Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy
Condition: Pituitary Adenomas; Prolactinomas
MeSH terms: Adenoma; Pituitary Neoplasms; Prolactinoma; Pituitary Diseases
Intervention: Lapatinib
Intervention description: All participants will be asked to take Lapatinib daily for six months during the research study.
Intervention MeSH terms: Lapatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: recurrent nonfunctioning adenoma; prolactinomas; resistant pituitary tumors; aggressive pituitary tumors; malignant pituitary adenomas

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with nonfunctioning adenomas who have undergone at least one prior surgical
             resection and have demonstrated recurrence on MRI

          -  Patients with prolactinomas who are resistant to dopamine agonist therapy

          -  Patients with malignant pituitary tumors

          -  Patients with visual field deficits and/or compression of the optic chiasm must be
             stable for at least 6 months

        Exclusion Criteria:

          -  Patients with compromised visual fields and/or compression of the optic chiasm on MRI
             that has not been stable for last 6 months.

          -  Patients that have reduced left ventricular ejection fraction less than 50%

          -  Patients with moderate to severe hepatic impairment

          -  Patients that are pregnant or lactating

          -  Patients under the age of 18

          -  Active hepatitis

          -  Known previous HIV Positive

          -  Concurrent cancers

          -  Life expectancy less than one year