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