Ignite Creation Date:
2024-05-06 @ 7:07 PM
Last Modification Date:
2024-10-26 @ 3:01 PM
Study NCT ID:
NCT05908643
Status:
RECRUITING
Last Update Posted:
2023-06-18
First Post:
2023-03-23
Brief Title:
A First-In-Human Trial of pTTL in Advanced Colorectal Cancer
Sponsor:
Neogap Therapeutics AB
Organization:
Neogap Therapeutics AB
Study Overview
Official Title:
A First-In-Human Phase IIIa Trial of the Novel T Cell Immunotherapy pTTL in Patients With Advanced Colorectal Cancer
Status:
RECRUITING
Status Verified Date:
2023-05
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:
This is an open-label non-randomised FIH trial investigating the safety and tolerability of a novel ATMP pTTL composed of autologous tumour-draining lymph node-derived T cells stimulated in vitro with personalised cancer neoantigens
The neoantigens are selected through a process starting with next generation sequencing NGS of tumour material from the patient followed by selection of neoantigenic mutations using an in-house software PIOR Selected neoantigen epitopes are expressed as recombinant proteins NAG and used to stimulate T cells to promote neoantigen-specific T cell expansion in vitro in pTTL production
pTTL is thus based on autologous cells stimulated with patient-specific neoantigens In consequence every pTTL product is unique and designated for use in one single individual
pTTL will be administered to patients with stage IV colorectal cancer CRC as a single intravenous dose
The neoantigens are selected through a process starting with next generation sequencing NGS of tumour material from the patient followed by selection of neoantigenic mutations using an in-house software PIOR Selected neoantigen epitopes are expressed as recombinant proteins NAG and used to stimulate T cells to promote neoantigen-specific T cell expansion in vitro in pTTL production
pTTL is thus based on autologous cells stimulated with patient-specific neoantigens In consequence every pTTL product is unique and designated for use in one single individual
pTTL will be administered to patients with stage IV colorectal cancer CRC as a single intravenous dose
Detailed Description:
STUDY RATIONALE The present trial is an open-label non-randomised FIH trial investigating the safety and tolerability of pTTL an immunotherapy consisting of autologous T cells activated and expanded in vitro using tumour-specific personalised neoantigens The scientific rationale for pTTL relies on the fact that somatic mutations in tumour cells arising during malignant transformation result in altered proteins or peptides so called neoantigens Each individual tumour harbours multiple mutations that form a unique mutation profile which enables personalisation of each therapeutic product The neoantigens distinguish tumour cells from normal cells and make the tumour cells targetable by the immune system and also allows targeting of several targets in the tumour simultaneously In the present trial up to 36 neoantigens will be targeted
The starting material for pTTL is derived from tumour-draining regional lymph nodes RLNs The choice of this source of T cells is based on several advantages The exposure to tumour antigens and in the case of metastasis tumour cells causes an enrichment of tumour- specific T cells These T cells also have the potential to be superior to tumour-infiltrating T cells due to less exposure to tumour-mediated immunosuppression
The production process for pTTL includes in vitro expansion which increases the neoantigen-reactive T cell population The selective T cell expansion is achieved by stimulation with protein constructs containing neoantigen epitopes based on sequencing data from each patients own tumour This improves the chance of effective cancer cell eradication by both increasing the number of cells able to recognise and respond to the tumour and by breaking immunological tolerance created in vivo by immunosuppressive mechanisms through activation in a non-suppressive environment
PATIENTS The selected target group of the trial is adults with stage IV CRC Patients may be considered eligible for inclusion if they have received treatments according to standard of care or if further standard of care treatment options are judged not to be in the patients best interest eg due to toxicity issues Patients could also be eligible for inclusion in the trial during a scheduled pause in ongoing palliative therapy at the discretion of the treating Investigator Eligible patients must have a primary or metastatic lesion that is accessible to biopsy or surgery to obtain tumour material for NGS analysis In addition it is a requirement that the patient can undergo surgical excision of RLNs for use in pTTL production Eligible patients should also have a good performance status ECOG 0-1 and organ function and no pre-existing conditionings deemed to increase their risk for severe side effects of pTTL therapy Materials for Part I of the trial can be collected while non-curative therapeutic options remain and cryopreserved for later use if the patient should become eligible for inclusion in Part II
METHODOLOGY The trial is composed of 3 parts referred to as Part I Part II and Part III
Patients will be consented separately for Part I and for Part IIIII a first consent is given for tissue collection and pTTL production and a second consent is given for pTTL treatment including pre-conditioning chemotherapy and follow-up
Part I of the trial entails patient identification recruitment and screening of trial patients It also comprises production of pTTL which is performed in 3 steps
1 Collection of tumour samples and normal samples for NGS and neoantigen selection Production of stimulatory NAG-coupled beads raw material TC0301
2 Collection of starting material for pTTL manufacturing from RLN
3 pTTL manufacturing
The time required from collection of tumour material and RLNs up until pTTL production and administration to the patient is approximately 8 to 12 weeks The RLN starting material is cryopreserved after initial processing enabling flexibility in the timing of pTTL administration
Part II of the trial entails pre-conditioning and supportive care therapy treatment with pTTL and 26 weeks safety follow-up
Pre-conditioning contains cyclophosphamide and fludarabine and will be administered between Day -7 and Day -5 before scheduled pTTL administration Supportive care treatment will start on Day -9 or Day -8 pTTL administration will normally be administered on Day 1 with the option of administration on Day -3 if cell expansion kinetics during pTTL production indicates this would be preferable Part II will end when the last treated patient has been followed for 26 weeks or earlier in case of death or patient withdrawal
Part III of the trial is a long-term follow-up initiated after completion of the initial 26 weeks safety follow-up period Patients will participate in Part III for up to 45 years after end of Part II or until death whichever comes first
pTTL DOSAGE AND ADMINISTRATION The drug product DP ie pTTL is composed of in vitro expanded RLN cells enriched for neoantigen-specific T cells It is formulated as a cell suspension with the excipients NaCl 9 mgmL and human serum albumin 25 mgmL in a transfusion bag intended for intravenous transfusion The product is administered fresh Each patient will receive a single administration of pTTLThe cell dose obtained during the manufacturing process will vary depending on the size of the neoantigen-reactive clones present in the starting material and their proliferative capacity The minimum dose of a pTTL unit is 20 million viable cells and the maximum dose is 1 billion viable cells
The starting material for pTTL is derived from tumour-draining regional lymph nodes RLNs The choice of this source of T cells is based on several advantages The exposure to tumour antigens and in the case of metastasis tumour cells causes an enrichment of tumour- specific T cells These T cells also have the potential to be superior to tumour-infiltrating T cells due to less exposure to tumour-mediated immunosuppression
The production process for pTTL includes in vitro expansion which increases the neoantigen-reactive T cell population The selective T cell expansion is achieved by stimulation with protein constructs containing neoantigen epitopes based on sequencing data from each patients own tumour This improves the chance of effective cancer cell eradication by both increasing the number of cells able to recognise and respond to the tumour and by breaking immunological tolerance created in vivo by immunosuppressive mechanisms through activation in a non-suppressive environment
PATIENTS The selected target group of the trial is adults with stage IV CRC Patients may be considered eligible for inclusion if they have received treatments according to standard of care or if further standard of care treatment options are judged not to be in the patients best interest eg due to toxicity issues Patients could also be eligible for inclusion in the trial during a scheduled pause in ongoing palliative therapy at the discretion of the treating Investigator Eligible patients must have a primary or metastatic lesion that is accessible to biopsy or surgery to obtain tumour material for NGS analysis In addition it is a requirement that the patient can undergo surgical excision of RLNs for use in pTTL production Eligible patients should also have a good performance status ECOG 0-1 and organ function and no pre-existing conditionings deemed to increase their risk for severe side effects of pTTL therapy Materials for Part I of the trial can be collected while non-curative therapeutic options remain and cryopreserved for later use if the patient should become eligible for inclusion in Part II
METHODOLOGY The trial is composed of 3 parts referred to as Part I Part II and Part III
Patients will be consented separately for Part I and for Part IIIII a first consent is given for tissue collection and pTTL production and a second consent is given for pTTL treatment including pre-conditioning chemotherapy and follow-up
Part I of the trial entails patient identification recruitment and screening of trial patients It also comprises production of pTTL which is performed in 3 steps
1 Collection of tumour samples and normal samples for NGS and neoantigen selection Production of stimulatory NAG-coupled beads raw material TC0301
2 Collection of starting material for pTTL manufacturing from RLN
3 pTTL manufacturing
The time required from collection of tumour material and RLNs up until pTTL production and administration to the patient is approximately 8 to 12 weeks The RLN starting material is cryopreserved after initial processing enabling flexibility in the timing of pTTL administration
Part II of the trial entails pre-conditioning and supportive care therapy treatment with pTTL and 26 weeks safety follow-up
Pre-conditioning contains cyclophosphamide and fludarabine and will be administered between Day -7 and Day -5 before scheduled pTTL administration Supportive care treatment will start on Day -9 or Day -8 pTTL administration will normally be administered on Day 1 with the option of administration on Day -3 if cell expansion kinetics during pTTL production indicates this would be preferable Part II will end when the last treated patient has been followed for 26 weeks or earlier in case of death or patient withdrawal
Part III of the trial is a long-term follow-up initiated after completion of the initial 26 weeks safety follow-up period Patients will participate in Part III for up to 45 years after end of Part II or until death whichever comes first
pTTL DOSAGE AND ADMINISTRATION The drug product DP ie pTTL is composed of in vitro expanded RLN cells enriched for neoantigen-specific T cells It is formulated as a cell suspension with the excipients NaCl 9 mgmL and human serum albumin 25 mgmL in a transfusion bag intended for intravenous transfusion The product is administered fresh Each patient will receive a single administration of pTTLThe cell dose obtained during the manufacturing process will vary depending on the size of the neoantigen-reactive clones present in the starting material and their proliferative capacity The minimum dose of a pTTL unit is 20 million viable cells and the maximum dose is 1 billion viable cells
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