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Mendeley readers
| Title |
Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine plus erlotinib with and without MK-0646 for advanced pancreatic adenocarcinoma
|
|---|---|
| Published in |
Journal of Hematology & Oncology, May 2018
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| DOI | 10.1186/s13045-018-0616-2 |
| Pubmed ID | |
| Authors |
Reham Abdel-Wahab, Gauri R. Varadhachary, Priya R. Bhosale, Xuemei Wang, David R. Fogelman, Rachna T. Shroff, Michael J. Overman, Robert A. Wolff, Milind Javle |
| Abstract |
Binding of insulin-like growth factor-I (IGF-1) to its receptor (IGF-1R) initiates downstream signals that activate PI3K/Akt/mTOR and MEK/Erk pathways, which stimulate cancer cell proliferation and induce drug resistance. Cross talk between IGF-1R and epidermal growth factor receptor (EGFR) mediates resistance to anti-EGFR agents. We studied safety, tolerability, and outcomes of MK-0646, IGF-1 monoclonal antibody, in combination with gemcitabine (G) ± erlotinib (E) in metastatic pancreatic cancer. Our study included a phase I dose escalation and phase II randomization and expansion cohorts. A 3 + 3 dose escalation protocol was used to determine MK-0646 maximum tolerable dose (MTD) in combination with G ± E standard doses. For phase II, patients were randomized to arm A (G + MK), arm B (G + MK + E), or arm C (G + E). Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, toxicity, and correlation between OS and IGF-1 in patients treated with MK-0646. MK-0646 MTD was 10 mg/kg in combination with G and 5 mg/kg in combination with G + E. In randomization cohort, 15 patients were treated in each arm. Disease control rates were 50, 60, and 40% respectively. PFS was not different between the three arms. OS was significantly different between arm A (10.4 months) and C (5.7 months) (P = 0.02). However, addition of erlotinib in arm B yielded no OS benefit compared to arm A (P = 0.6). Plasma and tissue IGF-1 levels did not correlate with OS (P = 0.64, 0.87). Grade 3-4 toxicity during phase II cohorts were neutropenia (10/arm A, 14/arm B, 5/arm C), leukopenia (5/A, 5/B, 7/C), thrombocytopenia (8/A, 9/B, 2/C), hyponatremia (1/A, 3/B), and hyperglycemia (8/A, 1/B). MK-0646 was tolerable in combination with G and associated with improvement in OS but not PFS as compared with G + E. Tissue and serum IGF-1 did not correlate with clinical outcome. This trial is registered in ClinicalTrial.gov under the Identifier NCT00769483 and registration date was October 9, 2008. |
Mendeley readers
The data shown below were compiled from readership statistics for 57 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 57 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 8 | 14% |
| Other | 5 | 9% |
| Student > Doctoral Student | 5 | 9% |
| Researcher | 3 | 5% |
| Student > Ph. D. Student | 3 | 5% |
| Other | 4 | 7% |
| Unknown | 29 | 51% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 14 | 25% |
| Biochemistry, Genetics and Molecular Biology | 5 | 9% |
| Nursing and Health Professions | 1 | 2% |
| Business, Management and Accounting | 1 | 2% |
| Immunology and Microbiology | 1 | 2% |
| Other | 1 | 2% |
| Unknown | 34 | 60% |