In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2760-2760
Abstract:
BACKGROUND: MK-0646 binds to IGF-1R and blocks its interaction with the IGF-I/ II ligands, enhances gemcitabine (G)-induced apoptosis and inhibits the MEK/ Erk and the PI3-kinase/ Akt signaling pathways which are important in cellular proliferation, survival and drug resistance in pancreatic cancer. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/ Akt pathways mediate resistance to anti-EGFR agents such as E. The combination of IGF-1R and EGFR antagonists has demonstrated synergy in preclinical pancreatic cancer models. METHODS: Patients with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0-1, adequate hematologic and organ function were enrolled. MK-0646 was escalated in two dose levels using 3+3 statistical design. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Blood was collected at study entry for IGF-1 and IGFBP-3 levels. Arm A: G 1000 mg/m2 over 100 min, weekly x 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly x 4; Arm B: G 1000 mg/m2 over 100 min, weekly x 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly x 4 + E 100 mg daily. Cycles were repeated q 4 weeks. Radiologic responses were measured with RECIST (study radiologist PB). Study endpoints: maximal tolerated dose, progression-free survival, response rate, toxicity and overall survival. RESULTS: 22 pts enrolled, 15 males, 2 prior Whipple, 20 PS 1, 2 PS 0. Median of 2 cycles (range 1-8) administered as of 9/09. Hematologic toxicity was common: grade 3 or 4 neutropenia (n=9) or thrombocytopenia (n=6). Other grade 3 toxicities: hyperglycemia (n=2), fatigue (n=2), ALT (n=3). Dose limiting toxicity reached in Arm B at dose level 2 (MK-0646 at 10 mg/kg + E + G): febrile neutropenia (n=1), hepatic transaminitis (n=1). Radiologic responses: 5 PR (including 1 hepatic CR), 7 PD, 8 SD, 1 not evaluated, 1 not treated. TTP range (based on 12 pts) was 4 to & gt;36 weeks. Ranges for: IGF-1 levels, 28-280 ng/mL; IGFBP-3 levels, 900-4000 ng/mL. The range of IGF-1 to IGFBP-3 ratios for patients with PR and SD was .027-.036 versus a range of .034-.058 for patients with PD. CONCLUSION: MK-0646 is tolerable in a dose of 10 mg/kg with G 1000 mg/m2 and at 5 mg/kg with G 1000 mg/m2 and E 100 mg. Promising anti-tumor activity was noted. A randomized phase II study will be conducted with the control arm of G+E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2760.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-2760
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
