A Phase II Trial of Sunitinib (S) in Previously-Treated

Pancreas Adenocarcinoma (PAC), CALGB 80603

E.M. O’Reilly, D. Niedzwiecki, D. Hollis, T. Bekaii-Saab, T. Pluard, A. Duffy, F. Overcash,

P. Ivy, R.M. Goldberg

Schrag, et al. ASCO, 2007 (Abst # 4524)

Second-Line Therapy Background in Pancreas Adenocarcinoma

• No established second-line therapy for PAC – by default – fluoropyrimidine

• Significant number of patients eligible for 2nd and subsequent line of therapy – data from recent phase III’s suggest 40- 50%

• Very small number of clinical trials targeting this patient population– 2% from CALGB 80303 (Gemcitabine +/-

bevacizumab) received a second-line of therapy on a clinical trial

Selected Second-Line Trials in Pancreas Adenocarcinoma

Phase III Trials N RR Survival Author

FU + LV + Oxali (OFF)130

- 10.4 mthsRiess. ASCO, 2007

vs FU + LV 8.3 mths

Rubitecan409

- 3.5 mthsPapish. ASCO, 2005

vs Dealer’s choice - 3.1 mths

Phase II Trials N RR Survival Author

Gem + Oxaliplatin 30 22% 6 mths Demols. B J Can, 2006

FU + LV + Oxaliplatin 30 23% ~6 mths Tsavaris. Inv New Drugs, 2005

Irinotecan + Oxaliplatin 30 10% 23% (I yr) Cantore. Oncology, 2004

Capecitabine + Oxaliplatin 41 2% 22% (1 yr) Xiong. ASCO, 2006

Pemetrexed 52 4% ~5 mths Boeck. Ann Oncology, 2007

Capecitabine 42 7% ~6 mths Cartwright. J Clin Oncol, 2002

Capecitabine + Erlotinib 30 10% 6.5 mths Kulke. J Clin Oncol, 2007

Docetaxel + Gefitinib 26 0% 2.9 mths Ignatiadis. Oncol, 2006

Ralitrexed38

0% 4.3 mthsUlrich-Pur. B J Can, 2003

vs Ralitrexed + Irinotecan 16% 6.5 mths

Rationale for Sunitinib in PAC

• Sunitinib: multi-targeted small molecule inhibitor of receptor tyrosine kinases (VEGFR 1-3, PDGFR, c-kit, TK of RET, Flt-3)– effects on proliferation, angiogenesis

• Multiple signalling pathways perturbed in PAC - logical to use a broad spectrum inhibitor which also targets the tumor microenvironment

Study Design

• NCI-sponsored phase II

• Single-arm, multi-center, Co-operative group (CALGB)

• 3-stage accrual plan

Key Inclusion Criteria

• PAC previously treated with one line of gemcitabine or a gemcitabine-based therapy fulfilling one of the following:– No other therapy for PAC– Progression of disease during or within 3

months of completion of adjuvant therapy– Newly metastatic disease following therapy

for locally advanced PAC

Inclusion Criteria II

• Histologic or cytologic confirmation of adenocarcinoma

• ECOG performance status 0-2• Measurable metastatic disease (RECIST)• No prior anti-VEGF therapy• No duodenal invasion on CT• At least 4 weeks from prior therapy• Low molecular weight heparin permitted

(therapeutic warfarin excluded)

Key Exclusion Criteria

• Significant QTc prolongation (QTc ≥ 500 msec)• Uncontrolled hypertension• History of CVA, TIA within 12 months• History of PE within 6 months• History of active concurrent other malignancy• History of significant bleeding/ fistula/ perforation

within 6 months• Use of proarrhythmic agents

Treatment Plan

• Sunitinib 50 mg PO daily, day 1-28, followed by 14 days of rest (1 cycle)

• Re-staging after the first 4 cycles of therapy (CT or MRI; Ca 19-9)

• MUGA or ECHO pre-treatment and every other cycle

Biostatistical Plan

• 3-stage design (N= 19, 39, 60)

• Planned accrual N= 64

• Primary endpoint: Response CR/PR/Stable disease at 6-weeks post protocol entry (by RECIST measurements)

• Expansion if:– CR/PR/Stable disease in 1/ 19 (1st stage)

– CR/PR/Stable disease in 2/ 39 (2nd stage)

Biostatistical Plan II

• Secondary Endpoints– Duration of response– Progression-free survival– Overall survival– Safety

Study Summary

• Recruitment 11/06- 11/07– N= 77– Expanded to 3rd stage– Exceeded target accrual due to very rapid

enrollment in last 2 weeks prior to closure– 1 withdrew consent– Reporting information on N= 74

*2 pts did not receive therapy (1 PD, 1 elevated bilirubin); 1 withdrew consent

DemographicsN= 77*

Male 40 (53%)

Female 35 (47%)

Age Median 65 years

Range 42- 87 years

PS 0

1

2

33 (44%)

37 (49%)

5 (7%)

Prior Therapy

(Gemcitabine-based)

Metastatic Disease 63 (82%)

Adjuvant Therapy 11 (14%)

Surgery 38 (51%)

Investigational therapy 3 (4%)

Tyrosine kinase inhibitor 9 (14%)

Baseline Sites of Disease

Liver 62 (84%)

Primary in-situ 48 (65%)

Lung 23 (31%)

Intra-abdominal 16 (22%)

Other 13 (18%)

Bone 1 (1%)

* Includes patients with POD

Treatment Summary

Reason off Therapy N (%)

Progression of Disease 50 (67%)

Adverse Event 7 (9%)

Death 11 (15%)*

Withdrew consent 7 (9%)

Treatment Administration

No. Cycles 1 55 (79%)

2 12 (17%)

3 3 (4%)

Dose Modifications 19 (27%)

Dose Reductions 4 (6%)

Missed Doses 34 (49%)

* Follow up information pending

Response Data (N= 70)Primary Endpoint: CR/PR/SD at 6-weeks

Overall ‘Response’ per protocol definition15/70 (21%, CI 12-33%)

Objective Response Rate: <1%

Complete Response 1 (1%)*

Stable Disease 14 (20%)

Progression of Disease 39 (56%)

Inevaluable 16 (23%)

Secondary Endpoints

• Current patient disposition (4-2008)– Dead 57 (76%)– Alive with POD 11 (15%)– Alive no POD 7 (9%)

• Progression-Free Survival– Median 1.35 months (CI 1.28- 2.07)

• Overall Survival– Median 3.2 months (CI 2.86- 4.17)

Toxicity: Hematologic (N= 72)

Adverse Event Gd 2 Gd 3 Gd 4

Hemoglobin 11 (15%) 4 (6%) -

Neutrophils 4 (6%) 5 (7%) -

Platelets 8 (11%) 6 (8%) 1 (1%)

Infection + neutropenia - 1 (1%)

DIC 1 (1%) - -

Thromobotic microang. - 1 (1%) -

Bleeding 1 (1%) 2 (3%) -

Epistaxis - 1 (1%)

Thrombosis/PE 1 (1%) 1 (1%)

Toxicity: Non-Hematologic (N= 72)

Adverse Event Gd 2 Gd 3 Gd 4 Gd 5

Hypertension 5 (7%) 3 (4%) - -

Fatigue 17 (24%) 10 (14%) 1 (1%) -

Dehydration 5 (7%) 3 (4%) - -

Rash 3 (4%) - - -

Mucositis 5 (7%) - - -

GI ulcer/perfor. - 1 (1%) - 1 (1%)

Diarrhea 9 (13%) 1 (1%) - -

Nausea 7 (10%) 6 (8%) - -

Vomiting 3 (4%) 3 (4%) - -

Renal/ creat 2 (3%) 1 (1%) - -

Dyspnea 1 (1%) 1 (1%) - (1%)

Confusion 1 (1%) 1 (1%) - -

Conclusions• Treatment of progressive PAC remains a major

therapeutic challenge

• Sunitinib has minimal activity in second-line therapy of PAC and is not recommended

• Brisk accrual to this co-operative group trial speaks to a need in oncology and provides a precedent for evaluation of other novel agents in a similar setting

Conclusions II• The data from this trial add to the emerging

evidence for a limited role for anti-vascular therapy in PAC - Ongoing front-line phase III studies with VEGF-trap and axitinib will provide further clarification

• Performance status is a critical determinant of prognosis and possibly more stringent eligibility criteria (i.e., restriction to PS 0 and/ or stratification for response to initial gemcitabine-based therapy) might provide clearer insights into a sub-population who could benefit from second-line therapies