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A Study Evaluating the Safety, Tolerability, and Initial Efficacy of Recombinant Human Anti-cluster Differentiation Antigen 47 (CD47) Monoclonal Antibody Injection (IBI188) in Patients With Advanced Malignant Tumors and Lymphomas

NCT03763149

Description:

This is an open-label, dose escalation, Phase I study to evaluate the safety, tolerability, pharmacokinetics and efficacy in patients with advanced malignancies.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating the Safety, Tolerability, and Initial Efficacy of Recombinant Human Anti-cluster Differentiation Antigen 47 (CD47) Monoclonal Antibody Injection (IBI188) in Patients With Advanced Malignant Tumors and Lymphomas
  • Official Title: A Phase 1a Study Evaluating the Safety, Tolerability, and Initial Efficacy of Recombinant Human Anti-cluster Differentiation Antigen 47 (CD47) Monoclonal Antibody Injection (IBI188) in Patients With Advanced Malignant Tumors and Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: CIBI188A102
  • NCT ID: NCT03763149

Conditions

  • Advanced Malignancies

Interventions

DrugSynonymsArms
IBI188IBI188

Purpose

This is an open-label, dose escalation, Phase I study to evaluate the safety, tolerability, pharmacokinetics and efficacy in patients with advanced malignancies.

Detailed Description

      The study is composed of two stages: Part 1 Accelerated Titration Phase and Part 2 Dose
      Escalation Phase with initial fixed priming dose.

      The starting dose for part 1 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 28 days.

      Part 2 will have 4 dose cohorts(3mg/kg QW、10mg/kg QW、20mg/kg QW and 30mg/kg QW). Conventional
      3+3 Dose Escalation will be adopted. DLT observation period is 28 days.
    

Trial Arms

NameTypeDescriptionInterventions
IBI188ExperimentalPart 1: Accelerated Titration Phase 0.1 mg/kg IV; QW 0.3 mg/kg IV QW; 1 mg/kg IV QW Part 2 : Dose Escalation Phase with initial fixed priming dose Priming dose of 1mg/kg on C1D1 followed by 3 mg/kg IV QW; 10 mg/kg IV QW; 20 mg/kg IV QW; 30 mg/kg IV QW.
  • IBI188

Eligibility Criteria

        Inclusion Criteria:

          1. Able to understand and willing to sign the ICF.

          2. Male or female subject above18 years.

          3. Histologically/cytologically confirmed, locally advanced unresectable or metastatic
             solid tumors and lymphomas that are refractory to standard therapy, or for which no
             standard therapy exists.

          4. For dose expansion at the RP2D: subject has measurable disease per RECIST v1.1. that
             was not in a prior radiation area within past 6 months, unless tumor growth was
             documented following radiation. Lymphomas have at least one measurable lesion and
             FDG-avid lesion according to the Lugano 2014 criteria.

          5. Separate informed consent for subjects who provide archived tissue biopsies for
             biomarker testing (Optional).

          6. ECOG Performance Status 0 to 1

          7. Subjects with life expectancy of ≥ 3 month

          8. No herbal/alternative medications within 14 days prior to the first dose of IBI188.

          9. Must have adequate organ function, prior to start of IBI188, including the following:

               1. Bone marrow reserve: absolute neutrophil count (ANC) ≥ 1.5 x109/L; platelet count
                  ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L; Lymphocyte counts ≥ 0.5
                  x109/L

               2. Hepatic: total bilirubin ≤ 1.5 times 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)

               3. Renal: serum creatinine ≤ 1.5 times the ULN or estimated creatinine clearance
                  ≥50mL/min (Cockroft and Gault formula
                  [https://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation]).

               4. Coagulation tests INR < 2.0, activated partial thromboplastin time (aPTT) ≤ 1.5 x
                  ULN

         10. Subjects (women of child-bearing potential and males) must be willing to use viable
             contraception method that is deemed effective by the investigator throughout the
             treatment period and for at least three months following the last dose of study drug.
             Postmenopausal women must have been amenorrhoeic for at least 12 months to be
             considered of non-childbearing potential.

        Exclusion Criteria:

          1. Pregnant or nursing females.

          2. Any remaining AEs > grade 1 from prior anti-tumor treatment as per CTCAE v5.0, with
             exception of the residual hair loss;

          3. Received a biologic G-CSF, GM-CSF or erythropoietin within 14 days prior to the first
             dose of study drug;

          4. Subjects participating in any other interventional clinical study

          5. Previous exposure to any anti-CD47 monoclonal antibody or SIRPα antibody.

          6. Subjects who had transfusion within 3 weeks

          7. Patients who are on anticoagulants and /or require concomitant aspirin or other
             nonsteroidal anti-inflammatory medications.

          8. Subjects who have a history of documented autoimmune disease, even if not clinically
             severe or never treated with systemic steroids or immunosuppressive agents, are not
             candidates for this clinical trial, except for autoimmune hypothyroidism and
             well-controlled Type 1 diabetes mellitus.

          9. Subjects with or w/o autoimmune condition requiring systemic treatment with either
             corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive
             medications within 14 days before the planned first dose of study drug. Inhaled or
             topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone
             equivalent are permitted in the absence of active autoimmune disease. Ophthalmologic,
             nasal and intra-articular injections or steroids are acceptable.

         10. Subject with primacy central nervous system (CNS) malignancy or symptomatic CNS
             metastases are not allowed. Subjects with asymptomatic CNS metastases are eligible if
             clinically controlled, which is defined as ≥8 weeks of stable neurologic function
             following CNS-directed therapy, and no evidence of CNS disease progression as
             determined by radiographic imaging ≥ 4 weeks prior to screening. No interim
             progression between the completion of CNS-directed therapy and the screening tumor
             assessment, and ≥ 2 weeks from discontinuation of anti-seizure and steroid therapies
             from screening.

         11. Subjects who have had major surgery within the 28-days from the screening;

         12. Subjects with idiopathic pulmonary fibrosis or unresolved active or chronic
             inflammatory pulmonary disease are excluded. Subjects with a history of radiation
             pneumonitis which has resolved are eligible.

         13. Positive for human immunodeficiency virus (HIV) infection.

         14. 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.

         15. History of primary immunodeficiency, stem cell or organ transplant, or previous
             clinical diagnosis of tuberculosis disease.

         16. Subject who have had severe infection deemed clinically significant per investigator
             within 4 weeks or signs and symptoms of any active infection within 2 weeks prior to
             the first dose administration.

         17. 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).

         18. Subjects who experienced immunotherapy-related adverse events (irAE) grade ≥ 3, or who
             had to discontinue prior immunotherapy treatment due to irAEs of any grade.

         19. 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 6 months,
             serious arrhythmias requiring medication (with exception of atrial fibrillation or
             paroxysmal supraventricular tachycardia).

         20. Any other serious underlying medical (e.g. uncontrolled diabetes mellitus,
             uncontrolled hypertension, active gastric ulcer, uncontrolled seizures,
             cerebrovascular incidents, gastrointestinal bleeding, severe signs and symptoms of
             coagulation and clotting disorders), psychiatric, psychological, familial or
             geographical condition that, in the judgment of the investigator, may interfere with
             the planned staging, treatment and follow-up, affect subject compliance or place the
             subject at high risk from treatment-related complications.

         21. Known history of hypersensitivity to any components of the IBI188 product.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients with AEs and SAEs
Time Frame:2 years
Safety Issue:
Description:To evaluate the safety and tolerability of IBI188 [Adverse events (AEs), Serious Adverse Events (SAE) ]

Secondary Outcome Measures

Measure:Pharmacokinetics: AUC
Time Frame:up to 2 years after enrollment
Safety Issue:
Description:The area under the curve (AUC) of serum concentration of the drug after the administration
Measure:Pharmacokinetics: Cmax
Time Frame:up to 2 years after enrollment
Safety Issue:
Description:Maximum concentration(Cmax) of the drug after administration
Measure:Immunogenicity: Percentage of ADA positive patients
Time Frame:up to 2 years after enrollment
Safety Issue:
Description:Number of Anti-Drug Antibodies (ADA) positive patients will be counted and percentage of ADA positive patients will be calculated to evaluate immunogenicity of IBI188.
Measure:Preliminary anti-tumor activity of IBI188 (Objective Response Rate)
Time Frame:up to 2 years after enrollment
Safety Issue:
Description:Objective Response Rate (ORR) is the percentage of Complete Response (CR) plus partial response (PR) assessed by iRECIST v1.1 criteria for solid tumors and Lugano2014 criteria for lymphoma.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Innovent Biologics (Suzhou) Co. Ltd.

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