Clinical Trials /

Safety, Tolerability and Pharmacokinetics of a Monoclonal Antibody Specific to B-and T-Lymphocyte Attenuator (BTLA) for Injection in Subjects With Advanced Malignancies

NCT04137900

Description:

The primary objective is to assess the safety and tolerability of TAB004 in subjects with selected advanced solid malignancies, including lymphoma, and to evaluate the recommended Phase 2 dose. The secondary objectives are to: 1) describe the pharmacokinetic (PK) profile of TAB004, 2) evaluate antitumor activity of TAB004; and 3) determine the immunogenicity of TAB004. The exploratory objectives are to: 1) evaluate pharmacodynamic effects of TAB004 on its target receptor BTLA, as well as effects on the immune system; 2) evaluate biomarkers that may correlate with activity of TAB004; 3) evaluate the utility of BTLA ligand, herpesvirus-entry mediator (HVEM), and additional exploratory biomarkers that could aid in selection of appropriate subjects for TAB004 therapy.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety, Tolerability and Pharmacokinetics of a Monoclonal Antibody Specific to B-and T-Lymphocyte Attenuator (BTLA) for Injection in Subjects With Advanced Malignancies
  • Official Title: A First-in-Human, Multicenter, Open-Label, Phase 1 Dose-Escalation and Cohort Expansion Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAB004 in Subjects With Advanced Solid Malignancies Including Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: TAB004-01
  • NCT ID: NCT04137900

Conditions

  • Advanced Unresectable Solid Tumor
  • Metastatic Solid Tumor

Interventions

DrugSynonymsArms
TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injectionJS0040.3 mg/kg repeat dose every 21 days up to 2 years

Purpose

The primary objective is to assess the safety and tolerability of TAB004 in subjects with selected advanced solid malignancies, including lymphoma, and to evaluate the recommended Phase 2 dose. The secondary objectives are to: 1) describe the pharmacokinetic (PK) profile of TAB004, 2) evaluate antitumor activity of TAB004; and 3) determine the immunogenicity of TAB004. The exploratory objectives are to: 1) evaluate pharmacodynamic effects of TAB004 on its target receptor BTLA, as well as effects on the immune system; 2) evaluate biomarkers that may correlate with activity of TAB004; 3) evaluate the utility of BTLA ligand, herpesvirus-entry mediator (HVEM), and additional exploratory biomarkers that could aid in selection of appropriate subjects for TAB004 therapy.

Detailed Description

      OVERVIEW: This is a Phase 1, multi-center, open-label, dose-escalation study of TAB004, a
      recombinant humanized IgG4κ monoclonal antibody specific to BTLA. It is estimated that up to
      144 subjects with selected advanced solid malignancies (i.e.; non-small cell lung cancer
      [NSCLC], melanoma, or other tumors), including lymphoma will be enrolled in the study.

      Subjects must have a histologically or cytologically confirmed advanced unresectable or
      metastatic solid tumor, including lymphoma.

      The study has 2 parts; Part A dose-escalation and Part B cohort expansion. In Part A, up to
      24 subjects will be enrolled who must have received, or be ineligible for, or intolerant of,
      all available approved or standard therapies know to confer clinical benefit including
      immunotherapy, or for whom no standard therapy exists.

      In Part B, subjects must have received at least one line of therapy for advanced or
      metastatic disease, but are not required to have received all standard therapies known to
      confer clinical benefit.

      Part A is the dose-escalation portion of the study. Four dose levels are planned and include:
      0.3, 1, 3 and 10 mg/kg. Part A will be the traditional 3 + 3 design with 3 to 6 subjects per
      dose level (cohort) and will receive their assigned dose every 21 days in the absence of a
      dose limiting toxicity (DLT) that would prevent further dosing.

      Part B will consist of up to 30 subjects in each advanced solid tumor indication (up to 120
      subjects) that may include but not be limited to lymphoma, melanoma, NSCLC, or other tumors
      with agreement of the Sponsor.

      Tumor response will be evaluated using the Response Evaluation Criteria in Solid Tumors
      (RECIST v1.1), the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), or
      the New Response Evaluation Criteria in Lymphoma (RECIL) 2017.

      In the absence of confirmed disease progression and intolerable toxicities, subjects will be
      allowed to continue TAB004 administration every 21 days for up to 2 years.

      DOSAGE AND ADMINISTRATION TAB004 doses are 0.3, 1, 3, and 10 mg.kg. TAB004 will be
      administered as a 60-minute i.v. infusion for the first dose and may be decreased at the
      investigators discretion to 30 minutes in subsequent infusions.

      SAFETY EVALUATIONS Assessment of safety will be determined by vital sign measurements,
      clinical laboratory tests, Eastern Cooperative Oncology Group (ECOG) performance status
      evaluations, diagnostic imaging, physical examinations, electrocardiograms, and the incidence
      and severity of adverse events.

      Safety will also include evaluations of immune safety and immunogenicity. Blockade of BTLA
      pathway by monoclonal antibodies has been demonstrated in several syngeneic mouse models to
      enhance specific T cell responses and inhibit tumor growth. In studies of BTLA deficient
      mice, diseases such as asthma, autoimmune involvement of the central nervous system, and
      systemic lupus erythematosus were exacerbated. Particular attention will be given to symptoms
      related to those diseases as well as the occurrence of adverse events that may follow
      enhanced T-cell activation such as pneumonitis, colitis, nephritis, severe skin reactions,
      endocrinopathies, or other immune-related adverse events (irAEs).

      An irAE is a clinically significant adverse event of any organ that is associated with drug
      exposure, of unknown etiology, and is consistent with an immune-mediated mechanism.

      EFFICACY EVALUATIONS will include best overall response, objective response rate, duration of
      response or duration of stable disease, progression free survival and overall response.

      PHARMACOKINETIC EVALUATIONS Pharmacokinetic parameters include AUC0-inf, AUC0-last, AUC0-21d,
      Cmax, Cmin trough, Tmax, t1/2, CL, and Vss.

      STATISTICAL METHODS The sample size for this study is not determined from power analysis. In
      Part A, it is based on the 3+3 design for dose escalation and safety evaluation requirements.

      All PK/Pharmacodynamic, immunogenicity, and safety data will be summarized and presented by
      cohort as well as overall for the study, using descriptive statistics (number of subjects,
      mean, median, standard deviation, minimum, and maximum) for continuous variables and using
      frequencies and percentages for discrete variables.

      ORR and the associated 2-sided 95% exact confidence limits will be calculated. The proportion
      of subjects who have experienced best response as CR, PR, SD, or progressive disease (PD)
      will be provided.
    

Trial Arms

NameTypeDescriptionInterventions
0.3 mg/kg repeat dose every 21 days up to 2 yearsExperimental
  • TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection
1 mg/kg repeat dose every 21days up to 2 yearsExperimental
  • TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection
3 mg/kg repeat dose every 21 days up to 2 yearsExperimental
  • TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection
10 mg/kg repeat dose every 21 days up to 2 yearsExperimental
  • TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection

Eligibility Criteria

        Inclusion Criteria:

          -  1. Able to understand and willing to sign the Informed Consent Form;

          -  2. Subjects with histologically or cytologically confirmed advanced unresectable or
             metastatic solid tumor, including lymphoma. In Part A, subjects must have received, or
             be ineligible for or intolerant of all available approved or standard therapies known
             to confer clinical benefit including immunotherapy, or for whom no standard therapy
             exists; in Part B, subjects with advanced solid tumors, including but not limited to
             lymphoma, melanoma, NSCLC, or other tumors with agreement of the Sponsor, who must
             have received at least one line of therapy for advanced or metastatic disease, but are
             not required to have received all standard therapies known to confer clinical
             benefit.;

          -  3. Measurable disease per RECISTv1.1 and iRECIST, or RECIL 2017 for lymphoma

          -  4. ECOG performance status of 0 or 1 with life expectancy of 3 months in the opinion
             of the investigator.

          -  5. Adequate organ and marrow function, as defined below:

               1. Hemoglobin 8.0 g/dL within first 2 weeks prior to first dose of TAB004
                  (transfusion allowed)

               2. Absolute neutrophil count (ANC) 1.0 x 109 /L (1,000 /mm3)

               3. Platelet count 75 x 109 /L (75,000 /mm3)

               4. Total bilirubin ≤ 1.5 x ULN except subjects with documented Gilbert's syndrome
                  who must have a baseline conjugated bilirubin ≤ 3.0 mg/dL

               5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN;
                  for subjects with hepatic metastases, ALT and AST ≤ 5 x ULN

               6. Serum creatinine ≤ 1.5 x ULN OR calculated creatinine clearance (CrCl) or 24 hour
                  urine CrCl ≥ 40 mL/minute

               7. Cockcroft-Gault formula will be used to calculate CrCl. 24-hour urine CrCl will
                  be derived using the measured creatinine clearance formula

               8. International normalized ratio (INR) ≤ 2.0 and activated partial thromboplastin
                  time (aPTT) ≤ 1.5 x ULN; applies only to subjects who do not receive therapeutic
                  anticoagulation; subjects receiving therapeutic anticoagulation (such as
                  low-molecular weight heparin or warfarin) should be on a stable dose

          -  6. Willingness to provide consent for biopsy samples (In Part A, fresh pre-treatment
             biopsies will be requested from subjects with safely accessible lesions. For subjects
             who cannot provide a fresh pre-treatment biopsy, an archival specimen will be
             required. In Part B, fresh pre-treatment biopsies will be required from subjects with
             safely accessible lesions. Archival specimens will be requested).

          -  7. Females of childbearing potential who are sexually active with a nonsterilized male
             partner must use effective contraception from time of screening, and must agree to
             continue using such precautions for 90 days after the final dose of TAB004; cessation
             of birth control after this point should be discussed with a responsible physician.
             Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable
             methods of birth control.

          -  8. Females of childbearing potential are defined as those who are not surgically
             sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete
             hysterectomy) or postmenopausal (defined as at least 12 months with no menses
             confirmed by follicle-stimulating hormone [FSH] levels. FSH testing will be conducted
             at the Screening visit to confirm post-menopausal status).

          -  9. Subjects must use effective contraception.

          -  10. Nonsterilized males who are sexually active with a female partner of childbearing
             potential must use effective contraception from Day 1 and for 90 days after receipt of
             the final dose of TAB004.

        Exclusion Criteria:

          -  1. Concurrent enrollment in another clinical study, unless it is an observational (non
             interventional) clinical study or the follow-up period of an interventional study.

          -  2. Any concurrent chemotherapy, radiotherapy, immunotherapy, or biologic therapy for
             cancer treatment. Concurrent use of hormones for non-cancer-related conditions (e.g.,
             insulin for type 2 diabetes and hormone replacement therapy) is acceptable.

        Note: Local treatment of isolated lesions for palliative intent is acceptable (e.g., by
        local surgery or radiotherapy).

          -  3. Receipt of any investigational anticancer therapy within 4 weeks prior to the first
             dose of TAB004.

          -  4. Current or prior use of immunosuppressive medication within 4 weeks prior to the
             first dose of TAB004, with the exception of intranasal and inhaled corticosteroids or
             systemic corticosteroids not to exceed 10 mg/day of prednisone or equivalent.

          -  5. Prior exposure to anti-BTLA, or anti-HVEM antibodies.

          -  6. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.

          -  7. Subjects with another active malignancy, or history or other malignancy within 5
             years prior to screening that would impact the assessment of any study endpoints.
             Subject with non-melanomatous skin cancer or cervical cancer that has been curatively
             surgically resected are eligible.

          -  8. Major surgery (as defined by the investigator) within 4 weeks prior to first dose
             of TAB004 or has not recovered to at least Grade 1 from adverse effects from such
             procedure, or anticipation of the need for major surgery during study treatment.

          -  9. Unresolved toxicities from prior anticancer therapy, defined as having not resolved
             to baseline or to NCI-CTCAE v5.0 Grade 0 or 1, or to levels dictated in the
             inclusion/exclusion criteria with the exception of alopecia. Subjects with
             irreversible toxicity that is not reasonably expected to be exacerbated by TAB004 may
             be included (e.g., hearing loss) after consultation with the medical monitor.

          -  10. Active or prior documented autoimmune disease, such as but not limited to systemic
             lupus erythematosus, multiple sclerosis, inflammatory bowel diseases, rheumatoid
             arthritis, autoimmune hepatitis, systemic sclerosis, autoimmune vasculitis, autoimmune
             neuropathies or type 1 insulin-dependent diabetes mellitus.

        Note: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic
        treatment other than thyroid hormone replacement (within the past 2 years) are not
        excluded.

          -  11. Clinically significant (intracranial, gastrointestinal) bleeding within 2 weeks
             prior to screening.

          -  12. Known history of tuberculosis.

          -  13. Subjects with history of or current drug-induced interstitial lung disease or
             pneumonitis ≥ Grade 2.

          -  14. Subjects who have discontinued prior immune therapy due to immune mediated adverse
             reaction(s).

          -  15. Subjects who are known to be human immunodeficiency virus positive.

          -  16. Subjects with evidence of hepatitis B or C virus infection, unless their hepatitis
             is considered to have been cured. (Note that subjects with prior hepatitis B virus
             infection must have HBV viral load < 100 IU/mL before study enrollment, and must be
             treated according to local standards; hepatitis C virus infection must have, before
             study enrollment, no detectable viral load and must be treated according to local
             standards).

          -  17. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis).

          -  18. History of anaphylaxis, eczema that cannot be controlled with topical
             corticosteroids, or asthma.

          -  19. History of primary immunodeficiency.

          -  20. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure according to New York Heart
             Association Functional Classification ≥ 3, uncontrolled hypertension, unstable angina
             pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric
             illness/social situations that would limit compliance with study requirements,
             substantially increase risk of incurring adverse events from TAB004, or compromise the
             ability of the subject to give written informed consent.

          -  21. Symptomatic or untreated central nervous system and leptomeningeal metastases or
             requiring ongoing treatment for these metastases, including corticosteroids and
             antiepileptic agents. Subjects with previously treated brain metastases may
             participate provided they are clinically stable for at least 4 weeks prior to study
             entry, have no evidence of new or enlarging metastases, and are off steroids.

          -  22. Receipt of live attenuated vaccination within 4 weeks prior to study entry or
             within 30 days of receiving TAB004.

          -  23. Any condition or treatment or diagnostic test that, in the opinion of the
             investigator or sponsor, would interfere with evaluation of TAB004 or interpretation
             of subject safety or study results.

          -  24. Pregnancy or breast feeding women.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:2 years
Safety Issue:
Description:Treatment-related adverse events as assessed by CTCAE v4.0

Secondary Outcome Measures

Measure:Objective Response Rate (ORR) by RECIST 1.1
Time Frame:2 years
Safety Issue:
Description:ORR
Measure:Duration of Response (DOR) by RECIST 1.1
Time Frame:2 years
Safety Issue:
Description:DOR
Measure:Disease Control Rate (DCR) by RECIST 1.1
Time Frame:2 years
Safety Issue:
Description:DCR
Measure:Time to response (TTR) by RECIST 1.1
Time Frame:2 years
Safety Issue:
Description:TTR
Measure:Progression-free survival (PFS) by RECIST 1.1
Time Frame:2 years
Safety Issue:
Description:PFS
Measure:Overall survival (OS) by RECIST 1.1
Time Frame:2 years
Safety Issue:
Description:OS
Measure:BTLA receptor occupancy (RO) of blood
Time Frame:2 years
Safety Issue:
Description:RO
Measure:Maximum Plasma Concentration (Cmax) after single dose injection of TAB004
Time Frame:2 years
Safety Issue:
Description:Cmax
Measure:Peak Time (Tmax) after single dose injection of TAB004
Time Frame:2 years
Safety Issue:
Description:Tmax
Measure:Area Under the Curve (AUC) after single dose injection of TAB004
Time Frame:2 years
Safety Issue:
Description:AUC
Measure:t1/2 after single dose injection of TAB004
Time Frame:2 years
Safety Issue:
Description:t1/2 half life
Measure:Plasma clearance (CL) after single dose injection of TAB004
Time Frame:2 years
Safety Issue:
Description:Plasma clearance (CL)
Measure:Apparent volume of distribution (V) after single dose injection of TAB004
Time Frame:2 years
Safety Issue:
Description:volume of distribution (V)
Measure:Minimum Plasma Concentration (Cmin) of steady state after multiple dose injection of TAB004
Time Frame:2 years
Safety Issue:
Description:Cmin
Measure:Apparent volume of distribution of steady state (Vss) after multiple dose injection of TAB004
Time Frame:2 years
Safety Issue:
Description:volume of distribution of steady state (Vss)
Measure:The presence of anti-drug antibody (ADA) after multiple dose injection of TAB004
Time Frame:2 years
Safety Issue:
Description:ADA

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Shanghai Junshi Bioscience Co., Ltd.

Trial Keywords

  • immunotherapy
  • BTLA
  • HVEM
  • check point inhibitor
  • solid tumor
  • non-small cell lung cancer
  • NSCLC
  • melanoma
  • lymphoma
  • monoclonal antibody
  • phase 1 trial

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