Capecitabine and Temozolomide for Treatment of Recurrent Pituitary Adenomas

Study Overview
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Brief Summary
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This is an open label study to assess the efficacy of capecitabine (CAP) and temozolomide (TMZ) in recurrent pituitary adenomas. There will be a safety run-in of at least three patients to establish any dose limiting toxicities. Enrolled patients will receive treatment in 28-day cycles: capecitabine 1500mg/m2 per day (divided into two doses with maximum daily dose of 2500mg) on days 1 through 14 and oral temozolomide 150 to 200 mg/m2 on days 10 through 14. This will be followed by 14 days off treatment. MRI imaging will be completed after every two cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Official Title
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Capecitabine and Temozolomide for Treatment of Recurrent Pituitary Adenomas

Conditions
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Recurrent Pituitary Adenomas

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:: Male or female ≥ 18 years of age. Patients with nonfunctioning tumors must have histologically confirmed pituitary adenoma. Patients with functioning tumors do not require surgery if there is clear diagnosis of functioning pituitary adenomas established based on endocrine evaluation. Karnofsky performance status ≥ 70%. Life expectancy of greater than six months. Residual or recurrent pituitary adenoma ≥1cm in maximal diameter on MRI Brain; patient must have received at least one prior therapy, such as surgery, radiation and/or medical therapy. Patients must have normal organ and marrow function as defined below. NOTE: Laboratory values must be taken within 7 days prior to chemotherapy administration. Transfusions and/or growth factor support may not be used to meet this criteria): Platelet count ≥ 100 × 109/L. Hemoglobin ≥ 9 g/dL. WBC ≥ 3 × 109/L Absolute neutrophil count (ANC) ≥ 1.5 × 109/L. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 x ULN if Gilbert's disease is documented. Aspartate transaminase (AST) ≤ 2.5 ULN. Alanine transaminase (ALT) ≤ 2.5 ULN. Serum creatinine ≤ 1.5 × ULN OR creatinine clearance≥60mL/min/1.73 m2 for patients with creatinine levels above institutional normal. Patients must be able to undergo a MRI Brain/Pituitary For women of child-bearing potential and for men with partners of child-bearing potential, subject must agree to take contraceptive measures for duration of treatment and at least 6 months after the last dose of chemotherapy. Patients must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Prior temozolomide and/or capecitabine therapy for treatment of the pituitary tumor. Other active malignancy outside of nonmelanoma skin cancer (patients in remission and with prior treatment more than two years ago will be accepted into trial). Clinically significant renal, hematologic or hepatic abnormalities. Use of Vitamin K antagonists such as warfarin (concentrations may be altered by concomitant use of capecitabine) Uncontrolled concurrent illness including, but not limited to, ongoing or active infection requiring IV antibiotics & psychiatric illness/social situations that would limit compliance with study requirements History of deficient dihydropyrimidine dehydrogenase activity. History of immunodeficiency. Patients who are taking any other concurrent investigational therapy. Patients who are pregnant or breastfeeding. Patients who have had prior radiation treatment in the last six months Patients who have had prior pituitary surgery within the last two months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Patients<br>All subjects will receive: Capecitabine (oral 5-Fluorouracil) 1500mg/m2 orally per day (divided into two doses with maximum daily dose of 2500mg) on days 1 through 14. Temozolomide (second generation alkylating agent) 150 to 200 mg/m2 orally on days 10 through 14. After completion of 6 cycles, patients achieving a complete or partial tumor response may continue to receive capecitabine temozolomide at the investigator's discretion in the absence of disease progression or unacceptable toxicity. Patients will be monitored for six months after they come off the study (either after completing 6 cycles or in setting of disease progression or unacceptable toxicity). | Drug: Capecitabine<br>* 1500mg/m2 orally per day (divided into two doses with maximum daily dose of 2500mg) on days 1 through 14.<br>Drug: Temozolomide<br>* 150 to 200 mg/m2 orally on days 10 through 14.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Radiographic Response, as Defined by the RECIST Criteria. | Evaluation of Target lesions: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum onstudy (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of the CAP and TMZ Combination on Pituitary Function, Measured by Changes in Pituitary Hormone Secretion in Patients | Serum prolactin, IGF-1, ACTH, FSH, LH and TSH levels are used to assess changes in pituitary hormone function. These tests will only be repeated if found to be abnormal at baseline. | At baseline and every 8 weeks, up to 6 months | 
| Safety, as Measured by the Number of Subjects With at Least One AE |  | 6 months | 
| Tolerability of the TMZ and Capecitabine Combination, as Measured by Number of Participants With a Dose-limiting Toxicity |  | 6 months | 
| Tumor Invasiveness and Aggressiveness, Determined by Assessing the Relationship Between Select Indicators With Response to Chemotherapy, Time to Progression, and Tumor Invasiveness. | Tumor invasiveness and aggressiveness, determined by assessing the relationship between select indicators (including Ki67 nuclear labelling index, p53 expression, MGMT expression/methylation status, and additional tumor genetic profiling) with response to chemotherapy, time to progression, and tumor invasiveness (based on the Knosp criteria). | 6 months |