1. Understanding some basic trial designs
in sarcomas (inclusive a placebo one)
Winette van der Graaf
Radboud University Medical Center
Nijmegen, The Netherlands
22-11-12

2. The aim and value of clinical trials
• Generating evidence for a treatment in a certain
situation for a certain patient population
• Evidence generated by clinical trials are the
basis of guidelines (phase 3 studies generate
the highest level evidence)
• Often study results are extrapolated for “daily
use”, but be aware: the study has been
performed for a certain disease, in a defined
patient population

3. A study population is not the same
as the general population

4. Study patients should not only be the
“athletes”

5. Age limits, but:

6. The incidence of soft tissue sarcomas

7. The incidence of soft tissue sarcomas
has a peak around 65 years of age..

8. Old and fit...

9. Old and frail (co-medication, other
relevant diseases!)

10. Also the disease varies a lot!
Variation in:
• Localisation primary tumor
• Primary tumor plus or minus metastases
• Histology: about 50 diagnoses
• Location of metastases: lymph node, lung, liver,
bone, etc
• Symptoms
• Q: If only metastases on X-ray and no symptoms: why
should you treat a patient in a study?

11. Talk of today...trials designs..
• From the very first clinical trial in sarcoma
to three recent randomised phase 3 trials
• With endpoint varying from response
to progression free and overall survival

12. Phase of trials
• Phase 1: first clinical trial in humans, aiming to
establish the optimal dosage of a drug
• Phase 2: efficacy of a new drug in a certain
patient population
• Phase 3: comparison of two treatment arms
- blinded, if possible, or not

13. The first “mixed bag phase 2 trial”
with adriamycin

14. The first efficacy trial with adriamycin
in “sarcomas”

15. A Classical Phase 3 design
• Standard treatment versus other standard
treatment
Or
• Standard treatment versus an experimental
treatment
Or
• Placebo versus new treatment

16. 3 Phase three trials
• EORTC 62012- chemotherapy in STS
- standard versus standard-
• PALETTE EORTC 62072- pazopanib in STS
- new versus placebo- no cross-over
• GRID trial: regorafenib in GIST
- new versus placebo- with cross-over

17. Results of a randomised phase III trial (EORTC 62012) of single
agent doxorubicin versus doxorubicin plus ifosfamide as first
line chemotherapy for patients with advanced, soft tissue
sarcoma: a survival study by the EORTC Soft Tissue and Bone
Sarcoma Group.
Ian Judson, Jaap Verweij, Hans Gelderblom, Jorg-
Thomas Hartmann, Patrick Schöffski, Jean-Yves
Blay, Angelo Paolo dei Tos, Sandrine Marreaud,
Saskia Litiere, Winette van der Graaf

18. PALETTE
A randomized double blind phase III trial of pazopanib
versus placebo in patients with soft tissue sarcoma (STS)
whose disease has progressed during or following prior
chemotherapy.
An EORTC STBSG and GSK global network study (EORTC 62072)
W. T. A. van der Graaf, J. Y. Blay, S. Chawla, D.W. Kim, B. Bui-Nguyen,
P. Casali, P. Schoeffski, M. Aglietta, A. Staddon, Y. Beppu, A. Le Cesne,
H. Gelderblom, I.Judson, N. Araki, M. Ouali, S. Marreaud, R A. Hodge,
M. Dewji, P. Dei Tos, P. Hohenberger, on behalf of the global PALETTE study team.

19. Randomized Phase III Trial of Regorafenib
in Patients (pts) with Metastatic and/or Unresectable
Gastrointestinal Stromal Tumor (GIST)
Progressing Despite Prior Treatment with at least
Imatinib (IM) and Sunitinib (SU): The GRID Trial
GD Demetri, P Reichardt, Y-K Kang, J-Y Blay, H Joensuu, RG Maki,
P Rutkowski, P Hohenberger, H Gelderblom, MG Leahy, M von Mehren,
P Schöffski, ME Blackstein, A Le Cesne, G Badalamenti, J-M Xu, T Nishida,
D Laurent, I Kuss, and PG Casali, on behalf of GRID Investigators
Demetri et al. ASCO 2012

20. Results of a randomised phase III trial (EORTC 62012) of single
agent doxorubicin versus doxorubicin plus ifosfamide as first
line chemotherapy for patients with advanced, soft tissue
sarcoma: a survival study by the EORTC Soft Tissue and Bone
Sarcoma Group.
Ian Judson, Jaap Verweij, Hans Gelderblom, Jorg-
Thomas Hartmann, Patrick Schöffski, Jean-Yves
Blay, Angelo Paolo dei Tos, Sandrine Marreaud,
Saskia Litiere, Winette van der Graaf

21. Rationale of the study
• The outcome of patients with soft tissue sarcomas with
locally advanced unresectable primary tumors and/or
metastatic disease is poor.
• Systemic treatment is usually given in this situation with
a palliative intent, but has toxicity.
• There is (transatlantic) debate about the best first-line
treatment in this situation:
single agent doxorubicin or a combination of
doxorubicin and ifosfamide
21

22. Rationale of the study (II)
Which situation justifies which treatment, especially the
more toxic combination treatment?
And in designing studies with new drugs/treatments:
what will be the standard treatment arm to compare
with?
22

23. The design
Stratification:
•Age (<50 vs ≥50)
•PS (0 vs 1)
•Liver metastases (0 vs +)
•Histological grade (2 vs 3)
Doxorubicin 75 mg/m2 d 1 or
as a 72 hour continous i.v. infusion
R
Doxorubicin 25 mg/m2 d 1-3
New Treatment: B
+ Ifosfamide 2.5 g/m2 d 1-4
+ Neulasta 6mg s.c. d5

24. End-points of the study
The primary end point:
overall-survival
The secondary end points:
response (RECIST)
toxicity (CTC 2.0)
treatment related mortality
24

25. Study status
Accrual:
• 455 patients entered the study
• 38 centers in 9 countries
• Start: 4-2003 (start EORTC), 5-2008 (NCIC- 13 patients)
»7 YEARS IS LONG, WHY?
• Study Closure: 5-2010
Clinical cut-off
• 5-7-2012
• Median follow-up: 56 months
25

26. Patient characteristics
Treatment
Doxo Doxo-Ifos Total
(n=228) (n=227) (n=455)
n (%) n (%) n (%)
Age group
< 40 yrs 52 (22.8) 60 (26.4) 112 (24.6)
40-49 yrs 78 (34.2) 70 (30.8) 148 (32.5)
≥ 50 yrs 98 (43.0) 97 (42.7) 195 (42.9)
Age (years)
Median 48 47 48
Range 18 - 60 18 - 63 18 - 63
Gender
Male 103 (45.2) 114 (50.2) 217 (47.7)
Female 125 (54.8) 113 (49.8) 238 (52.3)
Performance status
0 129 (56.6) 123 (54.2) 252 (55.4)
1 98 (43.0) 103 (45.4) 201 (44.2)
2 1 (0.4) 1 (0.4) 2 (0.4)
26

27. Overall survival
100
90
80
HR = 0.83 (95.5% CI 0.67 – 1.03)
Stratified logrank test, p = 0.076
70
60
50
40
30
20
10
0 (years)
0 1 2 3 4 5 6 7 8
O N Number of patients at risk : Treatment
188 228 113 54 29 19 14 9 2 Doxo
184 227 130 64 30 20 13 7 3 DxIf
27

28. Median overall survival:
• Doxorubicin: 12.8 months (95.5 CI 10.5-14.3)
• Doxorubicin-ifosfamide: 14.3 months (95.5% CI
12.5-16.5).
Survival at 1-year:
• Doxorubicin: 51% (95.5% CI 44-58)
• Doxorubicin-ifosfamide: 60% (95.5% CI 53-66)
28

29. Overall survival
29

30. Progression free survival
100
90
80
HR = 0.74 (95% CI 0.60 – 0.90)
70
Stratified logrank test, p = 0.003
60
50
40
30
20
10
0 (years)
0 1 2 3 4 5 6 7 8
O N Number of patients at risk : Treatment
215 228 38 15 8 6 5 4 1 Doxo
210 227 50 16 12 11 10 7 3 DxIf
30

31. Median PFS
Median PFS in the doxorubicin arm: 4.6 months (95%
CI 2.9 – 5.6),
in the combination arm 7.4 months (95% CI 6.6 – 8.3).
31

32. Progression free survival
32

33. Best overall response
Treatment
Doxo Doxo-Ifos Total
(n=228) (n=227) (n=455)
n (%) n (%) n (%)
Complete Response 1 (0.4) 4 (1.8) 5 (1.1)
Partial Response 30 (13.2) 56 (24.7) 86 (18.9)
ORR 13.6 26.5
No Change 105 (46.1) 114 (50.2) 219 (48.1)
Progressive Disease 74 (32.5) 30 (13.2) 104 (22.9)
Early Death - Progression 4 (1.8) 5 (2.2) 9 (2.0)
Early Death – Other cause 3 (1.3) 2 (0.9) 5 (1.1)
Significant difference between the two arms: p < 0.001(7.0)
Not evaluable 11 (4.8) 16 27 (5.9)
33

34. Adverse events (grade ≥ 3)
Doxo DxIf Total
(N = 223) (N = 224) (N = 447)
Neutropenia 37.2% 41.5% 39.4%
Leucopenia 17.9% 43.3% 30.7%
Febrile neutropenia 13.5% 45.9% 29.8%
Anemia 4.6% 34.9% 19.7%
Thrombocytopenia 0.4% 33.5% 17.0%
34

35. Treatment
Doxo DxIf
(N=215) (N=210)
N (%) N (%)
Post protocol Surgery 44 (20.5) 43 (20.5)
treatment Radiotherapy 69 (32.1) 83 (39.5)
Chemotherapy 136 (63.3) 134 (63.8)
Doxorubicin 12 (5.6) 27 (12.9)
Analog 3 (1.4) 1 (0.5)
Ifosfamide 99 (46.0) 32 (15.2)
Analog 6 (2.8) 13 (6.2)
Trabectedin 33 (15.3) 37 (17.6)
Docetaxel 25 (11.6) 34 (16.2)
Analog 5 (2.3) 6 (2.9)
Gemcitabine 32 (14.9) 40 (19.0)
Dacarbazine 7 (3.3) 18 (8.6)
Analog 0 (0.0) 1 (0.5)
Pazopanib 14 (6.5) 14 (6.7)
Eribulin 7 (3.3) 11 (5.2)
Etoposide 8 (3.7) 11 (5.2)
35

36. Conclusions
In this group of patients all below 60,
median age 48 years
The combination of doxorubicin and ifosfamide:
o doubled the response rate
o improved PFS significantly
o it did not significantly improve survival
o It was considerably more toxic than doxorubicin
alone.
36

37. This study supports personalised
medicine in daily practice...
• The standard treatment in the palliative setting remains
single agent doxorubicin
• If surgery for unresectable tumors or curative
metastasectomy is considered, combination therapy
gives the highest chance of response
• In highly symptomatic disease in patients without co-
morbidity combination treatment is optional
and pro’s and cons should – as always- be discussed
with the patient.
• ….and since we have the results of this study, these
discussions can be more balanced than before.
37

38. PALETTE
A randomized double blind phase III trial of pazopanib
versus placebo in patients with soft tissue sarcoma (STS)
whose disease has progressed during or following prior
chemotherapy.
An EORTC STBSG and GSK global network study (EORTC 62072)
W. T. A. van der Graaf, J. Y. Blay, S. Chawla, D.W. Kim, B. Bui-Nguyen,
P. Casali, P. Schoeffski, M. Aglietta, A. Staddon, Y. Beppu, A. Le Cesne,
H. Gelderblom, I.Judson, N. Araki, M. Ouali, S. Marreaud, R A. Hodge,
M. Dewji, P. Dei Tos, P. Hohenberger, on behalf of the global PALETTE study team.

39. Background
• Pazopanib: A multikinase angiogenesis inhibitor
targeting VEGFR, PDGFR, and c-Kit
• In a prior phase 2 study of pazopanib in patients with
advanced STS positive effect of pazopanib (PFR at 12
weeks):
 44% in leiomyosarcoma
 49% in synovial sarcoma
 39% in other STS types
• Insufficient activity in liposarcomas
• Acceptable toxicity

40. Phase III Study Design
10 20
Pazopanib*(800mg QD) Endpoint Endpoints Stratification factors
R (N = 246)  Performance status
A
N (0 vs 1)
D OS
ORR
N= 369 O 2:1 PFS
QoL  Number of prior lines of
(RECIST v1.0)
M Safety systemic therapy for
I advanced disease
Matching Placebo
S (0/1 vs 2+)
(N = 123)
E
Followed for
survival Disease assessment
at week 4-8-12-20 and
at 8 week intervals
thereafter
* Until disease progression, unacceptable toxicity,
withdrawal of consent for any reason, or death

41. Main Inclusion Criteria
• Patients ≥18 years, WHO PS 0-1
• Progressive disease before start of PALETTE study
• Prior doxorubicine and a maximum of four lines of prior
treatment for advanced disease (no more than 2
combination regimens)
• Measurable disease on X-rays
• No prior pazopanib or other angiogenesis inhibitors
• Adequate organ function
• No problems of hypertension, bleeding and/or brain
metastases

42. STS included Histology
• Included: strata: leio, synovial, other:
• Fibroblastic • MPNST
• Fibrohistiocytic • NOS
• Leiomyosarcoma • Vascular STS
• Synovial sarcoma • Malignant glomus tumors
• But not:
• liposarcoma
• GIST
• etc.

43. Study Status
• Accrual
 369 randomized patients over 17 months: FASTER THAN
EXPECTED, DESPITE PLACEBO DESIGN WITHOUT
CROSS-OVER!
 4 continents, 13 countries, 72 institutions
 EORTC: 45% - Other institutions: 55%

44. Who entered the study?
Placebo (N=123) Pazopanib (N=246)
Median (years) 51.9 56.7
Age
Range (years) 18.8 - 78.6 20.1 - 83.7
0 (WHO) 56 (46%) 113 (46%)
Performance
1 (WHO) 67 (55%) 133 (54%)
Leiomyosarcoma 50 (41%) 115 (47%)
Histology (local) Synovial sarcoma 14 (11%) 30 (12%)
Other type 59 (48%) 101 (41%)
I / low 3 (2%) 24 (10%)
Grade at initial
II / intermediate 30 (24%) 63 (26%)
diagnosis (local)
III / high 90 (73%) 159 (65%)

45. Principal prior drug therapies
Placebo (N=123) Pazopanib (N=246)
Prior (neo)adjuvant therapy 36 (29%) 58 (24%)
Prior systemic therapy for advanced
110 (89%) 232 (94%)
disease
0-1 line 52 (42%) 110 (45%)
2-4 lines 71 (58%) 136 (55%)
Including Anthracycline(s) 121 (98%) 243 (99%)
Ifosfamide 93 (76%) 164 (67%)
Gemcitabine 42 (34%) 85 (35%)
Docetaxel 35 (29%) 69 (28%)
Trabectedin 22 (18%) 38 (15%)
Dacarbazine 19 (15%) 38 (15%)
mTOR inhibitor(s) 6 (5%) 16 (7%)

46. RESULTS: Primary end-point
Progression Free Survival
(%)
100
90 Placebo Pazopanib
80 Median (months) 1.5 4.6
70 HazardWald test stratified : p<0.0001 0.31
ratio
1
95% CI (0.24,0.40)
60
Percent
P-value < 0.0001
50
40
30
20
10
0 (months)
0 6 12 Time 18 24
O N Number of patients at risk : Treatment arm
106 123 6 0 0 Placebo
168 246 63 12 1 Pazopanib

47. PFS by Histology
Consistent benefit in PFS across all 3 strata
n (%) HR CI P-value
Overall 369 (100%) 0.31 0.24-0.40 <0.0001
Leiomyosarcoma 158 (43%) 0.31 0.20-0.47 <0.0001
Synovial 38 (10%) 0.19 0.23-0.60 0.0002
other STS 173 (47%) 0.36 0.25-0.52 <0.0001

48. Interim Overall Survival
(%)
Placebo Pazopanib
Median (months) 10.7 12.5
100
Hazard ratio 0.86
1
90 95% CI (0.67,1.11)
80 P-value 0.25
70
60
Percent
50
40
30
20
10
0 (months)
0 6 12 Time 18 24
O N Number of patients at risk : Treatment arm
78 123 86 36 12 Placebo
137 246 184 83 23 Pazopanib

49. Best Overall Response
based on the independent review
Placebo (N=123) Pazopanib (N=239)
Partial response 0 (0%) 14 (6%)
Stable disease 47 (38%) 164 (67%)
Progression 70 (57%) 57 (23%)
Early death (progression) 6 (5%) 2 (1%)
Early death (other cause) 0 (0%) 1 (0.4%)
Unevaluable 0 (0%) 8 (3%)

50. Selected on-therapy Adverse Events
Placebo (N=123) Pazopanib (N=239)
Common Adverse Events All Grades Gr3 Gr4 All Grades Gr3 Gr4
Fatigue 60 (49%) 6 (5%) 1 (1%) 155 (65%) 30 (13%) 1 (0.4%)
Diarrhea 20 (16%) 1 (1) 0 138 (58%) 11 (5%) 0
Nausea 34 (28%) 2 (2%) 0 129 (54%) 8 (3%) 0
Weight loss 25 (20%) 0 0 115 (48%) 0 0
Hypertension 8 (7%) 4 (3%) 0 99 (41%) 16 (7%) 0
Anorexia 24 (20%) 0 0 95 (40%) 14 (6%) 0
Hypopigmentation hair 3 (2%) 0 0 92 (39%) 0 0
Vomiting 14 (11%) 1 (1%) 0 80 (34%) 8 (3%) 0
Dysgeusia 5 (4%) 0 0 64 (27%) 0 0
Rash/desquamation 13 (11%) 0 0 43(18%) 1 (0.4%) 0
Mucositis 4 (3%) 0 0 29 (12%) 3 (1%) 0
Adverse Events of Interest
Myocardial Dysfunction* 6 (5%) - - 21 (9%) 3 (1%) 1 (<1%)
Venous thromboembolic** 3 (2%) 1 (<1%) 2 (1%) 13 (5%) 5 (2%) 1 (<1%)
Pneumothorax - - - 8 (3%) - 1 (<1%)
* Grouping of MedDRA Terms including LV dysfunction, cardiac failure, restrictive cardiomyopathy, pulmonary edema
** 2 subjects with venous thromboembolic events died of pulmonary embolus

51. Selected on-therapy Adverse Events
Placebo (N=123) Pazopanib (N=239) STS Pazo renal
Common Adverse Events All Grades Gr3 and 4 All Grades Gr3 and 4 All grades
Fatigue 60 (49%) 7 (6%) 155 (65%) 31 (13%) 19%
Diarrhea 20 (16%) 1 (1) 138 (58%) 11 (5%) 52%
Nausea 34 (28%) 2 (2%) 129 (54%) 8 (3%) 26%
Weight loss 25 (20%) 0 115 (48%) 0
Hypertension 8 (7%) 4 (3%) 99 (41%) 16 (7%) 40%
Anorexia 24 (20%) 0 95 (40%) 14 (6%) 22%
Hypopigmentation hair 3 (2%) 0 92 (39%) 0 38%
Vomiting 14 (11%) 1 (1%) 80 (34%) 8 (3%) 21%
Dysgeusia 5 (4%) 0 64 (27%) 0
Rash/desquamation 13 (11%) 0 43(18%) 1 (0.4%)
Mucositis 4 (3%) 0 29 (12%) 3 (1%)
Adverse Events of Interest
Myocardial Dysfunction* 6 (5%) - - 21 (9%) 3 (1%) 1 (<1%)
Venous thromboembolic** 3 (2%) 1 (<1%) 2 13 (5%) 5 (2%) 1 (<1%)
(1%
)
* Grouping of MedDRA Terms including LV dysfunction, cardiac failure, restrictive cardiomyopathy, pulmonary edema
Pneumothorax - - -
** 2 subjects with venous thromboembolic events died of pulmonary embolus
8 (3%) - 1 (<1%)

52. Principal post-protocol Therapies
WAS IT REAL LAST RESORT THERAPY?
Placebo (N=122) Pazopanib (N=228)
Radiotherapy 28 (23%) 36 (16%)
Surgery 8 (7%) 16 (7%)
Trabectedin 37 (30%) 53 (23%)
Gemcitabine 24 (20%) 33 (15%)
Ifosfamide 15 (12%) 13 (6%)
Docetaxel 13 (11%) 17 (8%)
Medical
Dacarbazine 14 (12%) 12 (5%)
Treatment
Etoposide 9 (7%) 14 (6%)
Anthracycline(s) 8 (7%) 10 (4%)
Pazopanib 4 (3%) 4 (2%)
Sorafenib 7 (6%) 6 (3%)

53. Conclusions
• Pazopanib is an active drug in anthracycline pretreated
metastatic soft tissue sarcoma patients.
 : a 3-fold increase in PFS as compared to placebo!
3 months, is this worthwhile?
The overall survival is not statistically significant better.
WHY?

54. Randomized Phase III Trial of Regorafenib
in Patients (pts) with Metastatic and/or Unresectable
Gastrointestinal Stromal Tumor (GIST)
Progressing Despite Prior Treatment with at least
Imatinib (IM) and Sunitinib (SU): The GRID Trial
GD Demetri, P Reichardt, Y-K Kang, J-Y Blay, H Joensuu, RG Maki,
P Rutkowski, P Hohenberger, H Gelderblom, MG Leahy, M von Mehren,
P Schöffski, ME Blackstein, A Le Cesne, G Badalamenti, J-M Xu, T Nishida,
D Laurent, I Kuss, and PG Casali, on behalf of GRID Investigators
Demetri et al. ASCO 2012

55. GIST – Regorafenib In Progressive Disease
(GRID): Study Design
Regorafenib + best
supportive care
Metastatic/ R (BSC)
unresectable A 160 mg once daily Disease
N 3 weeks on, O
GIST pts D progression
progressing O 1 week off (n=133) per independent F
despite at least M 2:1 blinded central review F
I
prior imatinib ZA
and sunitinib TI T
O Placebo + BSC Unblinding R
(n=236 screened; N Crossover offered for
n=199 randomized) 3 weeks on, E
placebo arm or
1 week off (n=66) A
continued regorafenib
for treatment arm T
M
• Multicenter, randomized, double-blind, E
placebo-controlled phase III study Regorafenib N
(unblinded)
 Global trial: 17 countries across Europe, until next progression
T
North America, and Asia-Pacific
 Stratification: treatment line (2 vs >2 prior lines),
geographical location (Asia vs “Rest of World”)
Demetri et al. ASCO 2012

56. GRID Study: Endpoints
• Primary Endpoint: Progression-Free Survival (PFS)
• Secondary Endpoints:
 Overall survival
 And others
Demetri et al. ASCO 2012

57. GRID Study: Progression-Free Survival (primary
endpoint per blinded central review)
Regorafenib significantly improved PFS vs placebo (p<0.0001);
Demetri et al. ASCO 2012
primary endpoint met

58. GRID Study: Overall Survival
(following 85% cross-over of patients on
placebo arm)
Because of the crossover design, lack of statistical significance between
regorafenib and placebo was not unexpected
Demetri et al. ASCO 2012

59. Disease Control and Overall Response Rates
Regorafenib (N=133) Placebo (N=66)
n (%) n (%)
Disease control rate
70 (52.6) 6 (9.1)
CR + PR + durable SD (≥12wks)
Objective response rate 6 (4.5) 1 (1.5)
Complete response 0 (0.0) 0 (0.0)
Partial response 6 (4.5) 1 (1.5)
Stable disease
95 (71.4) 22 (33.3)
(at any time)
Progressive disease 28 (21.1) 42 (63.6)
Responses based on modified RECIST v1.1
Regorafenib improved rates of disease control vs placebo
Demetri et al. ASCO 2012

60. • GRID: NO overall survival benefit
• But this was expected due to the cross-over
design of this placebo-controlled study

61. CONCLUSIONS
• Placebo controlled trials are offered if no
standard treatment is avalailable
• These studies don’t have problems in fast
accrual in case new therapies are offered.
• Cross-over to the experimental study arm (new
treatment) is possible if overall survival is not
the end-point of the study