Objectives of Part A, B and C are the following: Part A: determination of the optimal mass dose of S095012 to inject with 89Zr-S095012 and optimal time point for PET scans for appropriate visualisation of 89Zr-S095012 through PET imaging. Part B…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Visual analysis of PET/CT scan images.
Quantitative parameters derived from PET scans for blood pool, organs and tumor
lesions (time-uptake curves, tumor to background ratio, *).
- Quantitative parameters derived from PET scan images to assess uptake in
tumor lesions and normal tissues reported with standardised uptake value (SUV)
and concentration for each volume of interest (VOI).
Serum PK parameters of 89Zr*S095012.
Comparison of 89Zr*S095012 tumor uptake (as described using SUV and
concentrations) before and on treatment with different doses of S095012.
- Incidence and severity of adverse events (AEs).
Discontinuing study intervention due to an AE.
Secondary outcome
Serum PK parameters of S095012.
-Organ and whole-body radiation exposure (mSv per Mega Becquerel (MBq):
Highest absorbed dose, specific absorbed dose to the target lesions, absorbed
dose per organ and cumulative absorbed organ doses.
-Assessment based on Response Evaluation Criteria in Solid Tumors (RECIST)
V1.1, objective response rate (ORR).
Background summary
S095012 is a monoclonal antibody (mAb)-like bispecific protein targeting the
programmed death-ligand 1 (PD-L1) and the immune receptor 4-1BB. S095012 is
constituted by the genetic fusion of a backbone-engineered anti-PD-L1 antibody
and an agonistic 4-1BB-targeting moiety, based on Anticalin® technology,
formulated as an aqueous solution for intravenous (IV) infusion. The antitumor
activity of S095012 combine both the checkpoint inhibition via the PD-1/PD-L1
axis and the activation of the 4-1BB mediated anticancer effect to thereby
provide a potent costimulatory signal to tumor antigen-specific activated-T
cells.
Non-clinical pharmacology data support the intended mechanism of action of
Studies validated the use of immuno-PET with Zirconium 89 to directly visualise
drug biodistribution in patients with a non-invasive approach, offering support
to drug development.
.
Molecular imaging with PET is a powerful and non-invasive tool for in vivo
visualisation, monitoring and quantification of the uptake of Zirconium-89
(89Zr)-labelled compounds in tumors and tissues of interest in humans.
Therefore, assessing the biodistribution and tumor uptake of S095012 through
PET imaging could provide important information to support dose and scheduling
selection for efficacy testing, when correlated to pharmacodynamic markers.
The present imaging study will run in a staggered manner with a first-in-human
(FIH) Phase 1/2 study (CL1-95012-001). The aim of the FIH study is to evaluate
the safety profile, tolerability and determine the maximum tolerated dose (MTD)
or maximum administered dose (MAD) of S095012, as well as the PK profile,
pharmacodynamic effects and preliminary anti-tumor activity of S095012.
The imaging study is designed to assess the whole-body biodistribution and
tumor uptake of 89Zr-S095012 at baseline and during treatment with S095012. The
study will be conducted in participants with histologically confirmed advanced
and/or metastatic solid tumors. Moreover, pharmacodynamic effects of S095012
will be followed through systemic 4-1BB specific biomarker and CD8 T cell
activation in the tumor (immunohistochemistry (IHC) on biopsies). During this
study, mass and treatment doses of S095012 administered will be based on safety
data collected during the FIH study. Reciprocally, safety data collected from
the imaging study will inform the safety profile of S095012 and will be taken
into account in the MTD (if any) and/or the RP2D determination.
Study objective
Objectives of Part A, B and C are the following:
Part A: determination of the optimal mass dose of S095012 to inject with
89Zr-S095012 and optimal time point for PET scans for appropriate visualisation
of 89Zr-S095012 through PET imaging.
Part B: whole body distribution and tumor uptake of S095012 visualised by the
administration of 89Zr-S095012 and PET imaging.
Part C: on treatment dose-dependent tumor uptake of 89Zr-S095012 in
participant with tumor uptake at baseline (in Part B); visualised by the
administration of 89Zr-S095012 on treatment and PET imaging. It is anticipated
that 89Zr-S095012 uptake in tumor lesions will be inversely correlated with the
level of saturation of tumor lesion by S095012.
Study design
This is a phase 1, multicentre, single arm, open-label, imaging study That will
be conducted in 3 parts (Part A, and Part B and C). Participants from the Part
A will be imaged at baseline only in order to determine the optimal
non-therapeutic mass dose of S095012 to inject along with 89Zr*S095012 and to
select the optimal time-points for PET/ computerised tomography (CT) scan
imaging. The first mass dose of S095012 will be based on the results from the
FIH PK data and data from literature. In the Part B and C, participants will be
imaged at baseline (Part B) and on-treatment (Part C).
All participants from each part will receive S095012 treatment doses
administered every two weeks as a 60-minute IV administration.
In participants included in Part A or Part B but not eligible for Part C,
S095012 will be administered at the maximum treatment dose determined as
tolerable and safe from the FIH study based on the 28-days DLT observation
period.
In participants included in Part C, S095012 will be administered at 4 dose
levels (60 mg, 180 mg, 500 mg and 1000 mg) in order to describe the
relationship between tracer tumor uptake and treatment dose. These treatment
dose could be adapted according to new information from this and the FIH study.
In any case, the treatment will not exceed the maximum treatment dose
determined as tolerable and safe from the FIH study based on the 28-days DLT
observation period.
. The dose escalation will be stopped when a plateau in decrease of tumor
uptake is reached and/or sufficient information to describe saturation of tumor
uptake is obtained, or for safety reason, or for sponsor decision, whatever
comes first.
Intra-participant dose escalation will be allowed in all participants up to the
maximum treatment dose determined as tolerable and safe from the FIH study
based on the 28-days DLT observation period, if not received before.
Intervention
For the Imaging Study, once or twice, depending on the group the patient is
participating in, a radioactive tracer 89-ZrS95012 +- a mass dose of the Study
drug S95012 will be administered, followed by 2 up to 4 PET-scans.
During the treatment part, the Study drug S95012 ill be administered
intravenously every fortnight and the patients attends the Study visits. Blood
and urine samples are taken, ECGs are made.
According to the group the patient is participating in, tumorbiopsies are made
at baseline and during treatment.
Tumorevolution is followed with CT/MRI.
Study burden and risks
The burden for study participation for patients is to undergo the mandatory
imaging part before having access to the treatment part of the study.
The imaging part involves 1 to 2 injections with 89-Zr S095012 and 4 PET-scans,
resulting in a total radiation dose of 32 mSv for part A participants and 52
mSv for part B/C patients. (26 mSv if only participating to part B). Patients
can go home after the procedure, no need to stay hospitalised.
The dose of the tracer used is the minimal dose mandatory for the measurement.
Optimisation of the radiation dose is achieved via splitting of the protocol
into parts. In conclusion, the radiation burden for this study has been
optimised, is justified, and falls within the dose limits as discussed in the
Netherlands Commission on Radiation, Report 26 (2016) and the International
Commission on Radiological Protection, Publication 62 (1992). Dosimetry will be
performed on the first participants included.
The burden for the treatment part is mainly because of the multiple site visits
and exams mandatory to follow-up on the patient*s safety and to obtain
information on the PK profile.
The risk: the doses of S95012 used in this study are dosages that have been
evaluated as safe in a parallel study. Mandatory biopsies at baseline and on
treatment are a risk for patients participating in part B/C. These biopsies are
optional for patients taking part in part A and having archived tissue
available. No information is available yet on the adverse reactions following
S095012 administration
Internationalelaan 57
Brussel 1070
NL
Internationalelaan 57
Brussel 1070
NL
Listed location countries
Age
Inclusion criteria
1. Men and women of >= 18 years of age on the day the consent is signed.
2. Participants with histologically confirmed diagnosis of unresectable,
locally advanced or metastatic solid tumor for which standard treatment options
are not available, no longer effective, or not tolerated. Participant should
have a documented disease progression on prior therapy before entry into this
study.
3. Participants must have at least one measurable target lesion as per RECIST
1.1.
4. ECOG performance status of 0 or 1
5. For participants in part B/C (optional for part A): Participant with no
available archived material must have one or more tumor lesions amenable to
biopsy. Baseline biopsies are not mandatory if archived tumor biopsy specimens
collected no later than 9 months before screening, are available. If no
archived material is available, a fresh biopsy must be collected at baseline.
6. Adequate organ function as assessed by laboratory tests within 72 hours
prior to the first IMP administration:
- Absolute neutrophil count (ANC) >= 1500/µL.
- Platelet count >= 75 000/µL (this criterion must be met without transfusion
and thrombopoietin for at least two weeks prior to IMP administration).
- Haemoglobin >= 8 g/dL (this criterion must not be met with the use of
transfusion and erythropoietin for at least two weeks prior to IMP
administration).
- Glomerular filtration rate (GFR) or measured or calculated creatinine
clearance (CrCl) >= 30 mL/min using the Cockcroft and Gault formula.
Alternatively, the GFR can be estimated using the Modification of Diet in Renal
Disease (MDRD) formula. However, the estimation of CrCl must be done using the
same methodology for a given participant (see Appendix 5).
- Total bilirubin <= 1.5×upper limit of reference range (ULN) (or total serum
bilirubin <3×ULN for participants with Gilbert*s disease).
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5×ULN.
- Serum albumin >= 3 g/dL
7. Woman must use a highly effective method of birth control during study
treatment and until 120 days after last dose of IMP
In case of use of oral contraception, women should have been stable on the same
contraceptive drug (same active principle) for at least 6 months prior to the
first IMP administration.
8. A male participant with childbearing potential partners must use a condom
during the study and until at least 120 days after the last dose of IMP.
Participants that are sterile or vasectomised must use a condom during sexual
intercourse with a childbearing potential partner in order to avid exposure of
an existing embryo/foetus. In addition, contraception should be considered for
their female partner. Contraceptive measures do not apply if the participant is
sterile, vasectomized or sexual abstinent. Sperm donation will not be allowed
during the study and for 120 days after the last dose of IMP.
9. Human immunodeficiency virus (HIV)-infected participants must have
well-controlled HIV or be on adequate antiretroviral therapy defined as:
CD4 lymphocyte count > 350 cells/µL at time of screening.
Achieving and maintaining virologic suppression defined as confirmed HIV
ribonucleic acid (RNA) level below 50 or lower limit of detection by the local
available assay at time of screening and for at least 12 weeks prior to
screening.
10. Written informed consent obtained prior to performing any study procedure
Exclusion criteria
11. Pregnant and lactating women.
12. Unlikely to cooperate in the study.
13. Participation in another interventional study at the same time;
participation in non-interventional registries or epidemiological studies is
allowed.
14. Participant already included in the study (informed consent signed).
15. Participants with previously treated brain metastases may participate
provided they are radiologically stable, clinically asymptomatic and are off
immunosuppressive therapies for at least 4 weeks. Low dose of steroid < 10
mg/day prednisone or equivalent is allowed.
16. Participants with primary central nervous system malignancies.
17. Participants with Child-Pugh Class B8 or higher or C liver cirrhosis.
18. Participants who have received prior:
a. chemotherapy, Small molecule inhibitors, and/or other similar
investigational agent: <= 2 weeks or 5 half-lives, whichever is shorter.
b. monoclonal antibodies, antibody-drug conjugates, or other similar
experimental therapies: <= 3 weeks or 5 half-lives, whichever is shorter.
c. Radioimmunoconjugates or other similar experimental therapies <= 6 weeks or 5
half-lives, whichever is shorter.
19. Participants must have recovered from any AE (from previous anti-cancer
therapy) to Grade 1 or lower by Common Terminology Criteria for Adverse Events
(CTCAE) v5.0. Grade 2 neuropathy is acceptable. Participants receiving
replacement hormone therapy due to previous AEs will not be excluded from
participation in this study if the associated AE has recovered to Grade 1 with
replacement therapy prior to the first IMP administration.
20. Participants who have received 4-1BB agonists in the past.
21. Participants who had a major surgery within 4 weeks prior to first
administration of IMP.
22. Participants with an active autoimmune disease that is currently requiring
systemic anti inflammatory treatment such as disease-modifying anti-rheumatic
drugs, steroids, or immunosuppressants), except vitiligo, alopecia areata,
asthma/atopy and psoriasis treated and controlled by topical therapies.
Participants with auto-immune endocrinopathies that are well treated by
replacement hormones therapies (e.g. thyroxine, insulin, physiological steroids
for adrenal or pituitary deficits) are eligible.
23. Participants with a history of immune related AEs from a previous line of
treatment must have recovered Grade <= 1 and have stopped any
immunosuppressive/steroid therapy. Participants with prior history of Grade >= 3
immune-related pneumonitis, colitis, hepatitis, myocarditis.
24. Participants receiving systemic steroids at a dose of more than 10 mg per
day equivalent of prednisone. Ocular, inhaled, intranasal, topical steroids are
allowed. Local steroid injections (intra-articular and/or epidural) are
allowed as a palliative therapeutic option only.
25. Participants who have received an allogenic solid organ or bone marrow
transplant.
26. Participants with a history of interstitial lung disease, pneumonitis
requiring systemic steroids for treatment, or current pneumonitis.
27. Participants with a clinically significant cardiovascular disease or
condition, including:
a. New York Heart Association classification III or IV, known symptomatic
coronary artery disease, or symptoms of coronary artery disease on systems
review, or known cardiac arrhythmias (atrial fibrillation or supraventricular
tachycardia).
b. Any concomitant serious health condition, which, in the opinion of the
investigator, would place the participant at undue risk from the study,
including uncontrolled hypertension and/or diabetes, clinically significant
pulmonary disease (e.g., chronic obstructive pulmonary disease requiring
hospitalization within 3 months) or neurological disorder (e.g., seizure
disorder active within 3 months). Participants with an active infection with a
viral, bacterial, or fungal agent requiring systemic treatment within seven
days before first IMP administration.
28. Participants with an active infection with a viral, bacterial, or fungal
agent requiring treatment within seven days before first IMP administration.
29. Participants seropositive for and with evidence of active viral infection
with hepatitis B virus (HBV). Participants who are hepatitis B surface antigen
(HBsAg) negative and HBV viral deoxyribonucleic acid (DNA) negative are
eligible.
a. Participants who had HBV but have received an antiviral treatment and show
non-detectable viral DNA for 6 months are eligible.
b. Participants who are seropositive because of HBV vaccine are eligible.
Note: a quantitative polymerase chain reaction (PCR) test result of < 10 IU/mL
is equivalent to being undetected (negative).
30. Participants seropositive for and with active viral infection with
hepatitis C virus (HCV).
a. Participants who had HCV but have received an antiviral treatment and show
no detectable HCV viral DNA for 6 months are eligible.
Note: a quantitative PCR test result of < 10 IU/mL is equivalent to being
undetected (negative).
31. Participants with HIV who have Kaposi*s or Castleman*s disease.
32. Participants who have received a live vaccine within four weeks before the
first IMP administration. Examples of live vaccines include but are not limited
to measles, mumps, rubella, varicella zoster, yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal injected influenza
vaccines are generally killed virus vaccines and are allowed, however
intranasal influenza vaccines are live attenuated vaccines and are not allowed.
33. Participants who have received any COVID-19 vaccine within 14 days prior to
first dose of IMP or who have a dose planned during Cycle 1.
34. Participants with a history of clinically significant hypersensitivity to
monoclonal antibodies or infused therapeutic proteins or any component of the
IMP.
35. Participants with significant pulmonary compromise including a requirement
for continuous supplemental oxygen to maintain adequate oxygenation.
36. Participants with any clinically significant medical condition (e.g. organ
dysfunction) or laboratory abnormality likely to jeopardise the participant*s
safety or to interfere with the conduct of the study, in the investigator*s
opinion.
37. Any psychiatric or substance abuse condition rendering the participant
unable to understand the nature, scope, and possible consequence of the study
and or evidence of an uncooperative attitude.
38. Participants with known previous or coexisting cancer that is distinct in
primary site or histology from the cancers being evaluated in this study except
for treated cervical cancer in situ, surgically removed prostate in situ
cancer, treated basal cell carcinoma, treated superficial bladder tumors
(non-invasive papillary carcinoma (Ta) and in situ carcinoma (Tis), all treated
for more than 1-month before study entry or any localised cancer curatively
treated < 3 years prior to study entry.
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 | EUCTR202100176420-NL |
| CCMO | NL76944.042.22 |