condom or female condom (cannot be
        used together) v) Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill
        or progestin -only pill), contraceptive skin patch, vaginal contraceptive ring, or
        subcutaneous contraceptive injection.
        20. Positive COVID-19 qRT-PCR and/or serology test result during screening; 21. Subjects
        with a history of arterial or deep venous thrombosis within 3 months before enrollment, or
        patients with evidence or history of bleeding tendency within 2 months before enrollment,
        regardless of severity.
        22. Severe dyspnea or pulmonary dysfunction or need for continuous supportive oxygen
        inhalation.
        23. Skin wound, surgical site, wound site, mucosal ulcer, or fracture not completely
        healed; 24. Conditions that may cause gastrointestinal bleeding or perforation (such as
        duodenal ulcer, intestinal obstruction, Crohn's disease, ulcerative colitis, large-scale
        gastrectomy, etc.); patients with previous history of intestinal perforation and intestinal
        fistula but not cured after surgical treatment; esophageal and gastric varices.
        25. Subjects received immune modulators treatment, including but not limited to
        cyclosporine and tacrolimus, within 2 weeks before enrollment.
        26. Inability to comply with study and follow-up procedures. 27. Patients who have history
        of interstitial lung disease or non-infectious pneumonitis (except factor of radiation
        therapy; such patients should be discussed with the Medical Monitor before enrollment.
        28. Subjects who in the judgement of the Investigator are not suited to participate in this
        trial.
        29. Uncontrolled arterial hypertension despite standard treatment (systolic blood pressure
        ≥160 mmHg or diastolic blood pressure ≥100 mmHg).
        30. Patients with > 2+ protein on urine dipstick should have a 24-hour urine collection;
        Patients with ≥ 2 g of protein in the urine on 24-hour collection are ineligible for study
        entry.