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.
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
Drug | Synonyms | Arms |
---|
TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection | JS004 | 0.3 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
Name | Type | Description | Interventions |
---|
0.3 mg/kg repeat dose every 21 days up to 2 years | Experimental | | - TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection
|
1 mg/kg repeat dose every 21days up to 2 years | Experimental | | - TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection
|
3 mg/kg repeat dose every 21 days up to 2 years | Experimental | | - TAB004, Recombinant humanized IgG4κ monoclonal antibody specific to BTLA for injection
|
10 mg/kg repeat dose every 21 days up to 2 years | Experimental | | - 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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