Overview

It is a single-arm, open-label, multicenter, phase II clinical study to evaluate the clinical efficacy and safety of HLX10 monotherapy for the treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors who have progressed or intolerable after standard therapy.This study consists of three periods, screening period (28 days), treatment period and follow-up period (including safety follow-up, survival follow-up).Subjects can be enrolled into this study only if they meet inclusion criteria and do not meet exclusion criteria. The enrolled subjects will receive an intravenous infusion of HLX10 (3 mg/kg) once every 2 weeks until the loss of clinical benefit, death, intolerable toxicity, withdrawal of informed consent or other reasons as specified in the protocol, or up to the longest treatment duration-2 years (52 dosing periods) (whichever occurs earlier).

Eligibility

Inclusion Criteria:

• Subjects who meet all of the following criteria are allowed to be enrolled into this

  study

  • Volunteer to participate in this clinical study; completely understand and know this study as well as sign the informed consent form (ICF); be willing to follow and be able to complete all study procedures;
  • Age ≥ 18 years and ≤ 75 years when ICF is signed;
  • Patients with unresectable or metastatic MSI-H or dMMR malignant solid tumors which are histopathologically or/and cytologically confirmed by the central laboratory or study sites;
  • Patients who have disease progression or intolerable reactions after the currently available standard anti-cancer treatment previously received;
  • The interval between the end of previous systemic anti-tumor treatment and the first dosing of if this study must be ≥ 2 weeks. In addition, treatment-related AEs recover to NCI-CTCAE v4.03 ≤ grade 1 (excluding grade 2 alopecia).
  • There is at least one measurable lesion assessed by IRRC according to the requirements of RECIST version 1.1 (Appendix 1).

        Note: measurable lesions cannot be selected from the previous radiotherapy sites. If the
        target lesion of the previous radiotherapy sites is the only one available lesion, the
        investigator is required to provide imaging data before and after significant progression
        of such lesion.
        • Subjects must provide tumor tissues and blood samples for the determination of MSI, tumor
        mutational burden (TMB), PD-L1 expression level (if the test results of the above
        parameters by the central laboratory specified by this study are available, the subjects
        are allowed not to receive repeated tests).
        Note: it is recommended to provide formalin fixed tumor tissue samples collected from
        non-radiotherapy sites within 6 months prior to the first dosing of investigational
        product, paraffin embedded tumor samples (preferred), or formalin fixed paraffin embedded
        tumor samples or unstained newly sliced serial sections (glass slides). Moreover, the
        corresponding pathological reports of the above samples must also be provided. Freshly
        collected samples, excision, core needle biopsy, resection, incision, punching or forceps
        biopsies are within the acceptable range (newly-obtained tissues preferred). The aspiration
        samples (i.e., lack of complete tissue structure and only cell suspension and/or cell
        smears are provided), brushing samples, cell precipitation samples from pleural or
        peritoneal effusion are not acceptable. The requirements for tissue samples are provided in
        laboratory operating manual in detail.
          -  ECOG performance status score (Appendix II) of 0 or 1 within 7 days before the first
             dose of invetigational product;
          -  Life expectancy ≥12 weeks;
          -  Negative HBsAg; patients with positive HBsAg or HBcAb test results can be enrolled
             only if Hepatitis B virus (HBV) DNA test results are negative.
             11.Negative HCV antibody; patients with positive HCV antibody or HCV-RNA test results
             can be enrolled only if ALT and AST are CTCAE v4.03 ≤ grade 1 (i.e., ≤ 3×ULN);
             subjects concurrently infected with hepatitis B and hepatitis C are excluded.
          -  Normal function of main organs, and the following criteria are met (within the 14 days
             before the first injection of investigational product, patients have not received the
             treatment with blood transfusion, albumin, recombinant human thrombopoietin or colony
             stimulating factor (CSF)):
          -  Female subjects must meet the following criteria:
             ① Menopause (defined as no menstruation for at least one year, and no other confirmed
             reasons other than menopause), or② Received surgical sterilization (ovariectomy and/or
             hysterectomy), or③ Subjects who are able to bear or father a child must meet the
             following criteria:
          -  Serum pregnancy test must be negative within 7 days before the first dosing, and
          -  Agree to use contraceptive methods with an annual failure rate of < 1% or maintain
             sexual abstinence (avoid heterosexual intercourse) (from the signing of informed
             consent form to at least 120 days after the last dose of investigational product)
             (contraceptive methods with an annual failure rate of < 1% include bilateral tubal
             ligation, male sterilization, correct use of hormonal contraceptives which may inhibit
             ovulation, hormone-releasing intrauterine device and copper intrauterine device), and
          -  Breast-feeding is not allowed.
          -  Male subjects should meet the criteria below: agree to maintain sexual abstinence
             (avoid heterosexual intercourse) or use contraceptive methods, with requirements
             detailed below: if the partners of male subjects have childbearing potential or become
             pregnant, male subjects must maintain sexual abstinence or use condoms to prevent drug
             exposure to embryos during administration period of investigational product and within
             at least 120 days after after the last dose of investigational product. The
             reliability of sexual abstinence should be evaluated based on the duration of clinical
             studies, preference of the subjects and daily life style. Regular sexual abstinence
             (e.g., calendar days, ovulation period, basal body temperature or post-ovulation
             period contraceptive methods) and coitus interruptus are disqualified contraceptive
             methods.
        Exclusion Criteria:
          -  Subjects who meet any of the following criteria are not allowed to be enrolled in this
             study:
               -  Subjects who plan to undergo or previously underwent organ or bone marrow
                  transplantation.
               -  Uncontrollable pleural effusion, pericardial effusion or ascites after
                  appropriate intervention measures.
               -  Subjects with known or screening test-confirmed active central nervous system
                  (CNS) metastasis and/or carcinomatous meningitis; However, the following subjects
                  are allowed to be enrolled: 1. subjects with asymptomatic brain metastasis (i.e.
                  without progressive central nervous system symptoms caused by brain metastatic
                  lesions, without the requirement of corticosteroids treatment, and lesion size
                  ≤1.5cm) are allowed to participate in this study, however, it is necessary to
                  perform regular brain imaging tests for disease sites. 2. subjects with brain
                  metastasis after treatment, and brain metastatic lesions are stable for at least
                  1 month, without evidence of new or expanded brain metastasis, and steroids are
                  discontinued 3 days prior to the first dose of the investigational product.
                  Stable brain metastasis in this definition should be confirmed before the first
                  dose of the investigational product.
               -  Subjects with spinal cord compression which cannot be radically treated through
                  surgery and/or radiotherapy, or subjects previously diagnosed with spinal cord
                  compression with no post-treatment clinical evidence showing stable disease ≥ 1
                  week before the first dose of the investigational product.
               -  Imaging test results show definit tumor invasion of thoracic great vessels.
               -  Occurrence of myocardial ischemia above grade Ⅱ , or myocardial infarction,
                  unstable angina pectoris, inadequately controlled arrhythmia (including QTc
                  interval ≥ 450 ms for males, and ≥ 470 ms for females) within half a year before
                  the first dose of the investigational product (QTc interval is calculated based
                  on Fridericia formula).
               -  Grade Ⅲ or Ⅳ cardiac dysfunction based on New York Heart Association (NYHA)
                  Functional Classification (appendix Ⅲ) or echocardiography test showing left
                  ventricular ejection fraction (LVEF) < 50%.
               -  Presence of peripheral neuropathy with CTCAE v4.03 ≥ grade 2.
               -  Infection with human immunodeficiency virus (HIV).
               -  Presence of active pulmonary tuberculosis.
               -  Previously or currently suffering from interstitial pneumonia, pneumoconiosis,
                  radiation pneumonitis, drug-related pneumonitis, seriously injured lung function
                  and other conditions which may interfere with the detection and treatment of
                  suspected drug-related pulmonary toxicity.
               -  Presence of know active or suspected autoimmune diseases; Patients who have
                  stable status and require no treatment with systemic immunosuppressive therapies
                  are allowed to be enrolled.
               -  Treatment with live vaccines within 28 days before the first administration of
                  investigational product.
               -  Subjects requiring treatment with systemic corticosteroids (> 10 mg/day
                  prednisone or equivalent dose of similar drugs) or other immunosuppressive
                  therapies within 14 days before the first administration of investigational
                  product or during the study period; However, the following conditions are allowed
                  to be enrolled: in the event of no active autoimmune diseases, inhalation or
                  topical use of steroids or adrenaline alternative treatment of effective dose of
                  prednisone ≤ 10 mg/day are allowed.
               -  Presence of any active infection requiring systemic anti-infection treatment
                  within 14 days before the first administration of investigational product.
               -  Subjects who have received major surgery within 28 days before the first
                  administration of investigational product, by "major surgery", it meant that the
                  patient needs at least three weeks to recover following the surgery before being
                  able to receive the study treatment. Enrollment through tumor puncture or lymph
                  node biopsy is allowed.
               -  Received radical radiotherapy within 3 months before the first administration of
                  investigational product.
        Note: palliative radiotherapies for bones or superficial lesions are acceptable. The course
        of treatment should be in accordance with the local standard and has ended 14 days before
        the first administration. Radiotherapy covering more than 30% of the bone marrow area is
        not allowed within 28 days prior to the first dose.
          -  Other anti-tumor treatments such as chemotherapy, targeted therapy or radiotherapy
             (excluding palliative radiotherapy) may be received during the study period.
          -  Previously received treatment with any T cells costimulation or immune checkpoint,
             including but not limited to cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)
             inhibitors, PD-1 inhibitors, PD-L1/2 inhibitors or other targeted T cells drugs.
          -  Subjects are participating in other clinical studies, or the time interval between the
             initiation of treatment planned in this study and end of investigational product
             treatment in the previous clinical study is less than 14 days.
          -  Known serious hypersensitivity history to any monoclonal antibody or the excipients of
             investigational product.
          -  Pregnant or lactating women.
          -  Known history of abuse of psychotropic drugs or drug addiction; Subjects who have
             stopped drinking are allowed to be enrolled.
          -  The subjects have other factors which may cause premature termination of this study at
             the discretion of the investigators.