Denosumab safety and efficacy in giant cell tumor of bone (GCTB): Interim results from a phase

1
Denosumab safety and efficacy in giant cell tumor
of bone (GCTB) Interim results from a phase 2
study
Abstract 10034

• Jean-Yves Blay1, Sant Chawla2, Javier Martin
  Broto3, Edwin Choy4, Martin Dominkus5, Jacob
  Engellau6, Robert Grimer7, Robert Henshaw8,
  Emanuela Palmerini9, Peter Reichardt10, Piotr
  Rutkowski11, Keith Skubitz12, David Thomas13,
  Yufan Zhao14, Yi Qian14, Ira Jacobs14
•  
• 1University Claude Bernard Lyon I, Centre Léon
  Bérard, Department of Medicine, Lyon, France
  2Sarcoma Oncology Center, Santa Monica, CA, USA
  3Hospital Son Dureta, Palma de Mallorca, Spain
  4Dana Farber/Harvard Cancer Center, Massachusetts
  General Hospital, Boston, MA, USA 5Medizinische
  Universitaet Wien, Vienna, Austria 6Skåne
  Universitetssjukhus, Lund, Sweden 7Royal
  Orthopaedic Hospital, Birmingham, UK 8Georgetown
  University College of Medicine, Washington, DC,
  USA 9Istituti Ortopedici Rizzoli, Bologna,
  Italy 10HELIOS Klinik Bad Saarow, Bad Saarow,
  Germany 11Maria Sklodowska-Curie Memorial Cancer
  Center and Institute of Oncology, Department of
  Soft Tissue/Bone Sarcoma and Melanoma, Warszawa,
  Poland 12Masonic Cancer Center, University of
  Minnesota, Minneapolis, MN, USA 13Peter
  MacCallum Cancer Centre, East Melbourne,
  Victoria, Australia 14Amgen Inc., Thousand Oaks,
  CA, USA

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BACKGROUND

• Giant cell tumor of bone (GCTB) is an aggressive
  primary osteolytic bone tumor that causes
  substantial morbidity.
• GCTB typically occurs in young adults between the
  second and third decades of life, causing
  localized tenderness and swelling, reduced joint
  mobility, and pain that is often severe and
  intractable.1
• GCTB grows rapidly, destroying bone and
  spreading into surrounding soft tissues.
• In the absence of treatment, the natural history
  of GCTB is continued growth, complete destruction
  of the affected bone, and massive tumor
  formation, all of which can lead to gross
  physical deformity and possibly loss of limb.
• To date, there is no approved or effective
  chemotherapeutic or medicinal therapy for GCTB.
• Surgical intervention is the only definitive
  therapy for patients with resectable tumors, but
  surgery is often associated with significant
  morbidity.2, 3
• GCTB tumors contain osteoclast-like giant cells
  that express RANK and stromal cells and RANK
  ligand (RANKL), a key mediator of osteoclast
  formation, activation, function, and survival.4-7
• Excessive secretion of RANKL causes an imbalance
  in bone remodeling in favor of bone breakdown
  (Figure 1).8-10

3
Figure 1. RANKL is a Central Mediator of the
Vicious Cycle of Bone Destruction in GCTB
4

• Denosumab is a fully human monoclonal antibody to
  RANKL that binds with high affinity and
  specificity to the soluble and cell
  membrane-bound forms of human RANKL (Figure 2).11
  
• In an initial open-label, proof-of-concept,
  phase 2 study (N 37)12
• Tumor response (defined as elimination of at
  least 90 of giant cells or no radiological
  progression of the target lesion up to week 25)
  was observed in 86 of subjects with GCTB
• Clinical benefit was reported in 84 of subjects
  (reduced pain or improvement in functional status
  per investigator report)2
• A second phase 2 follow-on study is in progress
  safety and efficacy results from the prespecified
  second interim analysis are reported here.

5
Figure 2. Denosumab May Interrupt the Vicious
Cycle of GCTB-induced Bone Destruction
6
OBJECTIVES

• Primary study objective
• Report the safety profile of denosumab
• Secondary and exploratory study objectives
• Report investigators assessments of disease
  progression in 2 separate cohorts (Figure 3)
• Cohort 1 Subjects with surgically unsalvageable
  disease
• Cohort 2 Subjects with surgically salvageable
  disease for whom a morbid surgery is planned
• Report the number of subjects in cohort 2 for
  whom surgery is no longer required or who are
  able to undergo a less morbid surgery than
  planned

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Figure 3. Study Design
Prespecified interim analysis
Surgical resection may occur at any time during
the study based on the clinical judgment of the
investigator Subjects not achieving a complete
resection after surgery may continue to receive
denosumab at a dose of 120 mg SC Q4W if clinical
benefit is determined It was strongly
recommended that subjects take daily
supplementation 500 mg of supplemental calcium
and 400 IU of vitamin D, except in the case of
pre-existing hypercalcemia SC subcutaneous Q4W
every 4 weeks
8
Subjects

• Cohort 1 Subjects with surgically unsalvageable
  disease (unresectable or metastatic disease eg,
  sacral or spinal GCTB or multiple lesions
  including pulmonary metastases)
• Cohort 2 Subjects with surgically salvageable
  (resectable) disease whose planned on-study
  surgery is associated with severe morbidity (eg,
  joint resection, limb amputation, or
  hemipelvectomy)
• Key inclusion criteria
• Adults or skeletally mature adolescents 12
  years of age, with weight 45 kg
• Pathologically confirmed GCTB 1 year before
  enrollment
• Measurable evidence of active disease 1 year
  before enrollment
• Karnofsky performance status 50
• Key exclusion criteria
• Current GCTB-specific treatment (eg, radiation,
  chemotherapy, or embolization) or bisphosphonates
• Known or suspected current diagnosis of
  underlying malignancy or Pagets disease, or
  known diagnosis of second malignancy within the
  past 5 years
• Prior history or current evidence of
  osteonecrosis/osteomyelitis of the jaw, an active
  dental or jaw condition requiring oral surgery or
  a non-healed dental/oral surgery, or a planned
  invasive dental procedure during the course of
  the study
• This prespecified interim analysis (data cut-off
  date, May 21, 2010) reports
• Safety results for all subjects who received 1
  dose of denosumab
• Efficacy results for subjects who had the
  opportunity to receive denosumab treatment for
  6 months

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RESULTS

• Table 1. Subject Disposition and Denosumab
  Exposure

Cohort 1 N 112 Cohort 2 N 50
Subjects receiving 1 dose of denosumab 109 49
Median (Q1, Q3) number of doses received 11 (7, 16) 9 (5, 12)
Median (Q1, Q3) number of months on study 7.8 (3.8, 13.4) 5.6 (2.0, 9.8)
Withdrew from study, n () 9 (8) 4 (8)

• Reasons for discontinuation included adverse
  events (5 subjects), consent withdrawn (2
  subjects), and administrative decision,
  protocol-specified criteria, disease progression,
  lost to follow-up, pregnancy, and requirement for
  alternative therapy (1 subject each).

• The efficacy assessment included 100 subjects who
  received at least 1 dose of denosumab and had the
  opportunity to be on denosumab treatment for at
  least 6 months.
• The safety assessment included 158 subjects who
  received at least 1 dose of denosumab.

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Table 2. Subject Demographics
Characteristic Cohort 1 Surgically unsalvageable N 112 Cohort 2 Salvageable, Surgery Planned N 50 Total N 162
Female, n () 71 (63) 29 (58) 100 (62)
Age , median (min, max) 32 (13, 76) 34 (17, 56) 32 (13, 76)
Race/ethnicity, n ()
White/Caucasian 85 (76) 40 (80) 125 (77)
Black or African American 8 (7) 4 (8) 12 (7)
Hispanic or Latino 9 (8) 3 (6) 12 (7)
Asian or other 10 (11) 3 (6) 13 (8)
Includes all enrolled subjects
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Table 3. Subject Disease Characteristics
Characteristic Cohort 1 Surgically unsalvageable N 112 Cohort 2 Salvageable, Surgery Planned N 50
Karnofsky performance status, n ()
50 -70 14 (12) 7 (14)
80 -100 98 (88) 43 (86)
Location of target lesion - n ()
Femur, tibia, patella/knee, or tarsus 7 (6) 32 (64)
 Lung 34 (30) 2 (4)
 Sacrum 25 (22) 3 (6)
 Pelvic bone 16 (14) 4 (8)
Cervical, thoracic, or lumbar vertebrae 11 (10) 1 (2)
Humerus, radius, ulna, or metacarpus 6 (5) 6 (12)
Skull 7 (6) 0 (0)
Thoracic or cervical soft tissue 3 (3) 1 (2)
Pelvis soft tissue 1 (1) 1 (2)
Abdomen 1 (1) 0 (0)
Prior therapies
Chemotherapy 22 (20) 2 (4)
Radiation 30 (27) 1 (2)
Surgery 91 (81) 28 (56)
IV bisphosphonates 28 (25) 6 (12)
Includes all enrolled subjects In order of
frequency data missing for 1 subject
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SafetyTable 4. Adverse Events
Subjects With Events, n () All Subjects N 158
All adverse events (AEs) 126 (80)
Serious AEs 11 (7)
AEs leading to denosumab discontinuation 6 94)
AEs of Grade 3 or 4 25 (16)
Deaths 2 (1)
AEs reported in 10 of subjects
Fatigue 23 (15)
Back pain 21 (13)
Headache 21 (13)
Pain in extremity 20 (13)
Arthralgia 18 (11)
Nausea 17 (11)
Includes all subjects who received 1 dose of
denosumab. The most frequently reported AE of
Grade 3 or 4 was hypophosphatemia, reported in 4
subjects. Two subjects reported back pain, pain
in extremity, or ONJ of Grades 3 or 4. All other
AEs of Grade 3 or 4 were reported in 1 subject
each. Deaths were attributed to progression of
bone sarcoma and respiratory failure, neither of
which was considered treatment related.
13

• Hypocalcemia and osteonecrosis of the jaw (ONJ),
  known risks of denosumab treatment described in
  the package insert, occurred at levels consistent
  with other denosumab studies no new risks were
  identified in subjects with GCTB.
• Hypocalcemia was reported in 7 subjects (4) no
  cases were serious.
• Osteonecrosis of the jaw was reported in 3
  subjects (1.9) 2 cases were serious.

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EfficacyFigure 4. No Disease Progression in the
Majority of Subjects
Cohort 1 Surgically unsalvageable N 73
Cohort 2Salvageable, surgery planned N 23
N the number of subjects for whom disease
progression data were available at the time of
analysis. If multiple responses are present in
the same time frame for an individual subject,
the best response is presented.
15

• Cohort 1
• Based on investigators assessment of best
  disease responses, there was no disease
  progression (Figure 4)
• In 72 of the 73 evaluable subjects (99) in
  cohort 1
• In 23 of the 23 evaluable subjects (100) in
  cohort 2
• Cohort 2
• Among 23 cohort-2 subjects who had surgery
  planned at baseline, 20 subjects (87) had no
  surgery or less morbid surgery than planned
  (Table 5).
• 22 subjects (96) had no surgery during the first
  6 months
• 15 (65) had no surgery during the first 12
  months
• 5 of 8 subjects (62) undergoing surgery had less
  morbid procedures than originally planned (Table
  5).

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Table 5. Most Cohort 2 Subjects Had No Surgery or
a Less Morbid Surgical Procedure Than Planned
Surgical Procedure Planned n () Actual n ()
Amputation 2 (9) 0 (0)
Joint/prosthesis replacement 2 (9) 1 (4)
Joint resection 1 (4) 2 (9)
Marginal excision, en bloc excision or en bloc resection 5 (22) 0 (0)
Curretage 2 (9) 4 (17)
Other 3 (13) 1 (4)
No surgery 0 (0) 15 (65)
In order from most morbid to least morbid
Other skeletal procedures included replacement of
proximal tibia, resection of sacral lesion
including bone resection, and pelvic resection.
17
Summary

• This interim analysis describes 158 adult and
  adolescent subjects with GCTB who received
  treatment with denosumab of an open-label phase 2
  study.
• Many of these subjects had recurrent or
  unresectable disease and had received previous
  treatment with surgery, chemotherapy,
  radiotherapy, and IV bisphosphonates.
• Denosumab was well tolerated by these subjects
  with GCTB and no new risks were observed in this
  population.
• For most subjects with surgically unsalvageable
  disease, denosumab treatment halted disease
  progression.
• For most subjects with surgically salvageable
  disease, denosumab treatment delayed, eliminated,
  or reduced the scope of surgery.
• This study is ongoing denosumab continues to be
  studied as a potential treatment alternative for
  GCTB.

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Disclosures

• Funding for the study and assistance with poster
  preparation was provided by Amgen Inc.
• J.Y. Blay has consulted for or received research
  funding or honoraria from Novartis, Pfizer,
  GlaxoSmithKline, Roche, PharmaMar, and ImClone
  Systems. S.P. Chawla has consulted for or
  received research funding from Amgen, ARIAD,
  Merck, ZIOPHARM Oncology, and Epeius
  Biotechnologies. E. Choi has consulted for and
  received honoraria from Amgen. R. Grimer has
  received research funding from Amgen. R. Henshaw
  has consulted for and received honoraria and
  research funding from Amgen. K. Skubitz has
  consulted for or received research funding from
  ARIAD, Keryx Biopharmaceuticals, Novartis,
  Johnson Johnson, Cellgene, Cell Therapeutics,
  Daiichi Sankyo, SMI, Schering-Plough,
  GlaxoSmithKline, and Bayer, and has provided
  expert testimony on behalf of a plaintiffs
  attorney. D.M. Thomas has received honoraria from
  Amgen. J.M. Broto, M. Dominkus, E .Palmerini, P.
  Reichardt, and P. Rutkowski have no potential
  conflicts of interest to disclose. Y. Zhao, Y.
  Qian, and I. Jacobs are employees of Amgen Inc.
  and have received Amgen stock/stock options.