A two-part phase I study with the antibody-drug conjugate SYD985 in combination with niraparib to evaluate safety, pharmacokinetics and efficacy in patients with HER2-expressing locally advanced or metastatic solid tumours.

Therapeutic background and study rationale Antibody-drug conjugates (ADCs) have
been recognized as a promising new class of therapeutic biological agents for
the treatment of cancer.

1. Byondis developed a new HER2-targeting therapy, SYD985, which is comprised
of Byondis' monoclonal IgG1 antibody trastuzumab (similar to Herceptin®)
covalently bound to a linker-drug. The linker-drug contains a cleavable linker
and the prodrug seco-DUocarmycin-hydroxyBenzamide-Azaindole (seco-DUBA). After
binding to HER2 on the cell membrane, SYD985 undergoes receptor mediated
internalization and the linker is cleaved in the lysosome at the dipeptide
valine-citruline (vc) motif by proteases. Upon cleavage, two selfelimination
reactions occur to generate the prodrug (seco-DUBA), which then spontaneously
rearranges to form the active toxin (DUBA, SYD986). The active toxin alkylates
DNA resulting in DNA damage in both dividing and non-dividing cells, and
ultimately cell death. SYD985 most likely also induces a bystander effect
through extra-cellular cleavage of the linker-drug within the tumour by
extracellular proteases. This bystander effect may not only kill the
HER2-positive cell but potentially also (HER2-negative) neighbouring cells.
SYD985 has been successfully evaluated in a phase I trial comprising multiple
HER2-expressing tumour types and is currently in phase III development as
monotherapy for third line HER2 positive metastatic breast cancer in the
SYD985.002/TULIP trial [ClinicalTrials.gov: NCT03262935].

2. Poly Adenosine diphosphate Ribose Polymerase (PARP) is a family of protein
enzymes involved in a number of cellular processes such as DNA repair, genomic
stability, and programmed cell death. Multiple PARP inhibitors have now been
successfully evaluated in several tumour types, including breast and ovarian
cancer.

3 Research is ongoing to expand indications to include other tumour types and
to further identify subgroups potentially sensitive to PARP inhibition due to
inherent or acquired alterations of DNA repair pathways, particularly resulting
from aberrations in DNA damage response (DDR) pathways such as BRCA gene
mutations and/or homologous recombination deficiency (HRD). Combining the
DNA-alkylating cytotoxic mechanism of SYD985 with drugs that impair DNA repair
mechanisms theoretically increases the sensitivity of such tumours for the
locally released cytotoxic payload of the ADC, resulting in synergistic effects
on tumour cell killing.

4. This synergistic mechanism of action has been shown in preclinical
experiments in which SYD985 has been combined with the PARP inhibitor niraparib
(See Investigator*s Brochure). Subsequent in vivo experiments were performed in
patient-derived xenograph models, with an example shown in Figure 1. Here, a
triple negative breast cancer model was treated with niraparib, SYD985 or the
combination. Resulting tumour volume changes indicate that the effect of the
combined treatment (in green) was larger than observed in the animals exposed
to either monotherapy (in red and blue) indicating an additive and/or
synergistic in vivo effect of the combination (Figure 1).
Although combinations of systemic cytotoxic therapy and PARP inhibition have
shown very good chemo-potentiation in preclinical models the combination of
these mechanism has been associated with increased myelotoxicity in clinical
trials.

5 Combining PARP inhibition with the SYD985 ADC may potentially reduce the risk
of such toxicity as the bone marrow will be less affected as SYD985 delivers
the cytotoxic load predominantly to the tumour. Moreover, a lower dose of both
the SYD985 ADC and niraparib may suffice to induce or maintain sufficient
tumour response with a similar or improved toxicity profile. This may be of
particular relevance to patients with HER2-low expressing cancers where it
would be possible to increase the response rate and/or to extend the duration
of tumour control resulting in increased progression free survival and overall
survival by introducing HER2-targeting treatment, which is currently not
indicated for these patients, in combination with PARP inhibition.

This protocol describes the phase I study with SYD985 in combination with
niraparib to determine the maximum tolerated dose (MTD) of the combination,
select the recommended combination dose regimen for expansion (RDE), and to
characterize the toxicity profile, pharmacokinetics, and preliminary anticancer
activity.

Objectives: The primary objectives of this study are:

• Part 1 (dose-escalation): To evaluate the safety of SYD985 in combination
with niraparib to determine the maximum tolerated dose (MTD) and recommended
combination dose regimen for expansion (RDE);

• Part 2 (expansion): To evaluate the objective tumour response rate (ORR) of
the combined SYD985/niraparib dose regimen. The secondary objectives of this
study are to evaluate the SYD985/niraparib combination at the RDE with respect
to: • Safety (including immunogenicity); • Pharmacokinetic parameters; •
Preliminary efficacy.

In Part 1, patients with locally advanced or metastatic HER2-expressing solid
tumours of any origin can be enrolled, whereas in Part 2 only patients with
advanced or metastatic breast, ovarian or endometrial cancer are eligible.

• Part 1: Dose-escalation Eligible patients will receive infusions of SYD985
every three weeks at a dose of 0.9 or 1.2 mg/kg in combination with niraparib
and will be monitored for safety and the occurrence of dose-limiting toxicities
(DLTs). Niraparib dosing will be explored per cohort by changing the daily dose
or the number of dosing days (see planned dose escalation schedule). At least 3
patients will be enrolled at each combination dose level. There will be no
further dose escalation once 2 or more patients out of 3 to 6 patients at a
certain dose level experience a DLT during the first treatment cycle (one cycle
is 21 days). The MTD is defined as the highest dose level at which doselimiting
toxicities (DLTs) occurred in not more than 1 out of 6 patients. The RDE will
be determined based on all available safety and pharmacokinetic data, and this
dose regimen will be administered in Part 2 of the study. If considered needed,
each dose level can be extended with additional patients. Based on Part 1
efficacy and safety data, it may be decided to further explore several suitable
dose regimens in expanded patient cohorts (Part 2) to determine the optimal
benefit/risk of these combinations.

• Part 2: Expanded cohorts. This part of the study will consist of 3 cohorts
comprising patients with either breast, ovarian or endometrial cancer as per
inclusion and exclusion criteria. Up to 16 patients will be enrolled in each
cohort. If there are two or more responders in the 16 patients, a maximum of 14
additional patients may be enrolled for a total of 30 patients per cohort.

Investigational medicinal product, mode of administration: SYD985 (Byondis BV,
The Netherlands): [vic-]trastuzumab duocarmazine Drug product vials contain 80
mg sterile lyophilized SYD985 which should be reconstituted prior to use with
8.0 mL sterile water for injection to yield a solution of 10 mg/mL. SYD985 drug
product vials should be stored at 2 to 8 °C until use. All patients will be
treated with SYD985 at a dose of 0.9 or 1.2 mg/kg every three weeks (Q3W). The
calculated amount of reconstituted solution should be added to an infusion bag
containing 100 mL 0.9% sodium chloride without other additives. SYD985 is to be
administered intravenously over 60 minutes for the first infusion and, if well
tolerated, subsequent infusions can be given over 30 minutes.

Niraparib (Zejula®, TESARO Bio Netherlands BV, The Netherlands): niraparib
tosylate monohydrate Hard capsule (white/purple) containing 100 mg niraparib
for oral administration as per protocol specific dosing instructions. Capsules
should be swallowed whole with water and should not be chewed or crushed.
Capsules can be taken without regard to meals.

Based on the Phase I experience with SYD985 it can be concluded that there is a
positive benefit/risk for patients with late-line HER2-expressing cancers to
consider treatment with SYD985 and that exploration of the SYD985/niraparib
combination is scientifically, mechanistically and clinically plausible.
Developing a tolerable combination regimen may provide a novel treatment option
for heavily pre-treated cancer patients included in Part 1 of this study.
Relevance is highest for the patients with breast, ovarian or endometrial
cancer, included in Part 2 of this study, as the frequency of an aberrant DDR
profile is relatively common in these patients for whom the combination of
HER2-targeting treatment with PARP inhibition is expected to further increase
benefit-risk compared to SYD985 or PARP inhibition alone.

Frequent safety assessments such as ophthalmological and physical examinations,
hematology/biochemistry and ECG/LVEF measurements are included in the study to
early detect and adequately monitor toxicities when they occur. Clear
instructions for dose modifications, i.e. dose delay, reduction or
discontinuation, are provided in Section 9.8 specifically for ocular, lung,
cardiac and haematologic toxicity. In addition, investigators will be
instructed to carefully evaluate the tumour evaluation scans for any lung
changes. Patients with a history or presence of keratitis, impaired cardiac
function and/or lung disease are excluded from the study as these patients may
potentially be at higher risk to develop significant treatment-related
toxicity.