An Open-label, Multi-center, Phase 2 Study of Denosumab in Subjects with Giant Cell Rich Tumors of Bone.

The current mainstay of treatment of giant cell rich tumors of bone is surgery,
like in aneurysmal bone cysts, giant cell granuloma, osteoblastoma,
fibroblastoma and chondromyoid fibroma. Novel treatment modalities are needed
in order to decrease the significant morbidity that is caused by surgical
intervention and to avoid recurrent disease.

Denosumab has been approved for the treatment of classical giant cell tumors of
bone, after the success of two phase 2 studies. Since the histological presence
of osteoclastic giant cells and expression of RANK/RANKL is something GCTB and
other giant cell rich tumors all have in common, we hypothesize that giant cell
rich tumors will show the same reponse to denosumab as previously seen in GCTB.
This study will investigate the effect of denosumab in subjects with giant cell
rich tumors that have recurred after surgery or require morbid surgery.

Primary:

Subjects with salvageable giant cell rich tumors:
- To evaluate subjects who do not require surgery during the study
- To evaluate subjects who are able to undergo a less morbid surgical procedure
compared with the planned surgical procedure at baseline during the study

Subjects with unsalvageable giant cell rich tumors (combined objective):
- To evaluate disease control:
o Radiological response assessed by combined RECIST, PET, inverse Choi when
available AND/OR
o No progression at 1 year (based on disease assessment)
- Stable pain score, defined as * 1 point increase on *worst pain* question in
Brief Pain Inventory - short form (BPI-SF)

Secondary:

- To evaluate the safety and tolerability of denosumab in subjects with giant
cell rich tumors
- To evaluate the proportion of recurrences after denosumab followed by surgery
- To evaluate symptomatic improvement after denosumab in subjects with giant
cell rich tumors
- To evaluate time to surgery (for subjects with salvageable disease), time to
recurrence after surgery, progression free survival

Translational:

- Translational studies. Systematic analysis of pathologic and molecular
markers on tumor material, including evaluation of pathological response for
subjects undergoing surgery

In this open-label, multi-center, phase 2 trial subjects with giant cell rich
tumors that would require morbid surgery or with tumors that have recurred
after previous surgery will be treated with denosumab.

Denosumab will be given in a dose of 120mg subcutaneous (SC) on day 1 of every
4 week cycle with a loading dose of 120mg SC on days 8 and 15 of only the first
cycle.

Surgical resection may occur at any time during the study based on the clinical
judgement of the Investigator. For subjects that undergo surgical tumor
resection, denosumab treatment will be discontinued after surgery. In all other
cases, denosumab treatment continues for a maximum of up to 3 years, or until
confirmation of disease progression, the Investigator*s or sponsor*s
recommendation of discontinuation, the subject*s decision to discontinue for
any reason or administration of any of the prohibited therapies listed in the
study protocol. For subjects that continue to show clinical benefit after 3
years of treatment with denosumab, ongoing treatment outside of study protocol
is optional after discussion with Amgen.

For assessment of histopathological response and for translational research
purposes a tumor sample will be requested either during study or at the end of
treatment visit (surgical sample only for the subject group that has undergone
surgery).

During the time the study is still open, re-treatment may be allowed for
subjects who demonstrated a response to denosumab and are currently not
receiving denosumab treatment (e.g., in the case of recurrent disease while
subject is in the safety follow-up phase or subjects that have completed the
study and have later experienced disease progression). The re-treatment
decision including the use of the loading dose and discontinuation of therapy
will be handled on a case-by-case basis; prior authorization from the Sponsor
is required. Subjects must meet all inclusion/exclusion criteria prior to being
considered for re-treatment, with the exception of the exclusion criterium of
previous denosumab treatment. The same subject number will be assigned to avoid
bias.

Denosumab will be given in a dose of 120mg subcutaneously (SC) on day 1 of
every 4 week cycle with a loading dose of 120mg SC on days 8 and 15 of the
first cycle. Maximum treatment period is 3 years. For subjects that continue to
show clinical benefit after 3 years of treatment with denosumab, ongoing
treatment outside of study protocol is optional after discussion with Amgen.

Burden subjects
- Vena puncture: possible discomfort / pain
- Hospital visits: 30-45 minutes per visit every 4 weeks (for blood withdrawal,
physical exam, administration of medication)
- Completing 2 questionnaires per visit, 5 minutes per questionnaire. During
first 6 months of study once every 4 weeks, after that once every 12 weeks

Risks / side-effects
- Side-effects study medication: common side effects (>10%) bone pain,
hypocalcemia / phosphatemia, shortness of breath. Rare serious side effects
are: osteonecrosis of the jaw, atypical femoral fractures, severe hypocalcemia.
These may lead to hospital admission, and in severe cases to prolonged
disability.
- In cases with operable tumors the planned surgical procedure will be
postponed in order to evaluate the effect of denosumab. This is justified since
these are slow growing lesions which are frequently monitored and that can
possibly regress as a result of denosumab.
- In cases of inoperable tumors there is no standard treatment procedure
outside of this study