Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy
Status:
Completed
Trial end date:
2018-12-01
Target enrollment:
Participant gender:
Summary
This study focuses on new therapies for a challenging disease in pituitary medicine, that of
aggressive pituitary tumors which have limited therapeutic options beyond standard surgical,
radiotherapy, and select medical therapies, each incurring significant morbidity and
mortality, and each not optimally effective. To improve this gap in knowledge, we seek to
translate findings from the laboratory into clinical practice and hone in on therapies
directed at pituitary molecular targets, namely ErbB receptors. We have shown that human
prolactinomas express nuclear EGFR and membranous ErbB2, ErbB3 and ErbB4, and expression
correlates with tumor invasion. Pituitary tumor cell lines transfected with EGFR and ErbB2
translated to downstream effects on prolactin (PRL) gene expression and secretion,as well as
cell proliferation. Animal models implanted with these cell lines developed larger tumors and
PRL elevations. Treatment with ErbB tyrosine kinase inhibitors (TKIs) led to regression of
tumors xenografted into these animals and attenuated PRL secretion. Primary culture of human
prolactinomas confirmed expression of ErbB receptors and inhibitory effects of TKIs on PRL
secretion and cell proliferation. Based on these exciting preliminary data, the objective of
this new proposal is to conduct a Phase IIa clinical trial as a trenchant test of our
translational hypothesis that tyrosine kinase inhibition constitutes highly effective
targeted biologic therapy for these hitherto refractory pituitary adenomas. Specifically, our
aims are to test the: 1) efficacy of TKI therapy with a clinical trial; 2) threshold level of
tumor receptor expression to achieve TKI clinical response. Nineteen subjects will be treated
with lapatinib for 6 months in combination with their current dopamine agonist therapy, with
monthly measurements of PRL levels and MRI imaging every 3 months to evaluate the primary
endpoints of achieving 40% reduction in tumor size and 50% reduction in PRL and secondary
endpoints of radiologic stabilization and/or reduction and PRL normalization. Mean ErbB
receptor protein expression will be compared between responders to lapatinib and
non-responders by immunohistochemistry in pituitary tumor samples of these subjects collected
from prior surgeries.