Ignite Creation Date:
2024-05-06 @ 1:48 PM
Last Modification Date:
2024-10-26 @ 1:20 PM
Study NCT ID:
NCT04137900
Status:
RECRUITING
Last Update Posted:
2024-02-05
First Post:
2019-10-21
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
Sponsor:
TopAlliance Biosciences
Organization:
TopAlliance Biosciences
Study Overview
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
Status:
RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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 ie 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 03 1 3 and 10 mgkg 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 v11 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 03 1 3 10 mgkg 20mg 70mg 200mg and 500mg Toripalimab dose is 240mg TAB004 alone or TAB004 plus toripalimab will be administered as a 60-minute iv 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 t12 CL accumulation and Vss
STATISTICAL METHODS Part A and Part C are based on the 33 design for dose escalation and safety evaluation requirements In Part B and Part D sample size is estimated using Simons two-phase design minimax method
All PKPharmacodynamic 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
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 03 1 3 and 10 mgkg 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 v11 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 03 1 3 10 mgkg 20mg 70mg 200mg and 500mg Toripalimab dose is 240mg TAB004 alone or TAB004 plus toripalimab will be administered as a 60-minute iv 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 t12 CL accumulation and Vss
STATISTICAL METHODS Part A and Part C are based on the 33 design for dose escalation and safety evaluation requirements In Part B and Part D sample size is estimated using Simons two-phase design minimax method
All PKPharmacodynamic 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None