Phase II Randomized, Double-Blind, Placebo-Controlled Symptomatic Metastatic Castrate-Resistant Prostate Cancer

Transcription

Published Ahead of Print on September 19, 2011 as 10.1200/JCO.2011.35.6295
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2011.35.6295
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Phase II Randomized, Double-Blind, Placebo-Controlled
Study of Tasquinimod in Men With Minimally
Symptomatic Metastatic Castrate-Resistant Prostate Cancer
Roberto Pili, Michael Häggman, Walter M. Stadler, Jeffrey R. Gingrich, Vasileios J. Assikis, Anders Björk,
Örjan Nordle, Goran Forsberg, Michael A. Carducci, and Andrew J. Armstrong
Roberto Pili, Roswell Park Cancer Institute, Buffalo, NY; Michael Häggman,
University Hospital of Uppsala, Uppsala;
Anders Björk, Örjan Nordle, and Goran
Forsberg, Active Biotech, Lund,
Sweden; Walter M. Stadler, University
of Chicago, Chicago, IL; Jeffrey R.
Gingrich, University of Pittsburgh, Pittsburgh, PA; Vasileios J. Assikis, Peachtree Hematology Oncology Consultants,
Atlanta, GA; Michael A. Carducci,
Sidney Kimmel Comprehensive Cancer
Center, Johns Hopkins University, Baltimore, MD; and Andrew J. Armstrong,
Duke Cancer Institute and Duke
Prostate Center, Duke University,
Durham, NC.
Submitted March 11, 2011; accepted
July 13, 2011; published online ahead
of print at www.jco.org on September
19, 2011.
Presented in part at the 46th Annual
Meeting of the American Society of
Clinical Oncology, June 4-8, 2010,
Chicago, IL, and 2011 Genitourinary
Cancers Symposium, February 17-19,
2011, Orlando, FL.
A
B
S
T
R
A
C
T
Purpose
The activity of the novel antitumor agent tasquinimod (TASQ) with S100A9 as a molecular target was
investigated in men with metastatic castration-resistant prostate cancer (CRPC) and minimal symptoms.
Patients and Methods
We conducted a randomized, double-blind, placebo-controlled phase II trial in men assigned (at a
ratio of two to one) to either oral once-daily TASQ 0.25 mg/d escalating to 1.0 mg/d over 4 weeks
or placebo. The primary end point was the proportion of patients without disease progression at
6 months, defined by Response Evaluation Criteria in Solid Tumors Group, Prostate Cancer
Working Group (PCWG2), or pain criteria, excluding prostate-specific antigen.
Results
Two hundred one men (134 assigned to TASQ; 67 to placebo) were evaluable, and baseline characteristics
were well balanced. Six-month progression-free proportions for TASQ and placebo groups were 69% and
37%, respectively (P ⬍ .001), and median progression-free survival (PFS) was 7.6 versus 3.3 months (P ⫽
.0042). In PCWG2 CRPC clinical subgroups, PFS in months was as follows: nodal metastases, 6.1 versus
3.1; bone metastases, 8.8 versus 3.4; and visceral metastases, 6.0 versus 3.0 for patients receiving TASQ
versus placebo, respectively. Bone alkaline phosphatase levels were stabilized in the TASQ group, whereas
the impact on PSA kinetics was less pronounced. Adverse events (AEs) occurring more frequently in the
TASQ arm included GI disorders, fatigue, musculoskeletal pains, and elevations of pancreatic and
inflammatory biomarkers. Grade 3 to 4 AEs, including asymptomatic elevations of laboratory parameters,
were reported in 40% of patients receiving TASQ versus 10% receiving placebo; deep vein thrombosis
(4% v 0%) was more common in the TASQ arm.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Conclusion
TASQ significantly slowed progression and improved PFS in patients with metastatic CRPC with
an acceptable AE profile.
Clinical Trials repository link available on
JCO.org.
J Clin Oncol 29. © 2011 by American Society of Clinical Oncology
Corresponding author: Roberto Pili, MD,
Roswell Park Cancer Institute, Elm and
Carlton Sts, Buffalo, NY 14263-0001;
e-mail: [email protected].
© 2011 by American Society of Clinical
Oncology
0732-183X/11/2999-1/$20.00
DOI: 10.1200/JCO.2011.35.6295
INTRODUCTION
Although treatment options for men with metastatic castration-resistant prostate cancer (CRPC)
have increased, novel therapeutic approaches are
needed.1-4 Current treatment options include autologous cellular therapy with sipuleucel-T, docetaxel, and cabazitaxel and secondary hormonal
manipulations such as abiraterone acetate, each
of which has demonstrated improved overall survival.1-4 Despite these improvements, treatments
that delay metastatic progression and defer the need
for chemotherapy are sought by both patients and
health care providers.
Tasquinimod (TASQ) is an oral quinoline-3carboxamide derivative with antiangiogenic proper-
ties5-7 and tumor growth–inhibiting activity against
human prostate cancer models,5,6 possibly mediated
through induction of the endogenous angiogenesis inhibitor thrombospondin-1.8 A molecular target for
TASQ is S100A9 (MRP-14), an immunomodulatory
protein expressed on myeloid-derived suppressor cells
(MDSCs),9 which are present in the tumor microenvironment and stimulate angiogenesis using both vascular endothelial growth factor (VEGF) –dependent
and VEGF-independent mechanisms.10 Tumor growth is impaired in S100A9 knockout mice, suggesting
S100A9 as a suitable therapeutic target.9
During phase I evaluation in men with CRPC,11
gradual dose escalation of oral TASQ from 0.25 mg/d
to a maximum-tolerated dose (MTD) of 1.0 mg/d over
4 weeks was well tolerated, with dose-limiting toxicities
© 2011 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on June 9, 2014. For personal use only. No other uses without permission.
Copyright © 2011 American Society of Clinical Oncology. All rights reserved.
Copyright 2011 by American Society of Clinical Oncology
1
Pili et al
of hyperamylasemia and sinus tachycardia. Few patients developed new
bone metastases during follow-up, indicating potential efficacy.11 Thus,
we conducted a randomized, placebo-controlled, double-blind, multicenter study to examine the efficacy of TASQ in men with minimally
symptomatic metastatic CRPC (protocol provided in Data Supplement).
PATIENTS AND METHODS
Eligibility Criteria
Eligible men had histologically confirmed prostate adenocarcinoma,
Karnofsky performance score (KPS) of 70 to 100, castrate levels of testosterone
(ⱕ 50 ng/dL), visual analog scale (VAS) pain score of 3 or greater (scale, 0 to
10), and radiologically confirmed metastatic disease with progression defined
by rising serum prostate-specific antigen (PSA) levels (confirmed by three
consecutive measurements within 1 year at least 14 days apart), progression of
bidimensionallymeasurablesoft-tissuemetastasis,ornewbonelesionsdetectedby
bone scan within 12 weeks before screening. The following laboratory values were
required: hemoglobin of 9 mg/dL or greater, creatinine of 1.5 times the upper limit
of normal (ULN) or less, total bilirubin of 1.5 times ULN or less, and AST and ALT
of 2.5 times ULN or less. Exclusion criteria included intake of opiates, prior cyto-
toxic chemotherapy within 3 years or previous anticancer therapy using biologics or vaccines within 6 months (bevacizumab not allowed), or any
treatment modalities within 4 weeks. Men with a history of pancreatitis or
cardiovascular disease including recent (⬍ 12 months) myocardial infarction, congestive heart failure, ventricular arrhythmias, or unstable angina
were excluded. Concomitant use of warfarin was not allowed, but a stable
dose of concomitant antiandrogen use was permitted, provided that criteria for progression were met. This study was approved by related institutional review boards, and all patients provided written informed consent.
Treatment Plan
Patients were stratified based on KPS score of 90 to 100 versus 70 to 80
and randomly allocated at a ratio of two to one to receive TASQ or placebo in
a double-blind fashion. Patients received once-daily oral dosing of 1.0 mg
TASQ or placebo after a titration phase (0.25 mg/d for 2 weeks followed by 0.5
mg/d for 2 weeks), leading to a maximum of 6 months of double-blind
treatment. Asymptomatic patients in the placebo group with disease progression during the first 6 months or without progression at 6 months were offered
open-label TASQ. Patients receiving TASQ with no disease progression at 6
months were offered open-label treatment until progression, whereas patients
with disease progression were withdrawn.
Randomly assigned 2:1
active:placebo (N = 206)
Double-blind phase
Tasquinimod
(n = 136)
Did not receive treatment
(n = 2)
Discontinued
Disease progression
Death
Adverse event
Withdrew consent
Other cancer therapy
Other reasons
Did not
receive treatment
(n = 3)
Placebo
(n = 70)
Discontinued
Disease progression
Death
Adverse event
Withdrew consent
Other reasons
(n = 86)
(n = 18)
(n = 4)
(n = 30)
(n = 14)
(n = 4)
(n = 16)
CT and bone scan evaluation
(n = 29)
(n = 13)
(n = 2)
(n = 1)
(n = 5)
(n = 3)
(n = 5)
CT and bone scan evaluation
Disease
progression,
asymptomatic
(n =18)
Completed
24 weeks
(n = 33)
Completed
24 weeks
(n = 48)
Open phase
Entered open-label treatment
(n = 35)
Discontinued
Disease progression
Adverse event
Withdrew consent
Other reasons
Completed
48 weeks
(n = 19)
Entered open-label treatment
(n = 41)
(n = 16)
(n = 7)
(n = 3)
(n = 1)
(n = 1)
(n = 4)
Discontinued
Disease progression
Death
Adverse event
Withdrew consent
Other reasons
(n = 32)
(n = 8)
(n = 1)
(n = 8)
(n = 4)
(n = 2)
(n = 9)
Completed
48 weeks
(n = 9)
Fig 1. Patient disposition during double-blind (above dashed line) and open-label (below dashed line) phases of study. CT, computed tomography.
2
Phase II Study of Tasquinimod in CRPC
Efficacy Outcome Measures
Disease progression was defined as any one or more of the following: one,
pain criteria, including regular consumption of narcotic analgesics (single intravenous dose or ⬎ 10 of 14 days of oral narcotic use), radiation therapy for control of
tumor-related pain, or VAS pain rating of more than 4 because of cancer pain on
two consecutive ratings; two, Response Evaluation Criteria in Solid Tumors
(RECIST; version 1.0) –defined progression (excluding bone scan progression)12;
three, appearance of two or more skeletal lesions not consistent with tumor flare as
per PCWG2 criteria,13 in which progression by bone scan at 3 months required
a second confirmatory scan 6 or more weeks later, with one or more
additional lesion required; and four, need for radiotherapy or surgery for
pathologic fracture or spinal cord compression. Bone and computed tomography scans were evaluated prospectively locally and retrospectively
centrally (Perceptive, Billerica, MA). Toxicity was evaluated using National Cancer Institute Common Toxicity Criteria (version 3.0) criteria.
Pretreatment and Follow-Up Evaluations
At baseline, patients underwent complete history, physical examination,
laboratory tests, and radiologic imaging for eligibility. Visits occurred at 2, 4, 8, 12,
18, and 24 weeks, and patients were radiographically assessed every 12th week and
at withdrawal, with confirmatory scan at week 18, if needed. PSA and VAS pain
scores were measured monthly; all laboratory studies were performed centrally,
and PSA results were blinded to patients and investigators. Biomarkers collected
monthly during the first 3 months and then every third month included fibrinogen, lactate dehydrogenase (LDH), bone alkaline phosphatase (BAP), amylase and
lipase, C-reactive protein (CRP), and erythrocyte sedimentation rate. Safety assessment and standard laboratory tests (complete blood count, hepatic and renal
function) were performed at every visit. Pharmacokinetics were analyzed in all
patients at 2, 4, 8, 12, 24, 36, and 48 weeks after treatment initiation and collected
2.5 to 3.0 hours post dose, as described by Bratt et al.11
Statistical Considerations
The primary end point was the progression-free proportion (PFP) at 6
months and was analyzed when all patients had completed 6 months of treatment,
progressed, or withdrawn from the study, whichever came first. Patients who
withdrewfromthestudyforanyreason,exceptdiseaseprogression,withinthefirst
6monthswereanalyzedaccordingtointention-to-treatanalysisasprogressionfree
for the primary end point. The primary efficacy variable was tested using CochranMantel-Haenszel statistics, stratified by baseline KPS. Equality of the treatment
effect(ie,oddsratio)acrossstratawasassessedbytheBreslow-Daytest.Samplesize
was determined using a null hypothesis for PFP at 6 months in the placebo arm of
10%14 and hypothesized PFP of 30% in the experimental arm, with assumptions
of 90% power and two-sided alpha error of 0.05. Assuming a 5% dropout rate, the
planned sample size was 67 in the placebo arm and 133 in the TASQ arm.
Progression-free survival (PFS) was defined as time from first dose to first progression or death. Time-to-event variables, including unblinded data up to 12 months,
were analyzed using Kaplan-Meier methods, and patients who withdrew before
progression were censored at the date of last progression assessment. Treatment
differences were tested using log-rank test, and a P value of less than .05 was
considered significant. Hazard ratios (HRs) and 95% CIs were estimated using
Cox proportional hazards model via SAS version 9.2 (SAS Institute, Cary, NC).
Standard descriptive statistics were used to describe biomarker values over time.
RESULTS
Patient Characteristics
Enrollment of 206 men between December 2007 and June 2009
occurred at 45 centers in the United States, Canada, and Sweden (Fig 1),
and of those, 201 (134 assigned to TASQ and 67 to placebo) started
treatment and were included in safety and efficacy analyses. Groups were
reasonably well balanced on most baseline characteristics (Table 1). Notably, the presence of tumor pain (28% v 11%) and visceral metastases
(24% v 15%) were more common in the TASQ group, which also had
highermedianbaselinePSAlevel,shortermedianPSAdoublingtime,and
higher proportion of African American patients (15% v 3%).
www.jco.org
Efficacy
For the primary end point, 69% of TASQ-treated patients (93
of 134) versus 37% of those receiving placebo (25 of 67) were
progression free at 6 months (Table 2; relative risk, 0.49; 95% CI,
0.36 to 0.67; P ⬍ .001; Cochran-Mantel-Haenszel). For the PFS
Table 1. Baseline Patient Demographics and Clinical Characteristics
Tasquinimod
(n ⫽ 134)
Baseline Variable
Race
Asian
Black/African American
White
Other
Ethnicity
Hispanic/Latino
Non-Hispanic/Latino
Age, years
Mean
Range
ⱕ 65
66-75
76-80
ⱖ 81
No. of bone lesions
Mean
SD
Measurable disease
Karnofsky performance score
90-100
70-80
Gleason score
⬍7
7
⬎7
Unknown
Tumor pain (VAS ⬎ 0)
Concomitant antiandrogen use
Plasma PSA concentration, ␮g/L
Median
SD
PSA doubling time, months
Median
SD
Plasma LDH, U/L
Median
SD
Plasma ALP, U/L
Median
SD
Hb, g/dL
Median
SD
PCWG2 prognostic group, metastases
Visceral
Bone ⫾ lymph node
Lymph node only
None
Placebo
(n ⫽ 67)
No.
%
No.
%
2
20
110
2
1
15
82
1
0
2
63
2
0
3
94
3
6
128
4
96
2
65
3
97
72.3
49-89
33
41
30
30
73.2
48-89
25
31
22
22
13
24
16
14
3.83
2.74
19
36
24
21
3.12
2.88
60
54
120
14
90
10
59
8
88
12
25
50
50
9
37
29
19
37
37
7
28
22
9
30
25
3
7
16
13
44
37
4
11
24
32
92
9
1
29
36
19.0
20
4.2
2.8
5.1
3.0
202
48
206
46
98
41
87
35
12.9
1.5
13.2
1.3
24
69
7
1
10
44
12
1
15
66
18
1
Abbreviations: ALP, alkaline phosphatase; Hb, hemoglobin; LDH, lactate dehydrogenase; PCWG2, Prostate Cancer Working Group 2; PSA, prostate-specific antigen;
SD, standard deviation; VAS, visual analog scale (linear pain rating, 0 to 10).
3
Pili et al
Table 2. Key Efficacy Findingsⴱ
Tasquinimod
(n ⫽ 134)
Variable
Primary objective
Progressive disease at 24 weeks
Median PFS, months
All patients
Patients age 48-75 years
Patients age 76-89 years
Median PFS by PCWG2 CRPC subgroups, months
Bone only
Bone metastases
Visceral ⫾ bone
Node only
Median PFS by central radiographic assessment, months
All patients
PSA change at 12 weeks v baseline
Median
SD
Radiographic response (RECIST nadir change v baseline)
Median
SD
Best radiographic response (RECIST by investigator)
PR
Stable disease
PD
No.
41
%
31
Placebo (n ⫽ 67)
No.
42
%
63
Hazard/
Risk Ratio
95% CI
0.49
0.36 to 0.67
P
⬍ .001
134
74
60
7.6
8.7
6.1
67
37
30
3.3
3.3
4.0
0.57
0.52
0.66
0.39 to 0.85
0.31 to 0.87
0.36 to 1.23
.0042
.010
.18
53
92
32
9
12.1
8.8
6.0
6.1
30
44
10
12
5.4
3.4
3.0
3.1
0.45
0.56
0.41
0.73
0.23 to 0.88
0.34 to 0.92
0.16 to 1.02
0.27 to 2.00
.016
.019
.045
.54
134
8.4
67
3.8
0.51
0.32 to 0.80
.0029
.063
91
55
8
59
80
11
52
10
6
30
19
5
4
32
25
7
52
41
0
12
27
0
31
69
.23
.0038
Abbreviations: CRPC, castration-resistant prostate cancer; PCWG2, Prostate Cancer Working Group 2; PD, progressive disease; PFS, progression-free survival; PR,
partial response; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors; SD, standard deviation.
ⴱ
Includes overall and subgroup analyses of PFS, PSA changes, and radiographic response as determined by RECIST 1.0 criteria (investigator and independent
radiologic review).
analyses, it should be noted that because of crossover, all patients
received open-label active treatment after 6 months. Median PFS
was 7.6 months for TASQ and 3.3 months for placebo (P ⫽ .0042;
HR, 0.57; 95% CI, 0.39 to 0.85; Fig 2A). In a retrospective central
radiologic review including 155 patients, PFS was 8.4 versus 3.8
months (P ⫽ .0029, inclusive of all 201 patients for composite end
point; Appendix Fig A1D, online only). A sensitivity analysis to
address potential biases on progression at 6 months because of
withdrawal as a result of toxicity was conducted. In the worst-case
scenario (withdrawal because of adverse event [AE] scored as disease progression at that date), relative risk for progression at 6
months was 0.80 (95% CI, 0.62 to 1.02) for TASQ versus placebo.
In the double-blind phase, 84% of patients with progressive disease
had radiographic progression, whereas symptomatic or clinical progression was documented in 22% of patients. Notably, progression on bone
scan was more common in the placebo group (26% v 15% of progression
events). Median radiographic PFS was 8.8 versus 4.4 months (HR, 0.54;
95% CI, 0.36 to 0.82), favoring TASQ (Table 2; Fig 2B).
We evaluated PFS according to PCWG2 CRPC subtypes13,15
defined by localization of metastatic lesions (Table 2; Fig 2; Appendix
Figs A1, A2, online only). For men with visceral metastases, bone
metastases with or without nodal metastases, and lymph node– only
metastases, median PFS in TASQ-treated men versus those receiving
placebo was 6.0 versus 3.0 months (P ⫽ .045; HR, 0.41; 95% CI, 0.16 to
1.02), 8.8 versus 3.4 months (P ⫽ .019; HR, 0.56; 95% CI, 0.34 to 0.92),
and 6.1 versus 3.1 months (P ⫽ .54; HR, 0.73; 95% CI, 0.27 to 2.00),
respectively. Among men with bone metastases only at baseline, median
4
PFSwas12.1versus5.4months(P⫽.016;HR,0.45;95%CI,0.23to0.88).
Subgroup analyses are shown in Appendix Figure A2 (online only).
In patients with measurable disease, 7% of TASQ-treated patients (four of 61) versus 0% of those receiving placebo (none of 39)
had a best overall partial response, including two with visceral disease,
whereas 52% versus 31% had stable disease, respectively (Table 2). A
waterfall plot of investigator-assessed RECIST responses demonstrates that 29% receiving TASQ versus 16% receiving placebo (lymph
nodes only) had reduction in tumor size (Figs 3A, 3B). Corresponding
independently scored radiologic responses were 3%, partial response;
58%, stable disease; and 39%, progressive disease (TASQ) versus 0%,
partial response; 35%, stable disease; and 65%, progressive disease
(placebo); correlation of RECIST changes between central and local
radiologists was good (Spearman r ⫽ 0.65; P ⬍ .001).
PSA and Biomarker Analysis
No significant differences in time to PSA progression or PSA kinetics
were observed between the two treatment groups. Waterfall plot analysis
showed that TASQ treatment had a minor effect on PSA; 4% of men
treated with TASQ had a 50% or greater confirmed PSA decline versus
0% in the placebo group (Appendix Figs A3A, A3B, online only).
During the first 3 months of treatment, median BAP levels were
suppressed below baseline in TASQ-treated patients, whereas BAP increased in patients receiving placebo (Appendix Fig A3C, online only).
Median VEGF levels increased in TASQ-treated patients over the first 3
months and were stable in those receiving placebo (Appendix Fig A3D,
+ Censored
Log-rank P = .0042
1.0
Progression-Free
Survival (probability)
B
0.4
0.2
Tasq
Placebo
1
Progression-Free
2
3
4
122 105
65 65
81
47
63
30
5
6
7
8
9
52
25
40
20
31
14
28
12
0
-50
-80
21
9
20
7
19
5
15
2
-90
+ Censored
Log-rank P = .0451
1.0
B
0.8
400
0.6
0.4
0.2
Tasq
Placebo
1
2
3
4
5
6
7
8
9
10 11 12
Time (months)
32
10
31
10
25
10
20
6
14
3
10
3
6
2
6
0
6
4
3
3
100
0
-50
3
-80
+ Censored
Log-rank P = .0163
1.0
-90
0.8
Fig 3. Response Evaluation Criteria in Solid Tumors (version 1.0) evaluation for
radiographic response in each treatment arm, including waterfall plots illustrating
change in sum of longest diameters (LDs) of tumor measurements during
double-blind phase using percent change (lowest value at treatment compared
with baseline) of sum LD of target lesions. (A) All evaluated tasquinimod-treated
patients (n ⫽ 52); (B) all evaluated patients receiving placebo (n ⫽ 30).
0.6
0.4
0.2
Tasq
Placebo
0
1
2
3
4
5
6
7
8
9
10 11 12
Time (months)
53
30
48
29
42
29
34
21
28
17
25
15
22
13
19
10
17
9
14
7
14
5
14
3
10
1
Fig 2. Kaplan-Meier estimates of progression-free survival (PFS) for patients receiving
tasquinimod (Tasq) versus placebo followed by crossover to Tasq at disease progression
or after 6 months. (A) All patients (PFS, 7.6 [n ⫽ 134] v 3.3 months [n ⫽ 67]); (B)
patients with visceral metastatic disease (PFS, 6.0 [n ⫽ 32] v 3.0 months [n ⫽ 10]);
(C) patients with bone metastases only at baseline (PFS, 12.1 [n ⫽ 53] v 5.4 months
[n ⫽ 30]).
onlineonly).MedianLDHlevelsdecreasedapproximately15%inTASQtreated patients over the first 8 weeks, whereas they increased 3% in those
receiving placebo.
Safety
Dose reduction or termination for any reason during the first 9
weeks was documented in 55% of TASQ-treated patients (74 of 134).
However, a majority of patients discontinuing because of AEs in the
TASQ arm withdrew because of grade 1 to 2 toxicities. Discontinuation
rate because of toxicity was 22% versus 1% for patients receiving placebo,
often occurring without protocol-specified dose reductions; thus, for a
majority of patients, TASQ had an acceptable toxicity profile, but in some
patients, particularly men older than age 75 years, TASQ was sufficiently
poorly tolerated that patients or providers felt it necessary to stop therapy.
The most notable AEs observed in the TASQ group were GI events,
muscle and joint pain, and fatigue (Table 3; Appendix Fig A4, online
www.jco.org
100
10 11 12
Time (months)
134
67
No. at risk
Tasq
Placebo
No. at risk
Tasq
Placebo
% Change
0.6
0
C
400
0.8
0
No. at risk
Tasq
Placebo
A
% Change
Progression-Free
A
only). A majority of AEs (89%, TASQ; 94%, placebo) were grade 1 to 2.
Grade 3 to 4 toxicities, most commonly asymptomatic changes in laboratory parameters, were observed in 53 versus eight patients (40% v 12%).
Incidence of grade 4 or higher AEs were infrequent and did not differ
between treatment groups. The most common grade 3 to 4 AEs in the
TASQ group were increased lipase, muscular weakness, deep vein thrombosis, anemia, asthenia, renal failure, and pneumonia. A minor decrease
inmeanbloodpressurewasseenintheTASQgroup,andnocorrectedQT
interval changes were noted. No difference in number of arterial thrombotic events was observed between the arms (3% v 3%). The most common reason for treatment discontinuation because of toxicity was muscle
and/or joint pain. Notably, patients older than 80 years of age were more
likely to develop AEs, with 73% (22 of 30) requiring dose reduction or
withdrawal during the first 9 weeks versus 50% of men age 80 years or
older (52 of 104).
TASQ treatment led to a transient increase in WBC count, amylase, lipase, pancreatic amylase, CRP, and fibrinogen after 1 to 2
months of treatment; these parameters generally returned to normal
within 6 months. Increases in CRP were retrospectively found to
correlate with joint/extremity pain.
Pharmacokinetics
TASQ was found to have a low clearance. Mean individual
clearance values were 0.17 at 0.25 mg, 0.19 at 0.5 mg, and 0.22 L/h
at the 1 mg dose level; thus the increase in systemic exposure was
5
Pili et al
Table 3. Most Common AEs and Important Grade 3 to 4 Toxicities During
Double-Blind Phase
Tasquinimod (grade)
1 to 4
3 to 4
Placebo (grade)
1 to 4
3 to 4
AE
No.
%
No.
%
No.
%
Fatigue
Nausea
Constipation
Back pain
Decreased appetite
Pain in extremity
Flatulence
Arthralgia
Anemia
Diarrhea
Insomnia
Weight loss
Abdominal pain
Vomiting
Blood amylase increase
Blood lipase increase
Myalgias
Peripheral edema
Musculoskeletal pain
Deep vein thrombosis
Myocardial infarction
39
36
34
32
27
25
22
21
16
16
16
16
14
14
13
13
13
13
12
5
1
29
27
25
24
20
19
16
16
12
12
12
12
10
10
10
10
10
10
9
4
1
1
2
2
2
1
1
1
1
1
1
1
1
2
4
1
1
3
1
12
11
11
7
5
4
7
5
4
9
4
18
16
16
10
7
6
10
7
6
13
6
1
1
4
5
6
7
3
4
5
4
6
7
1
7
1
1
5
1
5
1
4
1
No.
%
2
3
1
1
Abbreviation: AE, adverse event.
somewhat less than the dose increase. Volume of distribution was
5.9 L, similar to previous findings.11 TASQ clearance decreased
1.4% per year of age in the study population, which correlated with
a higher discontinuation rate with increasing age (Table 2). We
found no relationship between pharmacokinetic parameters and
race/ethnicity or hepatic function.
DISCUSSION
In this randomized, double-blind, placebo-controlled phase II trial of
men with metastatic CRPC, disease progression was significantly delayed
by TASQ. Median PFS improved from 3.3 to 7.6 months (P ⫽ .0042),
representing a clinically meaningful halving of the ongoing risk of progression or death over time over placebo. After 6 months of treatment,
63% of patients in the placebo group had progressed as compared with
31% in the TASQ group. Notably, patients treated with TASQ seemed
to have more adverse baseline factors (pain, visceral metastases) associated with greater likelihood of progression, indicating that the observed effect was unlikely caused by chance imbalances at
randomization. Improvements in PFS were observed despite crossover of a small number of men (n ⫽ 17) who were progression free at
6 months in the placebo arm, which would have the effect of biasing
our results toward a null effect. TASQ in general had acceptable
toxicity to a majority of men, particularly those men younger than age
75 years, with infrequent discontinuation because of AEs.
Men with metastatic CRPC are a heterogeneous population that
can be divided into prognostic subgroups depending on location of
metastases (visceral, bone, or lymph nodes), as defined by the
PCWG2.13,15 It seems that TASQ delays disease progression in each of
these CRPC subgroups, particularly those with bone metastases. Notably, to our knowledge, this is the first positive controlled phase II trial
6
in men with CRPC that successfully incorporated new PCWG2 guidelines, which de-emphasize PSA changes in the evaluation of novel
agents and require confirmatory bone scans to reduce the risk of early
discontinuation because of bone scan flare. Results from this study
confirm the feasibility of conducting clinical trials without focusing on
PSA, provided that both treating physicians and patients understand
that novel biologic agents may provide benefit without directly altering this traditional biomarker. Although PSA and LDH levels may
reflect tumor burden,16,17 their relevance as markers of clinical benefit
in the evaluation of noncytotoxic agents is controversial and therefore
of uncertain value, particularly given the present findings of a disconnect between the PFS benefit observed and PSA declines.13,18 Blinded
assessment of PSA levels in this study permitted an unbiased assessment of PFS, in which PSA was not used as a determinant. TASQ
treatment also strongly inhibited the natural increase in BAP levels
observed during progression, which may reflect a positive therapeutic
effect on delayed progression of osteoblastic bone metastases.
We observed an increase in circulating VEGF levels with TASQ
treatment, perhaps indicating interference with VEGF receptor signaling similar to that seen with sunitinib19 or a potential mechanism of
therapeutic resistance. Preclinical findings suggest that the antitumor
effect of TASQ is mediated through inhibition of angiogenesis5 with
an upregulation of thrombospondin-1,8 a potent endogenous inhibitor of angiogenesis and cellular migration.20-23 One molecular target
for TASQ is S100A9,9 a receptor expressed on MDSCs. MDSCs promote immune tolerance during cancer progression and facilitate
pathologic angiogenesis, in part mediated by S100A9 upregulation.10,24 We hypothesize that the antiangiogenic and antimetastatic
properties of TASQ are mediated through modulation of MDSC
activity within the tumor microenvironment. These unique characteristics and the observed clinical benefit in this study suggest that TASQ
should be further tested in larger phase III studies in the context of
other emerging therapies for men with CRPC.2,3,25
In general, TASQ treatment was safe, with an AE profile similar to
that observed in phase I11 but of a slightly greater magnitude. One important explanation for this is that the current trial had more men older than
80 years of age (22% v 6% in phase I); tolerability was noted to decrease
with age, likely attributable to slower hepatic clearance of TASQ. Importantly,however,inmostcases,AEsweretransientandreversibleandcould
be managed through dose reductions or supportive measures, with continuation of drug at individual MTDs. Future trials will more flexibly
allow patients to be treated at their individual MTDs.
TASQ treatment led to a transient increase in several laboratory
parameters such as amylase, lipase, CRP, and fibrinogen. Increased
levels of amylase and lipase were asymptomatic and did not correlate
with evidence of clinical or radiographic pancreatitis or bowel toxicity.
Additional studies are needed to address the mechanisms behind these
observations in more detail as well as clinical correlations.
Although the event rate was low, cardiovascular events seemed
slightly more frequent in TASQ-treated patients (Table 3). Antiangiogenic agents have been associated with higher risk of arterial/venous
thrombotic events in general.20,22,23 Although we carefully excluded
men with prior recent cardiovascular disease, subclinical cardiovascular disease was likely present in this elderly male population and may
have contributed to these findings, which need to be further investigated in larger phase III studies. The number of myocardial infarctions
was acceptably low (Table 3) in this study, and no adverse effects on
blood pressure or electrocardiogram abnormalities were observed.
In conclusion, TASQ delayed disease progression in men with metastatic minimally symptomatic CRPC by a median of 4.3 months, findings similar to or better than PFS improvements seen with existing US
Food and Drug Administration–approved therapies. This improvement
is clinically important given that it was achieved in a chemotherapy-naive
population without significant toxicities in a majority of men through
use of intrapatient stepwise dose escalation to individual MTDs. A
phase III trial to further evaluate overall clinical benefit in a larger
predocetaxel metastatic CRPC population is under way.
Michael Häggman, Active Biotech (C); Michael A. Carducci, Active Biotech
(C); Andrew J. Armstrong, Active Biotech (C), Dendreon (C) Stock
Ownership: Örjan Nordle, Active Biotech; Goran Forsberg, Active Biotech
Honoraria: Andrew J. Armstrong, Dendreon, sanofi-aventis, Johnson &
Johnson, Janssen Biotech Research Funding: Roberto Pili, Active Biotech;
Walter M. Stadler, Active Biotech; Jeffrey R. Gingrich, Active Biotech;
Michael A. Carducci, Active Biotech; Andrew J. Armstrong, Active Biotech,
sanofi-aventis, ImClone Systems, Bristol-Myers Squibb, Medivation,
Dendreon Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a “U” are those for which no compensation was received; those
relationships marked with a “C” were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: Örjan Nordle, Active Biotech (C);
Goran Forsberg, Active Biotech (C) Consultant or Advisory Role:
REFERENCES
1. de Bono JS, Oudard S, Ozguroglu M, et al:
Prednisone plus cabazitaxel or mitoxantrone for
metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised
open-label trial. Lancet 376:1147-1154, 2010
2. de Bono JS, Logothetis C, Fizazi K, et al:
Abiraterone acetate plus low dose prednisone improves overall survival in patients with metastatic
castration-resistant prostate cancer (CRPC) who
have progressed after docetaxel-based chemotherapy: Results of COU-AA-301, a randomized doubleblind placebo-controlled phase 3 study. Presented at
the 35th European Society for Medical Oncology
Congress, Milan, Italy, October 8-12, 2010
3. Kantoff PW, Higano CS, Shore ND, et al:
Sipuleucel-T immunotherapy for castration-resistant
prostate cancer. N Engl J Med 363:411-422, 2010
4. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med
351:1502-1512, 2004
5. Dalrymple SL, Becker RE, Isaacs JT: The
quinoline-3-carboxamide anti-angiogenic agent, tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without
effecting serum PSA directly in human xenografts.
Prostate 67:790-797, 2007
6. Isaacs JT, Pili R, Qian DZ, et al: Identification of
ABR-215050 as lead second generation quinoline-3carboxamide anti-angiogenic agent for the treatment of
prostate cancer. Prostate 66:1768-1778, 2006
7. Isaacs JT: The long and winding road for the
development of tasquinimod as an oral secondgeneration quinoline-3-carboxamide antiangiogenic
drug for the treatment of prostate cancer. Expert
Opin Investig Drugs 19:1235-1243, 2010
Conception and design: Roberto Pili, Anders Björk, Örjan Nordle,
Goran Forsberg, Michael A. Carducci, Andrew J. Armstrong
Administrative support: Andrew J. Armstrong
Provision of study materials or patients: Roberto Pili, Michael Häggman,
Walter M. Stadler, Jeffrey R. Gingrich, Michael A. Carducci, Andrew J.
Armstrong
Collection and assembly of data: Roberto Pili, Walter M. Stadler, Jeffrey
R. Gingrich, Vasileios J. Assikis, Örjan Nordle, Goran Forsberg, Michael
A. Carducci, Andrew J. Armstrong
Data analysis and interpretation: Roberto Pili, Walter M. Stadler, Anders Björk,
Örjan Nordle, Goran Forsberg, Michael A. Carducci, Andrew J. Armstrong
Manuscript writing: All authors
Final approval of manuscript: All authors
8. Olsson A, Björk A, Vallon-Christersson J, et al:
Tasquinimod (ABR-215050), a quinoline-3-carboxamide
anti-angiogenic agent, modulates the expression of
thrombospondin-1 in human prostate tumors. Mol
Cancer 9:107, 2010
9. Björk P, Björk A, Vogl T, et al: Identification of
human S100A9 as a novel target for treatment of
autoimmune disease via binding to quinoline-3carboxamides. PLoS Biol 7:e97, 2009
10. Murdoch C, Muthana M, Coffelt SB, et al: The
role of myeloid cells in the promotion of tumour
angiogenesis. Nat Rev Cancer 8:618-631, 2008
11. Bratt O, Häggman M, Ahlgren G, et al: Openlabel, clinical phase I studies of tasquinimod in
patients with castration-resistant prostate cancer.
Br J Cancer 101:1233-1240, 2009
12. Therasse P, Arbuck SG, Eisenhauer EA, et al:
New guidelines to evaluate the response to treatment in solid tumors: European Organisation for
Research and Treatment of Cancer, National Cancer
Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000
13. Scher HI, Halabi S, Tannock I, et al: Design and
end points of clinical trials for patients with progressive
prostate cancer and castrate levels of testosterone: Recommendations of the Prostate Cancer Clinical Trials
Working Group. J Clin Oncol 26:1148-1159, 2008
14. Small EJ, Schellhammer PF, Higano CS, et al:
Placebo-controlled phase III trial of immunologic
therapy with sipuleucel-T (APC8015) in patients with
metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089-3094, 2006
15. Armstrong AJ, Tannock IF, de Wit R, et al: The
development of risk groups in men with metastatic
castration-resistant prostate cancer based on risk
factors for PSA decline and survival. Eur J Cancer
46:517-525, 2010
16. Armstrong AJ, Garrett-Mayer ES, Yang YC,
et al: A contemporary prognostic nomogram for
men with hormone-refractory metastatic prostate
cancer: A TAX327 study analysis. Clin Cancer Res
13:6396-6403, 2007
17. Halabi S, Small EJ, Kantoff PW, et al: Prognostic model for predicting survival in men with
hormone-refractory metastatic prostate cancer.
J Clin Oncol 21:1232-1237, 2003
18. Armstrong AJ, Garrett-Mayer E, Ou Yang YC,
et al: Prostate-specific antigen and pain surrogacy
analysis in metastatic hormone-refractory prostate
cancer. J Clin Oncol 25:3965-3970, 2007
19. Motzer RJ, Michaelson MD, Redman BG, et al:
Activity of SU11248, a multitargeted inhibitor of vascular
endothelial growth factor receptor and platelet-derived
growth factor receptor, in patients with metastatic renal
cell carcinoma. J Clin Oncol 24:16-24, 2006
20. Choueiri TK, Plantade A, Elson P, et al: Efficacy of
sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol 26:127-131,
2008
21. Isenberg JS, Martin-Manso G, Maxhimer JB,
et al: Regulation of nitric oxide signalling by thrombospondin 1: Implications for anti-angiogenic therapies. Nat Rev Cancer 9:182-194, 2009
22. Nalluri SR, Chu D, Keresztes R, et al: Risk of
venous thromboembolism with the angiogenesis
inhibitor bevacizumab in cancer patients: A metaanalysis. JAMA 300:2277-2285, 2008
23. Scappaticci FA, Skillings JR, Holden SN, et al:
Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 99:1232-1239, 2007
24. Cheng P, Corzo CA, Luetteke N, et al: Inhibition of
dendritic cell differentiation and accumulation of myeloidderived suppressor cells in cancer is regulated by
S100A9 protein. J Exp Med 205:2235-2249, 2008
25. Scher HI, Beer TM, Higano CS, et al: Antitumour activity of MDV3100 in castration-resistant
prostate cancer: A phase 1-2 study. Lancet 375:
1437-1446, 2010
■ ■ ■
www.jco.org
7
Pili et al
Acknowledgment
This study was conducted within the Department of Defense Prostate Cancer Clinical Trials Consortium, and we are grateful to the
additional investigators who accrued to this study, including: Richy Agajanian, American Institute of Research, Whittier, CA; Göran Ahlgren,
Universitetssjukhuset MAS, Malmö, Sweden; Cal Andreou, Andreou Research, Surrey, United Kingdom; John Araujo, MD Anderson Cancer
Center, Houston, TX; Laurence Belkoff, Urologic Consultants of Southeastern Pennsylvania, Bala Cynwyd, PA; Guy Bernstein, Center for
Urological Care, Bryn Mawr, PA; Stanley Brosman, Pacific Institute of Urology, Santa Monica, CA; Sam Chang, Vanderbilt University Medical
Center, Nashville, TN; Franklin Chu, San Bernardino Urological Associates, San Bernardino, CA; William Clark, Alaska Clinical Research Center,
Anchorage, AK; Randil Clark, North Idaho Urology, Coeur d’Alene, ID; Giovanni Colombo, Midwest Urology, Peoria, IL; Barrett Cowan,
Urology Associates, Englewood, CO; Jan-Erik Damber, Sahlgrenska Hospital, Göteborg, Sweden; Samuel Denmeade, Johns Hopkins
Hospital, Baltimore, MD; James Elist, Pacific Clinical Center, Beverly Hills, CA; Hugh Fisher, Community Care Physicians, Albany, NY;
Mark Fleming, Virginia Oncology Associates, Norfolk, VA; Jeffrey Frankel, Seattle Urology Research Center, Burien, WA; Russell Freid,
Lawrenceville Urology, Lawrenceville, NJ; Richard Harris, Midwest Urology/RMD Research, Melrose Park, IL; Eric Hirchberg, Guelph Urology
Associates, Guelph, Ontario, Canada; Ron Israeli, Staten Island Urological Research, Staten Island, NY; Richard Kane, Wake Urological
Associates, Raleigh, NC; Danny Keiller, Urology Physicians of San Diego, San Diego, CA; Jeffrey Marks, Plantation, FL; Jonathan Polikoff, Kaiser
Permanente Medical Group, San Diego, CA; Charles Redfern, Medical Oncology Associates of San Diego, San Diego, CA; Ilan Shapira, Beth Isreal
Medical Center, New York, NY; Daniel Shevrin, North Shore University Health System, Evanston, IL; Paul Sieber, Urological Associates of
Lancaster, Lancaster, PA; Frederick Snoy, Urology Group of New Mexico, Albuquerque, NM; Todd Webster, Owen Sound, Ontario, Canada;
Joseph Williams, Idaho Urologic Institute, Meridian, ID; and Edward Woods, Scarborough, Ontario, Canada. We are indebted to the many
patients and their families for their participation in this trial.
Appendix
0.8
0.6
0.4
0.2
Tasq
Placebo
0
Progression-Free
9
12
3
4
5
6
7
8
9
12
9
12
6
9
5
4
5
4
4
3
2
2
2
1
9
10 11 12
1
1
1
1
0
1
0
+ Censored
Log-rank P = .0027
1.0
0.8
0.6
0.4
0.2
0
No. at risk
Tasq
Placebo
2
Time (months)
No. at risk
Tasq
Placebo
C
1
Tasq
Placebo
1
2
3
4
5
6
7
8
9
122 105
65 65
81
47
63
30
52
25
40
20
31
14
28
12
21
9
20
7
19
5
15
2
+ Censored
Log-rank P = .019
1.0
0.8
0.6
0.4
0.2
Tasq
Placebo
0
D
1
92
44
3
4
5
6
7
8
82
42
73
42
55
31
42
31
36
18
30
15
23
12
20
11
9
10 11 12
16
8
16
6
16
4
12
2
+ Censored
Log-rank P = .0029
1.0
0.8
0.6
0.4
0.2
0
No. at risk
Tasq
Placebo
2
Time (months)
No. at risk
Tasq
Placebo
10 11 12
Time (months)
134
67
B
Progression-Free
+ Censored
Log-rank P = .5405
1.0
Progression-Free
Progression-Free
A
Tasq
Placebo
1
2
3
4
5
6
7
8
9
10 11 12
21
19
Time (months)
134
67
122 105
65 65
76
45
56
25
46
21
36
11
29
0
27
18
13
Fig A1. Kaplan-Meier estimates of progression-free survival (PFS; months/N) for patients receiving tasquinimod (Tasq) versus placebo followed by crossover to Tasq
at disease progression or after 6 months. (A) Patients with nodal metastases only at baseline (6.1 [n ⫽ 9] v 3.1 months [n ⫽ 12]); (B) patients with bone lesions with
or without nodal metastases at baseline (8.8 [n ⫽ 92] v 3.4 months [n ⫽ 44]); (C) radiographic PFS using local review (8.8 [n ⫽ 134] v 4.4 months [n ⫽ 67]); (D) PFS
using composite definition, including central review of radiologic events in 155 patients (8.4 [n ⫽ 134] v 3.8 months [n ⫽ 67]).
8
Population
TASQ (months)
Placebo (months)
P
HR
ITT (n = 201)
7.6
3.3
.0042
0.57
ITT (n = 201)*
8.8
4.4
.0027
0.54
Karnofsky ≤ 80 (n = 22)
4.9
3.2
.1633
0.46
Karnofsky ≥ 90 (n = 179)
8.7
3.3
.0120
0.59
Age 40-75 (n = 111)
8.7
3.3
.0103
0.52
Age 76-99 (n = 90)
6.1
4.0
.1826
0.66
Alk. Ph. > ULN (n = 43)
8.7
6.8
.6716
0.81
Alk. Ph. ≤ ULN (n = 158)
6.2
3.2
.0045
0.55
Hemoglobin < LLN (n = 96)
6.0
3.9
.1217
0.64
Hemoglobin ≥ LLN (n = 105)
8.9
3.2
.0274
0.55
LDH > ULN (n = 31)
8.9
6.8
.7132
0.82
LDH ≤ ULN (n = 170)
7.6
3.3
.0030
0.54
PSA DT < 4.4 months (n = 100)
8.7
3.1
.0184
0.52
PSA DT > 4.4 months (n = 101)
6.2
4.9
.0617
0.59
PSA day1 < 24 µg/L (n = 100)
8.9
3.2
.0073
0.48
PSA day1 ≥ 24 µg/L (n = 101)
5.9
3.8
.3433
0.77
Bone Only (n = 83)
12.1
5.4
.0163
0.45
Bone metastases (n = 136)
8.8
3.4
.0191
0.56
Node only (n = 21)
6.1
3.1
.5405
0.73
Visceral (n = 42)
6.0
3.0
.0451
0.41
0
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2
Favors Tasq
Favors placebo
Fig A2. Forest plot showing median progression-free survival and hazard ratios (HRs) with 95% CIs for all patients and subgroups comparing tasquinimod (TASQ) with
placebo. Alk. Ph., alkaline phosphatase; DT, doubling time; ITT, intent to treat; LDH, lactate dehydrogenase; LLN, lower limit of normal; PSA, prostate-specific antigen;
ULN, upper limit of normal.
www.jco.org
9
Pili et al
A
400
400
100
100
% Change
% Change
B
0
-50
0
-50
-80
-80
-90
-90
D
C
Tasq
Placebo
40
30
30
% Change
% Change
Tasq
Placebo
40
20
10
20
10
0
0
-10
-10
0
1
2
3
4
5
6
0
1
Time (months)
2
3
4
5
6
Time (months)
Fig A3. Prostate-specific antigen (PSA) and biomarker analysis during double-blind phase. (A) Waterfall plot illustrating change in PSA levels after 12 weeks as
compared with baseline PSA (tasquinimod [Tasq]); (B) waterfall plot illustrating change in PSA levels as compared with baseline PSA (placebo). Median (⫾ SE) levels
of biomarkers (C) bone alkaline phosphatase and (D) vascular endothelial growth factor are shown over time normalized to day 0 during double-blind treatment period.
Nausea
Fatigue
Constipation
Decreased appetite
Flatulence
Tasq Grade 4
Diarrhea
Tasq Grade 3
Back pain
Tasq Grade 2
Pain in extremity
Tasq Grade 1
Arthralgia
Blood amylase increased
Placebo Grade 4
Lipase increased
Placebo Grade 3
Vomiting
Placebo Grade 2
Anemia
Placebo Grade 1
Headache
Abdominal pain
0
5
10
15
20
25
30
Fig A4. Most common related adverse events (AEs) and percent of patients with grade 1 to 4 AEs in double-blind phase. Tasq, tasquinimod.
10

Phase II Randomized, Double-Blind, Placebo-Controlled Symptomatic Metastatic Castrate-Resistant Prostate Cancer

Transcription

Similar documents

TASQ POS Solutions

Maintenance in Lung cancer – Yes ? Dr. Ryvo Larisa TASMC

More E.P.I.C. Recommends - E.P.I.C. Empowering People, Inspiring

- Highland Church

ShapeWayTM Metabolic Energizer

Foreword - touchONCOLOGY

What is a Placebo Controlled Trial?

ISIS 301012: The Reduction of Atherogenic Lipids in