A First-In-Human study of 89ZR-DFO-REGN5054 (anti-CD8) Positron Emission Tomography in patients with solid malignancies treated with cemiplimab

89Zr-DFO-REGN5054 is an investigational tracking substance (tracer), which
means it has not yet been approved by a health authority for imaging of tumors.
89Zr-DFO-REGN5054 is being studied as an agent for imaging tumors and will be
administered by infusion (through the vein).
89Zr-DFO-REGN5054 is an antibody labeled with tiny amounts of a radioactive
atom called Zirconium-89 (89Zr). 89Zr can be detected from outside the body
with positron emitting tomography scans (PET scans), with machines similar to
CT scanners. 89Zr-DFO-REGN5054 binds to a substance in the body called CD8,
located on immune cells called T-cells. 89Zr-DFO-REGN5054 may image CD8, which
is present on T-cells in tumors, and could in this way possibly provide useful
information on which tumors are more likely to respond to certain new
anti-cancer therapies, where the body's immune cells are activated to kill
tumor cells.
Cemiplimab is a PD-1 antibody immune checkpoint inhibitor, which is approved in
Europe by the EMA (European Medicines Agency) for the treatment of a type of
skin cancer called metastatic (widespread) cutaneous squamous cell carcinoma
(CSCC) or locally advanced CSCC for patients who cannot be treated with
intended curative surgery or curative radiation. Cemiplimab has not been
approved for the treatment of any other types of cancer. Therefore, if you have
a type of cancer other than CSCC, the treatment with cemiplimab is still
considered to be investigational.

The primary objective:
To determine the safety and tolerability of 89Zr*DFO*REGN5054 alone and in
combination with cemiplimab.

Secondary Objectives
For Part A:
• To characterize the radioactivity pharmacokinetic (PK) profile of 89Zr DFO
REGN5054
• To establish an adequate mass dose and activity dose of 89Zr-DFO-REGN5054 and
optimal post-infusion time for imaging
For Parts A and B:
• To evaluate the association of CD8 expression in tissue biopsies (via IHC)
with tumor 89Zr*DFO*REGN5054 uptake in vivo (via PET) and ex vivo (via
autoradiography)
• To evaluate the uptake of 89Zr*DFO*REGN5054 in tumors, normal CD8 expressing
tissues, and blood

The exploratory objectives of the study are:
• To evaluate the association of 89Zr-DFO-REGN5054 signal at baseline and on
treatment with tumor response after cemiplimab treatment
• To evaluate the association between 18F-fluorodeoxyglucose (18F-FDG) and 89Zr
DFO REGN5054 uptake in tumor lesions
• To characterize association of 89Zr-DFO-REGN5054 signal at baseline and on
treatment with the mRNA and protein biomarkers of tumor
infiltrating lymphocyte density and effector function
• To assess anti-tumor activity of cemiplimab

This is a phase 1, first-in human (FIH) trial evaluating 89Zr-DFO-REGN5054 as
an imaging agent to evaluate intra-tumoral expression of CD8 on T-cells at
baseline and in the context of cemiplimab therapy.
The study comprises 2 parts, Part A and Part B. Part A is a dose-finding and
safety study in which subjects receive a single 89Zr-DFO-REGN5054 dose,
followed by serial PET/computed tomography (CT) scans over a 7-day period.
Part A will evaluate dosimetry and establish an adequate mass dose of 89Zr
DFO-REGN5054 and an optimal post-infusion imaging time. In Part B, subjects
will receive 2 doses of 89Zr-DFO-REGN5054. CD8 immuno-positron emission
tomography (iPET) signal will be measured after 89Zr DFO REGN5054 infusion at
the defined mass dose and at a post-infusion imaging time point (both
determined in Part A) at baseline and post-cemiplimab administration, for
comparison with CD8 IHC and tumor response. Subjects who enroll in study Part
A will not be eligible to participate in study Part B.
Subjects in both Part A and Part B will receive cemiplimab therapy after the
first 89Zr-DFO-REGN5054 PET/CT scan until confirmed progression or for up to
102 weeks (~2 years) followed by a 90-day follow-up period.
Tumor burden will be assessed according to Response Evaluation Criteria in
Solid Tumors version 1.1 (RECIST 1.1) and immune-based Response Evaluation
Criteria in Solid Tumors (iRECIST) at the end of each treatment cycle, through
cycle 4 and every other cycle thereafter.
Part A
For Part A, 7 ascending 89Zr-DFO-REGN5054 mass dose cohorts are planned (2 mg,
5 mg, 10 mg, 20 mg, 40 mg, 60mg, and 80 mg), with up to 6 subjects per cohort.
Subjects will receive 89Zr-DFO-REGN5054 on day 1, followed by 3 PET/CT scans
over the course of 1 week (days 1, 5, and 8). The first 2 subjects in each
mass dose cohort will be monitored in the medical facility for at least 24
hours after 89Zr DFO REGN5054 infusion. A minimum of 1 week will be required
between completion of the first 89Zr-DFO-REGN5054 administration for the
initial 2 subjects at each dose level to allow for evaluation of acute
toxicity. Evaluation of 89Zr-DFO-REGN5054 safety will continue for at least 7
days following infusion of the imaging agent until the day 8 PET/CT scan, prior
to cemiplimab therapy. Cemiplimab treatment will then be initiated, at a fixed
dose of 350 mg Q3W, any time up to 7 days after the last 89Zr-DFO-REGN5054
PET/CT scan and/or the optional biopsy.
Dose Escalation Strategy
For each mass dose cohort in Part A, an initial 2 subjects will be dosed with
89Zr-DFO-REGN5054, with a minimum 1-week interval between the dosing of each
subject.
Upon completion of the day 8 PET scan for the second subject at a given mass
dose, a Dose Escalation Review meeting will take place. Upon review of all
available imaging, 89Zr-DFO-REGN5054 serum activity concentration, clinical
dosimetry, and safety data on these subjects, a decision will be made to
undertake 1 of the following:
• Expand the cohort to up to 6 subjects , based on adequate safety and adequate
blood pool serum 89Zr-DFO-REGN5054 activity and
uptake in CD8-expressing normal tissues (spleen).
• Ascend to the next mass dose cohort, based on adequate safety but inadequate
serum 89Zr-DFO-REGN5054 activity concentration and
uptake in CD8-expressing normal tissues (spleen) and/or tumor uptake.
• Proceed with the next mass dose cohort at a lower mass dose, based on
inadequate uptake in CD8-expressing normal tissues (spleen,
marrow) and/or tumor uptake, but adequate serum 89ZrDFOREGN5054
activity concentration. This lower mass dose will allow for
evaluation of potential competition from unlabeled antibody,
resulting in dampening of the iPET signal at higher mass doses.
Upon completion of dosing of each cohort (up to 6 subjects ), a Dose Escalation
Review meeting will take place to review all available safety and imaging data
to decide on one of the following:
• Ascend to the next mass dose cohort,
• Close Part A and proceed with Part B, based on any given cohort of up to 6
subjects with adequate serum 89Zr-DFO-REGN5054 activity
concentration, uptake in CD8 expressing normal tissues, and/or tumor
uptake at the optimal time point post infusion.
In the event of occurrence of 1 or more adverse events of special interest
(AESIs) or serious adverse events (SAEs) assessed as related to
89Zr*DFO*REGN5054 by the investigator, the study will be suspended for safety
review in a Dose Escalation Review meeting, followed by a decision to undertake
1 of the following:
• Resume the study as planned if it is determined by the sponsor and confirmed
by this committee that the index AESIs/SAEs are unlikely
related to 89Zr*DFO*REGN5054.
• Expand the current cohort up to 6 subjects for further safety evaluation.
• Terminate the study.
In addition, an occurrence of 1 or more AESIs/SAEs, assessed as related to
89Zr*DFO*REGN5054 by the investigator, will trigger a review of the safety data
by the Regeneron Safety Oversight Committee (RSOC)
Part B
Part B subjects will be imaged twice using the safe and well tolerated 89Zr
DFO-REGN5054 dose and optimal post-infusion imaging time determined in Part A.
Subjects will receive 89Zr-DFO-REGN5054 infusion on day 1, followed by a PET/CT
scan at the optimal post-infusion imaging time. A mandatory tumor biopsy will
be performed following the PET/CT scan prior to initiation of cemiplimab
therapy. Any time up to 7 days after the first PET/CT scan, cemiplimab will be
administered at a fixed dose of 350 mg Q3W. Approximately 4 weeks (up to 8
weeks) after the initial dose of cemiplimab, a second dose of 89Zr DFO REGN5054
will be administered, and a subsequent PET/CT scan will be performed. In
addition, a biopsy of the tumor (optional) may be performed following this
PET/CT scan.

For Part A, 89Zr*DFO*REGN5054 will be administered intravenously (IV) at a
single mass dose of 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 60 mg and 80 mg. For Part
B subjects will be administered 89Zr-DFO-REGN5054 at the defined mass dose
determined in Part A.
Cemiplimab will be administered IV at dose of 350 mg every 3 weeks (Q3W)

Taking into account the measures implemented in the protocol to minimize
important risks to subjects, the potential for therapeutic benefit, evaluation
of cemiplimab in subjects with advanced or metastatic solid CD8 tumors is
justified.

89Zr-DFO-REGN5054 is a positron-emitting radioimmunoconjugate, specific for
human CD8 that is being developed for immuno-PET imaging. 89Zr-DFO-REGN5054 has
not yet been administered to humans. Therefore, there are no identified risks
with clinical use. The potential risks to study participants are considered
minimal and there is adequate risk minimization described in the protocol. The
findings from nonclinical studies demonstrate an adequate safety margin for the
planned mass dose range of 89Zr-DFO-REGN5054 in humans. The radiation exposure
is expected to be similar to that of other immuno-PET tracers. Taken together,
these data justify the evaluation of 89Zr-DFO-REGN5054 as an immuno-PET agent
in humans.

Based on the currently available safety information for cemiplimab, and other
anti-PD-1/PD-L1 antibodies, the identified risks and minimization measures, and
the emerging preliminary activity of cemiplimab in solid malignancies
(including CSCC, NSCLC and cervical), the benefit-risk is considered favorable
for continued clinical studies in these and other indications.