Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy

NCT00939523 | Completed Phase 2 Results

• 1 other identifier: 18129
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Pituitary Adenomas; Prolactinomas

Keywords

recurrent nonfunctioning adenoma; prolactinomas; resistant pituitary tumors; aggressive pituitary tumors; malignant pituitary adenomas

Outcome Measures

Primary Outcomes (2)

• Change in Tumor Volume

  Tumor volume will be assessed on MRI at 6 months on therapy and compared to baseline MRI.

  baseline and at 6 months

• Number of Participants With 50% Reduction in Prolactin Levels

  50% reduction in prolactin level measured monthly on 6 months therapy compared to baseline level.

  every month, up to 6 months

Secondary Outcomes (2)

• % Change in Prolactin From Baseline to Study End

  Baseline and at 6 months

• ErbB Receptor Expression

  at 6 months

Study Arms (1)

Lapatinib

EXPERIMENTAL

All participants will be asked to take Lapatinib daily for a total of six months during the research study.

Drug: Lapatinib

Interventions

Lapatinib DRUG

All participants will be asked to take Lapatinib daily for six months during the research study.

Also known as: Tykerb

Lapatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Cedars-Sinai Medical Center: lead

Study Sites (3)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Related Publications (2)

• Dong W, Shi W, Liu Y, Li J, Zhang Y, Dong G, Dong X, Gao H. CHST7 Methylation Status Related to the Proliferation and Differentiation of Pituitary Adenomas. Cells. 2022 Aug 4;11(15):2400. doi: 10.3390/cells11152400.

  PMID: 35954244 DERIVED

• Cooper O, Bonert VS, Rudnick J, Pressman BD, Lo J, Salvatori R, Yuen KCJ, Fleseriu M, Melmed S. EGFR/ErbB2-Targeting Lapatinib Therapy for Aggressive Prolactinomas. J Clin Endocrinol Metab. 2021 Jan 23;106(2):e917-e925. doi: 10.1210/clinem/dgaa805.

  PMID: 33150390 DERIVED

MeSH Terms

Conditions

Pituitary Neoplasms; Prolactinoma

Interventions

Lapatinib

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Hypothalamic Neoplasms; Supratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypothalamic Diseases; Pituitary Diseases; Endocrine System Diseases; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

For one of the secondary outcomes, the ErbB receptor expression, only 3 subjects had tumor specimens available to immunostain. Therefore, only results on 3 subjects were reported for this outcome.

Results Point of Contact

• Title: Odelia Cooper
• Organization: Cedars-Sinai Medical Center

coopero@cshs.org

310-423-4774

Study Officials

• Odelia Cooper, MD

  Cedars-Sinai Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: July 14, 2009
• First Posted: July 15, 2009
• Study Start: July 1, 2009
• Primary Completion: December 1, 2018
• Study Completion: December 1, 2018
• Last Updated: January 22, 2020
• Results First Posted: January 13, 2020

Record last verified: 2020-01

Locations

US (3)