Ignite Creation Date:
2024-05-06 @ 7:59 PM
Last Modification Date:
2024-10-26 @ 3:17 PM
Study NCT ID:
NCT06204991
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-01-12
First Post:
2023-12-15
Brief Title:
To Evaluate the Safety and Efficacy of ADP-TILIL7 in Patients With Locally Advanced or Metastatic Melanoma
Sponsor:
Inge Marie Svane
Organization:
Herlev Hospital
Study Overview
Official Title:
Phase 1 Study to Evaluate the Safety and Efficacy of TILs Transduced With IL-7 ADP-TILIL7 in Patients With Locally Advanced or Metastatic Melanoma
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-01
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:
ADP-TILIL7
Brief Summary:
The primary objective of this Phase 1 clinical trial is to evaluate the feasibility and tolerability of a novel generation of gene-modified tumor infiltrating lymphocytes TILs in a cohort of 10 patients aged 18-75 diagnosed with unresectable or metastatic melanoma TILs will undergo transduction with the Interleukin-7 IL-7 gene for IL-7 production upon antigen engagement
Participants will undergo
screening
tumor operation following autologous TIL production incl transduction - takes approximately 4-6 weeks
admission for lymphodepleting chemotherapy Cyclophosphamide and Fludarabine phosphate TIL infusion and high-dose IL-2 infusions for a maximum of 6 doses
Following treatment patients will undergo systematic and regularly planned assessments encompassing clinical evaluation biochemistry analyses and PETCT scans This thorough follow-up regimen will be continued until any of the following events occur progressive disease withdrawal from study or end of study which spans a duration of 15 years for trials involving genetically modified organisms
Participants will undergo
screening
tumor operation following autologous TIL production incl transduction - takes approximately 4-6 weeks
admission for lymphodepleting chemotherapy Cyclophosphamide and Fludarabine phosphate TIL infusion and high-dose IL-2 infusions for a maximum of 6 doses
Following treatment patients will undergo systematic and regularly planned assessments encompassing clinical evaluation biochemistry analyses and PETCT scans This thorough follow-up regimen will be continued until any of the following events occur progressive disease withdrawal from study or end of study which spans a duration of 15 years for trials involving genetically modified organisms
Detailed Description:
Synopsis
Over the last decade treatment for malignant melanoma MM has seen remarkable progress particularly with checkpoint inhibitors anti-PD-1 and anti-CTLA-4 The combination of these inhibitors has elevated the 5-year overall survival OS from 5 to 50 However many patients still lack a durable response
Results from a Phase III trial conducted in part at CCIT-DK have illuminated the promising potential of adoptive cell therapy utilizing tumor infiltrating lymphocytes TILs in the treatment of malignant melnaoma In this trial 168 patients were randomly assigned to receive either standard anti-CTLA-4 treatment or TILs The outcomes revealed a notably superior overall response rate ORR and a higher number of complete responses CR among those treated with TILs
In this phase I study the investigators intend to treat 10 subjects with locally advanced or metastatic MM Included subjects undergo surgical removal of tumor tissue for TIL manufacturing During TIL manufacture the investigators will genetically modify the TILs and enable them to produce Interleukin-7 IL-7 This modification is anticipated to confer additional functionality to the TILs enhancing their proliferation and persistence The lentiviral vector used to integrate the IL-7 gene to the TILs is manufactured and provided by the BritishAmerican biotechnological company Adaptimmune The genetically modified TILs are therefore called ADP-TILIL7
Lymphodepleting LD chemotherapy is administered 7 days prior to ADP-TILIL7 infusion ADP-TILIL7 infusion is followed by high dose HD Interleukin IL-2 for a maximum of 6 doses or until tolerance
Purpose
The primary objective of this study is to evaluate the tolerability and safety of treatment with ADP-TILIL7 The secondary objective is to assess the clinical effect of the treatment by use of the objective response rate using RECIST 11 Overall survival OS progression-free survival PFS duration of response DoR and disease control rate DCR will be determined In addition to this replication competent lentivirus RCL will be monitored
Exploratory objectives are to characterize the tumor and tumor microenvironment pre- and post infusion ex by genomic profiling of tumor tissue to investigate the mutational landscape Furthermore the expression of tumor-associated immunerelated markers including markers of phenotype and frequency of tumor infiltrating blood-derived cells The investigators want to characterize subjects peripheral blood which includes but is not limited to the phenotype and funcitionality of transduced TILs and non-transduced TILs as well as the pharmacodynamic changes in whole blood and serum pre- and post infusion which might include gene expression TCRB-cell receptor repertoire cytokines and soluble markers All this the investigators want to explore to understand factors that can influence response or resistance to ADP-TILIL7 therapy
Study design
This is a phase I First-in-human study Ten 10 subjects with locally advanced or metastatic MM will be included and treated at the Department of Oncology Herlev Hospital Subjects can be referred from other oncology centers
Subjects will undergo a comprehensive screening process to confirm subjects eligibility before enrollment Included subjects will undergo surgical tumor removal for the subsequent manufacturing of TILs TheTIL manifacturing process is expected to take approximately 4-6 weeks During TIL manufacture a subset of the TILs will be transduced with genetic material encoding the production of IL-7
Lymphodepleting chemotherapy Cyclophosphamide and Fludarabine phosphate will be administered for 7 days prior to ADP-TILIL7 infusion ADP-TILIL7 infusion is followed by high-dose IL-2 for a maximum of 6 doses or until tolerance After the end of treatment the subjects will be followed with clinical- and imaging controls for up to 15 years
The inclusion period is set to commence in early 2024 with the goal of enrolling all ten patients within a span of three years The studys completion is defined as the moment when the last subject reaches and complete the 12 months follow-up visit The study ends once all treated subjects complete 15 years of follow-up passes away or withdraw from the study
The study will be monitored by the Good Clinical Practice GCP-unit of the Capital Region of Denmark The Danish Medicines Agency The GCP-unit and Adaptimmune are allowed to audit this trial
Population
This study targets subjects aged 18 to 75 histologically confirmed with malignant melanoma who have experienced progression following at least one line of immune checkpoint inhibitor in the advanced or metastatic setting Eligibility is contigent on meeting specific inclusion criteria including acceptable performance status kidney- and liver function and the absence of major co-morbidities Crucially treatment will proceed only for the subjects with successful manufacturing of TILs Previous clinical trials have demonstrated a success rate of TIL manufacturing from malignant melanoma exceeding 90
Toxicity
The amount of toxicity caused by ADP-TILIL7 is not known The systemic treatment with IL-7 infusion has been used in treatment of several malignancies and HIV and as an adjunct to allogeneic stem cell transplantation In these studies IL-7 has exhibited a generally well-tolerated safety profile At CCIT-DK investigators boast substantial experience in treating subjects with TILs that have not been genetically modified TIL therapy has generally been well-tolerated with most adverse events expected to be associated with chemotherapy and high-dose IL-2 treatment
Dosing in the first three subjects will be staggered Each subject will have safely completed a minimum observation period of 14 days from the ADP-TILIL7 infusion before lymphodepletion of the next subject commences
Toxicity assessment including evaluation of treatment limiting toxicity TLTs will be performed using National Cancer Institute NCI Common Terminology Criteria for Adverse Events CTCAE version 50 The TLT observation period will be during the first 21 days following the ADP-TILIL7 infusion
Evaluation of clinical response
Subjects enrolled in the study will undergo comprehensive clinical evaluations during treatment and hospitalization as well as 6 12 and 24 weeks post-treatment with ADP-TILIL7 Thereafter clinical evaluation will take place every 3 months the first two years year 1-2 every 6 months year 3-5 followed by evaluations every 12 months year 6-15 Diagnostic imaging preferably PETCT scans will be conducted before the treatment initiation and in conjunction with the clinical evaluations commencing 6 weeks post-TIL treatment
Immunological response evaluation
Blood samples for research purposes will be systematically collected at Baseline pre- and post-TIL infusion day 0 during IL-2 up to a maximum 3 days before discharge and at week 6 week 12 and the final collection 12 months post-ADP-TILIL7progressive diseasewithdrawal whichever occurs first Blood samples for research purposes will be selectively collected contigent upon feasibility as assessed by the investigator Biopsies from metastatic tumor tissue will be systematically obtined at key time points before treatment initiation 6 weeks post-treatment and if applicable and deemed safe in case of disease progression
Over the last decade treatment for malignant melanoma MM has seen remarkable progress particularly with checkpoint inhibitors anti-PD-1 and anti-CTLA-4 The combination of these inhibitors has elevated the 5-year overall survival OS from 5 to 50 However many patients still lack a durable response
Results from a Phase III trial conducted in part at CCIT-DK have illuminated the promising potential of adoptive cell therapy utilizing tumor infiltrating lymphocytes TILs in the treatment of malignant melnaoma In this trial 168 patients were randomly assigned to receive either standard anti-CTLA-4 treatment or TILs The outcomes revealed a notably superior overall response rate ORR and a higher number of complete responses CR among those treated with TILs
In this phase I study the investigators intend to treat 10 subjects with locally advanced or metastatic MM Included subjects undergo surgical removal of tumor tissue for TIL manufacturing During TIL manufacture the investigators will genetically modify the TILs and enable them to produce Interleukin-7 IL-7 This modification is anticipated to confer additional functionality to the TILs enhancing their proliferation and persistence The lentiviral vector used to integrate the IL-7 gene to the TILs is manufactured and provided by the BritishAmerican biotechnological company Adaptimmune The genetically modified TILs are therefore called ADP-TILIL7
Lymphodepleting LD chemotherapy is administered 7 days prior to ADP-TILIL7 infusion ADP-TILIL7 infusion is followed by high dose HD Interleukin IL-2 for a maximum of 6 doses or until tolerance
Purpose
The primary objective of this study is to evaluate the tolerability and safety of treatment with ADP-TILIL7 The secondary objective is to assess the clinical effect of the treatment by use of the objective response rate using RECIST 11 Overall survival OS progression-free survival PFS duration of response DoR and disease control rate DCR will be determined In addition to this replication competent lentivirus RCL will be monitored
Exploratory objectives are to characterize the tumor and tumor microenvironment pre- and post infusion ex by genomic profiling of tumor tissue to investigate the mutational landscape Furthermore the expression of tumor-associated immunerelated markers including markers of phenotype and frequency of tumor infiltrating blood-derived cells The investigators want to characterize subjects peripheral blood which includes but is not limited to the phenotype and funcitionality of transduced TILs and non-transduced TILs as well as the pharmacodynamic changes in whole blood and serum pre- and post infusion which might include gene expression TCRB-cell receptor repertoire cytokines and soluble markers All this the investigators want to explore to understand factors that can influence response or resistance to ADP-TILIL7 therapy
Study design
This is a phase I First-in-human study Ten 10 subjects with locally advanced or metastatic MM will be included and treated at the Department of Oncology Herlev Hospital Subjects can be referred from other oncology centers
Subjects will undergo a comprehensive screening process to confirm subjects eligibility before enrollment Included subjects will undergo surgical tumor removal for the subsequent manufacturing of TILs TheTIL manifacturing process is expected to take approximately 4-6 weeks During TIL manufacture a subset of the TILs will be transduced with genetic material encoding the production of IL-7
Lymphodepleting chemotherapy Cyclophosphamide and Fludarabine phosphate will be administered for 7 days prior to ADP-TILIL7 infusion ADP-TILIL7 infusion is followed by high-dose IL-2 for a maximum of 6 doses or until tolerance After the end of treatment the subjects will be followed with clinical- and imaging controls for up to 15 years
The inclusion period is set to commence in early 2024 with the goal of enrolling all ten patients within a span of three years The studys completion is defined as the moment when the last subject reaches and complete the 12 months follow-up visit The study ends once all treated subjects complete 15 years of follow-up passes away or withdraw from the study
The study will be monitored by the Good Clinical Practice GCP-unit of the Capital Region of Denmark The Danish Medicines Agency The GCP-unit and Adaptimmune are allowed to audit this trial
Population
This study targets subjects aged 18 to 75 histologically confirmed with malignant melanoma who have experienced progression following at least one line of immune checkpoint inhibitor in the advanced or metastatic setting Eligibility is contigent on meeting specific inclusion criteria including acceptable performance status kidney- and liver function and the absence of major co-morbidities Crucially treatment will proceed only for the subjects with successful manufacturing of TILs Previous clinical trials have demonstrated a success rate of TIL manufacturing from malignant melanoma exceeding 90
Toxicity
The amount of toxicity caused by ADP-TILIL7 is not known The systemic treatment with IL-7 infusion has been used in treatment of several malignancies and HIV and as an adjunct to allogeneic stem cell transplantation In these studies IL-7 has exhibited a generally well-tolerated safety profile At CCIT-DK investigators boast substantial experience in treating subjects with TILs that have not been genetically modified TIL therapy has generally been well-tolerated with most adverse events expected to be associated with chemotherapy and high-dose IL-2 treatment
Dosing in the first three subjects will be staggered Each subject will have safely completed a minimum observation period of 14 days from the ADP-TILIL7 infusion before lymphodepletion of the next subject commences
Toxicity assessment including evaluation of treatment limiting toxicity TLTs will be performed using National Cancer Institute NCI Common Terminology Criteria for Adverse Events CTCAE version 50 The TLT observation period will be during the first 21 days following the ADP-TILIL7 infusion
Evaluation of clinical response
Subjects enrolled in the study will undergo comprehensive clinical evaluations during treatment and hospitalization as well as 6 12 and 24 weeks post-treatment with ADP-TILIL7 Thereafter clinical evaluation will take place every 3 months the first two years year 1-2 every 6 months year 3-5 followed by evaluations every 12 months year 6-15 Diagnostic imaging preferably PETCT scans will be conducted before the treatment initiation and in conjunction with the clinical evaluations commencing 6 weeks post-TIL treatment
Immunological response evaluation
Blood samples for research purposes will be systematically collected at Baseline pre- and post-TIL infusion day 0 during IL-2 up to a maximum 3 days before discharge and at week 6 week 12 and the final collection 12 months post-ADP-TILIL7progressive diseasewithdrawal whichever occurs first Blood samples for research purposes will be selectively collected contigent upon feasibility as assessed by the investigator Biopsies from metastatic tumor tissue will be systematically obtined at key time points before treatment initiation 6 weeks post-treatment and if applicable and deemed safe in case of disease progression
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
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