Phase II trial of irinotecan/docetaxel for advanced pancreatic cancer with randomization

between irinotecan/docetaxel and irinotecan/docetaxel plus C225, a monoclonal

antibody to the epidermal growth factor receptor (EGF-r) : an Eastern Cooperative Oncology

Group Study (E8200)

B. A. Burtness, M. Powell, J. Berlin, D. Liles, A. Chapman, E. Mitchell, A. B. Benson, Eastern Cooperative Oncology

Group

Fox Chase Cancer Center, Philadelphia; Dana-Farber Cancer Institute, Boston; Vanderbilt University, Nashville; East Carolina University School of

Medicine , Greenville; Thomas Jefferson University, Philadelphia; Northwestern University, Chicago

Background

• Gemcitabine is standard for metastatic pancreatic cancer– median survivals of < 6 mo

• Second cytotoxic or biologic agents do not substantially advance survival

• EGFR is expressed on PC• A phase II trial of gemcitabine plus

cetuximab resulted in median survival 6.7 and 1 year survival 32.5%

Irinotecan/Docetaxel Phase II

• Irinotecan and docetaxel are synergistic in preclinical models• Cetuximab/irinotecan active in irinotecan-refractory colon

cancer• A phase II trial of the Murren regimen of weekly

irinotecan/docetaxel (I/D) chemotherapy reported a median survival for metastatic patients (pts) of 9 mo and RR 27%

• We conducted this randomized phase II trial to confirm the activity of this non-gemcitabine regimen, and determine whether combining it with cetuximab was feasible and active

E8200 Eligibility

• Histologically confirmed adenocarcinoma of the pancreas that is metastatic

• No prior chemotherapy for metastatic disease

• Prior gemcitabine or 5FU in the neoadjuvant or adjuvant setting permitted if > 6 months have elapsed

• ECOG 0 or 1

E8200 Eligibility

• AST ≤ 2.5 x ULN if alk phos normal• Alk phos ≤ 4 x ULN if transaminases

normal• Transaminases > 1.5 x ULN and alk phos

> 2.5 x ULN -> Ineligible• Tissue from core biopsy or open

procedure available for IHC (this requirement was removed by amendment midway through the trial to ease accrual)

E8200 Study Design

• Dexamethasone premedication• Docetaxel 35 mg/m2 followed by irinotecan 50

mg/m2 weekly x 4, q 6 weeks• Randomized phase II, 2 arms:

– Irinotecan/docetaxel– Irinotecan/docetaxel + cetuximab loading dose of 400

mg/m2 followed by 250 mg/m2 weekly• All pts receive prophylactic enoxaparin if not on

therapeutic anticoagulation

Statistical Considerations

• Primary endpoint response in each arm• Secondary endpoints

– Time to progression– Overall survival– Toxicity– Rate of thromboembolic events with use of

prophylactic enoxaparin– Prospective determination of EGFR expression in

population of patients with metastatic pancreatic cancer

Statistical Considerations

• Null hypothesis is RR 5%• Response rate of interest 20%• 2 responses in first 22 patients required for

either arm to proceed to second stage• Accrual to Arm B allowed for 3 patients to

be replaced in the event of hypersensitivity to cetuximab

Disease Evaluation

• CT scan and tumor markers at baseline.• Reevaluate q 2 cycles (ie after 12 weeks).• Patients attaining objective response had

CT scan and tumor markers repeated after one further cycle of chemotherapy (ie at 18 weeks).

E8200

• Final accrual 94 patients from 7/31/03 to 8/23/06

• 8 patients were ineligible– Died prior to receiving therapy, prior chemo,

outdated scans, laboratory results out of range, no measurable disease

Demographics Treatment Arm

A (N=43) B (N=43) Total

(N=86)

N % N % N %

Sex

Male 23 53.5 37 86.0 60 70

Female 20 46.5 6 14.0 26 30

PS

0 15 34.9 19 44.2 34 40

1 28 65.1 24 55.8 52 60

Age

Treatment Arm N Mean Std Dev Minimum Median Maximum

A 43 58.1 9.6 41.0 60.4 77.1

B 43 59.6 9.0 41.0 60.6 74.2

Total 86 58.9 9.3 41.0 60.5 77.1

Treatment Information

A BMean cycle# 2.6 3.3Median cycle# 2 2Pts with >4 cycles 9.3% 20.9%

Common Grade 3/4 Toxicity A BN % N %46 45

Neutrophils 11 (24) 14 (31) Fatigue 10 (22) 8 (18)Anorexia 8 (17) 4 (9)Nausea 14 (30) 9 (20)Vomiting 6 (13) 9 (20)Diarrhea 14 (30) 20 (44)Hyperglycemia 3 (7) 5 (11)Hypomagnesemia 0 3 (7)Neutropenic Fever/Inf 3 (6) 4 (9)

Worst 33 (72) 35 (78)

Bleeding Events

A BN % N %46 45

Epistaxis, gd 1 0 7 (16)Rectal bldg, gd 1 0 1 (2)Hematemesis, gd 1 2 (4) 0Hematuria, gd 2 0 1 (2)Hemorrhage/other, gd1 0 1 (2)

Treatment-Related Death

A BN 46 45Neutropenia with

fever or infection 1 1Diarrhea with sepsis 1

Total 2.2% 4.4%

Response

A BUnknown 4.7% 0%PR 2.3% 7%SD 39.5% 37.2%PD 34.9% 25.6%Uneval 18.6% 30.2%

Progression-Free Survival

A BData available, N= 41 38

Median PFS 2.8 4.595% CI 2.4,4.8 2.7,5.3

Treatment Arm ALIVEDEAD MEDIANTOTALA 41 37 4 2.8B 38 35 3 4.5

Survival Probability

PFS by Treatment Arm - E8200

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Progression-Free Survival (Months)0 2 4 6 8 10 12 14

Overall SurvivalKaplan-Meier

A BMedian 6.5 5.3

95% CI 5.3-8.6 4.4-9.5Known to have died 86.1% 93%

Treatment Arm ALIVEDEAD MEDIANTOTALA 43 37 6 6.5B 43 40 3 5.3

Survival Probability

Overall Survival by Treatment Arm - E8200

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Overall Survival Time in Months0 5 10 15 20 25 30 35

50% Decline in CA19-9

A BN 37 3650% drop 11 (30%) 14 (39%)Median PFS

without 50% drop 2.6m (2.3,3.9) 2.9m (2.2,4.9)with 50% drop 4.9m (2.9,7.2) 5.7m (5.1,8.3)

Median OS without 50% drop 5.8m (4.1-7.4) 4.4 (3.7-11)with 50% drop 9.9m (6.5,11.9) 9.5 (5.0,15.5)

CA19-9-Pooled DataBsl CA19-9 < median PFS 5.1m (2.9, 5.6)

> median PFS 2.6m (2.3,2.9) p*=0.048Median PFS

without 50% drop 2.6m (2.3,2.9)with 50% drop 5.3m (4.8,6.5) p=0.001

Median OS without 50% drop 5.6m (4.1-7.4)with 50% drop 9.9m (6.5,12)p=0.02

*2-sided log-rank test

ALIVEDEAD MEDIANTOTALAbove Median Baseline CA19-9 No 28 24 4 5.1Yes 26 24 2 2.6

Survival Probability

p=0.048

PFS by Above / Below Median Baseline CA19-9: E8200 Pooled Data

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Progression-Free Survival (Months)0 2 4 6 8 10 12 14

ALIVEDEAD MEDIANTOTALAbove Median Baseline CA19-9 No 16 14 2 6.1Yes 48 41 7 5.3

Survival Probability

p=0.51

OS by Above / Below Median Baseline CA19-9: E8200 Pooled Data

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Overall Survival (Months)0 5 10 15 20 25 30 35

ALIVEDEAD MEDIANTOTAL50% Drop in CA19-9 No 43 39 4 2.6Yes 24 21 3 5.3

Survival Probability

p=0.002

PFS by 50% Drop From Baseline CA19-9: E8200 Pooled Data

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Progression-Free Survival (Months)0 2 4 6 8 10 12 14

ALIVEDEAD MEDIANTOTAL50% Drop in CA19-9 No 48 42 6 5.6Yes 25 22 3 9.9

Survival Probability

p=0.020

OS by 50% Drop From Baseline CA19-9: E8200 Pooled Data

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Overall Survival Time in Months0 5 10 15 20 25 30 35

ALIVEEGFR Intensity/Density DEAD MEDIANTOTALIntensity = 3+ and Density > 50%15 9 6 4.5 Otherwise 45 39 6 4.2

Survival Probability

p=0.27

PFS by EGFR Intensity/Density: E8200 Pooled Data

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Progression-Free Survival (Months)0 2 4 6 8 10 12 14

ALIVEEGFR Intensity/Density DEAD MEDIANTOTALIntensity = 3+ and Density > 50%15 12 3 5.0 Otherwise 45 42 3 8.4

Survival Probability

p=0.87

Overall Survival by EGFR Intensity/Density: E8200 Pooled Data

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Overall Survival Time in Months0 5 10 15 20 25 30 35

ALIVEDEAD MEDIANTOTALClot No 66 57 9 3.9Yes 19 14 5 2.9

Survival Probability

p=0.91

PFS by Clot: E8200 Pooled Data

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Progression-Free Survival (Months)0 2 4 6 8 10 12 14

ALIVEDEAD MEDIANTOTALClot No 66 60 6 6.5Yes 19 16 3 6.8

Survival Probability

p=0.87

Overall Survival by Clot: E8200 Pooled Data

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Overall Survival (Months)0 5 10 15 20 25 30 35

Conclusions• Non-gemcitabine containing chemotherapy has

activity in metastatic pancreatic cancer• Response rate by RECIST on a 12 week

reassessment schedule is not a useful endpoint in pancreatic cancer in the cooperative group setting – 19-30% unevaluable

• 50% drop in CA19-9 correlates with PFS and OS and may represent a more reproducible endpoint in cooperative group trials in metastatic pancreatic cancer

Conclusions• The routine use of prophylactic LWM heparin is

feasible in patients with metastatic pancreatic cancer, with a low rate of hemorrhage on study

• Toxicity of irinotecan/docetaxel with or without cetuximab is high – Grade 3/4 diarrhea 33-40%– Treatment related death 2-4%– UGT1A1 testing not performed