IBI308 in Subjects With Advanced/Metastatic Solid Malignancies
Condition: Advanced/Metastatic Solid Malignancies
MeSH terms: Neoplasms
Intervention: IBI308
Intervention description: IBI308 200mg IV infusion, every 3 weeks.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 39.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced/metastatic solid malignancies, TMB high

Summary:

      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)
    

Eligibility criteria:

        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.