A phase 1-2 immunoPET imaging study with ZED88082A in patients before and during treatment with 1) MPDL3280A or 2) PD-1 antibody plus or minus ipilimumab

The rapidly evolving fields of tumor immunology and cancer immunotherapy have
recently resulted in several FDA and EMA approved immune checkpoint inhibitors
for several tumor types. However, not all patients respond to these drugs, so
it may be advantageous to combine current immune checkpoint inhibitors with
other drugs. Moreover, immunotherapeutic drugs can elicit severe 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 therefore raised significant interest in objectifying
the status of the microenvironment, but 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.
Currently, CD8+ cytotoxic T-cells are considered to play a critical effector
role in anti-tumor immunity. Analysis of tumor-infiltrating lymphocytes (TIL)
has demonstrated the importance of tumor immune microenvironment and indicated
that the presence of cytotoxic CD8+ T cells can predict overall survival in
several tumor types. Noninvasive serial whole body monitoring of the tumor
immune response to therapy by means of imaging CD8+ cytotoxic T-cells might
thus provide major insights. RED88822 is an 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 immune checkpoint inhibitors, the radioactivity uptake in primary and
metastatic tumor 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
during ICI treatment will provide information about systemic and intratumoral
alterations in response to immunotherapy.

Primary objectives: To evaluate safety of ZED88082A in combination with
CED88004S. To determine appropriate ZED88082A/CED88004S dosing and PET imaging
time-points. To evaluate pharmacokinetics (PK) of ZED88082A/CED88004S in
patients before and during ICI treatment. To evaluate immunogenicity/anti-drug
antibodies (ADA) of ZED88082A/CED88004S in patients before and during ICI
treatment.

Secondary objectives: i) To assess heterogeneity of ZED88082A/CED88004S tumor
uptake. ii) To correlate normal organ ZED88082A/CED88004S uptake to (serious)
adverse events (possibly) related to ICI treatment. iii) To correlate tumor
ZED88082A/CED88004S uptake with tumor and immune cell CD8-expression as
assessed by a fresh contemporaneous tumor biopsy. iv) To correlate
ZED88082A/CED88004S normal tissue kinetics with ZED88082A/CED88004S blood
kinetics. v) To assess dosimetry.

This is a phase-1 first in human, open-label, single-center, single-arm trial
designed to evaluate the PK of ZED88082A/CED88004S-PET in patients prior to and
during treatment with checkpoint inhibitors. The study is divided in two parts:

Part A contains initial safety assessment, dose finding and PET-scan scedule
finding of ZED88082A/CED88004S-PET.
Part B contains evaluation of pharmacokinetics of the tracer
ZED88082A/CED88004S in patients before and during checkpoint inhibitor
therapie.

In part A of this imaging trial, a dose finding study will be performed to
establish safety, to assess the appropriate protein dose for PET-scanning
(consisting of a fixed dose of ZED88082A and if required with limited amount of
*cold* CED88004S for proper imaging performance), and to assess the appropriate
PET scanning interval. Approximately 4 cohorts of about 2-3 patients each will
undergo ZED88082A/CED88004S-PET imaging at 4 time points (day of
ZED88082A/CED88004S injection, day 2, day 4 and day 7 after injection).
Afterwards, eligible (non melanoma) patients will be allowed to enter the
MPDL3280A treatment trial (MPDL3280A-treatment-IST-UMCG) provided they continue
to meet the eligibility criteria to receive this drug. Patients with melanoma
may receive standard treatment with PD-1 antibody plus or minus ipilimumab.
The purpose of part B of the study is to analyze the PK of ZED88082A/CED88004S
before and during treatment with ICIs in patients, with appropriate
ZED88082A/CED88004S protein dosing and at appropriate PET scanning time point
as determined in part A.

In part B, approximately 30 patients will be enrolled to undergo
ZED88082A/CED88004S-PET imaging twice; one at baseline before ICI treatment,
and one during treatment with ICIs at early cycle 2, to minimize morphological
changes in tumors responding to the therapy (with flexibility to adjust the
timing of on-treatment scans based on an ongoing review of the data). Patients
from part B1 will be treated with MPDL3280A in the MPDL3280A treatment trial
(MPDL3280A-treatment-IST-UMCG). In part B2, approximately 10 melanoma patients
eligible for standard of care PD-1 antibody therapy plus or minus ipilimumab
will be enrolled. All patients participating in the imaging trial part A and B
will undergo at least one tumor biopsy. The biopsy procedure will be performed
at baseline after the last ZED88082A/CED88004S-PET scan, but before start of
ICI treatment. In addition, in part B, on-treatment tumor biopsies will be
performed if possible at the end of the second ZED88082A/CED88004S-PET scan
period.

For this imaging study, patients have to make a maximum of 10 extra visits to
the clinic for screening, to receive ZED88082A/CED88004S injection, to have up
to 4 PET-scan visits, and the biopsies taken before and/or after starting
treatment with ICI. 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 in part A undergoing 4
PET-scans, will receive an exposure of about 24 mSv. Patients in part B will
receive two 37 MBq doses of ZED88082A/CED88004S and undergo up to 4 PET-scans.
The radiation exposure will be approximately 42 mSv. Besides PET imaging,
patients will be asked to provide in total 15 blood samples in part A (110 mL)
and 11 samples in part B (98 mL). A tumor 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. 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. However, the
first three patients in part A will be hospitalized the first night after
ZED88082A/CED88004S injection in order to minimize the risk that significant
side effects will occur outside of the hospital (e.g. in case of cytokine
production). If the second cohort in part A concerns an escalated dose of
ZED88082A/CED88004S, likewise the first three patients in this cohort will also
be hospitalized for observation. 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 be allowed to enter the MPDL3280A treatment trial
(MPDL3280A-treatment-IST-UMCG), provided they continue to meet the eligibility
criteria to receive MPDL3280A.