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Abstract
Patients with metastatic bone cancer report life-altering pain. Nerve growth factor is involved in pain signaling. Tanezumab, a nerve
growth factor monoclonal antibody, has demonstrated efficacy in chronic pain. Placebo-controlled parent (NCT00545129; study
1003) and noncontrolled open-label extension (NCT00830180; study 1029) studies evaluated efficacy and safety of tanezumab in
patients with painful bone metastases taking daily opioids. Patients in study 1003 received a single intravenous injection of 10 mg
tanezumab or placebo and were followed up to 16 weeks. Efficacy analyses included change from baseline in daily average and
worst pain at week 6 on an 11-point numeric rating scale. At week 8, patients could enroll in study 1029 and receive 4 infusions of
10 mg tanezumab at 8-week intervals with follow-up to 40 weeks. Safety assessments included adverse events and physical and
neurologic examinations. Overall, 59 patients were randomized and treated (placebo, n 5 30; tanezumab, n 5 29). At the primary
endpoint of study 1003, least squares mean (SE) difference in change from baseline in daily average pain vs placebo was 20.26
(0.45; P 5 0.569). Post hoc analyses suggested that tanezumab had greater efficacy in patients with lower baseline opioid use
and/or higher baseline pain. Mean (SE) pain scores in study 1029 were reduced through week 40 compared with study 1029 or 1003
baselines (20.21 [0.76] and 21.27 [0.68], respectively). Adverse event incidence of study 1003 was similar between groups.
Although the primary endpoint was not achieved, tanezumab may provide additional sustained analgesia in patients with metastatic
bone pain taking daily opioids. Additional larger studies are warranted.
Keywords: Bone metastases, Cancer pain, Efficacy, Nerve growth factor, Safety, Tanezumab
1. Introduction
An estimated 30% to 50% of patients with cancer experience
moderate to severe cancer-related pain, and in advanced or
metastatic cancer, 75% to 95% report life-altering cancerinduced pain.31 Although pain arises from numerous causes,
bone metastasis is the most common cause of cancer pain,
occurring in 60% to 84% of patients.25,27 Therapeutics such as
opioids, which are commonly used in these patients, are not fully
effective in many patients and often have significant side
effects.26 Thus, a significant unmet need remains for development of novel agents for cancer pain treatment.
The neurotrophin nerve growth factor (NGF) plays an important
role in pain signaling. In animal studies, elevated NGF levels are
observed with increased pain behavior.2,17,20,32,42 In human
clinical trials, NGF administration has resulted in hyperalgesia,
pressure allodynia, and generalized muscle pain.3,13 A number of
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2. Methods
Study 1003 was a randomized, double-blind, placebo-controlled,
parallel-group, phase 2 study in patients with cancer with chronic
pain due to bone metastases who were being treated with opioids
(Clinicaltrials.gov identifier: NCT00545129). Study 1029 was
a phase 2 open-label extension study (Clinicaltrials.gov identifier:
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(1) Total daily dose (fixed component plus rescue doses) of the opioid
regimen had not changed by more than 120% from day 1 to day
2 and from day 1 to day 3 of the baseline assessment period.
(2) There had been #3 IR rescue episodes per day from day 1 to
day 3 of the baseline assessment period for breakthrough pain.
(3) The mean value of the average pain intensity over the last 24
hours scores from day 1 to day 3 of the baseline assessment
period must have been $4 on an 11-point NRS (scores range
from 0 to 10).
(4) There were no intolerable side effects in the judgment of the
patient from day 1 to day 3 of the baseline assessment period.
The treatment phase lasted up to 113 days. Patients were
randomized to receive a single dose of 10 mg tanezumab or
matching placebo (tanezumab vehicle) in a 1:1 ratio (Fig. 1). After
week 8 but no later than week 16, patients had the option of
enrolling in the extension study; patients who did not were
followed through week 16 in study 1003.
2.1.3. Efficacy
The primary efficacy endpoint was change from baseline to week 6
in daily average pain as measured by an 11-point NRS recorded
daily through an e-diary (0 5 no pain, 10 5 pain as bad as you can
imagine). Secondary endpoints included change from baseline to
weeks 1, 2, 4, 6, 8, 12, and 16 in daily worst pain score; change
from baseline to the same time points (excluding week 6) in daily
average pain; and percentage of patients with a response (defined
by $30%, $50%, $70%, or $90% reduction from baseline in
daily average pain NRS). Additional secondary assessments
included the Brief Pain Inventory Short Form (BPI-sf), consisting
of questions designed to measure pain intensity and interference of
pain with daily activities; responses were provided on an 11-point
NRS ranging from 0 to 10.9 Although the landmark analysis was
prespecified as week 6 after dosing, week 8 was deemed a highinterest time point because of intended 8-week dosing intervals for
tanezumab in the treatment of chronic pain conditions.
2.2. Study 1029
2.2.1. Study population
Inclusion criteria required patients to have been treated in study
1003 with enrollment in study 1029 after 8 weeks but no later
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3. Results
Studies 1003 and 1029 were conducted in 32 and 27 centers,
respectively, in Europe, North America, South America, Latin
America, and Asia. Demographics and baseline characteristics of
study 1003 were comparable across treatments (Table 1). In
study 1003, 7 of 29 (24.1%) patients randomized to the
tanezumab 10-mg treatment group received concomitant
chemotherapy and 5 of 30 (16.7%) patients randomized to
placebo received concomitant chemotherapy. In this study, 7 of
29 (24.1%) patients randomized to the tanezumab 10-mg
treatment group and 3 of 30 (10%) patients randomized to
placebo received a concomitant bisphosphonate.
Excluding the single renal cell carcinoma patient, the mean
duration of cancer was generally 3 to 6 years, and the duration
since bone metastasis diagnosis was generally 0.5 to 1.9 years
(Table 2). All patients were on an opioid regimen upon
study 1003 entry. The average daily total opioids dosage at
baseline was similar between groups; small reductions in the
average daily total dosage occurred through week 8 for both
groups, but differences were not statistically significant (P 5
0.744; Table 1). The mean tanezumab treatment duration in
the parent and extension studies combined was 225 days;
most patients received at least 4 doses of tanezumab
(Table 3).
3.1. Study 1003
Overall, 101 patients were screened; 59 were randomized and
treated (placebo, n 5 30; tanezumab 10 mg, n 5 29; Fig. 2).
3.1.1. Efficacy
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Table 1
Study 1029
Placebo, n 5 30
Tanezumab 10 mg, n 5 29
Tanezumab 10 mg, n 5 41
16 (53.3)
16 (55.2)
21 (51.2)
55.8 6 11.9
32-77
62.1 6 11.9
40-90
58.7 6 12.4
32-91
21 (70.0)
9 (30.0)
0 (0.0)
23 (79.3)
4 (13.8)
2 (6.9)
32 (78.0)
9 (22.0)
0 (0.0)
5.3 6 0.98
5.4 6 1.02
4.21 6 2.21
6.4 6 1.06
6.3 6 1.30
5.34 6 2.63
102.0 6 112.78
111.8 6 134.59
101.59 (6.05)
103.20 (7.02)
12 (40.0)
15 (50.0)
2 (6.7)
1 (3.3)
13 (44.8)
16 (55.2)
0 (0.0)
0 (0.0)
18 (43.9)
20 (48.8)
2 (4.9)
1 (2.4)
1 (3.3)
6 (20.0)
13 (43.3)
5 (16.7)
5 (16.7)
0 (0.0)
78.0 6 10.9
0 (0.0)
6 (20.7)
9 (31.0)
9 (31.0)
5 (17.2)
0 (0.0)
75.5 6 10.2
1 (2.4)
10 (24.4)
14 (34.1)
7 (17.1)
7 (17.1)
2 (4.9)
76.3 6 12.4
* Daily average and daily worst pain scores rated on an 11-point numeric rating scale (0-10), ranging from 0 5 no pain to 10 5 pain as bad as you can imagine.
Baseline of study 1029 (includes tanezumab- and placebo-treated patients from study 1003).
Least squares means were estimated from the corresponding ANCOVA model.
ANCOVA, analysis of covariance; MED, morphine equivalent dose.
differences between treatments did not reach statistical significance (Fig. 4). Changes from baseline suggested modestly
greater efficacy with tanezumab-treated vs placebo-treated
patients toward the end of the 8-week postdose period. The
observed treatment differences were below that assumed in the
sample size estimation.
Post hoc dichotomization of baseline pain yielded consistently
greater improvements in daily average pain scores in patients with
baseline pain scores .5 in the tanezumab group vs placebo. At
Table 2
Placebo, n 5 30
Tanezumab 10 mg, n 5 29
12
4.02 (0.50-11.91)
1.92 (0.03-6.12)
15
3.82 (0.52-8.58)
1.59 (0.06-6.22)
2
6.64 (2.69-10.60)
0.59
1
0.37
0.37
13
3.44 (1.54-8.01)
1.69 (0.08-4.87)
16
6.8 (0.09-16.01)
1.74 (0.09-5.92)
0
0
0
0
0
0
* n 5 1.
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Table 3
Study 1003
No. i.v. doses, n (%)
1
2
3
4
5
6
7
8
Patients remaining in study
At wk 6
At wk 8
Duration in study, d
Mean
Range
Placebo, n 5 30
Tanezumab 10 mg, n 5 29
30
29
9 (22.0)
7 (17.1)
3 (7.3)
10 (24.4)
11 (26.8)
0 (0.0)
0 (0.0)
1 (2.4)
27
25
25
25
68.9
15-125
83.1
20-127
225
15-619
* Tanezumab-treated only.
week 6, change from baseline vs placebo was 21.11 (95% CI, 22.81
to 0.59) and at week 8 was estimated at 21.67 (95% CI, 23.41 to
0.08) and approached significance (P 5 0.061).
In post hoc analyses of patients with high baseline pain
scores (.5) and low baseline opioid use (#60.5 mg/d MED),
the LS mean (SE) change from baseline at week 8 was 23.55
(1.36) with tanezumab treatment (n 5 6) and 20.83 (1.18) with
Figure 2. Patient disposition. a Does not include death of a single patient during extended-use period or 4 patients who died after extended-use period.
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Figure 3. Least squares (LS) mean change (SE) from baseline at weeks 6 and 8
in (A) daily average pain and (B) daily worst pain scores in study 1003.
Figure 4. (A) Daily average pain scores or (B) daily worst pain scores in study
1003 (intent to treat, observed data). BL, baseline.
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Table 4
Subgroup analyses for daily average pain score, change from baseline to weeks 6 and 8 in study 1003 (intent-to-treat population;
baseline observation carried forward).
Week 6
Low baseline pain* and low opioid use
N
Change from baseline, LS mean (SE)
Change from baseline vs placebo, LS mean
(95% CI)
P
Low baseline pain* and high opioid use
N
Change from baseline, LS mean (SE)
Change from baseline vs placebo, LS mean
(95% CI)
P
High baseline pain{ and low opioid use
N
Change from baseline, LS mean (SE)
Change from baseline vs placebo, LS mean
(95% CI)
P
High baseline pain{ and high opioid use
N
Change from baseline, LS mean (SE)
Change from baseline vs placebo, LS mean
(95% CI)
P
Week 8
Placebo, n 5 30
Tanezumab 10 mg, n 5 29
Placebo, n 5 30
Tanezumab 10 mg, n 5 29
9
22.77 (0.93)
7
23.15 (0.96)
20.38 (22.09 to 1.33)
9
22.24 (1.03)
7
22.99 (1.06)
20.75 (22.65 to 1.15)
0.647
7
0.45 (0.78)
8
0.75 (1.09)
0.31 (21.80 to 2.41)
0.420
7
20.01 (0.87)
0.765
7
21.72 (1.06)
6
23.39 (1.23)
21.67 (23.82 to 0.48)
0.921
7
20.83 (1.18)
0.121
7
21.56 (1.46)
8
21.70 (1.22)
20.14 (22.47 to 2.18)
0.899
8
0.11 (1.21)
0.11 (22.23 to 2.46)
6
23.55 (1.36)
22.72 (25.11 to 20.33)
0.027
7
21.36 (1.62)
8
21.57 (1.35)
20.21 (22.79 to 2.38)
0.870
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4. Discussion
Two studies examined tanezumab 10 mg i.v. in the treatment of
patients with cancer-taking background opioids for chronic pain
caused by bone metastases. Study 1003 was an initial proof-ofconcept study, designed without previous clinical data on the
use of an anti-NGF agent in this patient population. Although no
statistically significant changes were noted, numeric improvement in analgesic efficacy after a single tanezumab 10-mg dose
compared with placebo was demonstrated based on the
prespecified primary comparison of change in daily average
pain from baseline to week 6 and on additional comparison at
week 8; also, the data suggest that tanezumab treatment
resulted in sustained analgesic improvements throughout both
studies.
Subgroup analysis indicated statistically significant improvement with tanezumab 10 mg at week 8 in patients with higher
baseline daily average pain scores (.5) and lower total opioid
usage (,60.5 mg/d MED). Those results suggest demonstrating
overall tanezumab efficacy was challenging, because having
patients on a stabilized background analgesic regimen with the
option of IR opioids as rescue medication leads to lower baseline
values for daily average pain (;5). Baseline pain scores in study
1003 were lower than those typically reported in tanezumab
osteoarthritis studies,5,6,8,24,29,35,36,39 making it difficult to
achieve substantial improvements because there was less room
for improvement.16
Clinically meaningful pain relief is often described as a reduction
in pain intensity of $30% from baseline.33,34 Among secondary
Figure 6. Change from study 1003 baseline in Brief Pain Inventory short form
score for (A) daily average pain and (B) daily worst pain for patients who rolled
over to study 1029 by parent and extension study treatment (intent to treat,
observed data). BL, baseline. a Transition between studies #8 weeks.
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Table 5
Study 1029
18 (60.0)
4 (13.3)
1 (3.3)
18 (62.1)
7 (24.1)
1 (3.4)
35 (85.4)
23 (56.1)
8 (19.5)
36 (87.8)
23 (56.1)
8 (19.5)
2 (6.7)
0 (0.0)
2 (6.7)
1 (3.3)
2 (6.7)
0 (0.0)
0 (0.0)
2 (6.7)
1 (3.3)
2 (6.7)
1 (3.3)
2 (6.7)
2 (6.7)
1 (3.3)
3 (10.0)
5 (17.2)
2 (6.9)
0 (0.0)
0 (0.0)
2 (6.9)
2 (6.9)
0 (0.0)
2 (6.9)
0 (0.0)
3 (10.3)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (3.4)
8 (19.5)
6 (14.6)
6 (14.6)
6 (14.6)
5 (12.2)
5 (12.2)
4 (9.8)
4 (9.8)
3 (7.3)
3 (7.3)
3 (7.3)
3 (7.3)
3 (7.3)
3 (7.3)
1 (2.4)
9 (21.6)
7 (17.1)
6 (14.6)
6 (14.6)
5 (12.2)
7 (17.1)
4 (9.8)
5 (12.2)
3 (7.3)
5 (12.2)
3 (7.3)
3 (7.3)
3 (7.3)
3 (7.3)
1 (2.4)
* An adverse event in study 1029 was defined as one that started during study 1029 (even if a separate event of the same adverse event term occurred in study 1003) or started during study 1003 and worsened in study 1029.
An adverse event for studies 1003 and 1029 combined was defined as one that started or worsened while the patient was receiving tanezumab.
Includes 2 patients discontinued from study 1029 classified in other discontinuation categories (progressive disease and death) in Fig. 2.
Presentation order for adverse events based on incidence in study 1029.
Table 6
Study 1029
Placebo, n 5 30
Tanezumab 10 mg, n 5 29
Tanezumab 10 mg, n 5 41
28
4 (14.3)
0 (0.0)
4 (14.3)
24 (85.7)
28
3 (10.7)
2 (7.1)
1 (3.6)
25 (89.3)
37
5 (13.5)
0 (0.0)
5 (13.5)
32 (86.5)
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Acknowledgements
Editorial support was provided by Joseph Oleynek of Engage
Scientific Solutions and was funded by Pfizer Inc.
Article history:
Received 7 January 2015
Received in revised form 8 April 2015
Accepted 17 April 2015
Available online 25 April 2015
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