This study has been transitioned to CTIS with ID 2024-514962-38-00 check the CTIS register for the current data. -To assess the safety and tolerability of CLDN6 CAR-T +/- CLDN6 RNALPX and to assess the comparability of CLDN6 CAR-T from the manualand…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary
- Occurrence of TEAEs within a patient including >= Grade 3, serious, fatal
TEAEs by relationship
- Occurrence of dose reduction and discontinuation of IMP within a patient due
to TEAEs
- Occurrence of DLTs within a patient during the DLT evaluation period
Long term follow-up - Primary
- Occurrence of AEs during the LTFU period suspected to be related to CLDN6
CAR-T/CLDN6 CAR-T(A) +/- CLDN6 (mod)RNA-LPX, such as:
o New malignancy (hematologic or solid)
o New neurologic disorder, or exacerbation of a pre-existing disorder
o New rheumatologic or autoimmune disorder, or exacerbation of a prior
rheumatologic or other autoimmune disorder
o New hematologic disorder
o Other new clinical condition considered by the Investigator to be related to
the prior genetically engineered T cell therapy
Long term follow-up - Secondary
- Progression-free survival
- Overall survival. Survival status will be collected until 15 years from last
genetically engineered T cell infusion or until death, whichever occurs first
Secondary outcome
-To describe the profile of soluble immune factors in CLDN6 CAR-T +/- CLDN6
RNA-LPX
-To evaluate anti-tumor activity of CLDN6 CAR-T +/- CLDN6 RNA-LPX according to
response evaluation criteria in solid tumors version 1.1
(RECIST 1.1)
Background summary
Outcome remains poor for patients with relapsed or refractory advanced solid
tumors. Treatment options include further targeted therapies, immunotherapies,
radiotherapy or palliative chemotherapy, which might be less tolerated after
previous repeated exposure to cytotoxic compounds, or best supportive care.
Therapy in this population is not curative with an expected OS of a few months.
The oncofetal antigen CLDN6 has emerged as an attractive therapeutic target
because of its absence from toxicity-relevant adult healthy tissues, and high
expression in cancers with high unmet medical need. Thus, CLDN6 is a suitable
target antigen for the development of a CAR-T against these cancers. The
combination of CLDN6 CAR-T/CLDN6 CAR-T(A) with CLDN6 encoding RNA-LPX mediates
controlled in vivo expansion, improved CAR-T persistence and anti-tumor
efficacy in preclinical models, and constitutes an innovative concept for the
specific and effective treatment of CLDN6-expressing tumors.
The main purpose of the trial is to determine a safe and potentially
efficacious dose of CLDN6 CAR-T/CLDN6 CAR-T(A) +/- CLDN6 (mod)RNA-LPX. In a
phase 1 dose escalation with CLDN6 CAR-T/CLDN6 CAR-T(A) (Part 1) and CLDN6
CAR-T/CLDN6 CAR-T(A) with CLDN6 (mod)RNA-LPX (Part 2) according to the
classical 3+3 design, the RP2D of the CLDN6 CAR-T/CLDN6 CAR-T(A) +/- CLDN6
(mod)RNA-LPX will be determined. The RP2D will be further explored in phase IIa
(Part 3) for efficacy signal seeking. So far, no drug targeting CLDN6 in cancer
patients has been approved.
Study objective
This study has been transitioned to CTIS with ID 2024-514962-38-00 check the CTIS register for the current data.
-To assess the safety and tolerability of CLDN6 CAR-T +/- CLDN6 RNALPX and to
assess the comparability of CLDN6 CAR-T from the manual
and automated processes
-To identify the maximum tolerated dose (MTD)/RP2D for each IMP (i.e. CLDN6
CAR-T +/- CLDN6 RNA-LPX) based on the occurrence of doselimiting toxicities
(DLT) using the following definitions:
-MTD is defined as the highest tolerated dose of CLDN6 CAR-T +/- CLDN6 RNA-LPX
where less than 33% of the patients experience a DLT
-Recommended phase 2 dose (RP2D) of CLDN6 CAR-T +/- CLDN6 RNALPX based on
integrated evaluation of safety and other data for all dose
levels tested
Study design
This is a FIH, open-label, multicenter phase 1/2a dose escalation trial of
CLDN6 CAR-T/CLDN6 CAR-T(A) with or without the CLDN6 (mod)RNA-LPX vaccine with
expansion cohorts in patients with CLDN6 positive relapsed or refractory
advanced solid tumors.
The trial is outlined in Figure 1 and consists of three parts:
For CLDN6 CAR-T manufactured using a manual process (IMP-1), the following
applies:
1. Part 1 will be a CLDN6 CAR-T dose escalation in lymphodepleted patients
until the maximum tolerated dose and/or recommended phase 2 dose of CLDN6 CAR-T
as monotherapy are defined (Figure 2).
2. Part 2 will be a vaccine-modulated dose escalation until the maximum
tolerated dose and/or recommended phase 2 dose of CLDN6 CAR-T + CLDN6
(mod)RNA-LPX are defined. Patients will be pretreated with an LD regimen
(standard, Figure 3), or they may be pretreated with a reduced-dose LD regimen
(optional, Figure 4) or without LD (optional Figure 5), as decided by the SRC
per SRC charter. If satisfactory expansion and persistence is seen at a certain
dose level, cohorts testing vaccine-modulated CLDN6 CAR-T without may also be
activated. All decisions concerning opening the LD-free cohorts will be made by
the safety review committee.
*Patients treated in Part 1 may be additionally treated with CDLN6 RNA-LPX
according to the SoTP (Section 1.3.2) under the following conditions:
• The dose level has been deemed safe by the SRC.
• The patient consents to the additional treatment in a separate consent form.
• The SRC approves the use of CLDN6 RNA-LPX based on the available safety and
CLDN6 CAR T expansion data of the respective patient.
• Safety criteria include:
o No significant, unacceptable or irreversible toxicities related to trial
treatment.
o The patients must meet the inclusion criteria for hematologic, renal, hepatic
and coagulation functions.
This is a summary, for more detailed information please refer to the protocol
section 4.
Intervention
All patients will receive one infusion of CLDN6 CAR-T/CLDN6 CAR-T(A) with or
without additional treatment with the CLDN6 (mod)RNA-LPX vaccine. Patients in
Part 1 may be re-dosed at month 2.
Study burden and risks
Benefit-Risk Assessment
Since CLDN6 is exclusively expressed by tumor cells and no protein expression
has been detected on any analyzed adult normal tissue, no off-tumor on-target
toxicities are expected. Importantly, CLDN6 is known to be expressed on
embryonic stem cells, thus pregnant women must not participate in the trial and
should not become pregnant thereafter. qRT-PCR analysis suggest that CLDN6 mRNA
expression was either negative in the vast majority of normal tissues or
slightly above the defined cut-off in a single sample each of a few tissue
types (placenta, testis and umbilical cord, cerebellum, lung). Notably, CLDN6
protein was not detected in any of these samples. Even though on-target,
off-tumor toxicities are not expected, they cannot be ruled out, hence patients
will be observed clinically for 14 d after CLDN6 CAR-T/CLDN6 CAR-T(A) and
(mod)RNA-LPX administration.
To date, RNA-LPX based cancer vaccines have demonstrated a favorable safety and
tolerability profile in different indications, in different treatment settings
(metastatic, post neo-adjuvant, adjuvant), and with different types of cancer
vaccine antigens (see IB for details). In the clinical trials with RNA-LPX, no
DLTs were reported during dose escalation, the TEAEs considered related to
trial drug were transient, mostly Grade 1 and 2, and associated with the
specific format of encoding and delivering the vaccine antigens, namely
single-stranded RNA formulated as a 1,2 di O octadecenyl-3-trimethylammonium
propane chloride/dioleoly-sn-glycero-phophoethanolamine (DOTMA/DOPE) lipoplex.
None of the potential risks, except for class-intrinsic risks, described above
is considered likely and relevant for the patients. Based on the experience
from the ongoing clinical trials with RNA-LPX, the class-intrinsic potential
risks are expected to manifest as mild-to-moderate, transient and manageable
flu-like AEs and transient lymphopenia (by sequestration).
The occurrence of AEs related to LD, CLDN6 CAR-T/CLDN6 CAR-T(A) and CLDN6
(mod)RNA-LPX may overlap making it difficult to assess the causality at the
time of occurrence.
As of 10th of March 2022 15 patients have been treated with the combination of
CLDN6 CAR-T and CLDN6 RNA-LPX in the BNT211-01 trial. Apart from the
anticipated flu-like symptoms occurring within hours of CLDN6 RNA-LPX
injection, no aggravation of adverse events (AEs) attributed to CLDN6 CAR-T
could be confirmed although it is premature to draw conclusions based on the
limited number of CLDN6 RNA-LPX injections administered.
Risks such as myelosuppression with associated cytopenias and febrile
neutropenias are known risks of the LD chemotherapy. Lymphodepletion as such
cannot be avoided at this stage of clinical development as it was shown to be
beneficial for T-cell engraftment and persistence. To account for the fact that
patients may experience febrile neutropenias at the same time as the signs and
symptoms of cytokine release syndrome (CRS) typically occurred in patients
treated with CD19 CAR-T, all patients will be monitored as in-patients for 14
days after the administration of CLDN6 CAR-T/CLDN6 CAR-T(A). IN BNT211-01,
pronounced cytopenias were observed in patients with testicular cancers who
were pretreated with a recent HDCT/ASCT..
After careful assessment of all emerging safety, expansion and persistence data
the sponsor opened a LD-free cohort in Part 2 of the trial, to further lower
the risk for the patients. However, due to unsatisfactory expansion of CLDN6
CAR-T cells, this cohort was closed and all patients with a recent HDCT/ASCT
are now treated with a reduced dose of lymphodepletion. To further mitigate the
risk of cytopenias, patients receiving LD after a HDCT/ASCT should have an
autologous stem cell back-up.
Based on inclusion criteria and published literature, eligible patients will
not have available standard treatment options, leaving a very poor prognosis
for this population. It is possible that the CLDN6 CAR-T/CLDN6 CAR-T(A) therapy
alone or with CLDN6 RNA-LPX will exert an anti-tumor effect, as demonstrated by
first clinical data as well as preclinical data in mice, for patients with
advanced CLDN6 expressing solid tumors.
Taken together, the risk-benefit ratio in the heavily pretreated patient
population suffering from advanced tumor diseases is regarded as positive.
Nevertheless, all ongoing and planned clinical trials contain regular safety
monitoring of laboratory and clinical parameters to ensure patient safety and
well-being.
An der Goldgrube 12
Mainz 55131
DE
An der Goldgrube 12
Mainz 55131
DE
Listed location countries
Age
Inclusion criteria
-Must have a CLDN6-positive tumor regardless of tumor histology defined as >=
50% of tumor cells expressing >= 2+ CLDN6 protein using a
semi-quantitative immunohistochemistry (IHC) assay for specific detection of
CLDN6 protein expression in formalin-fixed, paraffinembedded neoplastic tissues.
-Must have measurable disease per RECIST 1.1 (except for germ cell tumor or
ovarian cancer patients).
-Germ cell cancer patients without initial measurable disease per RECIST 1.1
and evaluable by cancer antigen (CA)-125, alphafetoprotein (AFP) or human
chorionic gonadotropin (hCG; as applicable) are eligible for the trial.
-Ovarian cancer patients without initial measurable disease per RECIST 1.1. and
evaluable by CA-125 are eligible for the trial.
-Must have a histologically confirmed solid tumor that is metastatic or
unresectable and for which there is no available standard therapy likely to
confer clinical benefit, or patient who is not a candidate for such available
therapy.
Exclusion criteria
-Have received prior CAR-T therapy, except CLDN6 CAR-T therapy.
-Have received vaccination with live virus vaccines within 6 weeks prior to the
start of lymphodepletion (LD).
-Receives concurrent systemic (oral or intravenous [i.v.]) steroid therapy > 10
mg prednisolone daily, or its equivalent, for an underlying condition.
-Current evidence of new or growing brain or spinal metastases during
screening. Patients with known brain or spinal metastases may be eligible if
they:
-Have had radiotherapy or another appropriate therapy for the brain or spinal
metastases,
-Have no neurological symptoms,
-Have stable brain or spinal disease on the computer tomography or magnetic
resonance imaging scan within 4 weeks before signing of the informed consent,
-Must not be undergoing acute corticosteroid therapy or steroid taper. Chronic
steroid therapy is acceptable provided that the dose is stable for the last 14
d prior to screening (<= 10 mg prednisolone daily or equivalent),
-Do not require steroid therapy within 7 d before the first dose of CLDN6
CAR-T,
-Do not have anticipated imminent fracture or cord compression due to spinal
bone metastases.
-Has history of another primary cancer within the 2 years prior to enrollment
except for the following: non-melanoma skin cancer, cervical carcinoma in situ,
superficial bladder cancer, prostate cancer with currently undetectable
prostate specific antigen, or other non-metastatic carcinoma that has been in
complete remission without treatment for more than 2 years.
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 | CTIS2024-514962-38-00 |
| EudraCT | EUCTR2019-004323-20-NL |
| CCMO | NL72581.000.20 |