Study Schema

1. Phase I Phase II Phase I Phase II 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) Phase I Phase II • Panc adenoca • Metastatic • No prior Chemotherapy • PS 0 or 1 • Normal fasting blood glucose 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 Background Phase I Dose Levels Toxicity of cixutumumab/Gemcitabine/Erlotinib Non-hematological Toxicity to Gemcitabine/Erlotinib/Cixutumumab in Phase I (N = 10) • 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 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 Treatment cycles every 28 days Definitions of Dose-Limiting Toxicity (DLT) Using CTCAE V3.0 Study Schema Hyperglycemia Non-hematological Toxicity to Gemcitabine/Erlotinib/Cixutumumab in Phase II (N = 11) Phase I Phase II (6/1/09 - ) • 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 > 38.5oC • 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 N Cixutumumab Erlotinib Gemcitabine R A N D O M I Z E Panc adenoca Metastatic No prior Chemotherapy PS 0 or 1 Normal fasting blood glucose Cixutumumab Erlotinib Gemcitabine Phase II Dose Erlotinib Gemcitabine Endpoint = PFS N = 106 Patient Characteristics • 3/8 patients with grade >2 had known history of diabetes mellitus • Majority of grade >2 hyperglycemia started in cycle #1 Major Eligibility Criteria • 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 Hematological Toxicity to Gemcitabine/Erlotinib/Cixutumumab in Phase I (N = 10) CONCLUSIONS • 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 Recommended Phase II Dose of IMC-A12 • 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