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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00939523
Recruitment Status : Completed
First Posted : July 15, 2009
Results First Posted : January 13, 2020
Last Update Posted : January 22, 2020
Sponsor:
Information provided by (Responsible Party):
Odelia Cooper, Cedars-Sinai Medical Center

Tracking Information
First Submitted Date  ICMJE July 14, 2009
First Posted Date  ICMJE July 15, 2009
Results First Submitted Date  ICMJE November 18, 2019
Results First Posted Date  ICMJE January 13, 2020
Last Update Posted Date January 22, 2020
Study Start Date  ICMJE July 2009
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 24, 2019)
  • Change in Tumor Volume [ Time Frame: baseline and at 6 months ]
    Tumor volume will be assessed on MRI at 6 months on therapy and compared to baseline MRI.
  • Number of Participants With 50% Reduction in Prolactin Levels [ Time Frame: every month, up to 6 months ]
    50% reduction in prolactin level measured monthly on 6 months therapy compared to baseline level.
Original Primary Outcome Measures  ICMJE
 (submitted: July 14, 2009)
  • Primary outcome in nonfunctioning adenomas: stabilization of tumor volume and mean tumor diameter on MRI. Stabilization is defined as < 2 mm change in any dimension. MRIs will be performed at baseline and at 3 and 6 months.
  • Primary outcome in prolactinomas: normalization of prolactin levels. Prolactin levels will be measured at baseline and monthly.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 13, 2020)
  • % Change in Prolactin From Baseline to Study End [ Time Frame: Baseline and at 6 months ]
    Percent prolactin change from start of lapatinib to end of study participant participation
  • ErbB Receptor Expression [ Time Frame: at 6 months ]
    Mean percent positive expression of EGFR and ErbB2 will be tested on pathologic tumor specimens from subjects treated with lapatinib
Original Secondary Outcome Measures  ICMJE
 (submitted: July 14, 2009)
Secondary outcomes: In both nonfunctioning adenomas and prolactinomas, patients will undergo visual field testing and pituitary hormone profiles. Pituitary hormones and serum EGFR and erbB2 will be assayed at baseline and at 3 and 6 months.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy
Official Title  ICMJE Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy
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.
Detailed Description

PURPOSE

The drug Lapatinib has been shown to inhibit both epidermal growth factor receptor (EGFR) and erbB2 tyrosine kinases resulting in an effective slowing of disease progression in breast cancer. It has also been demonstrated that erbB is overexpressed in human pituitary adenomas. The investigators are therefore assessing tumor size stabilization and pituitary tumor secretory profiles during the course of a six month therapy of lapatinib. The purpose of this trial will be to estimate the activity of lapatinib in slowing the growth rate of pituitary tumors. Lapatinib is an FDA approved drug used to treat breast cancer. However, in this study, the drug will be used to treat pituitary cancer.

STUDY POPULATION

This study will recruit patients from the Pituitary Center at CSMC who are over the age of 18 that have a recurrent nonfunctioning adenoma after at least one surgical resection as well as patients with prolactinomas who are resistant to dopamine agonist therapy and patients with recurrent Cushing's disease.

PARTICIPANT'S JOURNEY THROUGH THE RESEARCH

The principal investigator (PI) or co-investigator will determine patients' potential eligibility for the study based on inclusion and exclusion criteria.

The PI or the co-investigator will then approach subjects with recurrent nonfunctioning adenomas or prolactinomas resistant to dopamine agonist therapy or recurrent Cushing's disease during a visit in the clinic office and ask if these subjects would be interested in participating in this study. If the subjects express interest, they will be given the consent form to review. They will be encouraged to review it with family, friends, and/or other physicians. The PI, co-investigators, or research nurse will be available for any questions the subjects might have. If the subjects are still interested, they will be asked to sign and return the consent form to the office and a study visit will be scheduled.

The PI, co-investigator, or member of study staff may also attempt to contact current patients by phone to assess interest in participating in the study. The purpose and overall structure of the study will be discussed with the possible participant. They will be reminded that the study is strictly voluntary and that their involvement or disinterest in the study will not affect their ongoing care. If the patient is interested they will be mailed a consent to review and will be asked to call the center to schedule an appointment to further discuss the study if they decide they are interested.

Each participant will undergo 8 visits of the course of the study. Each participant will have a baseline visit where a medical history will be taken, a physical, visual field test, electrocardiogram (ECG), echocardiogram (ECHO), and blood draw will be performed. At this point lapatinib therapy will begin and the patients will be asked to take the drug daily for the next six months. Patients will take Lapatinib 1250 mg daily (orally), which is the standardized dose used to treat breast cancer patients. Visit 2 will be 1 month after the participant has started lapatinib. At visit 2 all participants will receive a physical exam, a history will be taken, an ECG will be performed, and a blood draw will occur. Visit 3 will be 2 months after starting lapatinib. A physical exam and history will be performed along with an ECG and echocardiogram and blood draw. Visit 4 will be 3 months after starting lapatinib. A physical, history, blood draw, ECG, visual field test, and a magnetic resonance imaging (MRI) of the pituitary will be performed. Visit 5 will occur 4 months after starting lapatinib. A physical exam and history along with a blood draw and ECG and echocardiogram will occur. Visit 6 will be 5 months after starting lapatinib. A physical exam, history, ECG, and a blood draw will occur. Visit 7 will occur 6 months after the start of lapatinib. A physical exam, history, blood draw, visual field test, ECG, echocardiogram and MRI of the pituitary will occur. At this point lapatinib will be discontinued. Visit 8 will occur 1 month after visit 7 and a physical exam, history, blood draw, and ECG and and echocardiogram will occur.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Pituitary Adenomas
  • Prolactinomas
Intervention  ICMJE Drug: Lapatinib
All participants will be asked to take Lapatinib daily for six months during the research study.
Other Name: Tykerb
Study Arms  ICMJE Experimental: Lapatinib
All participants will be asked to take Lapatinib daily for a total of six months during the research study.
Intervention: Drug: Lapatinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 24, 2019)
9
Original Estimated Enrollment  ICMJE
 (submitted: July 14, 2009)
21
Actual Study Completion Date  ICMJE December 2018
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00939523
Other Study ID Numbers  ICMJE 18129
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Odelia Cooper, Cedars-Sinai Medical Center
Study Sponsor  ICMJE Cedars-Sinai Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Odelia Cooper, MD Cedars-Sinai Medical Center
PRS Account Cedars-Sinai Medical Center
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP