5 understanding some basic trial designs in sarcomas (inclusive a placebo one) prof van der graaf nl
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Transcript of 5 understanding some basic trial designs in sarcomas (inclusive a placebo one) prof van der graaf nl
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
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
A study population is not the same as the general population
Study patients should not only be the “athletes”
Age limits, but:
The incidence of soft tissue sarcomas
The incidence of soft tissue sarcomas has a peak around 65 years of age..
Old and fit...
Old and frail (co-medication, other relevant diseases!)
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?
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
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
The first “mixed bag phase 2 trial” with adriamycin
The first efficacy trial with adriamycin in “sarcomas”
A Classical Phase 3 design
• Standard treatment versus other standard treatment
Or • Standard treatment versus an experimental
treatment Or • Placebo versus new treatment
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
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
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.
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
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
• 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
Rationale of the study
21
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?
Rationale of the study (II)
22
The design
Stratification: •Age (<50 vs ≥50) •PS (0 vs 1) •Liver metastases (0 vs +) •Histological grade (2 vs 3)
R
Doxorubicin 75 mg/m2 d 1 or as a 72 hour continous i.v. infusion
New Treatment: B Doxorubicin 25 mg/m2 d 1-3 + Ifosfamide 2.5 g/m2 d 1-4
+ Neulasta 6mg s.c. d5
The primary end point: overall-survival The secondary end points: response (RECIST) toxicity (CTC 2.0) treatment related mortality
End-points of the study
24
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
Study status
25
Treatment Total
(n=455) Doxo
(n=228) Doxo-Ifos (n=227)
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)
Patient characteristics
26
Overall survival
27
(years)
0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment188 228 113 54 29 19 14 9 2184 227 130 64 30 20 13 7 3
DoxoDxIf
HR = 0.83 (95.5% CI 0.67 – 1.03) Stratified logrank test, p = 0.076
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)
29
Overall survival
Progression free survival
30
(years)
0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment215 228 38 15 8 6 5 4 1210 227 50 16 12 11 10 7 3
DoxoDxIf
HR = 0.74 (95% CI 0.60 – 0.90) Stratified logrank test, p = 0.003
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).
Median PFS
31
Progression free survival
32
Best overall response
33
Treatment Total
(n=455) Doxo
(n=228) Doxo-Ifos (n=227)
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) Not evaluable 11 (4.8) 16 (7.0) 27 (5.9) Significant difference between the two arms: p < 0.001
Doxo (N = 223)
DxIf (N = 224)
Total (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%
Adverse events (grade ≥ 3)
34
35
Treatment
Doxo (N=215)
DxIf (N=210)
N (%) N (%)
Surgery 44 (20.5) 43 (20.5)
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)
Post protocol treatment
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.
Conclusions
36
• 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.
This study supports personalised medicine in daily practice...
37
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.
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
Phase III Study Design
* Until disease progression, unacceptable toxicity, withdrawal of consent for any reason, or death
Matching Placebo (N = 123)
RANDOMI S E
2:1
Pazopanib*(800mg QD) (N = 246)
N= 369 PFS (RECIST v1.0)
OS ORR QoL Safety
10 Endpoint
20 Endpoints
Followed for survival
Stratification factors Performance status
(0 vs 1)
Number of prior lines of systemic therapy for advanced disease (0/1 vs 2+) Disease assessment at week 4-8-12-20 and at 8 week intervals
thereafter
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
STS included Histology
• Included: strata: leio, synovial, other:
• But not:
• liposarcoma
• GIST
• etc.
• Fibroblastic • MPNST • Fibrohistiocytic • NOS • Leiomyosarcoma • Vascular STS • Synovial sarcoma • Malignant glomus tumors
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%
Who entered the study?
Placebo (N=123) Pazopanib (N=246)
Age Median (years) 51.9 56.7
Range (years) 18.8 - 78.6 20.1 - 83.7
Performance 0 (WHO) 56 (46%) 113 (46%)
1 (WHO) 67 (55%) 133 (54%)
Histology (local)
Leiomyosarcoma 50 (41%) 115 (47%)
Synovial sarcoma 14 (11%) 30 (12%)
Other type 59 (48%) 101 (41%)
Grade at initial diagnosis (local)
I / low 3 (2%) 24 (10%)
II / intermediate 30 (24%) 63 (26%)
III / high 90 (73%) 159 (65%)
Principal prior drug therapies
Placebo (N=123) Pazopanib (N=246)
Prior (neo)adjuvant therapy 36 (29%) 58 (24%)
Prior systemic therapy for advanced disease 110 (89%) 232 (94%)
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%)
(months) 0 6 12 18 24
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment arm 106 123 6 0 0 168 246 63 12 1
Placebo Pazopanib
Wald test stratified : p<0.0001
Per
cent
RESULTS: Primary end-point Progression Free Survival
Placebo Pazopanib
Median (months) 1.5 4.6
Hazard ratio 95% CI 1 0.31
(0.24,0.40)
P-value < 0.0001
(%)
Time
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
(months)0 6 12 18 24
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment arm78 123 86 36 12
137 246 184 83 23PlaceboPazopanib
Interim Overall Survival
Placebo Pazopanib
Median (months) 10.7 12.5
Hazard ratio 95% CI 1 0.86
(0.67,1.11)
P-value 0.25
(%)
Per
cent
Time
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%)
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
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
(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
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%)
Medical Treatment
Trabectedin 37 (30%) 53 (23%) Gemcitabine 24 (20%) 33 (15%) Ifosfamide 15 (12%) 13 (6%) Docetaxel 13 (11%) 17 (8%) Dacarbazine 14 (12%) 12 (5%) Etoposide 9 (7%) 14 (6%) Anthracycline(s) 8 (7%) 10 (4%) Pazopanib 4 (3%) 4 (2%)
Sorafenib 7 (6%) 6 (3%)
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?
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
OF F
TREATMENT
Disease progression
per independent blinded central review
GIST – Regorafenib In Progressive Disease (GRID): Study Design
• Multicenter, randomized, double-blind, placebo-controlled phase III study Global trial: 17 countries across Europe,
North America, and Asia-Pacific Stratification: treatment line (2 vs >2 prior lines),
geographical location (Asia vs “Rest of World”)
2 : 1
Regorafenib + best supportive care
(BSC) 160 mg once daily
3 weeks on, 1 week off (n=133)
Placebo + BSC 3 weeks on,
1 week off (n=66)
RANDOM I
ZAT I ON
Unblinding Crossover offered for
placebo arm or continued regorafenib
for treatment arm
Regorafenib (unblinded)
until next progression
Metastatic/ unresectable
GIST pts progressing
despite at least prior imatinib and sunitinib
(n=236 screened; n=199 randomized)
Demetri et al. ASCO 2012
GRID Study: Endpoints
• Primary Endpoint: Progression-Free Survival (PFS)
• Secondary Endpoints: Overall survival
And others
Demetri et al. ASCO 2012
GRID Study: Progression-Free Survival (primary endpoint per blinded central review)
Regorafenib significantly improved PFS vs placebo (p<0.0001); primary endpoint met
Demetri et al. ASCO 2012
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
Disease Control and Overall Response Rates
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 (at any time) 95 (71.4) 22 (33.3)
Progressive disease 28 (21.1) 42 (63.6)
Responses based on modified RECIST v1.1
Regorafenib improved rates of disease control vs placebo
Regorafenib (N=133) n (%)
Placebo (N=66) n (%)
Disease control rate CR + PR + durable SD (≥12wks)
70 (52.6) 6 (9.1)
Demetri et al. ASCO 2012
• GRID: NO overall survival benefit
• But this was expected due to the cross-over design of this placebo-controlled study
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