Primary objectives:The objective is to study the distribution of CD8+ T-cells before and after CAR T-cell therapy in the patient by ZED88082A/CED88004S-PET imaging. We will correlate the pretreatment CD8+ T-cell distribution and CD8+ CAR T-cell…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints:
- To determine the whole-body biodistribution of the ZED88082A tracer in normal
tissues and tumor lesions before and after CAR T-cell therapy.
Secondary outcome
Secondary endpoints:
- Assess safety and dosimetry ZED88082A/CED88004S uptake in the setting of
CD19-directed CAR T-cell therapy
- Correlative expression analysis between ZED88082A tracer standard uptake
volume (SUV) parameters in the tumor, CD8 expression in tumor biopsy, and
response to CAR T-cell therapy.
- To perform correlative expression analysis between SUV parameters of
ZED88082A tracer in the tumor, CD8 expression in tumor biopsy, and SUV
parameters in the tumor and whole-body and CAR T-cell persistence, peak level
and CAR T-cell phenotype as measured in the peripheral blood.
- Correlative expression analysis between ZED88082A tracer SUV parameters in
the tumor, and grade 1-5 adverse events to CAR T-cell therapy, including
cytokine release syndrome and neurotoxicity.
- Correlative expression analysis between ZED88082A tracer uptake in irradiated
versus non-irradiated lymphoma lesions in patients who require radiotherapy as
bridging strategy prior to CAR T-cell infusion.
Background summary
Anti-CD19 Chimeric Antigen Receptor (CAR)-T cell therapy has changed the
treatment landscape of patients with (Diffuse) Large B-cell Lymphoma (LBCL) and
other types of Non-Hodgkin Lymphoma (NHL). Patients with LBCL who do not
respond to first-line therapy, have a relapse within 6 months (primary
refractory), or after second-line therapy, including high-dose chemotherapy and
autologous stem cell rescue, have a poor prognosis and only 6% of these
patients have a long-term survival. The recent results of 3 pivotal studies
with 3 different anti-CD19 CAR T-cell products administered to patients with
relapsed/refractory (R/R) LBCL resulted in high response rates and long-term
remissions in almost half of the patients. Unfortunately, some patients do not
respond to CAR T-cell. Moreover, CAR T-cell therapy can elicit severe side
effects. Therefore, it would be of major interest to know whether CAR T-cell
therapy induces an immune response in a specific patient. The dynamic lymphoma
microenvironment and tumor heterogeneity have therefore raised significant
interest in objectifying the status of the microenvironment in the setting of
CAR T-cell therapy, but the ability to monitor changes in the immune status of
lymphoma and CAR T-cell therapy is very scarce. Current methods to monitor
lymphocytes from whole blood or biopsies from heterogeneous tumors do not
necessarily reflect the dynamic and spatial information required to monitor
immune responses to therapeutic intervention. Moreover, these responses may
elicit whole body changes in immune cell numbers and localization. Molecular
imaging can noninvasively monitor whole-body systemic and intratumoral
alterations. Assessing abundance and localization of immune cells before and
during therapy would increase the understanding of the dynamics of
immunotherapeutic mechanisms, with the potential to provide translatable
methods for predicting and/or assessing responses and side effects. Preinfusion
of CAR product T-cell subsets with a definable polyfunctional profile has been
associated with a favorable outcome of CAR T-cell therapy in NHL. In addition,
biopsies taken from lymphoma lesions demonstrated that the best responses after
CD19-directed CAR T-cell therapy were noted in patients where the CAR T-cells
were able to infiltrate the tumor and in patients who did have a higher
expansion of CD3+/CD8+ CAR T cells in peripheral blood. It is, therefore, of
high interest to determine the distribution of CD8+ T-cells within the tumor
and elsewhere in the body, before and after CAR T-cell therapy. Noninvasive
serial whole-body monitoring of the lymphoma immune response to CAR T-cell
therapy using imaging CD8+ cytotoxic T-cells might thus provide major insights.
RED88822 is a one-armed anti-CD8 antibody, which is called CED88004S when
DFO-conjugated and ZED88082A when it is 89Zr-labeled- DFO-conjugated, that was
designed to enable whole-body PET imaging of CD8+ T-cells. By performing
ZED88082A/CED88004S-PET scans prior to treatment with CAR T-cells, the
radioactivity uptake in lymphoma lesions and normal organ distribution can be
evaluated and ZED88082A/CED88004S-PET serve as a potential complementary tool
for patient and treatment selection in the future. Repeat
ZED88082A/CED88004S-PET imaging after CAR T-cell treatment will provide
information about systemic and intratumoral alterations in response to CAR
T-cell therapy.
Study objective
Primary objectives:
The objective is to study the distribution of CD8+ T-cells before and after CAR
T-cell therapy in the patient by ZED88082A/CED88004S-PET imaging. We will
correlate the pretreatment CD8+ T-cell distribution and CD8+ CAR T-cell tumor
invasion, as measured by the intensity of ZED88082A/CED88004S-PET imaging
positive lesions.
Secondary objectives:
a) Assess safety and dosimetry ZED88082A/CED88004S uptake in the setting of
CD19-directed CAR T-cell therapy
b) To assess heterogeneity of ZED88082A/CED88004S tumor uptake
c) To correlate normal organ ZED88082A/CED88004S uptake to (serious) adverse
events (possibly) related to CAR T-cell treatment
d) To correlate tumor ZED88082A/CED88004S uptake with tumor and immune cell
CD8-expression as assessed by a fresh contemporaneous tumor biopsy
e) To correlate ZED88082A/CED88004S uptake in irradiated versus non-irradiated
lymphoma lesions in patients who require bridging with radiotherapy prior to
CAR T-cell infusion.
Study design
This is a single-center, single-arm trial designed to evaluate the distribution
of endogenous CD8+ T-cells in patients with LBCL prior to CAR T-cell therapy
and after CD19-directed CAR T-cell therapy.
Intervention
In this imaging trial, the purpose is to explore the feasibility of anti-CD8
PET imaging to gain insights into the biodistribution of CD8+ T-cell before and
after CD19-directed CAR T-cell therapy in R/R LBCL. Patients with R/R LBCL
after 2 prior lines of therapy will receive standard of care CD19-directed CAR
T-cell therapy according to the eligibility criteria as formed by the Dutch
Immune Effector Cell tumor board.
Study burden and risks
For this imaging study, patients have to make a maximum of 4 extra visits to
the clinic for screening, to receive ZED88082A/CED88004S injection, to have 1
PET-scan visit (1 PET will be performed during hospitalization after the CAR
T-cell infusion), and the biopsies taken before and/or after starting treatment
with CAR T-cell therapy.
In practice, most procedures will be combined with visits to the hospital in
the context of clinical care, to minimize the burden.
The first intravenous tracer injection ZED88082A/CED88004S is on day -27 (+/- 2
days) of the CAR T-cell infusion (or on day -15 (+/- 2 days) of the CAR T-cell
in case radiation therapy is planned as bridging to CAR T-cell infusion). All
patients will be observed for at least 30 minutes after ZED88082A/CED88002S
injection to monitor for possible acute infusion related adverse events. The
subsequent ZED88082A/CED88004S-PET imaging scan is 48 hrs later followed by a
biopsy. The second intravenous tracer injection ZED88082A/CED88004S is on day
of CAR T-cell infusion. The second ZED88082A/CED88004S-PET imaging scan and
biopsy is then scheduled on day +2. On day +4 another ZED88082A/CED88004S-PET
imaging scan will be done, and in case there are measurable lesions at day +4
aonother one at day +7. During the second tracer injection and
ZED88082A/CED88004S-PET imaging scans the patients are hospitalized as part of
the CAR T-cell observation.
The radiation burden following administration of 37 MBq of ZED88082A/CED88004S
is about 18 mSv, in addition to 1.5 mSv per low-dose attenuation correction
CT-scan. Thus, patients will receive two 37 MBq doses of ZED88082A/CED88004S
and undergo to 3 à 4 low-dose CT-scans. The total radiation exposure will be
approximately (2x18)+(4x1.5)=42 mSv. Besides PET imaging, patients will be
asked to provide 8 blood samples (160 mL). The easiest and safest accessible
tumor lesion will be biopsied at the same time points as the anti-CD8 PET
scans. Based on a literature review, the risk of tumor biopsies is considered
low with a small risk of significant or major complications or death. The risk
associated with the ZED88082A/CED88004S is considered acceptable based on
extensive preclinical testing, which showed no signs of T-cell activation or
inhibition, and clinical safety data from the ongoing CD8 PET imaging study,
where no ZED88082A/CED88004S infusion related adverse events have been reported
to date (see IMPD). Although patients do not directly benefit from this study,
results from this study will be valuable for our understanding of the tumor
immune response and will guide further prospective research and hopefully,
treatment decisions. After participation within the imaging trial, eligible
patients will proceed with CD19-directed CAR T-cell treatment, provided they
continue to meet the eligibility criteria to receive CD19-directed CAR T-cells.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
1. Subjects with histologically confirmed LBCL and subtypes according to the
WHO 2016 criteria
2. Tumor lesion(s) of which a histological biopsy can safely be obtained
according to standard clinical care procedures.
3. Measurable disease, as defined by Lugano criteria.
4. Signed informed consent.
5. Age >=18 at the time of signing informed consent.
6. Life expectancy >=12 weeks.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
8. Ability to comply with the protocol.
9. For female patients of childbearing potential and male patients with
partners of childbearing potential, agreement (by patient and/or partner) to
use a highly effective form(s) of contraception (i.e., one that results in a
low failure rate [<1% per year] when used consistently and correctly).
Exclusion criteria
1. Signs or symptoms of infection within 2 weeks prior to ZED88082A/CED88004S
injection.
2. Prior immune checkpoint inhibitor bi-specific antibody, including but not
limited to anti-PD1 and anti- PD-L1 therapeutic antibodies.
3. History of severe allergic, anaphylactic, or other hypersensitivity
reactions to chimeric or humanized antibodies or fusion proteins.
4. Any other diseases, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or
condition that contraindicates the use of ZED88082A/CED88004S, or that may
affect the interpretation of the results or render the patient at high risk
from complications.
5. Pregnant or lactating women.
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 |
|---|---|
| EudraCT | EUCTR2020-004749-35-NL |
| CCMO | NL75607.042.20 |
| Other | NL9034 |