A Phase III, Multicentre, Randomised, Double-Blind Study to Assess the Safety and Efficacy of
Emactuzumab vs. Placebo in Subjects with Tenosynovial Giant Cell Tumour.

TGCTs are a group of generally benign intra-articular and soft tissue tumours
with common histologic features, broadly divided into localised (lTGCT) and
diffuse (dTGCT) types. The lTGCT include giant cell tumours of tendon sheath
and pigmented villonodular synovitis and are generally indolent. dTGCT
encompass conventional pigmented villonodular synovitis and diffuse-type giant
cell tumour and are locally aggressive, invading extra-articular tissue with
high risk for recurrence post surgery in at least 50% of cases. Most TGCTs are
located in the knee, hip, ankle, wrist, and foot and are often severe and
seriously debilitating. TGCT often leads to severe morbidity with accompanying
pain and inability for patients to undertake daily activities. Surgery is often
restricted due to the location and characteristics of the tumour. Further,
surgery is often associated with long recovery times, poor outcomes and high
recurrence rates, depending on the nature of the lesion. The disease often
affects young adults who would otherwise be healthy and active, and can have a
significant impact on education, work and family life (Mastboom et al, 2018a).

All TGCTs are clonal neoplastic tumours driven by overexpression of macrophage
colony stimulating factor-1 (CSF-1). CSF-1 is a secreted
cytokine/haematopoietic growth factor that plays an essential role in the
proliferation, differentiation, and survival of monocytes, macrophages, and
related cells. It is localised to the 1p13 breakpoint and appears to have a
major oncogenic role in TGCT.

The M2-like subtype of tumour associated macrophages (TAMs) is implicated in
promoting tumourigenesis and suppressing tumour immunity. Tumours are able to
recruit and polarise macrophages into the M2-like subtype by secreting various
cytokines such as CSF-1 and interleukin 10 (IL-10). CSF-1 is linked to
neoplasia and poor prognosis. The CSF-1R tyrosine kinase, responsible for
mediating the cellular effects of CSF-1, is therefore an attractive target to
selectively inhibit TAMs of the M2-like subtype.

Emactuzumab is an investigational humanised mAb which binds specifically to
human CSF-1R. Emactuzumab is not approved in any regulatory territory.
Non-clinical data support its potential utility in TGCT reduction via CSF-1R
inhibition. Emactuzumab shows non-linear pharmacokinetics (PK) and
target-mediated drug disposition. After iv administration of emactuzumab at
dose-levels >= 900 mg and different dosing intervals in man target saturation in
excess of 90% was achieved over the entire dosing cycle, therefore leading to
the selection of the 1000 mg dose every two weeks (Q2W).

Emactuzumab demonstrated pre-liminary clinical activity in a Phase Ia/b study
(BP27772) involving 216 subjects with various underlying tumours. Of these, 63
subjects with TGCT received emactuzumab monotherapy, which included 51 subjects
who received a dose of 1000 mg emactuzumab. The number of subjects with TGCT
with a best unconfirmed complete response (CR) or partial response (PR; by
central assessment) in the 1000 mg dose cohort was 35 of 51 subjects (68.6%).
The Clinical Benefit Rate (CBR), ie, number of subjects with confirmed CR, PR,
or stable disease (SD) by central assessment in the total cohort of subjects
with TGCT was 96.8% (61 of 63 subjects). The confirmed CBR in the 1000 mg dose
cohort (n = 51) was 98.0%.

Primary:
To estimate the treatment effect of emactuzumab on objective response rate
(ORR) by 6 months from initiation of therapy in the blinded phase compared to
placebo

Secondary:
the effect of emactuzumab on clinical outcome assessments (COAs) for:
o Physical functioning
o Range of motion (ROM)
o Pain
o Stiffness
o Patient Global Impressions (PGIs)
o QoL

Further antitumour activity of emactuzumab in TGCT compared to placebo

Surgical Intervention Rate

SNX-301-202 is a Phase III, Multicentre, Randomised, Double-Blind Study to
Assess the Safety and Efficacy of
Emactuzumab vs. Placebo in Subjects with Tenosynovial Giant Cell Tumour. in
adult and adolescent subjects aged >=12 years. At study start subjects will be
randomized in a 2:1 ratio to receive an intravenous (iv) infusion of either
emactuzumab or placebo to one of the following treatment groups:

Group 1: 1000 mg emactuzumab administered as biweekly iv infusion over 90
minutes beginning on D1 for up to 5 cycles.

Group 2: placebo administered as biweekly iv infusion over 90 minutes beginning
on D1 for up to 5 cycles.

Each adolescent subject (12 -17 years) will receive biweekly iv infusions of
emactuzumab beginning on D 1 for up to 5 cycles (no randomization).
Group 3: 1000 mg emactuzumab administered as biweekly iv infusion over 90
minutes.

The approximate total duration of study participation for each subject is 2
years comprising the following periods:
• Screening: within 14 days prior to randomisation (Screening Visit).
• Double-Blind Treatment Period: 3 months from D 1 (Visit 1) to D 91 (Visit
7/End of Treatment/Early Discontinuation Visit).
• Double-Blind Follow-up Period: 21 months beginning after D 91 (Visit 7) to D
721 (Visit 14/End of Study Visit).

Crossover of Subjects Randomised to Placebo to Open-Label Treatment with
Emactuzumab
If the adult subject is randomised to placebo, they will be eligible for
treatment with emactuzumab in the Open-Label Phase under the following
conditions:
• have completed at least the 6-month visit D 181 (Visit 10; 3 months treatment
and 3 months observation) of the Double-Blind Phase
• have i) progressed according to RECIST v1.1 (objective progressive disease on
MRI imaging centrally confirmed) within 6-18 months of initial treatment on D 1
(Visit 1), or ii) have stable disease according to RECIST v1.1 (on MRI imaging
centrally confirmed) and clinically relevant deterioration as assessed by the
Investigator and confirmed by the Medical Monitor within 6-18 months of initial
treatment on D 1 (Visit 1)
• are determined to have received placebo upon unblinding. Note: unblinding
should only take place after all D 181 (Visit 10) assessments, including
subject interviews, have been performed.

Retreatment of Subjects Receiving Emactuzumab as Initial Treatment
Adult and adolescent subjects who respond based on RECIST v1.1 to initial
treatment with emactuzumab and then progress (objective progressive disease on
MRI imaging centrally confirmed) within 9-18 months of initial treatment on D 1
(Visit 1), will be eligible for retreatment in the Open-Label Phase of the
study. Retreatment will be at the discretion of the local Investigator
following agreement with the Sponsor. A minimum 6-month washout period is
included between treatments.

For subjects that are eligible for crossover treatment or retreatment with
emactuzumab, the study will include the following additional periods:
• Open-Label Treatment Period: 3 months from D 1 - open-label (ol) (Visit 1-ol)
to D 91-ol (Visit 7-ol/End of Treatment/Early Discontinuation Visit).
• Open-Label Follow-up Period: up to 2 years after randomisation in the
Double-Blind Phase (ie, depending on time of subject entry into the Open-Label
Phase, subjects may have a longer or shorter Open-Label Follow-up Period).

The current study evaluates intravenously administered doses of emactuzumab.
Each treatment dose is 1000mg, administered as IV infusion over 90 minutes,
repeated Q2W for a maximum of 10 weeks (5 cycles).

Placebo will be presented as a sterile, colourless concentrate of excipients
only, buffered at pH 6.0, in a single-use 10 mL vial. The placebo will be
administered as iv infusion over 90 minutes, repeated Q2W for a maximum of 10
weeks (5 cycles).

Patients participating will receive 5 cycles of treatment on a biweekly basis
over a period of 10 weeks. After end of treatment the patient will visit the
clinic on a monthly basis for 3 months and on a 6 monthly basis for a year.
Total duration will be 2 years.
the following will be assessed these visits: MRIs (6 in total), ECGs (5 in
total), physical examinations, questionnaires on health and quality of life
(each visit) and blood sampling at each visit (15-30mL at each visit), and
assessment of any side effect at every visit.

A Data safety monitoring board is installed that will review study safety
listings on a regular basis. Responsibilities are:
1. To be responsible for safeguarding the interests of trial subjects and to
assess in an unblinded way the safety of the IMPs.
2. To monitor evidence for treatment harm vs benefit, ie, toxicity, SAEs,
deaths.
3. To confirm the acceptability of study continuation.
4. To advise on and/or review any major protocol modifications suggested by the
Investigator or the Sponsor.
5. After the end of the trial, to read and comment on the Clinical Study Report.
At the end of each safety review meeting, the DSMB will issue a blinded report
to the Sponsor, which should confirm whether study treatment should continue at
the current dose, or if any Urgent Safety Measures/ protocol amendments are
required.