Phase I/II study of the Src inhibitor dasatinib in combination with erlotinib in advanced non-small-cell lung cancer.
OBJECTIVE
Src family kinase (SFK) proteins are frequently activated in cancer and can coordinate tumor cell growth, survival, invasion, and angiogenesis. Given the importance of SFK signaling in cancer, known cooperation between SFK and epidermal growth factor receptor (EGFR) signaling, and efficacy of EGFR inhibitors, we performed a phase I trial combining dasatinib, an SFK and multikinase inhibitor, with erlotinib, an EGFR inhibitor, in patients with advanced non-small-cell lung cancer.


METHODS
Patients received erlotinib for 1 week before addition of dasatinib; pharmacokinetics were performed after weeks 1 and 2. Four cohorts were examined, including twice-daily and daily dasatinib dosing. Responses were assessed after 8 weeks. Plasma levels of angiogenic markers (vascular endothelial growth factor [VEGF], interleukin-8, and basic fibroblast growth factor [bFGF]) were determined before and during treatment.


RESULTS
Thirty-four patients were enrolled. The average duration of treatment was 73 days. The main adverse events include GI (diarrhea, anorexia, and nausea), skin rash, cytopenias, pleural effusions, and fatigue. No effect of escalating doses of dasatinib was observed on erlotinib pharmacokinetics. Two partial responses and one bone response were observed, and the disease control rate was 63%. Reductions in plasma VEGF and bFGF were observed, and reductions in VEGF correlated with disease control.


CONCLUSIONS
The combination of erlotinib and dasatinib is tolerable, with adverse effects consistent with the two agents. Disease control and inhibition of plasma angiogenesis markers were observed. Personalized strategies for deployment of SFK should receive further attention.
Department of Thoracic Oncology and Biostatistics, Clinical Trials and Clinical Pharmacology Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612-9497, USA. Eric.haura@moffitt.org
Eric B
EB
Haura
Tawee
T
Tanvetyanon
Alberto
A
Chiappori
Charles
C
Williams
George
G
Simon
Scott
S
Antonia
Jhanelle
J
Gray
Sharon
S
Litschauer
Leticia
L
Tetteh
Anthony
A
Neuger
Lanxi
L
Song
Bhupendra
B
Rawal
Michael J
MJ
Schell
Gerold
G
Bepler
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000069439:Dasatinib; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D054316:Biomarkers, Pharmacological; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000069439:Dasatinib