Description:
The primary objective is to assess the safety and tolerability of TAB004 as monotherapy and
in combination with toripalimab 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
monotherapy and in combination with toripalimab and to describe the PK profile of toripalimab
when administered with TAB004, 2) evaluate antitumor activity of TAB004 monotherapy and in
combination with toripalimab; and 3) determine the immunogenicity of TAB004 monotherapy and
in combination with toripalimab and to determine the immunogenicity of toripalimab when
administered with 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 as monotherapy and in combination with toripalimab; 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
monotherapy and in combination with toripalimab.
Title
- Brief Title: Safety, Tolerability and Pharmacokinetics of a Monoclonal Antibody Specific to B-and T-Lymphocyte Attenuator (BTLA) as Monotherapy and in Combination With an Anti-PD1 Monoclonal Antibody 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 as Monotherapy and in Combination With Toripalimabin 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 | JS004 | TAB004 0.3 mg/kg repeat dose every 21 days up to 2 years |
Toripalimab | TAB001, JS001 | TAB004 200mg and Torpalimab 240mg repeat dose every 21 days up to 2 years |
Purpose
The primary objective is to assess the safety and tolerability of TAB004 as monotherapy and
in combination with toripalimab 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
monotherapy and in combination with toripalimab and to describe the PK profile of toripalimab
when administered with TAB004, 2) evaluate antitumor activity of TAB004 monotherapy and in
combination with toripalimab; and 3) determine the immunogenicity of TAB004 monotherapy and
in combination with toripalimab and to determine the immunogenicity of toripalimab when
administered with 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 as monotherapy and in combination with toripalimab; 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
monotherapy and in combination with toripalimab.
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 when administered alone and
in combination with toripalimab, a human IgG4k monocloncal antibody that specifically binds
to the programmed death 1 (PD-1). It is estimated that up to 499 subjects with selected
advanced solid malignancies (i.e.; non-small cell lung cancer [NSCLC], melanoma, renal cell
carcinoma (RCC), urothelial carcinoma (UC), 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 4 parts; Part A dose-escalation, Part B cohort expansion, Part C
dose-escalation and Part D 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, C and D, 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 monotherapy dose-escalation portion of the study. Four TAB004 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 is the monotherapy cohort expansion portion of the study and will consist of up to 50
subjects in each advanced solid tumor indication (up to 200 subjects) that may include but
not be limited to lymphoma, melanoma, NSCLC, or other tumors with agreement of the Sponsor.
Part C is the combination therapy dose-escalation portion of the study. Four dose levels are
planned as follows: Cohort 1 - TAB004 20 mg and toripalimab 240mg; Cohort 2 - TAB004 70 mg
and toripalimab 240 mg; Cohort 3 -TAB004 200 mg and toripalimab 240 mg; Cohort 4- TAB004 500
mg and toripalimab 240 mg. Part C will be the traditional 3 + 3 design with 3 to 6 subjects
per dose level (cohort) and will receive their assigned doses every 21 days in the absence of
a DLT that would prevent further dosing.
Part D is the combination therapy cohort expansion portion of the study. Up to 50 subjects
will be enrolled in each advanced solid tumor indication (melanoma, NSCLC, RCC, UC, lymphoma)
(up to 250 subjects). Doses of TAB004 and toripalimab will be determined based upon safety
and efficacy data from Part C.
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 (Part A and B) or TAB004 and toripalimab (Part C and D)
administration every 21 days for up to 2 years.
DOSAGE AND ADMINISTRATION TAB004 doses are 0.3, 1, 3, 10 mg/kg, 20mg, 70mg, 200mg and 500mg.
Toripalimab dose is 240mg. TAB004 alone or TAB004 plus toripalimab 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 and PD-1 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. 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) will be evaluated for
subjects receiving TAB004 alone or in combination with toripalimab.
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, accumulation and Vss.
STATISTICAL METHODS Part A and Part C are based on the 3+3 design for dose escalation and
safety evaluation requirements. In Part B and Part D, sample size is estimated using Simon's
two-phase design minimax method.
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 by cohorts in Part B and Part D.
Trial Arms
Name | Type | Description | Interventions |
---|
TAB004 0.3 mg/kg repeat dose every 21 days up to 2 years | Experimental | | |
TAB004 1 mg/kg repeat dose every 21days up to 2 years | Experimental | | |
TAB004 3 mg/kg repeat dose every 21 days up to 2 years | Experimental | | |
TAB004 10 mg/kg repeat dose every 21 days up to 2 years | Experimental | | |
TAB004 200mg repeat dose every 21 days up to 2 years | Experimental | | |
TAB004 20mg and Torpalimab 240mg repeat dose every 21 days up to 2 years | Experimental | | |
TAB004 70mg and Torpalimab 240mg repeat dose every 21 days up to 2 years | Experimental | | |
TAB004 200mg and Torpalimab 240mg repeat dose every 21 days up to 2 years | Experimental | | |
TAB004 500mg and Torpalimab 240mg repeat dose every 21 days up to 2 years | Experimental | | |
Eligibility Criteria
Inclusion Criteria:
- 1. Able to understand and willing to sign the Informed Consent Form;
- 2. Male or female ≥ 18 years;
- 3. Subjects with histologically or cytologically confirmed advanced unresectable or
metastatic solid tumor, including lymphoma that have progressed following prior
treatment. 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 or metastatic 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; In Part C,
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; In Part D, subjects with advanced or metastatic solid tumors that
may include but not limited to lymphoma, melanoma, NSCLC, RCC or UC 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.
- 4. Measurable disease per RECISTv1.1 and iRECIST, or RECIL 2017 for lymphoma
- 5. ECOG performance status of 0 or 1 with life expectancy of 3 months in the opinion
of the investigator.
- 6. Adequate organ and marrow function, as defined below:
1. Hemoglobin 8.0 g/dL within first 2 weeks prior to first dose of TAB004 (are not
requiring a transfusion within 14 days prior to dosing)
2. Absolute neutrophil count (ANC) 1.0 x 109 /L (1,000 /mm3)
3. Absolute lymphocyte count ≥ 0.6 x 109/L (600/mm3)
4. Platelet count 75 x 109 /L (75,000 /mm3), and not requiring platelet transfusions
within the 5 days prior to dosing
5. Total bilirubin ≤ 1.5 x ULN except subjects with documented Gilbert's syndrome
who must have a baseline total bilirubin ≤ 3.0 mg/dL
6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN;
for subjects with hepatic metastases, ALT and AST ≤ 5 x ULN
7. Serum creatinine ≤ 1.5 x ULN OR calculated creatinine clearance (CrCl) or 24 hour
urine CrCl ≥ 40 mL/minute 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
- 7. 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, request for the most recent
accessible archival specimen will be required. In Part B, C and D, fresh pre-treatment
biopsies will be required from subjects with safely accessible lesions. The most
recent archival specimens will also be requested).
- 8. 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 or
toripalimab; 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.
- 9. 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).
- 10. Subjects must use effective contraception. 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 or
toripalimab.
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 anti-cancer therapy, such as but not limited to chemotherapy,
targeted therapy, radiotherapy, immunotherapy, or biologic therapy. Radiation
treatment for palliative intent is allowed provided that lesions other than those
receiving radiation are available to measure response. 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 28 days prior to the first
dose of TAB004 or, provided documentable, 5 half lives whichever is shorter, except
for lymphoma in which the exclusionary period is 2 weeks for immune checkpoint
inhibitors only.
- 4. Current or prior use of immunosuppressive medication within 2 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 for subjects enrolled into
Part A and B only; prior treatment with anti-PD-1 or anti-PDL-1is allowed,including
toripalimab for all subjects.
- 6. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
- 7. Subjects with another malignancy, or history or other malignancy within 3 years
that is not expected to relapse. Subjects 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 28 days 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 neuropathies that are stable or
improving and 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 the following are not excluded: vitiligo; alopecia; Grave's disease not
requiring systemic treatment other than thyroid hormone replacement (within the past 2
years) psoriasis not requiring systemic treatment; controlled celiac disease; subjects with
a history of autoimmune hypothyroidism requiring only thyroid hormone replacement therapy;
And type 2 diabetes, provided that it is adequately controlled.
- 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). Infection-related bowel inflammation, such as Clostridium
difficile colitis, is not excluded provided that it has been fully resolved for ≥ 6
weeks.
- 18. History of anaphylaxis, or eczema that cannot be controlled with topical
corticosteroids asthma.
- 19. Adult asthma that is moderate or severe, or asthma that has required:
hospitalization in the last 2 years; invasive mechanical ventilation ever; systemic
corticosteroids in the past year for exacerbations; or more than two short acting beta
agonist (e.g., albuterol) administrations per month for breakthrough asthma symptoms.
A history of childhood asthma or the presence of mild adult asthma that at baseline
has symptoms that can be controlled well with inhaled corticosteroids or short acting
beta agonists will not be excluded.
- 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. Untreated central nervous system and leptomeningeal metastases or requiring
ongoing treatment for these metastases, including corticosteroids. Subjects with
previously treated brain metastases may participate provided they are clinically
stable for at least 28 days prior to study entry, have no evidence of new or enlarging
metastases, and are off steroids.
- 22. Receipt of live attenuated vaccination within 28 days 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 and for toripalimab |
Time Frame: | 2 years |
Safety Issue: | |
Description: | Cmax |
Measure: | Peak Time (Tmax) after single dose injection of TAB004 and for toripalimab |
Time Frame: | 2 years |
Safety Issue: | |
Description: | Tmax |
Measure: | Area Under the Curve (AUC) after single dose injection of TAB004 and for toripalimab |
Time Frame: | 2 years |
Safety Issue: | |
Description: | AUC |
Measure: | t1/2 after single dose injection of TAB004 and for toripalimab |
Time Frame: | 2 years |
Safety Issue: | |
Description: | t1/2 half life |
Measure: | Plasma clearance (CL) after single dose injection of TAB004 and for toripalimab |
Time Frame: | 2 years |
Safety Issue: | |
Description: | Plasma clearance (CL) |
Measure: | Apparent volume of distribution (V) after single dose injection of TAB004 and for toripalimab |
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 and for toripalimab |
Time Frame: | 2 years |
Safety Issue: | |
Description: | Cmin |
Measure: | Apparent volume of distribution of steady state (Vss) after multiple dose injection of TAB004 and for toripalimab |
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 and for toripalimab |
Time Frame: | 2 years |
Safety Issue: | |
Description: | ADA |
Measure: | Accumulation after multiple dose in injection of TAB004 and for toripalimab |
Time Frame: | 2 years |
Safety Issue: | |
Description: | Accumulation |
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
Last Updated
August 27, 2021