1. Phase II trial of erlotinib in advanced pancreatic cancer
P.A. Tang 1,4, S. Gill 2, H. J. Au 3, E. X. Chen 1, D. Hedley 1, M. Leroux 1, L. Wang 1, M. J. Moore 1
Princess Margaret Hospital, Toronto, Canada1; BC Cancer Agency, Vancouver, Canada 2; Cross Cancer Institute, Edmonton, Canada 3, Tom Baker Cancer Centre, Calgary, Canada 4
Disclosures: Drs Tang and Moore received research funding from OSI Pharmaceuticals

2. Background
The epidermal growth factor receptor (EGFR) is commonly over-expressed in pancreatic cancer and over-expression is associated with a poor prognosis 1-3
Erlotinib, an oral EGFR tyrosine kinase inhibitor, has antitumor activity in pancreatic cancer in preclinical models4, and clinically in combination with gemcitabine 5
Based on preclinical animal models, erlotinib concentrations of 500 ng/mL have been estimated to provide sufficient EGFR inhibition to lead to anti-proliferative activity OSI-420 is the major metabolite of erlotinib.
1 Yamanka et al. Anticancer Res 13:565-9, 1993
2 Ueda et al. Pancreas 29:e1-8, 2004
3 Tobita et al. Int J Mol Med 11:305-9, 2003
4 Ng et al. Mol Cancer Ther 1:777-83, 2002
5 Moore et al. J Clin Oncol , 2007
6 Hidalgo et al. J Clin Oncol , 2001

3. Background
Clinical benefit from erlotinib correlates with a dose-dependent skin rash 1
The purpose of this phase II trial was to determine the efficacy of erlotinib dosed to achieve rash in pts with advanced pancreatic cancer (PC) who had progressed on or were unable to tolerate gemcitabine based chemotherapy
1 Wacker et al. Clin Cancer Res 3913, 2007

4. Key eligibility criteria
Locally advanced or metastatic PC
Progressed on or unable to tolerate gemcitabine
Measurable disease (RECIST)
Adequate hematological, renal, hepatic function
No prior treatment with EGFR inhibitors permitted

5. Schema Continue Erlotinib 150 mg/d Rash Cycle 1, Days 1-14
Archival Tissue
EGFR IHC, Kras mutation
Continue Erlotinib
150 mg/d
Rash
Cycle 1, Days 1-14
Erlotinib 150 mg/d
Intrapatient dose
Escalation to rash
Increase erlotinib by
50 mg/2wks until
Rash, max 300mg/d
No Rash
Trough Erlotinib PK All patients
Baseline, Cycle 1 D 15, Cycle 2 D 1
Trough Erlotinib PK
Dose escalation pts only
Cycle 2, d 22

6. Statistical Considerations
Two stage phase II trial, responses evaluated using RECIST
Primary endpoint: prolonged disease control = PR + SD > 8 wks
α = 0.05; β = 0.10
Stage I: If > 3/18 evaluable pts respond or have prolonged SD (> 8 wks), proceed to stage II
Stage II: accrue an additional 17 pts. If > 7/35 pts respond or have prolonged SD, erlotinib considered active.

7. Results
Between November 2006 and December 2008, 51 pts were enrolled from 5 Canadian centres
Pts received a median of 2 cycles, range (1-15).
3 pts never took study drug
48 pts evaluable for toxicity, TTP, and OS.
38 pts evaluable for response

8. Patient Characteristics
Number of pts (n=51)
Median Age (Range)
62 (37-79)
Female:Male
26:25
ECOG 0:1:2
5:42:4
Locally advanced:Metastatic
6:45
Prior gemcitabine
None: adjuvant : with RT: palliative
2:16:5:33
Dose escalation
Erlotinib 200mg:250mg:300mg 10
7:1:2

9. Pharmacokinetics Trough concentrations of erlotinib and OSI-420
Erlotinib dose
Erlotinib concentration
OSI-420 concentration
No escalation (n=24)
ng/mL 1
ng/mL
Dose escalation (n=8)
ng/mL 2
ng/mL
P value
0.08
0.04
1 6 pts had an erlotinib concentration below 500 ng/mL
2 1 pt had an erlotinib concentration below 500 ng/mL
There was wide inter-patient variability with respect to erlotinib and OSI-420
trough concentrations.

10. Trough concentrations of erlotinib
No escalation Dose escalation
Line denotes 500 ng/mL

11. Trough concentrations of OSI-420
No escalation Dose escalation

12. Results Best response to erlotinib (n=38)
Number of pts
Percent
(95% CI)
Partial response
Stable disease
Prolnoged stable disease (> 8 wks) 13 10
34 (19-49)
26 (12-40)
Progressive disease 25 66
13 pts were inevaluable
Dose escalation 10 pts: 2 inevaluable, 3 PD, 5 SD (3 prolonged SD range wks)
Median TTP was 1.61 mo (95% CI: )
Medial OS was 4.08 mo (95% CI: )

13. Kaplain meier curve of time to progression

14. Kaplain meier curve of overall survival

15. Treatment related adverse events (CTC AE v 3.0)
All Grades
Grade 3/4
# pts %
Rash 40
83.3 2
4.2
Diarrhea 21
43.8 3
6.3
AST increased 11
22.9 1
2.1
Fatigue 10
20.8
Nausea 8
16.7
Anorexia
Dry skin 7
14.6
Pruritis

16. Treatment related adverse events continued
All Grades
Grade 3/4
# pts %
ALP increased 7
14.6 1
2.1
Hypoalbuminemia 2
4.2
Vomiting
Anemia 6
12.5
Lymphopenia
Mucositis 5
10.4
Hypocalcemia
Grade 3+ Treatment related AEs in 1 pt each: Bilirubin increased, cecum perforation, lower GI bleed, renal failure, hypokalemia

17. Correlation between rash and stable disease
The presence of grade 2+ rash was associated with stable disease (p = 0.018)

18. Conclusions
Erlotinib is associated with prolonged stable disease in a subset of patients with advanced refractory pancreatic cancer
Grade 2 + rash was associated with disease control
Dose escalation in the absence of toxicity is feasible and safe
Wide inter-patient variability was observed in erlotinib trough levels

19. Acknowledgements Trial was supported by OSI Pharmaceuticals Inc.
This protocol was developed at the FECS-AACR-ASCO Methods in Clinical Cancer Research