A Phase IIB, Open Label, Study of Zirconium Zr 89 Crefmirlimab Berdoxam PET-CT in Subjects with Selected Advanced or Metastatic Malignancies including Melanoma, Merkel Cell, Renal Cell and Non-Small Cell Lung Cancers, Scheduled to Receive Standard-of-Care Immunotherapy (IOT) as a Single Agent or Combination, to Predict Response to Therapy

Immuno-oncology therapy (IOT) has altered the treatment options in subjects
with selected solid tumors and lymphoma. Despite tremendous advances, not all
subjects benefit from this type of therapy, and many develop immune-related
toxicities. The presence of CD8+ Tumor Infiltrating Lymphocytes (TILs) in the
tumor microenvironment is critical for the establishment of an IOT response.
Current methods for determining CD8+ TILs require invasive procedures which
suffer from sampling errors due to tumor heterogeneity.
Zirkonium-Zr-89-crefmirlimab-berdoxam is a promising novel radiotracer that can
provide whole body PET assessments of the CD8+ cell distribution in tumor
lesions and other tissues.
It is not known whether pre-treatment CD8+ assessment or the change from
pre-treatment to on-treatment CD8+ assessment would be more clinically
valuable. In the former case CD8+ assessment may perform better to select
patients for standard IOT and identify those patients who may not benefit. This
last group can be preferentially enrolled in clinical trials. In the latter
case it may provide mechanistic insights of the working mechanism of IOT. Also
it is studied if it performs better than standard assessments to represent
response or progression on IOT.
In this protocol, ImaginAb will evaluate the performance of
zirkonium-Zr-89-crefmirlimab-berdoxam PET-CT (pre-treatment and on treatment)
for predicting subsequent RECIST 1.1 responses in subjects with selected solid
malignancies treated with IOT (as single or combination IOT agents).

For iTOX:
With this study we want to further explore one of the exploratory objectives of
the iPREDICT study: to evaluate the predictive value of the zirconium Zr 89
crefmirlimab berdoxam PET/CT scans. The results of the additional analyzes in
the iTOX can make an important contribution to understanding and predicting
toxicity reactions after immunotherapy. Characterizing the immune cells during
immune checkpoint inhibitor induced toxicity can contribute to early
recognition of these side effects and to identify patients who are more likely
to develop toxicity. It is also a stepping stone to future intervention studies
focusing on the underlying mechanism of immuno-toxicity.

Primary objective: evaluate the performance of zirconium Zr 89 crefmirlimab
berdoxam PET-CT for predicting patient response to immunotherapy.

Secondary objectives:
- evaluate the performance of zirconium Zr 89 crefmirlimab berdoxam PET-CT for
predicting lesion response to immunotherapy.
-to assess safety of the repeat zirconium Zr 89 crefmirlimab berdoxam
infusions/injections.

Exploratory objectives:
- Evaluate zirconium Zr 89 crefmirlimab berdoxam PET-CT as a discriminator of
pseudo-progression.
- Evaluate zirconium Zr 89 crefmirlimab berdoxam PET-CT in subjects who develop
clinical and/or radiographic progression to explore mechanisms for treatment
resistance.
- Evaluate zirconium Zr 89 crefmirlimab berdoxam PET-CT as a predictor or
surrogate for immunotherapy immune related AEs.
- Correlate zirconium Zr 89 crefmirlimab berdoxam PET uptake with CD8
expression and PD-1/PD-L1 expression as determined by immunohistochemistry
- Evaluate zirconium Zr 89 crefmirlimab berdoxam PET-CT as a predictor of
Progression Free Survival (PFS) and Duration of Response (DoR).

For iTOX:
- To deepen exploratory objective 3 of iPREDICT, which is to evaluate zirconium
Zr 89 crefmirlimab berdoxam PET/CT as a predictor for immune-oncology therapy
(IOT) immune related adverse events (irAEs)
- To understand the irAE zirconium Zr 89 crefmirlimab berdoxam PET/CT results
by integration with additional immunological parameters. iTOX specific
endpoints will be correlated with occurrence of irAEs and zirconium Zr 89
crefmirlimab berdoxam PET/CT scan data.

Eligible subjects who meet Inclusion/Exclusion criteria will receive up to 3
zirconium Zr 89 crefmirlimab berdoxam PET-CT scans as an IV infusion/injection
as follows:
- first scan within 14 days prior to the onset of immunotherapy,
- second scan 4 to 6 weeks after start of immunotherapy.
The second zirkonium-Zr-89-crefmirlimab-berdoxam infusion/injection and scan
should be completed prior to the start of the third cycle of IOT. Subjects who
are determined by the treating physician to have progressive disease (PD) on
immunotherapy can receive the optional third
zirkonium-Zr-89-crefmirlimab-berdoxamPET scan at the PI*s discretion. All
PET-CT scans will be obtained at 24 ± 3 hours after each infusion/injection of
zirconium Zr 89 crefmirlimab berdoxam.

Conventional contrast enhanced CT Chest, Abdomen and Pelvis (including Neck,
Brain and Extremities, if applicable) or MRI will be performed within 30 days
prior to 1st infusion/injection of zirconium Zr 89 crefmirlimab berdoxam.

Whole Body 18FDG-PET scan within 30 days prior to 1st infusion/injection of
zirconium Zr 89 crefmirlimab berdoxam at sites where Whole Body 18FDG-PET is a
SOC scan. 18FDG-PET scans will not be a required assessment to enroll patients
onto the study or determine eligibility.

Anti-drug antibody (ADA) blood samples will be collected at the following time
points:
- baseline, prior to receiving zirconium Zr 89 crefmirlimab berdoxam
infusion/injection.
- at Visit 2, 5, and 7: the days on which the PET-CT scan are being made

End of Study Visit: 48 weeks after the start of immunotherapy or following
confirmation of progressive disease and/or treatment discontinuation, whichever
occurs first.

Follow up Standard of Care (SOC) imaging should be performed in coordination
with the subjects treatment schedule. It is anticipated that subjects who
receive IOT every 2 or 4 weeks will undergo SOC imaging every 8 weeks ± 3 days
while subjects who receive IOT every 3 weeks will undergo SOC imaging every 9
week ± 3 days. SOC images will be requested by ImaginAb for up to 48 weeks
after the start of immunotherapy or following confirmation of progressive
disease and/or treatment discontinuation, whichever occurs first.

For iTOX:
Patients will be taking part in the iPREDICT. When an immunotherapy related
event occurs, the patients will come for an additional zirconium Zr 89
crefmirlimab berdoxam PET-CT scan. Therefore 2 extra visits, iTOX1 and iTOX2
are needed, one for administration of the IP, one for the PET-CT scan. These
visits are similar to visits 1 and 2 respectively. For iTOX some extra tests
will be added to Visit 1 and Visit 4 and are also in Visit iTOX-1: a blood
sample, a stool sample and a sigmoid biopsy.

Subjects will receive up to 3 PET-CT scans with the tracer zirconium Zr 89
crefmirlimab berdoxam (up to 1.0 mCi +/- 20% at 1.5 mg API per scan, for a
total of up to 3.0 mCi +/- 20% and 4.5 mg API) as an IV infusion or injection
as follows:
- first scan within 14 days prior to the onset of standard of care
immunotherapy,
- second (scan 4 to 6 weeks after start of standard of care immunotherapy. The
second zirconium Zr 89 crefmirlimab berdoxam infusion or injection and scan
should be completed prior to the start of the third cycle of IOT.
- subjects who are determined by the treating physician to have progressive
disease (PD) on immunotherapy can receive the optional third zirconium Zr 89
crefmirlimab berdoxam PET scan.

Fresh tumor biopsies are optional. Archival tumor tissue or on treatment biopsy
material, if available, will be requested for correlation of CD8+ cells by IHC
with zirconium Zr 89 crefmirlimab berdoxam uptake. Samples collected during the
study will be correlated to the CD8 PET-CT scan results.
A maximum of 2 or 3 biopsies will be done, for which separate consent will be
requested.

Extra for iTOX:
In case of irAEs grade >=2 subjects will have an extra PET-CT scan with
zirconium Zr 89 crefmirlimab berdoxam. iTOX patients will have a sigmoid biopsy
at visit 1, and visit 4. The sigmoid biopsy at the moment of the irAE is done
per Standard of Care. Furthermore a blood test and a stool sample will be taken
at these visits.

Patients will visit the hospital up to 8 times for this study. Each visit will
take 1-2 hours.
First there is a screening visit with the following assessments: an Informed
Consent procedure, medical history, demography, physical examination including
ECOG, vital signs, blood tests (safety and Anti Drug Antibody sampling) and
review of concomitant medications. CT/MRI is expected to be done as standard of
care. If FDG-PET scan is available the results will be used, but the test is
not needed for inclusion.

After inclusion patient will come for visit 1, with vital signs, ECG, Safety
labs, urine pregnancy test, adverse event assessment and concomitant
medication. During this visit the IP zirconium Zr 89 crefmirlimab berdoxam will
be infused.

The next day patients will come for visit 2, with safety labs, blood sample for
Anti Drug Antibody analyses, an optional tumor biopsy and the zirconium Zr 89
crefmirlimab berdoxam scan.

After this their standard of care immunotherapy will start at visit 3. Details
of the administration of immunotherapy will be recorded


After 2 cycles of immunotherapy they will have visits 5 and 6, which are
similar to visits 1 and 2.

The results of the immunotherapy will be followed with standard of care CT
imaging. After disease progression there are again 2 visits visit 6 and 7, with
the same assessments. These are visits optional.

48 weeks after the start of the immunotherapy, or following confirmation of
progressive disease and/or treatment discontinuation, whichever occurs first,
an End of Study visit will take place. During this visit physical examination
including ECOG, vital signs, safety labs, urine pregnancy test. adverse event
review and concomitant medication review will be done.

The patients themselves will not have benefits from the study.

For iTOX:
On top of the above the patients will visit the hospital 2 extra times when the
experience their first irAE.
On visit 1, visit 4 and one of these iTOX visits a blood sample, a stool sample
and a sigmoid sample will be taken.
Per standard of care patients will visit the hospital when experiencing an irAE
as well, and they would have a sigmoid sample being taken as well on that
occasion.