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

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ClinicalTrials.gov Identifier: NCT04137900
Recruitment Status : Recruiting
First Posted : October 24, 2019
Last Update Posted : November 1, 2019
Sponsor:
Collaborators:
CTI Clinical Trial and Consulting Services
TopAlliance Biosciences, Inc.
Information provided by (Responsible Party):
Shanghai Junshi Bioscience Co., Ltd.

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Advanced Unresectable Solid Tumor Metastatic Solid Tumor Drug: TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 30, 2019
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 0.3 mg/kg repeat dose every 21 days up to 2 years Drug: TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection
Intravenous infusion
Other Name: JS004

Experimental: 1 mg/kg repeat dose every 21days up to 2 years Drug: TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection
Intravenous infusion
Other Name: JS004

Experimental: 3 mg/kg repeat dose every 21 days up to 2 years Drug: TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection
Intravenous infusion
Other Name: JS004

Experimental: 10 mg/kg repeat dose every 21 days up to 2 years Drug: TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection
Intravenous infusion
Other Name: JS004




Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 2 years ]
    Treatment-related adverse events as assessed by CTCAE v4.0


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) by RECIST 1.1 [ Time Frame: 2 years ]
    ORR

  2. Duration of Response (DOR) by RECIST 1.1 [ Time Frame: 2 years ]
    DOR

  3. Disease Control Rate (DCR) by RECIST 1.1 [ Time Frame: 2 years ]
    DCR

  4. Time to response (TTR) by RECIST 1.1 [ Time Frame: 2 years ]
    TTR

  5. Progression-free survival (PFS) by RECIST 1.1 [ Time Frame: 2 years ]
    PFS

  6. Overall survival (OS) by RECIST 1.1 [ Time Frame: 2 years ]
    OS

  7. BTLA receptor occupancy (RO) of blood [ Time Frame: 2 years ]
    RO

  8. Maximum Plasma Concentration (Cmax) after single dose injection of TAB004 [ Time Frame: 2 years ]
    Cmax

  9. Peak Time (Tmax) after single dose injection of TAB004 [ Time Frame: 2 years ]
    Tmax

  10. Area Under the Curve (AUC) after single dose injection of TAB004 [ Time Frame: 2 years ]
    AUC

  11. t1/2 after single dose injection of TAB004 [ Time Frame: 2 years ]
    t1/2 half life

  12. Plasma clearance (CL) after single dose injection of TAB004 [ Time Frame: 2 years ]
    Plasma clearance (CL)

  13. Apparent volume of distribution (V) after single dose injection of TAB004 [ Time Frame: 2 years ]
    volume of distribution (V)

  14. Minimum Plasma Concentration (Cmin) of steady state after multiple dose injection of TAB004 [ Time Frame: 2 years ]
    Cmin

  15. Apparent volume of distribution of steady state (Vss) after multiple dose injection of TAB004 [ Time Frame: 2 years ]
    volume of distribution of steady state (Vss)

  16. The presence of anti-drug antibody (ADA) after multiple dose injection of TAB004 [ Time Frame: 2 years ]
    ADA


Other Outcome Measures:
  1. Correlation analysis of HVEM expression of tumor and ORR [ Time Frame: 3 years ]
    BTLA ligand expression with ORR

  2. Correlation analysis of HVEM expression of tumor and DCR [ Time Frame: 3 years ]
    BTLA ligand expression with DCR

  3. Correlation analysis of HVEM expression of tumor and PFS [ Time Frame: 3 years ]
    BTLA ligand expression with PFS

  4. Correlation analysis of HVEM expression of tumor and OS [ Time Frame: 3 years ]
    BTLA ligand expression with OS



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04137900


Contacts
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Contact: Elias Anaissie, MD 800-753-2389 eanaissie@ctifacts.com
Contact: Stanley Pillemer, MD 301-512-4172 pillemers@americanbiopharma.com

Locations
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United States, North Carolina
Carolina BioOncology Institute Recruiting
Huntersville, North Carolina, United States, 28078
Contact: Ashley Wallace    980-441-1021    amcclain@carolinabiooncology.org   
Principal Investigator: John Powderly, MD         
Sponsors and Collaborators
Shanghai Junshi Bioscience Co., Ltd.
CTI Clinical Trial and Consulting Services
TopAlliance Biosciences, Inc.
Investigators
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Study Director: Sheng Yao, PhD TopAlliance Biosciences, Inc.

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Responsible Party: Shanghai Junshi Bioscience Co., Ltd.
ClinicalTrials.gov Identifier: NCT04137900     History of Changes
Other Study ID Numbers: TAB004-01
First Posted: October 24, 2019    Key Record Dates
Last Update Posted: November 1, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Shanghai Junshi Bioscience Co., Ltd.:
solid tumor
non-small cell lung cancer
immunotherapy
BTLA
HVEM
check point inhibitor
NSCLC
melanoma
lymphoma
monoclonal antibody
phase 1 trial
Additional relevant MeSH terms:
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Neoplasms
Antineoplastic Agents, Immunological
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents