This study has been transitioned to CTIS with ID 2024-516795-15-00 check the CTIS register for the current data. Primary: i) To determine the optimal 89Zr-DFO-REGN3767 protein dose and optimal PET imaging timepoint. ii) To evaluate the…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Comparison of standardized uptake values in tumor lesions and tumor-to-blood
ratios at different time points and different 89Zr-DFO-REGN3767 antibody dose
levels.
• To evaluate the biodistribution and PK of 89Zr-DFO-REGN3767 antibody by
measuring standardized uptake value (SUV) on 89Zr-DFO-REGN3767 PET scans in
patients with histologically or cytologically documented locally advanced or
metastatic solid tumors who based on available clinical data may benefit from
treatment with cemiplimab with or without platinum-based chemotherapy.
• Safety evaluation through summaries of adverse events, changes in laboratory
test results and changes in vital signs after exposure to 89Zr-DFO-REGN3767.
Secondary outcome
• Comparison of tracer uptake, expressed as standardized uptake values, in
different tumor lesions within and between patients on 89Zr-PET scans.
• Correlation of tumor tracer uptake with tumor and immune cell LAG3 expression
as assessed by immunohistochemistry on a tumor biopsy sample.
• Correlation of tumor tracer uptake with response to cemiplimab with or
without platinum-based chemotherapy, according to RECIST v1.1.
• Assessment of change in tumor and normal organ tracer uptake after 2 cycles
of cemiplimab with or without chemotherapy
Background summary
The rapidly evolving fields of tumor immunology and cancer immunotherapy have
resulted in several Food and Drug Administration (FDA) and European Medicines
Agency (EMA) approved immune checkpoint inhibitors (ICI) for different tumor
types. However, not all patients respond to these drugs. Moreover,
immunotherapeutic drugs require careful management of potential side effects.
Therefore, it would be of major interest to be able to know whether a specific
treatment induces an immune response.
The dynamic tumor microenvironment and tumor heterogeneity have raised
significant interest in objectifying the status of the microenvironment. Still,
the ability to monitor changes in the immune status of metastatic cancers is
limited. 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.
The immune checkpoint lymphocyte activation gene-3 (LAG-3, cluster of
differentiation (CD)223)) is a cell surface molecule expressed on activated T
cells, natural killer (NK) cells, B cells and several additional hematopoietic
cell types including plasmacytoid dendritic cells. The fully human anti-LAG-3
antibody fianlimab (REGN3767) has been radiolabeled with deferoxamine (DFO)
Zirconium-89 (89Zr). In a preclinical mouse model, this tracer visualized LAG-3
expressing intratumoral T cells after co-implantation of human Raji Burkitt
lymphoma cells with human peripheral blood mononuclear cells.1
89Zr-DFO-REGN3767 positron emission tomography (PET) allows visualization of
the 89Zr-DFO-REGN3767 antibody uptake in tumor and lymphoid tissues which might
be an early marker of immune response that could guide ICI treatment.
Chemotherapy is thought to increase LAG-3 expression. Such a tracer might be
extremely informative regarding T cell behavior during established ICI therapy
with anti-programmed cell death protein 1 (PD1) antibody with or without
platinum-based chemotherapy.
Noninvasive serial whole-body monitoring of the tumor immune response to
therapy by means of imaging activated immune cells might provide major
insights. By performing 89Zr-DFO-REGN3767 PET scans prior to and during
treatment with anti-PD-1 antibody cemiplimab with or without platinum-based
chemotherapy, the radioactivity uptake in primary and metastatic tumor lesions
and normal organ distribution can be evaluated. 89Zr-DFO-REGN3767 PET can serve
as a potential complementary tool for patient and treatment selection in the
future as well as could potentially lead to early treatment decisions.
Study objective
This study has been transitioned to CTIS with ID 2024-516795-15-00 check the CTIS register for the current data.
Primary: i) To determine the optimal 89Zr-DFO-REGN3767 protein dose and optimal
PET imaging timepoint. ii) To evaluate the pharmacokinetics (PK) of
89Zr-DFO-REGN3767 by measuring standardized uptake value (SUV) on
89Zr-DFO-REGN3767 PET scans in patients with histologically or cytologically
documented locally advanced or metastatic solid tumors who based on available
clinical data, may benefit from treatment with the PD1 antibody cemiplimab +/-
platinum- based chemotherapy. iii) To evaluate the safety of 89Zr-DFO-REGN3767.
Secondary: i) To assess the heterogeneity of 89Zr-DFO-REGN3767 antibody tumor
uptake within a lesion and between lesions. ii) To correlate tumor tracer
uptake with tumor and immune cell LAG3 expression as assessed by biopsy. iii)
To correlate the tumor tracer uptake with response to cemiplimab antibody with
or without platinum-based chemotherapy. iv) To assess change in tumor and
normal organ uptake after 2 cycles of cemiplimab with or without chemotherapy
Study design
An investigator-initiated, single-center (University Medical Center Groningen
(UMCG)), open-label clinical trial designed to evaluate the safety, in vivo
biodistribution and tumor / organ pharmacodynamics of the PET tracer
89Zr-DFO-REGN3767 in patients with histologically documented locally advanced
or metastatic solid tumors who according to the opinion of the investigator,
based on available clinical data, may benefit from cemiplimab with or without
platinum-based chemotherapy.
Intervention
Part A will serve to find the optimal tracer dose and the optimal interval
between tracer injection and PET scanning. Approximately 4 cohorts of about 2-3
patients each will undergo 89Zr-DFO-REGN3767 PET imaging at 4 time points (day
of 89Zr-DFO-REGN3767 injection, day 2, day 4 and day 7 after injection).
Depending on the tumor saturation and scanning results, additional patients can
be included. At least six patients will be enrolled at the dose level
considered appropriate for further testing; additional patients may be enrolled
at that dose level if considered necessary to collect additional imaging and/or
safety data prior to starting part B. After completion of imaging, patients
will receive the PD1 antibody cemiplimab at a dose of 350 mg every 3 weeks
with or without platinum-based chemotherapy.
Part B, using the optimal protein tracer dose and at the optimal PET scan
timepoint, will serve to evaluate the PK and imaging characteristics of
89Zr-DFO-REGN3767 before and during treatment with cemiplimab with or without
platinum-based chemotherapy. In part B, approximately 22 patients will be
enrolled to undergo 89Zr-DFO-REGN3767 PET imaging twice; the first
89Zr-DFO-REGN3767 PET scan will be performed at baseline, before starting
therapy. The second 89Zr-DFO-REGN3767 PET scan will be performed early in cycle
2 (within 7 days after administration of cycle 2), to minimize morphological
changes in tumors responding to the therapy. In part B, one cohort of 11
patients will be treated with cemiplimab every 3 weeks and another cohort of 11
patients will be treated with cemiplimab every 3 weeks with platinum-based
chemotherapy. All patients participating in the imaging trial part A and B will
undergo at least one tumor biopsy. The biopsy procedure will be performed after
the last 89Zr-DFO-REGN3767 PET scan that occurs before the start of treatment.
In addition, in part B, on-treatment tumor biopsies will be performed if
possible, at the end of the second 89Zr-DFO-REGN3767 PET scan period.
Study burden and risks
For this study, patients have to make a maximum of 9 extra visits to the clinic
for screening, to receive 89Zr-DFO-REGN3767 injection, to have up to 4 PET-scan
visits, and the biopsies taken before and/or after starting treatment with
cemiplimab with or without platinum-based chemotherapy. In practice, most
procedures will be combined with visits to the hospital in the context of
clinical care to minimize the burden.
89Zr-DFO-REGN3767 is a radioactive compound and therefore, will cause radiation
burden to the patient. The projected effective dose after receiving 37 MBq of
89Zr-DFO-REGN3767 is about 18 mSv. Each PET scan will be made with a low dose
attenuation correction CT scan, which has an effective dose of 1.5 mSv. Thus,
patients in part A undergoing 4 PET/CT scans, will receive an exposure of
approximately 18 + (4x1.5) = 24 mSv. Patients in part B will receive two 37 MBq
doses of 89Zr-DFO-REGN3767 and undergo 2 PET/CT-scans. The radiation exposure
will be approximately (2x18) + (2x1.5) = 39 mSv.
Besides PET imaging, patients will be asked to provide a total of 11 blood
samples in part A (86 mL) and 12 samples in part B (96 mL). A tumor lesion will
be biopsied. Based on a literature review, the risk of tumor biopsies is
considered low, with a small risk of significant or major complications or
death. To keep this risk as low as possible only patients that have safely
accessible tumor lesions will be included in the study.
The risk associated with 89Zr-DFO-REGN3767 is considered very low based on
extensive preclinical testing and preliminary data of an ongoing phase 1 trial
where REGN3767 is given (NCT03005782, EudraCT 2016-002789-30). This study will
enroll patients who have exhausted standard therapy and are believed by the
investigator to potentially benefit from PD1 antibody with or without
platinum-based chemotherapy. Available clinical data will be used to inform
the investigator*s decision. Although patients that have a standard treatment
option of ICI therapy plus or minus chemotherapy 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.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years at the time of signing informed consent.
2. Patients with histologically confirmed diagnosis of locally advanced or
metastatic solid cancer types who, according to the opinion of the
investigator, based on available clinical data, may benefit from PD1 antibody
with or without platinum-based chemotherapy.
3. At least 1 lesion that is accessible per investigator*s assessment and
eligible for biopsy according to standard clinical care procedures.
4. Measurable disease, as defined by standard RECIST v1.1. Previously
irradiated lesions should not be counted as target lesions except for lesions
that have progressed after radiotherapy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Life expectancy >= 12 weeks.
7. Adequate organ and bone marrow function as defined below:
a. Hemoglobin >=9.0 g/dL
b. Absolute neutrophil count >=1.5 x 109/L
c. Absolute lymphocyte count >=0.75 x 109/L
d. Platelet count >=100 x 109/L
e. Serum creatinine <=1.5 x upper limit of normal (ULN) or estimated glomerular
filtration rate > 30 mL/min/1.73 m2. A 24-hour urine creatinine collection may
substitute for the calculated creatinine clearance to meet eligibility
criteria.
f. Adequate hepatic function:
i. Total bilirubin <=1.5 x ULN (<=3 x ULN if liver tumor involvement); Patients
with Gilbert*s syndrome do not need to meet total bilirubin requirements,
provided their total bilirubin is unchanged from their baseline. Gilbert*s
syndrome must be documented appropriately as past medical history.
ii. Aspartate aminotransferase (AST) <=2.5 x ULN (<=5 x ULN if liver tumor
involvement)
iii. Alanine aminotransferase (ALT) <=2.5 x ULN (<=5 x ULN if liver tumor
involvement)
iv. Alkaline phosphatase (ALP) <=2.5 x ULN (<=5 x ULN if liver or bone tumor
involvement)
8. Signed informed consent.
9. Willingness and ability to comply with all protocol required procedures.
Exclusion criteria
1. Treatment with any approved anti-cancer therapy, investigational agent, or
participation in another clinical trial with therapeutic intent within 28 days
prior to 89Zr-DFO-REGN3767 injection.
2. Prior ICI treatment, including but not limited to anti-PD1 and anti-PD-L1
therapeutic antibodies in the past 12 months or >= 12 months ago, in case the
ICI treatment was terminated for progressive disease or toxicity.
3. Encephalitis, meningitis, or uncontrolled seizures in the year prior
inclusion.
4. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer
therapy. Subjects with irreversible toxicity that is not reasonably expected
to be exacerbated by the investigational product may be included (e.g., hearing
loss, peripherally neuropathy)
5. Symptomatic, untreated brain metastasis, leptomeningeal disease, or spinal
cord compression. Patients are eligible if central nervous system (CNS)
metastases are adequately treated and neurologically stable for at least 2
weeks prior to enrollment.
6. Documented allergic or acute hypersensitivity reaction attributed to
antibody treatments
7. Major surgical procedure other than for diagnosis within 28 days prior to
89Zr-DFO-REGN3767 injection or anticipation of need for a major surgical
procedure during the course of the study.
8. For patients that will be treated with cemiplimab in combination with
platinum containing chemotherapy, the following additional criteria apply:
• Leucopenia <3 x 109/L
• Estimated glomerular filtration rate < 60 mL/min/1.73 m2
• Cardiovascular disease, such as New York Heart Association cardiac disease
(Class II or greater), unstable angina, unstable cardiac arrhythmias,
myocardial infarction < 3 months ago, or cerebrovascular accident < 6 months
ago.
• Hearing loss
• Any other exclusion criteria, according to the local clinical practice
guidelines for the chosen chemotherapy regimen.
9. History of autoimmune disease, including but not limited to myasthenia
gravis, myositis, autoimmune hepatitis, systemic lupus erythematous, rheumatoid
arthritis, inflammatory bowel disease, vascular thrombosis associated with
antiphospholipid syndrome, Wegener*s granulomatosis, Sjögren*s syndrome,
Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis.
• Patients with a history of autoimmune-related hypothyroidism on a stable dose
of thyroid replacement hormone may be eligible for his study.
• Patients with controlled type I diabetes mellitus on a stable dose of insulin
regimen may be eligible for this study.
10. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,
bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis.
• History of radiation pneumonitis in the radiation field (fibrosis) is
permitted.
11. Treatment with systemic immunosuppressive medications (including but not
limited to prednisone, cyclophosphamide, azathioprine, methotrexate,
thalidomide, and anti-tumor necrosis factor agents) within 4 weeks prior to
89Zr-DFO-REGN3767 injection.
• Patients who have received acute, low-dose, systemic immunosuppressant
medications (e.g., a one-time of dexamethasone for nausea) may be enrolled in
the study after discussion with and approval by the sponsor.
• The use of inhaled corticosteroids for chronic obstructive pulmonary disease,
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic
hypotension, and low-dose supplemental corticosteroids for adrenocortical
insufficiency are allowed.
12. Prior allogeneic bone marrow transplantation or solid organ transplant.
13. Active infection with human immunodeficiency virus (HIV), hepatitis B,
hepatitis C or tuberculosis infection; or diagnosis of immunodeficiency
• Patients will be tested for hepatitis C virus (HCV) and hepatitis B virus
(HBV) at screening.
• Patients with known HIV infection who have controlled infection (undetectable
viral load (HIV ribonucleic acid (RNA) polymerase chain reaction (PCR)) and CD4
count above 350 either spontaneously or on a stable antiviral regimen are
permitted. For patients with controlled HIV infection, monitoring will be
performed per local standards.
• Patients with hepatitis B who have a controlled infection (serum HBV
deoxyribonucleic acid (DNA) PCR below the limit of detection AND receiving
anti-viral therapy for hepatitis B) are permitted. Patients with controlled
infections must undergo periodic monitoring of HBV DNA. Patients must remain
on anti-viral therapy for at least 6 months beyond the last dose of
investigational study drug.
• Patients who are HCV antibody positive who have controlled infection
(undetectable HCV RNA by PCR either spontaneously or in response to a
successful prior course of anti-HCV therapy) are permitted.
• Patients positive for HCV antibody are eligible only if PCR is negative for
HCV RNA.
14. Active infection that requires systemic antibiotics within 2 weeks prior to
89Zr-DFO-REGN3767 injection.
15. 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 89Zr-DFO-REGN3767, or that may affect
the interpretation of the results or render the patient at high risk from
complications.
16. Receipt of a live vaccine (including attenuated) within 30 days of planned
start of study medication.
17. Altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent.
18. Sponsor employee/member of the clinical site study team and/or his or her
immediate family
19. Women with a positive serum chorionic gonadotropin HCG pregnancy test at
the screening/baseline visit. Breastfeeding women are also excluded.
20. Women of childbearing potential* and sexually active men who are unwilling
to practice highly effective contraception prior to the first dose of study
therapy, during the study, and for at least 6 months after the last dose.
Highly effective contraceptive measures include:
• stable use of combined (estrogen and progestogen containing) hormonal
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal
contraception (oral, injectable, implantable) associated with inhibition of
ovulation initiated 2 or more menstrual cycles prior to screening
• intrauterine device (IUD); intrauterine hormone-releasing system (IUS)
• bilateral tubal ligation
• vasectomized partner (provided that the male vasectomized partner is the sole
sexual partner of the women of childbearing potential (WOCBP) study participant
and that the vasectomized partner has obtained medical assessment of surgical
success for the procedure)
• and/or sexual abstinence
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 | CTIS2024-516795-15-00 |
| EudraCT | EUCTR2020-004052-15-NL |
| ClinicalTrials.gov | NCT04706715 |
| CCMO | NL74943.042.20 |