Final presentation will be as poster. This slide deck is temporary, for initial
content review.
Denosumab in Giant Cell Tumor of
Bone: Interim Results From a
Phase 2 Study
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
INTRODUCTION
• Giant cell tumor of bone (GCTB) is a primary osteolytic bone
tumor with substantial skeletal morbidity.
• Symptoms include:1
– 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
Figure 1. RANK and RANKL Expression
in Giant Cell Tumor of Bone
Human RANK (AMG N-2B10)8
Human RANKL (AMG M366)8
Figure 2. RANKL is a central mediator of the vicious cycle of bone destruction
in GCTB
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 by:8, 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
Figure 3. Denosumab May Interrupt the “Vicious Cycle” of GCTB-Induced
Bone Destruction
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
METHODS
Figure 4. Study Design
S
C
R
E
E
N
I
N
G
Informed
Consent
Signed
E
N
R
O
L
L
M
E
N
T
Enroll
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†
Study Study
Day 1 Day 8
Study
Day 15
Week
5
Week
9
Surgery*
Week
13
Week
17
+
Q4W
Q4W
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
E
N
D
F
O
L
L
O
W
O
F
S
T
U
D
Y
End of
Treatment
U
P
End of
Study
End of
Follow-up
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 Paget’s 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
RESULTS
Table 1. Patient Disposition and Denosumab Exposure
Denosumab 120 mg sc
Withdrew from study , n (%)*
Patients receiving ≥ 1 dose of denosumab
Median (Q1, Q3) months on study
Median (Q1, Q3) number of doses received:
Cohort 1
N = 77
Cohort 2
N = 25
Total
N = 102
3 (4)
0 (0)
3 (3)
76
24
100
6.6 (2.8, 8.8)
4.3 (2.3, 5.8)
5.7 (2.3, 8.5)
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).
RESULTS
Table 1. Baseline Demographics and Disease Characteristics
Characteristic
Denosumab 120 mg sc
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
Black or African American
Hispanic or Latino
Asian or other
Karnofsky performance status, n (%)
50 -70%
80 -100%
GCT disease type, , n (%)
Primary resectable
78 (76)
6 (6)
9 (10)
9 (9)
9 (12)
68 (88)
4 (16)
21 (84)
13 (13)
89 (87)
0 (0)
15 (60)
15 (15)
Primary unresectable
17 (22)
0 (0)
17 (17)
Recurrent resectable
0 (0)
10 (40)
10 (10)
60 (78)
0 (0)
60 (59)
Recurrent unresectable
Table 1 continued on next page
Graphic artist: please keep Table 1 all together (not split as in this draft)
Table 1, continued
Characteristic
Denosumab 120 mg sc
Cohort 1
N = 77
Cohort 2
N = 25
Total
N = 102
Location of target lesion - n (%)
Lung
29 (38)
0 (0)
29 (28)
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 (<1)
3 (12)
4 (4)
Skull
2 (3)
0 (0)
2 (2)
Pelvis soft tissue
1 (<1)
1 (4)
2 (2)
Other
9 (12)
2 (8)
11 (11)
Femur, tibia, or patella/knee
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.)
Table 2. Denosumab Exposure
Denosumab 120 mg sc
Patients receiving ≥ 1 dose of denosumab
Median (Q1, Q3) months on study
Median (Q1, Q3) number of doses received:
Cohort 1
N = 77
Cohort 2
N = 25
Total
N = 102
76
24
100
6.6 (2.8, 8.8)
4.3 (2.3, 5.8)
5.7 (2.3, 8.5)
9 (5, 12)
7 (5, 10)
9 (5, 11)
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.
Table 3. Adverse Events
Patients with Events
Denosumab 120 mg sc
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.
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 )
Proportion of Patients (%)
100
80
60
40
20
0
No Disease Progression
Disease Progression
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
30
Proportion of Patients (%)
•
25
20
15
10
5
0
Planned
Actual
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.
References
1.
2.
Mendenhall WM et al. Am J Clin Oncol. 2006; 29:96-9.
Malawer M et al. Giant cell tumour of the bone. In: DeVita V et
al., eds. Principles and Practice of Oncology, 8th ed. Philadelphia:
Lippincott, Williams, and Wilkins, 2008.
3. Balke M et al. J Cancer Res Clin Oncol. 2009; 135: 149–58.
4. Atkins GJ et al. J Bone Miner Res. 2006; 21:1339-49.
5. Huang L et al. Am J Pathol. 2000; 156:761-7.
6. Lau YS et al. Hum Pathol. 2005;36:945-54.
7. Roux S et al. Am J Clin Pathol. 2002; 117:210-6.
8. Roudier et al. Connective Tissue Oncology Society, November 5-7,
2009.
9. Bekker PJ et al. J Bone Miner Res. 2004;19:1059-1066.
10. Thomas D et al. Lancet Oncol. 2010;11:275-80.