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01.02.2012 | Original Article

A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies

verfasst von: Julie Bauman, Claire Verschraegen, Steven Belinsky, Carolyn Muller, Teresa Rutledge, M. Fekrazad, Meera Ravindranathan, Sang-Joon Lee, Dennie Jones

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2012

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Abstract

Introduction

The epidermal growth factor receptor (EGFR) is a validated target in malignancy; however, patients with wild type EGFR obtain little sustained benefit from anti-EGFR monotherapy. Epigenetic therapy to reactivate tumor suppressor genes may enhance the anti-proliferative effect of erlotinib. This phase I study evaluated the combination of erlotinib and 5-azacytidine for safety and maximal tolerated dose (MTD).

Methods

Thirty patients with advanced solid tumors were treated in a standard 3 + 3 cohort design. Erlotinib was dosed at 150 mg daily, and 5-azacytidine was escalated by increasing the number of daily doses of 75 mg/m² per cycle. Patients were followed for dose-limiting toxicity (DLT). Efficacy was assessed by RECIST criteria.

Results

Common non-hematologic toxicities included rash, diarrhea, nausea, and fatigue; the majority was ≤ Grade 2. DLTs included conjunctivitis in cohort 1 and infusion reaction in cohort 2. No DLTs occurred in cohorts 3, 4, or 5; however, 2 serious neutropenic infections arose in cohort 5 after cycle 1. Cohort 4 was expanded to 6 patients and was the MTD. Partial response (lung, ovarian) and stable disease occurred in 2 and 11 patients, respectively. Median progression-free survival was 2 months. Two patients with lung and larynx cancer had prolonged stable disease.

Conclusion

The combination of erlotinib and 5-azacytidine was well tolerated with interesting clinical activity in lung, head and neck, and ovarian cancer. The recommended dose for phase II study is erlotinib 150 mg daily and 5-azacytidine 75 mg/m² daily on days 1–4 and 15–18 of a 28-day cycle.

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Titel: A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies
verfasst von: Julie Bauman
Claire Verschraegen
Steven Belinsky
Carolyn Muller
Teresa Rutledge
M. Fekrazad
Meera Ravindranathan
Sang-Joon Lee
Dennie Jones
Publikationsdatum: 01.02.2012
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2012
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1729-2

Springer Medizin

A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies