1. Activation of insulin like growth factor 1 receptor (IGF-1R) signaling pathway is implicated in proliferation, survival, and angiogenesis in pancreatic adenocarcinoma Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that adds marginal benefit to gemcitabine in advanced pancreatic adenocarcinoma Cross talk between EGFR and IGF-1R pathways contributes to acquired resistance to EGFR blockers Cixutumumab is a fully human IgG1/λ monoclonal antibody targeting IGF-1R with pre-clinical activity against pancreas cancer Recommended dose of single agent cixutumumab for Phase II studies was 6 mg/kg IV on a once weekly basis Southwest Oncology Group S0727: A Phase I and Randomized Phase II Trial of Gemcitabine + Erlotinib + Cixutumumab (IMC-A12) versus Gemcitabine + Erlotinib as First-Line Treatment in Patients with Metastatic Pancreatic Cancer (Preliminary Toxicity Data) P.A. Philip, B. Goldman, R.K. Ramanathan, H.J. Lenz, A.M. Lowy, R. P. Whitehead, S. Iqbal, V. Chung, J.K. Benedetti, C.D. Blanke Karmanos Cancer Institute, Detroit, MI; Southwest Oncology Group Statistical Center, Seattle, WA; TGen Clinical Research Services, Scottsdale, AZ; University of Southern California, Los Angeles, CA; University of California at San Diego, San Diego, CA; Medical University of South Carolina, Charleston, S.C.; City of Hope National Medical Center, Duarte, CA; University of British Columbia, and British Columbia Cancer Agency, Vancouver BC, Canada; Support: NCI,DHHS: CA32102, CA38926, CA58882, CA46368, CA14028, CA45807, CA35178 and CA45808 Study Schema Phase I Dose Levels CONCLUSIONS Phase I Phase II Panc adenoca Metastatic No prior Chemotherapy PS 0 or 1 Normal fasting blood glucose Phase I Phase II Panc adenoca Metastatic No prior Chemotherapy PS 0 or 1 Normal fasting blood glucose Phase I Phase II Cixutumumab Erlotinib Gemcitabine Cixutumumab Erlotinib Gemcitabine Phase II Dose Phase II Dose Cixutumumab Erlotinib Gemcitabine Cixutumumab Erlotinib Gemcitabine Erlotinib Gemcitabine Erlotinib Gemcitabine RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE Major Eligibility Criteria LevelGemcitabine IV per week Erlotinib PO QD Cixutumumab IV Q 1 week 1 starting 1,000 mg/m 2 100 mg6 mg/kg 21,000 mg/m 2 100 mg4 mg/kg 31,000 mg/m 2 100 mg3 mg/kg Treatment cycles every 28 days Grade > 3 non-hematological toxicity (excluding alopecia and inadequately treated nausea, vomiting, diarrhea, hyperglycemia or allergic reaction) Grade 4 neutropenia for > 7days or grade 3 or 4 PLUS fever > 38.5 o C Grade 4 thrombocytopenia or grade 3 for either > 7 days or PLUS bleeding Delay in treatment for > 7 days with any of the drugs for treatment related toxicity Definitions of Dose-Limiting Toxicity (DLT) Using CTCAE V3.0 Background Phase IPhase II (6/1/09 - ) Endpoint = PFS N = 106 Phase I Part of the Study (N = 10) Median Age61 (40-82) Male/Female7/3 PS 0/15/5 Diabetes Mellitus4 (40%) Race White Black Other 622622 Patient Characteristics 10 patients were accrued to dose level 1 1 DLT at dose level 1 (allergic reaction gr 3) Phase I completed without dose de- escalation Cixutumumab 6 mg/kg IV weekly was the recommended Phase II dose in combination with gemcitabine and erlotinib Recommended Phase II Dose of IMC-A12 Grade 1Grade 2Grade 3Grade 4 Phase I N = 10 00100 Phase II N = 11 0532 Toxicity of cixutumumab/Gemcitabine/Erlotinib Maximum Grade any Adverse Event No patient was removed from study because of toxicity No dose reductions in cixutumumab were required One patient discontinued cixutumumab because of a grade 3 allergic reaction Grade 1234 Phase I 104320 Phase II + cixutum 111210 Phase II No cixutum 110000 3/8 patients with grade >2 had known history of diabetes mellitus Majority of grade >2 hyperglycemia started in cycle #1 Hyperglycemia N Toxicity Grade 1234 Neutropenia2230 Platelets3420 Anemia3500 Neutropenic fever 0010 The use of cixutumumab at 6 mg/kg is feasible with no apparent increase in gemcitabine/erlotinib related toxicities There is an increase in the frequency of hyperglycemia (mostly grades 1 and 2) that may occur in the absence of pre- existing diabetes Grade 3 infusion reaction to cixutumumab was seen in one patient The Phase II portion of the study is ongoing with the accrual of 38 patients as of 1/04/2010 Non-hematological Toxicity to Gemcitabine/Erlotinib/Cixutumumab in Phase I (N = 10) Toxicity Grade 1234 Nausea3340 Vomiting1220 Diarrhea2120 Dehydration0030 Allergic reaction0010 Fatigue0540 Acne3310 AST/ALT8400 Non-hematological Toxicity to Gemcitabine/Erlotinib/Cixutumumab in Phase II (N = 11) Hematological Toxicity to Gemcitabine/Erlotinib/Cixutumumab in Phase I (N = 10) Toxicity Grade 1234 Nausea2410 Vomiting2310 Diarrhea1310 Dehydration0210 Allergic reaction0000 Fatigue2510 Acne3200 AST/ALT3310 Bilirubin2220 Histologic or cytologic proof of pancreatic adenocarcinoma Metastatic disease Measurable or evaluable disease Performance status of 0 or 1 AST/ALT < 2.5 x ULN Normal bilirubin ANC > 1,500 and Platelets > 100,000 No prior systemic therapy for metastatic pancreas cancer No prior gemcitabine Fasting blood sugar below the institutional upper limit of normal No major comorbidities Serum creatinine < 1.5 x ULN