This study has been transitioned to CTIS with ID 2024-512579-11-00 check the CTIS register for the current data. Primary:- To evaluate the short-term safety and tolerability of TX200-TR101 from the day of TX200 TR101 infusion within 28 days post…
ID
Source
Brief title
Condition
- Immune disorders NEC
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary:
- Incidence and grade of TEAEs, including SAEs, within 28 days post TX200 TR101
infusion.
Secondary outcome
Key Secondary: Clinical
From the day of TX200-TR101 infusion through to Week 84:
- Incidence of BCAR according to the Banff criteria.
- Time to first BCAR episode.
- Type and severity of any BCAR episodes according to the Banff criteria.
From the day of TX200-TR101 infusion through to Week 84:
- Incidence and grade of TEAEs, including SAEs.
- Incidence of opportunistic infections, specifically BKV, EBV and CMV
reactivation.
- Incidence of neoplasia.
- Proportion of subjects who are receiving tacrolimus monotherapy at Week 84.
- Cumulative dose of immunosuppression, including but not limited to MPA/MMF
and tacrolimus through to Week 84.
Key Secondary: Biomarkers
- Presence of CD4 RNA transcript positive cells that are also positive for
HLA-A2 CAR RNA transcripts in the renal transplant biopsy at Week 16.
Other Secondary: Clinical
From the day of TX200-TR101 infusion through to Week 84:
- Incidence and severity of chronic graft dysfunction, as measured by eGFR.
- Incidence and severity of chronic graft dysfunction, as measured by the Banff
criteria for chronic rejection including the Banff lesion score i-IFTA.
- Incidence of graft loss due to rejection.
- Incidence and (semi-quantitative) intensity of de novo DSA.
Exploratory: Clinical
- Changes from baseline in laboratory parameters, 12-lead ECG and vital signs
from the day of TX200-TR101 infusion through to Week 84.
- Incidence of hypertension, dyslipidaemia and new onset diabetes at Week 60
and Week 84 after transplantation.
- Absolute value and change from baseline in SF 36v2® through to Week 84.
Exploratory: Biomarkers
- Proportion of CD4 RNA transcript positive cells that are also positive for
HLA-A2 CAR RNA transcripts in the renal transplant biopsy at Week 16, Week 36
and Week 60 (if available).
- Proportion of other RNA transcript positive and negative cells in the renal
transplant biopsy at Week 16, Week 36 and Week 60 (if available).
- Levels and changes from baseline in biomarkers in blood and in urine relating
to the presence of HLA-A2 CAR Tregs from the day of TX200 TR101 infusion
through to Week 84
- Changes from baseline in donor/recipient MLR assays from the day of TX200
TR101 infusion through to Week 60.
- Transcriptomic and proteomic status of cells obtained from the renal biopsies
at Day 0, Week 16, Week 36 and Week 60.
- Transcriptomic and proteomic status of cells in blood samples at 1 day before
infusion, at 6 and 24 hours post infusion, at Week 14, Week 16, Week 36 and
Week 60 (if available).
- 25-hydroxyvitamin D levels in blood samples at screening, and leukapheresis.
Background summary
Solid organ transplantation is the treatment of choice for patients with
end-stage renal disease (ESRD). Despite improvements in short-term outcome,
long-term outcome is suboptimal due to the increased morbidity and mortality
associated with the toxicity of immunosuppressive regimens and chronic
rejection. In the setting of organ transplantation, the requirement for
immunosuppressive treatments is lifelong, requiring strict compliance from the
patients.
Therapy begins at the time of transplant using induction therapy with high dose
intravenous corticosteroids and biological therapies that suppress T cell
function or cause T cell depletion. These biologics are potent and only used
for specific total doses and in the short time period post operatively.
Long-term suppression of the immune response requires a combination of agents
taken orally. These typically consist of corticosteroids, a calcineurin
inhibitor such as tacrolimus, and an anti metabolite, often mycophenolic acid.
These agents are specific to mitigating T cell responses against the allograft.
Conditioning the immune response of solid organ transplant recipients towards
allograft acceptance using cell-based therapies is clinically promising and has
recently become technically feasible. In early-phase poly-T regulatory cell
(Treg) trials in humans T regulatory cell (Treg) appeared to be safe and
tolerated over a range of doses. Phase 2 trials have recently commenced and aim
to assess the therapeutic potential of these cellular therapies.
With the exception of ABO blood type compatibility, donor/recipient mismatch in
HLA antigens such as HLA A*02 is the main contributor for transplant
incompatibility and ultimately immune-mediated allograft rejection. TX200-TR101
is a genetically modified cell therapy product. It consists of ex vivo expanded
autologous Tregs collected from an HLA-A*02 negative organ recipient prior to
transplant, which are genetically modified to express a CAR specific to the
donor HLA A*02 at their surface membrane. The aim of this therapeutic approach
is the induction of tolerance to the transplanted organ and gradual withdrawal
of long-term pharmacological immunosuppression.
Study objective
This study has been transitioned to CTIS with ID 2024-512579-11-00 check the CTIS register for the current data.
Primary:
- To evaluate the short-term safety and tolerability of TX200-TR101 from the
day of TX200 TR101 infusion within 28 days post TX200 TR101 infusion.
Key Secondary: Clinical
- To evaluate the effect of TX200 TR101 on acute graft-related outcomes from
the day of TX200 TR101 infusion through to Week 84 in terms of BCAR (including
type, severity and timing).
- To evaluate the effect of TX200 TR101 on long term safety outcomes from the
day of TX200 TR101 infusion through to Week 84 in terms of TEAEs.
- To evaluate the reduction of immunosuppression over time through to Week 84.
Key Secondary: Biomarkers
- To evaluate TX200-TR101 localisation in the graft at Week 16.
Other Secondary: Clinical
- To evaluate the effect of TX200 TR101 on chronic graft related outcomes from
the day of TX200-TR101 infusion through to Week 84.
Exploratory: Clinical
- To evaluate the effect of TX200 TR101 on other long-term safety outcomes from
the day of TX200-TR101 infusion through to Week 60.
- To evaluate the effect of study treatments on hypertension, hyperlipidaemia
and new onset diabetes at Week 52 and Week 60 after transplantation.
- To evaluate quality of life over time through to Week 60.
Exploratory: Biomarkers
- To evaluate TX200-TR101 localisation and its potential impact in the graft at
Week 16, Week 36 and Week 60 (if available).
- To characterise the pharmacodynamics of TX200 TR101 from the day of TX200
TR101 infusion through to Week 84, as measured by a panel of biomarkers.
- To explore transcriptomic and proteomic status of cells in the graft and
blood via single-cell next generation sequencing.
- To explore 25-hydroxyvitamin D status and its potential influence on Treg
cell number and function, and on other immune cells.
Study design
See section 3 in the protocol (page 39-53)
This is a first-in-human, Phase I/IIa, multicentre, open-label, single
ascending dose, dose ranging study with a control cohort. The primary objective
is to evaluate the short-term safety and tolerability of TX200 TR101 when given
as a single ascending dose to HLA-A*02 mismatched living donor renal transplant
recipients (HLA A*02 negative recipient and HLA-A*02 positive donor).
All transplant recipients will undergo a screening period to confirm the
criteria for participation in the study. Subjects to be administered TX200
TR101 will undergo leukapheresis prior to transplantation. Leukapheresis is not
required for control subjects. All transplant recipients will undergo
pre-transplant baseline assessments on the day before transplant surgery (Day -
1) and will undergo transplant surgery on Day 0. Subjects to be administered
TX200 TR101 will receive a single intravenous infusion of TX200-TR101 at Week
12 (±10 days) post-transplant surgery. All transplant recipients (including
control subjects) will be followed for 84 weeks post-transplant. The end of
this clinical trial is defined as the day when the last subject has completed
his/her last visit.
The immunosuppressive regimen will start on the day of transplant surgery. The
immunosupppressive regimen will consist of ATG induction, together with
intravenous corticosteroids and maintenance with progressive reduction of oral
corticosteroids, MPA/MMF and tacrolimus. Discontinuation of the MPA/MMF dose
will be possible for subjects administered TX200-TR101, leading ultimately to
tacrolimus monotherapy, depending on the investigator*s decision. Investigators
are required at all times to use clinical judgement when considering the
immunosuppressive regimen and act in the subject*s best interest to preserve
allograft function.
Subjects in the control cohort will undergo transplantation and will receive
the same background immunosuppressive agents as the transplant recipients to be
administered TX200-TR101, although the dosage of some of the agents will differ.
The duration of study participation will be up to 112 weeks for transplant
recipients to be administered TX200-TR101 and up to 88 weeks for control
transplant recipients. The duration of study participation for transplant
donors will up to 4 weeks (for screening assessments and collection of blood
samples for biomarker analysis). The duration and manner of the follow-up of
transplant donors should be carried out according to the local institution
guidelines. Transplant recipients (including control participants) will be
asked if they will participate in an additional, optional long term follow-up
study (with separate protocol).
Intervention
See section 7.1 in the protocol (page 71-75).
The investigational medicine (TX200 TR101) is an autologous gene therapy
medicinal product composed of Treg (CD4+/CD45RA+/CD25+/CD127low/neg) that have
been ex vivo expanded and transduced with a lentiviral vector encoding for a
CAR to recognise HLA A*02. The CAR is composed of a ScFv from a humanised
antibody that recognises HLA-A*02 molecules, coupled to a transmembrane domain
and signalling modules. The composition of the drug product includes purified
HLA-A2 CAR Tregs and the components of the cryopreservation medium (CryoStor®
CS10) as excipients.
Following TX200 TR101 manufacture, the product will be cryopreserved at a
temperature of <= -140°C. The drug product will be provided to the
investigational sites in 2 mL sealed vials. Each vial will contain a cell
suspension of TX200 TR101 at a fixed cell concentration. The total volume in
each vial and the total number of vials for each dose will depend on the dose
cohort the transduction efficiency which would give the total number of
transduced viable CAR Tregs.
The following premedication will be administered prior to infusion of TX200
TR101:
- Single prophylactic dose of low-molecular-weight heparin, dose adjusted to
renal function and body weight as per local policy, to prevent potential
thromboembolic complications, if not contraindicated, on the morning of the day
of infusion.
- Paracetamol 1 g orally or intravenously to for symptomatic relief of
potential allergic reactions, 30-60 minutes prior to infusion.
- Dimethindene (Fenistil® or similar anti-histamine) 4 mg intravenously to
prevent allergic/anaphylactic reactions associated with Treg infusion, 30-60
minutes prior to infusion.
Administration of paracetamol and dimethindene can be repeated every 6 hours if
needed.
TX200 TR101 will be infused slowly under the supervision of the study
investigator, by trained study staff via a large bore (>=18G) peripheral
intravenous cannula in accordance with the infusion rates described in the Cell
Therapy Manual. The infusion should be completed as soon as possible following
the start of thawing TX200-TR101, please refer to the Cell Therapy Manual for
further details.
Study burden and risks
Transplant recipients to be administered TX200-TR101: an up to 112 week
participation with approx. 31 study visits. Additional blood draws and biopsies
are performed. A leukapheresis procedure will be required. These participants
will be exposed to the investigational medicine and subsequent risks. However,
these participants can potentially benefit from the study medicine (when
compared to standard post-transplant care). Moreover, they will contribute to
increased knowledge about solid organ transplants and this may be of future
benefit to those who will undergo this procedure and receive post-transplant
care.
Control transplant recipients: an up to 64 week participation with approx. 22
study visits. Additional blood draws are done and there are (optional extra)
biopsies performed. Additional assessments and monitoring will take place for
control participants. They will also get the option for a (separate) long-term
follow-up study. Moreover, they will contribute to increased knowledge about
solid organ transplants and this may be of future benefit to those who will
undergo this procedure and receive post-transplant care.
Live transplant donors: a up to 4 week participation with 1 or 2 study visits.
The only invasive procedure is the collection of blood. Donors will not
personally benefit from the study. However, they will contribute to increased
knowledge about solid organ transplants and this may be of future benefit to
those who will undergo this procedure and receive post-transplant care.
Les Cardoulines HT1, Allée de la Nertière -
Valbonne 06560
FR
Les Cardoulines HT1, Allée de la Nertière -
Valbonne 06560
FR
Listed location countries
Age
Inclusion criteria
Inclusion Criteria (All Transplant Recipients)
1. Willing and able to provide written informed consent (IC) in accordance with
local regulations and governing Independent Ethics Committee
(IEC)/Institutional Review Board (IRB) requirements prior to any procedure or
evaluation performed specifically for the sole purpose of the study.
2. Male or female aged between 18 and 70 (inclusive) years.
3. Have diagnosis of ESRD and currently waiting for a new kidney from an
identified live donor.
4. Subjects who will be single organ recipients (kidney).
5. Normal or non-clinically significant abnormality in the electrocardiogram
(ECG), at investigator*s discretion.
6. Women who are of childbearing potential must have a negative serum pregnancy
test at screening and before transplantation.
7. Able and willing to use a highly effective method of contraception from the
signing of the informed consent through the last study visit, for male and
female subjects with reproductive potential.
Additional Inclusion Criteria (Transplant Recipients to be Administered TX200
TR101 Only)
1. HLA-A*02 negative typing (the kidney graft needs to be HLA A*02 positive).
2. HLA-A*69 negative typing.
3. Adequate venous access for leukapheresis, and no other contraindications for
leukapheresis.
4. Subjects that have a transplant planned or scheduled for at least 10
weeks after the time of enrolment.
Inclusion Criteria (All Transplant Donors)
1. Willing and able to provide written IC in accordance with local regulations
and governing IEC/IRB requirements prior to any procedure or evaluation
performed specifically for the sole purpose of the study.
2. Aged at least 18 years on the day of signing the IC form.
3. ABO blood type compatible with the organ recipient.
4. Negative serology for HIV, HBV, HCV and syphilis.
5. Willing to provide personal and medical/biological data and samples for the
study analysis.
Additional Inclusion Criterion (Transplant Donors for Transplant Recipients to
be Administered TX200 TR101 Only)
1. HLA-A*02 positive typing.
Exclusion criteria
Exclusion Criteria (All Transplant Recipients) 1. HLA identical to the
prospective organ donor. 2. Subjects with prior organ transplant. 3. Known
hypersensitivity to study medication ingredients or a significant allergic
reaction to any drug as determined by the investigator, such as anaphylaxis
requiring hospitalisation. 4. Known hypersensitivity or contraindications for
anti-thymocyte globulin (ATG), tacrolimus or mycophenolic acid (MPA)/
mycophenolate mofetil (MMF). 5. Positive serology for human immunodeficiency
virus (HIV) or syphilis. 6. Evidence of active or occult hepatitis B virus
(HBV) or active hepatitis C virus (HCV) infection. 7. Subjects who are
Epstein-Barr Virus (EBV) seronegative. 8. Positive flow cytometric crossmatch
using donor lymphocytes (T and B cells) and recipient serum. 9. Subjects with
panel-reactive antibody (PRA) >20% within 6 months prior to enrolment. 10.
Subjects with current, recent or historical donor-specific antibodies. 11.
Previous treatment with any desensitisation procedure (with or without
intravenous immunoglobulin) 12. Subjects with underlying renal disease with a
high risk of disease reoccurrence in the transplanted kidney including primary
focal segmental glomerulosclerosis, C3 glomerulopathy, types I or II
membranoproliferative glomerulonephritis or haemolytic-uraemic syndrome (HUS),
including a typical HUS. If the subject has ESRD of unknown aetiology and/or
has no histologically confirmed diagnosis the subject may be enrolled into the
study if there are no clinical, laboratory, histological or genetic features
suggestive of a diagnosis of primary focal segmental glomerulosclerosis, types
I or II membranoproliferative glomerulonephritis, C3 glomerulopathy, or HUS,
including atypical HUS, as deemed by the investigator. 13. Concomitant
clinically active local or systemic infection. 14. Use of any experimental
medicinal product within 3 months or 5 half-lives prior to the screening visit,
whichever is longer, and agreement to not take any experimental medicinal
product throughout the trial. 15. Subjects who are currently receiving systemic
immunosuppressive agents (e.g., methotrexate, infliximab, adalimumab,
corticosteroids) for other indications such as autoimmune diseases, or subjects
with comorbidities for which treatment with such agents are likely during the
study, with the following exception: • Subjects who are receiving or may
require short-term and/or low dose (e.g., prednisone or prednisone equivalent <
5 mg daily) or methotrexate (e.g. 15 mg weekly) courses of corticosteroids are
not precluded from enrolment, at the discretion of the investigator in
consultation with the Sponsor*s Medical Monitor. 16. Clinical evidence of
significant unstable or poorly controlled acute or chronic diseases (i.e.,
cardiovascular, pulmonary, haematologic, gastrointestinal, hepatic,
neurological, or infectious diseases) or laboratory abnormality (except ESRD)
which, in the opinion of the investigator, could confound the results of the
study or put the subject at undue risk. • Subjects who, at the discretion of
the investigator, are deemed at high risk of a renal thrombotic event. 17.
Subjects with current or previous history of clinically relevant central
nervous system pathology (including but not limited to seizures within the last
5 years, stroke within the last 5 years, severe brain injury, cerebellar
disease or CNS vasculitis). 18. Current or previous history within the last 5
years of malignancy, with the following exceptions: • Subjects with any
previous history of haematological malignancy are precluded from enrolment. •
Subjects who have had non-melanoma skin cancer or cervical carcinoma in situ
that has been successfully treated with no evidence of recurrence are not
precluded from enrolment. 19. Subjects whose life expectancy is severely
limited by disease state other than renal disease. 20. Subjects with a history
of substance abuse (drug or alcohol) within the past 2 years or that is
considered not compatible with adequate study follow-up, or psychiatric
disorder or other condition that is not compatible with adequate study
follow-up. 21. Subjects with laboratory values that meet the following criteria
are to be excluded (retesting once during the screening period is permitted at
the investigator*s discretion): • Haemoglobin < 9 g/dL (or <5.59 mmol/L) •
Platelets < 80 x 10^9/L • White blood cells (WBC) < 3 X 10^9/L • Aspartate
transaminase (AST) and or alanine transaminase (ALT) >= 3 x upper limit of
normal (ULN) • Total bilirubin >= 2 x ULN (except for subjects with Gilbert*s
disease) 22. Subjects who will have received a live attenuated vaccine (LAV)
within 30 days prior to their transplantation surgery. 23. Subjects who are
currently pregnant, planning pregnancy or breast feeding/lactating while
enrolled in the study. 24. Any other reason that, in the opinion of the Site
Investigator or Medical Monitor, would render the subject unsuitable for
participation in the study. This includes, but is not limited to, subjects
unable to give their own consent (e.g. those under guardianship, curatorship or
sauvegarde de justice). Investigators, employees of the investigative site, and
their immediate families. Immediate family is defined as the Investigator's or
employees* current spouses, parents, natural or legally adopted children
(including stepchildren), grandparents, or grandchildren. Sponsor employees.
Subjects institutionalised because of legal or regulatory order, inmates of
psychiatric wards, prison or state institutions. Wards of court. Exclusion
Criteria (All Transplant Donors) 1. Genetically identical to the prospective
organ recipient. 2. Exposure to investigational agents at the time of kidney
donation or within 28 days or 5 half-lives whichever is longer, prior to the
donation. 3. Any form of substance abuse considered not compatible with
adequate study follow up, psychiatric disorder or other condition that in the
opinion of investigator may compromise study participation.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-512579-11-00 |
| EudraCT | EUCTR2019-001730-34-NL |
| CCMO | NL70193.000.19 |