Denosumab in Giant Cell Tumor of Bone: Interim Results From a Phase

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Denosumab in Giant Cell Tumor of Bone Interim
Results From a Phase 2 Study
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• Sant Chawla1, Angela Cioffi2, Judith R. Kroep3
  Alex Powell4, Peter Reichardt5, Scott M.
  Schuetze6, Silvia Stacchiotti7, Arthur Staddon8,
  Yi Qian9, Kay Noonan9, Ira Jacobs9
•  
• 1Sarcoma Oncology Center, Santa Monica, CA
  2Institut Gustave Roussy, Villejuif, France
  3Leids Universitair Medisch Centrum, Leiden,
  Netherlands 4Sir Charles Gairdner Hospital,
  Nedlands WA, Australia 5HELIOS Klinikum Bad
  Saarow, Bad Saarow, Germany 6Univeristy of
  Michigan Department of Internal Medicine, Ann
  Arbor, MI 7Fondazione IRCCS Istituto Nazionale
  per lo Studio e la Cura dei Tumori, Milan, Italy
  8University of Pennsylvania School of Medicine,
  Philadelphia, PA 9Amgen Inc., Thousand Oaks, CA

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INTRODUCTION

• Giant cell tumor of bone (GCTB) is a primary
  osteolytic bone tumor with substantial skeletal
  morbidity.
• Symptoms include1
• Localized tenderness swelling
• Reduced joint mobility
• Pain that is often severe and intractable
• Surgery, the definitive therapy for GCT, is often
  associated with significant morbidity2,3
• GCTB contains osteoclast-like giant cells and
  precursors that express RANK and mononuclear
  cells that express RANKL, which mediates
  osteoclast activation. RANK and RANKL are
  involved in the pathophysiology of GCTB (Figures
  1-2).4-8

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Figure 1. RANK and RANKL Expression in Giant Cell
Tumor of Bone
Human RANK (AMG N-2B10)8
Human RANKL (AMG M366)8
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Figure 2. RANKL is a central mediator of the
vicious cycle of bone destruction in GCTB
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INTRODUCTION, continued

• Denosumab is a fully human antibody that binds
  RANKL, inhibiting osteoclast activity and
  osteoclast-mediated bone destruction (Figure 3)9
• In an initial proof-of-concept phase 2 study of
  37 patients with GCTB, 86 responded to
  denosumab, demonstrated by8, 9
• Elimination of giant cells
• Reduction of RANKL-expressing-stromal cells
• Formation of cartilage, pre-adipocytes, and bone
• In the initial phase 2 study, 84 of patients
  experienced clinical benefit (reduced pain or
  improvement in functional status) 2

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Figure 3. Denosumab May Interrupt the Vicious
Cycle of GCTB-Induced Bone Destruction
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OBJECTIVES

• A second international, open-label phase 2 study
  is evaluating the safety and efficacy of
  denosumab in patients with GCTB (Figure 4).
• Primary study objective evaluate the safety
  profile of denosumab, indicated by adverse events
  and laboratory abnormalities for each cohort
• Secondary study objectives
• Evaluate subjective assessments of disease
  progression
• Evaluate the proportion of patients in cohort 2
  for whom surgery was delayed, reduced in scope,
  or not required
• This interim analysis reports
• Safety results for all patients who received 1
  dose of denosumab as of the 6-month data cut-off
  date
• Efficacy results for patients who had the
  opportunity to receive denosumab treatment for
  6 months

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Figure 4. Study Design
METHODS
F O L L O W U P
E N D O F S T U D Y
Cohort 1 Unsalvageable Denosumab 120 mg SC Q4W
Loading dose of 120 mg SC Days 8 and 15
Continue denosumab 120 mg SC Q4W if clinical
benefit
Cohort 2 Salvageable Denosumab 120 mg SC Q4W
Loading dose of 120 mg SC Days 8 and 15
Complete resection if pathologic response,
then denosumab 120 mg SC Q4W for 6 doses
Surgery
Q4W
Q4W
Protocol-specified 6-month 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
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METHODS, continued

• Patients
• Cohort 1 Patients with surgically unsalvageable
  disease (eg, sacral or spinal GCT or multiple
  lesions including pulmonary metastases)
• Cohort 2 Patients with surgically salvageable
  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, active GCTB 1 year
  before enrollment
• Karnofsky performance status 50
• Key exclusion criteria
• Current GCT-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

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RESULTS
Table 1. Patient Disposition and Denosumab
Exposure
Denosumab 120 mg sc Denosumab 120 mg sc Denosumab 120 mg sc
Cohort 1 N 77 Cohort 2 N 25 Total N 102
Withdrew from study , n () 3 (4) 0 (0) 3 (3)
Patients receiving 1 dose of denosumab 76 24 100
Median (Q1, Q3) months on study 6.6 (2.8, 8.8) 4.3 (2.3, 5.8) 5.7 (2.3, 8.5)
Median (Q1, Q3) number of doses received 9 (5, 12) 7 (5, 10) 9 (5, 11)
Reasons for study withdrawal were disease
progression, adverse event (sarcoma) and other
(clinical worsening without radiological
progression).
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RESULTS

• Table 1. Baseline Demographics and Disease
  Characteristics

Characteristic Denosumab 120 mg sc Denosumab 120 mg sc Denosumab 120 mg sc
Characteristic Cohort 1 N 77 Cohort 2 N 25 Total N 102
Female, n () 55 (54)
Age , mean (SD) 35 (13)
Race/ethinicity, n ()
White/Caucasian 78 (76)
Black or African American 6 (6)
Hispanic or Latino 9 (10)
Asian or other 9 (9)
Karnofsky performance status, n ()
50 -70 9 (12) 4 (16) 13 (13)
80 -100 68 (88) 21 (84) 89 (87)
GCT disease type, , n ()
 Primary resectable 0 (0) 15 (60) 15 (15)
 Primary unresectable 17 (22) 0 (0) 17 (17)
 Recurrent resectable 0 (0) 10 (40) 10 (10)
 Recurrent unresectable 60 (78) 0 (0) 60 (59)
Table 1 continued on next page
Graphic artist please keep Table 1 all together
(not split as in this draft)
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• Table 1, continued

Characteristic Denosumab 120 mg sc Denosumab 120 mg sc Denosumab 120 mg sc
Characteristic Cohort 1 N 77 Cohort 2 N 25 Total N 102
Location of target lesion - n ()
 Lung 29 (38) 0 (0) 29 (28)
Femur, tibia, or patella/knee 4 (5) 15 (60) 19 (19)
 Sacrum 16 (21) 1 (4) 17 (17)
 Pelvic bone 9 (12) 2 (8) 11 (11)
Cervical, thoracic, or lumbar vertebrae 6 (8) 1 (4) 7 (7)
Humerus, metacarpus, or radius 1 (lt1) 3 (12) 4 (4)
Skull 2 (3) 0 (0) 2 (2)
Pelvis soft tissue 1 (lt1) 1 (4) 2 (2)
Other 9 (12) 2 (8) 11 (11)
Prior therapies
Chemotherapy 20 (26) 2 (8) 22 (22)
Radiation 22 (29) 1 (4) 23 (22)
Surgery 62 (80) 13 (52) 75 (74)
IV bisphosphonates 23 (30) 4 (16) 27 (26.)
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Table 2. Denosumab Exposure
Denosumab 120 mg sc Denosumab 120 mg sc Denosumab 120 mg sc
Cohort 1 N 77 Cohort 2 N 25 Total N 102
Patients receiving 1 dose of denosumab 76 24 100
Median (Q1, Q3) months on study 6.6 (2.8, 8.8) 4.3 (2.3, 5.8) 5.7 (2.3, 8.5)
Median (Q1, Q3) number of doses received 9 (5, 12) 7 (5, 10) 9 (5, 11)
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Safety

• Three patients experienced serious adverse
  events, including progression of osteosarcoma and
  wound dehiscence, anemia, and complications of
  endotracheal intubation none were considered
  treatment related.
• Hypocalcemia (including calcium deficiency and
  blood calcium decreased) was reported in 9
  patients (9) no cases were serious.
• Potential cases of ONJ were adjudicated by an
  independent expert panel. No cases of ONJ were
  reported.

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Table 3. Adverse Events
Patients with Events Denosumab 120 mg sc
Patients with Events N 100
All adverse events (AEs) 81 (81)
Serious AEs 3 (3)
Serious AEs considered by investigator to be related to denosumab treatment 0 (0)
AEs leading to denosumab discontinuation 3 (3)
AEs of Grade3, 4, or 5 10 (10)
Deaths 1 (1)
AEs reported in 5 of patients
Fatigue 16 (16.0)
Headache 15 (15.0)
Nausea 14 (14.0)
Arthralgia 9 (9.0)
Back pain 9 (9.0)
Pain in extremity 9 (9.0)
Bone pain 6 (6.0)
Constipation 6 (6.0)
Hypocalcemia (including calcium deficiency and blood calcium decreased) 9 (9.0)
Hypophosphatemia 6 (6.0)
Myalgia 6 (6.0)
Nasopharyngitis 6 (6.0)
Anaemia 5 (5.0)
Diarrhea 5 (5.0)
Hot flush 5 (5.0)
Paresthesia 5 (5.0)
Includes all patients who received 1 dose of
denosumab. Death attributed to progression of
bone sarcoma, not considered treatment related.
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Efficacy

• The efficacy assessment included 49 patients who
  had the opportunity to be on denosumab treatment
  for at least 6 months.
• After 6 months, 47 patients (96) were free of
  disease progression based on subjective
  assessment of disease status (Figure 5).

Figure 5. Disease Progression After 6 Months of
Denosumab Treatment (Subjective Assessment )
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Efficacy, continued

• The efficacy analysis included 6 patients in
  cohort who were on treatment for at least 6
  months.
• Of the 6 patients in cohort 2 who had surgery
  planned at study entry, none had surgery during
  the first 6 months (Figure 6).

Figure 6. Planned vs. Actual Surgery After 6
Months of Denosumab Treatment
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Summary

• This interim analysis describes adult and
  adolescent patients (N 100) with GCTB who
  received treatment with denosumab 120 mg sc
  during the first 6 months of an open-label phase
  2 study.
• Many of these patients had recurrent or
  unresectable disease and had received previous
  treatment with surgery, chemotherapy,
  radiotherapy, and IV bisphosphonates.
• In this population, denosumab had an acceptable
  safety profile, with only 3 serious AEs (3).
• Most patients (96) had no disease progression
  based on subjective assessment.
• Of the patients who had planned surgery at study
  entry, none had surgery during the first 6
  months.
• Denosumab continues to be studied as a potential
  treatment alternative for GCTB.

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References

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