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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

Status
Active
Cancer Type
Lung Cancer
Lymphoma
Melanoma
Trial Phase
Phase I
Eligibility
18 Years and older, Male and Female
Study Type
Treatment
NCT ID
NCT04137900
Protocol IDs
TAB004-01 (primary)
NCI-2020-00511
Study Sponsor
Shanghai Junshi Bioscience Co., Ltd.

Summary

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.

Objectives

OVERVIEW: This is a Phase 1, multi-center, open-label, dose-escalation study of TAB004, a
recombinant humanized IgG4? 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.

Eligibility

  1. Able to understand and willing to sign the Informed Consent Form;
  2. 2. Male or female = 18 years;
  3. 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. 4. Measurable disease per RECISTv1.1 and iRECIST, or RECIL 2017 for lymphoma
  5. 5. ECOG performance status of 0 or 1 with life expectancy of 3 months in the opinion of the investigator.
  6. 6. Adequate organ and marrow function, as defined below:
  7. 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)
  8. Absolute neutrophil count (ANC) 1.0 x 109 /L (1,000 /mm3)
  9. Absolute lymphocyte count = 0.6 x 109/L (600/mm3)
  10. Platelet count 75 x 109 /L (75,000 /mm3), and not requiring platelet transfusions within the 5 days prior to dosing
  11. Total bilirubin = 1.5 x ULN except subjects with documented Gilbert's syndrome who must have a baseline total bilirubin = 3.0 mg/dL
  12. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 x ULN; for subjects with hepatic metastases, ALT and AST = 5 x ULN
  13. 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
  14. 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
  15. 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).
  16. 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.
  17. 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).
  18. 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.
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