| General information |
| Database: | DB00665 |
| Objective: | Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. they tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulinlike growth factor receptor1 (IGF1R) pathways would significantly improve progression free survival (PFS) by abrogating reciprocal signaling that promote drug resistance |
| Authors: | Philip PA, et al |
| Title: | Dual blockade of epidermal growth factor receptor and insulinlike growth factor receptor1 signaling in metastatic pancreatic cancer:phase Ib and randomizedphase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). |
| Journal: | cancer |
| Year: | 2014 |
| PMID: | 25041791 |
| Trial Design |
| Clinical Trial Id: | NCT00617708 |
| Agent: | erlotinib, cixutumumab
|
| Target: | NA
|
| Cancer Type: | pancreatic cancer |
| Cancer Subtype: | advanced pancreatic cancer |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | gemcitabine, erlotinib, + cixutumumab versus gemcitabine + erlotinib |
| Study Type: | a phase Ib/II study |
| Key Patients Feature: | Patients with metastatic histologically proven adenocarcinoma of the pancreas who were previously not treated withsystemic therapy were eligible (ClinicalTrials.gov Identifier: NCT00617708). patients were to have a Zubrod performance status (PS) 1, have evaluable or measurable disease, and be without major comorbidities that wouldpreclude treatment with study medications. patients wereto have adequate organ function determined by the following parameters: AST/ALT 2.5 times the upper limit ofnormal, bilirubin within the normal range, creatinine 1.5 mg/dL, neutrophil count 1500/mm3, plateletcount 100, 000/mm3, and fasting blood glucose withinthe normal limits. Patients with a history of diabetes mellitus were allowed entry into the study, provided it was wellcontrolled |
| Biomarker: | Polymorphisms in genes involved in G metabolism and in the EGFR pathway |
| Biomark Analysis: | No significant differences in PFS by genotype were seen for any of the polymorphisms. |
| Control Group Info: | gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib |
| Treatment Info: | Patients received gemcitabine 1000 mg/m2 intravenously over 30 minutes administered once weekly for 3 of 4 weeks. Erlotinib 100 mg was administered orally once perday continuously. In the phase Ib portion of the study cixutumumab 6 mg/kg (starting dose level) was administered on days 1, 8, 15, and 22 of each 28day cycle in addition to the gemcitabine and erlotinib. The starting dose of cixutumumab (6 mg/g) in the combination was determinedto be sufficiently safe, and was used in the randomizedphase II portion of the study. The doses of cixutumumabwere planned to be reduced if sufficient adverse events occurred in dose levels 1, 2, and 3 of 6, 4, and 3 mg/kg, respectively. Forphase II, patients were randomly assigned to receive gemcitabine and erlotinib with or without cixutumumab. |
| Primary End Point: | progression free survival |
| Secondary End Point: | overall survival and objective tumor respons |
| Patients Number: | 10 |
| Trial Results |
| DLT_MTD: | the phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28day cycle. |
| Objective Response Rate: | NA |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | In the RP2 portion (116 eligible patients; median age, 63), the median PFS was 3.6 months, on the cixutumumab arm, 3.6 months. |
| Median OS A vs. C: | In the RP2 portion (116 eligible patients; median age, 63), the median overall survival (OS) was 7.0 months, on the cixutumumab arm, 6.7 months. |
| Adverse Event(agent arm): | Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). |
| Conclusions: | Adding the IGF1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC. |