A Phase 1 Open-Label, Dose Escalation and Expansion Trial to Investigate the Safety, pharmacokinetics and Pharmacodynamics of CB307, a Trispecific Humabody® T-cell Enhancer, in Patients with PSMA+ Advanced and/or Metastatic Solid Tumours (POTENTIA)

This is a FIH dose escalation and expansion study to assess safety,
tolerability, PK, pharmacodynamics and immunogenicity, to determine MTD and
RP2D and to assess preliminary anti-tumour activity of CB307 in patients with
advanced and/or metastatic PSMA+ solid tumours following weekly IV
administration.
CB307 is a trispecific Humabody® that binds to CD137, PSMA and HSA. CB307 will
bind to PSMA on tumour cells and CD137 on immune cells to enhance the
anti-tumour immune response.
CD137 (4-1BB) is a co-stimulatory receptor that is induced on T cells and NK
cells. It is expressed on T cells that have undergone antigen recognition, and
subsequent ligation of CD137 induces T-cell effector functions. CD137
signalling is initiated by clustering brought about by trimeric CD137 ligand;
this can also occur with anti-CD137 antibody engagement. The consequence for T
cells is enhanced proliferation, proinflammatory cytokine secretion, increased
tumour cytotoxicity and prolonged T cell survival. PSMA is highly upregulated
on tumour cells and tumour neovasculature in prostate cancer and other solid
tumours, including lung (NSCLC), kidney (clear cell RCC), bladder and
colorectal cancers (Salas Fragomeni et al. 2018). Therefore, by simultaneously
binding to PSMA and CD137, CB307 not only enables the bridging of the tumour
cell and T cell for immune recognition, but also directs T cell co-stimulation
to the tumour microenvironment by a *conditional* mechanism that is dependent
upon the co localisation of both targets. Thus, CB307 has no agonistic activity
in the absence of PSMA. Furthermore, CB307 lacks an antibody fragment
crystallisable (Fc) domain so it does not drive CD137 clustering via
non-specific interactions with FcγR on immune cells. The dependency on PSMA and
lack of FcγR binding are thought to reduce the risk of potential off target
immune pathology including potential hepatotoxicity seen with urelumab (Segal
et al. 2017).
Human serum albumin is an abundant serum protein with long circulatory
half-life. CB307 engages HSA to enable extension of its half-life and to
promote drug distribution into tissue and tumours.
As seen with bispecific antibodies in haematological malignancies (Bargou et
al. 2008), engaging T cells in solid tumours is expected to result in T cell
expansion at tumour sites and lead to a durable response. It is worth noting
that there is no cytokine release syndrome (CRS) reported for CD137 agonistic
antibodies including urelumab and utomilumab (Segal et al. 2017, Segal et al.
2018). Urelumab was effective as monotherapy at a higher dose but due to the
dose-dependent hepatotoxicity observed (Segal et al. 2017), urelumab has been
further evaluated at a lower dose. The observed hepatotoxicity is likely due to
CD137 cross-linking via FcγRIIb-expressing liver-resident cells such as hepatic
myeloid and sinusoidal endothelial cells. It is not expected that CB307 will
have this effect due to the lack of an Fcγ region. In addition, unlike CD3
targeting bispecific molecules, there was no CRS or neurotoxicity reported for
CD137 a targeting bispecific molecule (Piha-Paul et al. 2019). CB307 engages
only antigen experienced T cells and thus is expected to reduce the cytokine
release syndrome often observed in T-cell-redirecting treatment.
PSMA is known to express in normal prostate as well as duodenal mucosa and a
subset of proximal renal tubules (Silver et al. 1997). However, CD137 positive,
antigen experienced T cells are rarely observed in the normal tissues (Wang et
al. 2008). Indeed, there is no neurotoxicity or critical on target, off tumour
toxicities reported in PSMA targeting CD3 bispecific molecules tested in clinic
(Bendell et al. 2020; Hummel et al. 2019). While seizure (n = 1) and syncope (n
= 1) were observed with HPN424, the details of these events and their cause
have not been disclosed (Piha-Paul et al. 2019). Overall, CB307 may have a
better safety profile than CD3 targeting T-cell bispecific antibodies, opening
the potential for a range of combination therapies and delivering durable anti
tumour responses for PSMA+ solid tumours.
PSMA is frequently expressed in prostate cancer and corelates with poor
prognosis. High Gleason score and castration resistance is positively
correlated with membrane PSMA expression. Interestingly, CRPC with high DNA
damage repair mutation including BRCA1/2 or ATM also associates with PSMA
expression (Paschalis et al. 2019). Recent data suggests that BRCA1/2 mutation
or CDK12 loss in CRPC is known to have more T cell infiltration in tumour among
immune-cold prostate cancer (Jenzer et al. 2019, Hegde et al. 2020, Yi-Mi et
al. 2018).

Primary Objective:
To assess the safety and tolerability and determine the MTD and the RP2D of
CB307 in patients with PSMA+ tumours
Secondary Objectives:
• To characterise the serum PK of CB307
• To characterise the immunogenic potential of CB307 and assess the
relationship with safety endpoints
• To evaluate the preliminary CB307 dose/anti-tumour activity relationship
• To evaluate clinical efficacy in mCRPC patients with known or likely
deleterious genetic alterations in any of: breast cancer susceptibility
genes (BRCA1/ BRCA2), ataxia telangiectasia mutated (ATM) genes,
cyclin-dependent kinase 12 (CDK12) genes or patients with tumours that
are defective in DNA mismatch repair for example that display a microsatellite
instability-high (MSI-high) phenotype.
Exploratory Objectives:
• To assess tumour response by CT or MRI based on RECIST 1.1 for PSMA-PET
positive lesion(s) at baseline.
• To assess and characterise the treatment-induced pharmaco-dynamic effects of
CB307 (change from baseline and on study treatment) on the following:
o Peripheral blood lymphocytes
o Soluble serum markers
• To assess and characterise the treatment-induced pharmaco-dynamic effects of
CB307 (change from baseline and on study treatment) in the tumour
microenvironment (if tissue is available)
• To identify the biologically active dose of CB307, defined as the dose at
which maximal pharmacodynamic changes in blood and the tumour are induced
• To evaluate the response of tumours with BRCA1/2 and/or CDK12, and/or ATM
alterations to treatment in metastatic prostate cancer patients compared to
patients with tumours that do not have any of these alterations.
• To assess PSMA-PET signal change after CB307 treatment.

This is a FIH, Phase 1, open-label, multi centre, non randomised study of
CB307, a trispecific Humabody® T-cell enhancer, in patients with advanced
and/or metastatic PSMA+ solid tumours.
The study will consist of a dose escalation phase (Part 1) and a cohort
expansion phase (Part 2). Up to 50 patients will participate (approximately
20-30 patients in Part 1 and the remainder in Part 2). The study population
will be the same in both parts, and dosing will continue until loss of clinical
benefit, intolerable toxicity is observed, withdrawal of consent or the study
is stopped, whichever comes first.
Patients will receive CB307 IV infused over 60 minutes starting on Cycle 1 Day
1 every 7 days, until loss of clinical benefit, unacceptable toxicity or end of
study. The duration of the infusion may be adapted by the SRC pending clinical
experience and safety review.
Part 1 Dose escalation phase:
Part 1 will evaluate escalating doses of CB307 starting at 1.0 mg. The
following doses will be tested:1.0, 3.0, 10, 25, 50, 100 and 200 mg.
Initially, in the accelerated titration phase of the study (single patient
cohorts), CB307 doses will be escalated from the starting dose of 1.0 mg up to
and including the 10 mg dose level or until a treatment-related grade 2 or
higher toxicity is observed during the 21-day DLT assessment period, whichever
occurs first. If a DLT or any treatment-related grade >=2 toxicity is observed,
the sponsor will immediately employ 3 patients per cohort to further assess the
observed safety data. Once a DLT is observed, mCRM will be applied to estimate
the next dose level.
Dose escalation decisions will be guided by a BLRM and EWOC algorithm. For the
remainder of Part 1 (starting with a dose of 25 mg), cohorts of 3 patients per
dose level will be enrolled, unless a DLT is observed in which case the mCRM
will be applied. If no DLT is observed in the single patient accelerated
titration phase at 10 mg, the next cohort will enrol 3 patients at 25 mg.
The first patient in each cohort will not be enrolled until all patients at the
immediately lower cohort have completed the DLT-monitoring period and the SRC
has reviewed the safety data to decide whether to proceed to the next dose
level.
The duration of a treatment cycle is defined as 21 days (3 doses administered
plus 7 days), in line with a DLT-monitoring period of 3 doses of CB307 plus 7
days (21 days). In Part 1, the MTD and RP2D will be determined in approximately
20-30 patients.
Intra-patient dose escalation may be possible to the declared safe dose level
(i.e., 1 dose level below the dose level currently under DLT assessment) at the
discretion of the investigator and in agreement with the sponsor and/or medical
monitor. If the declared safe dose level is increased subsequently, an
intra-patient dose increase may be allowed to the new declared safe dose level.

Guide of Dose Escalation Steps:
Dose Level Dose (mg) Next Dose (mg), (Increment Between Dose Levels [%]
if no DLT)
1 1.0 3.0 (200)
2 3.0 10 (233)
3 10 25 (150)
4 25 50 (100)
5 50 100 (100)
6 100 200 (100)
7 200
Note: Subsequent dose escalation steps will be guided by the emerging safety
data

After all patients in a cohort of Part 1 have completed the DLT monitoring
period, an SRC will review the safety data generated to date to decide whether
to proceed to the next dose level. The SRC will also be able to de-escalate to
an intermediate dose level in between the current and previous dose levels,
should this be deemed necessary to investigate at a dose not specified in the
table above. An SRC can also recommend enrolling more patients in the
declared safe dose levels as well as suggest alternative dosing schedule (e.g.,
Q2W) to explore further efficacy without impacting on dose escalation
decision. Each dose escalation/de-escalation will be agreed by the SRC and
recommended to the investigators.
Once the CB307 dose escalation is confirmed as having reached the MTD and/or
RP2D, enrolment will close within Part 1 and enrolment into the Part 2
expansion cohort will commence at one of these doses/schedules (as agreed by
the SRC).
The sponsor may recommend an RP2D less than or equal to the MTD. The RP2D is
further defined as a dose (less than or equal to the MTD) with confirmed
biological or clinical activity and acceptable tolerability.
Part 1 enrolment will end after the last patient*s DLT-monitoring period is
completed, at which time Part 2 may commence. At screening, patients will
provide an historical IHC tumour sample and/or a fresh biopsy sample, if
available. These samples will also be utilised for various exploratory
endpoints.
Any somatic mutations in CRPC tumours of sponsor*s interest (including
BRCA1/2 and/or CDK12, and/or ATM) will also be assessed at screening, if the
tumour is available for testing. Where genetic results are already known from
either germline, ctDNA or tumour analysis, a copy of the genetics report is
requested to be shared with the sponsor, if the patient consents. If somatic
mutation testing (mutations, deletion or frame shift) for BRCA1/BRCA2/ATM/CDK12
has already been performed, then the sponsor has the discretion to accept
these results without additional testing. Otherwise, if tissue is available,
this will be tested by the sponsor.

Part 2 Dose expansion phase:
Part 2 will be initiated after the MTD/RP2D decision and is a cohort expansion
phase to explore efficacy signals in PSMA+ solid tumours. Part 2 will
evaluate safety and preliminary efficacy at the MTD or RP2D determined
in Part 1. Up to 20 patients will be enrolled in Part 2 (up to a maximum of
50 patients across the entire study in Parts 1 and 2). Patients will receive
CB307 at the SRC-approved dose (MTD or RP2D). Patients in Part 1 can continue
on their current dosing schedule after Part 2 commences or adjust to the
determined dosing and schedule for Part 2, if deemed appropriateby the
investigator and approved by the sponsor.
Although Part 2 is aimed at exploring the preliminary clinical efficacy as
well as assessing safety in various PSMA+ solid tumours, the sponsor
anticipates that a minimum of 3 patients who have prostate cancer with either
BRCA1/2 and/or CDK12 and/or ATM mutations will be enrolled.
After the end of treatment with CB307, survival follow-up information will be
collected via telephone calls, patient medical records and/or clinic visits
every 12 weeks until withdrawal of consent or the study is stopped, whichever
comes first.

Infusion of CD307

There is no clinical data available for CB307 to date. Preclinical studies
suggest that activation CD137-positive T cells is observed with CB307 in the
presence of PSMA-expressing tumours. Hepatotoxicity observed in urelumab may be
mitigated, as CB307 does not contain an Fc region and does not induce
nonspecific macrophage activation. In addition, the starting dose of the first
in human study is selected carefully based on the toxicology and pharmacology
studies. Based on the preliminary result of PRS343, a CD137 targeting
bispecific agent and the results of AMG212 and HPN424, both PSMA-and CD3
targeting bispecific molecules, CB307 may demonstrate efficacy in a clinical
trial with an acceptable safety profile and it is considered that the potential
benefits outweigh the potential risks.