Clinical trial NCT03930771
Conditions: Recurrent Pituitary Adenomas
Sponsor: Weill Medical College of Cornell University
Start date: 2019-05-21; Completion date: 2021-10-01
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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.

Detailed description:

Arms: arm 1: All subjects will receive:

1. Capecitabine (oral 5-Fluorouracil) 1500mg/m2 orally per day (divided into two doses with maximum daily dose of 2500mg) on days 1 through 14.
2. 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).
Interventions: intervention 1: Capecitabine intervention 2: Temozolomide
Intervention descriptions: intervention 1: 1500mg/m2 orally per day (divided into two doses with maximum daily dose of 2500mg) on days 1 through 14. intervention 2: 150 to 200 mg/m2 orally on days 10 through 14.

Protocol documents:
Prot_SAP_000.pdf: 
 
Page 1 of 36 
 
 
 
 
 
 
 
Title: Capecitabine and Temozolomide for Treatment of Recurrent Pituitary Adenomas 
IRB Protocol #: 1809019558 
NCT #: NCT03930771 
Version Date: June 15, 2018 
 
 


 
Page 2 of 36 
 
 
 
 
 
 
 
 
 
Capecitabine and Temozolomide for Treatment of Recurrent Pituitary Adenomas 
 
IRB Protocol #: 1809019558 
IND # (if applicable): 
Version Date: June 15, 2018 
 
Principal Investigator: 
 
Rajiv Magge, MD 
1305 York Avenue, 10th floor  
New York, NY 10021 
Telephone: 646-962-2185 
Fax: 212-746-5509 
ram9116@med.cornell.edu 
 
Statistician:  
Karla Ballman, PhD  
Professor, Weill Cornell Graduate School of Medical Sciences 
(646) 962-8023 
kab2053@med.cornell.edu 
 
 
Yao Lu, M.S 
 
Research Biostatistician 
yal2015@med.cornell.edu  
(646) 962-8029 
 
Study Coordinator: 
Alexandra Mavracick 
407 East 61st Street, 2nd Floor 
New York, NY 10065 
T 646.962.8169 
F 646.962.0536 
alm2074@med.cornell.edu 
Research Nurse:  
Monique Tarrant, RN, MSN, MPH 
523 East 70th Street, Suite 811 
New York, NY 10021 
Tel: 212-746-4154 
Fax: 212-746-1011 
 
 
 


 
Page 3 of 36 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others 
without written authorization from WCMC. 
 
 


 
Page 4 of 36 
 
List 
of 
Abbreviations 
 
All abbreviations used throughout the protocol must be defined.  
 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
ICF 
IND 
Informed Consent Form 
Investigational New Drug 
IRB 
PHI 
Institutional Review Board 
Protected Health Information 
PI 
REDCap 
Principal Investigator 
Research Electronic Data Capture 
SAE 
SUSAR 
UAP 
WCMC 
Serious Adverse Event 
Suspected Unexpected Serious Adverse Reaction  
Unanticipated Problem 
Weill Cornell Medical College 
 
 
 


 
Page 5 of 36 
 
Protocol Summary 
 
 
Full Title:  
 
 
 
Capecitabine and Temozolomide for Treatment of Recurrent 
Pituitary Adenomas 
 
Short Title:  
 
 
CAP and TMZ for Pituitary Adenomas  
 
Clinical Phase: 
 
 
Phase II (with safety run-in) 
 
Principal Investigator: Rajiv Magge MD 
 
Sample Size: 
 
N=21 
 
Accrual Ceiling: 
 
This study will enroll 21-33 subjects (based on results of safety-
run)  
 
Study Population: 
 
Patients with residual or recurrent pituitary adenomas with 
relatively good performance status. 
 
Accrual Period: 
 
36 months.   
 
Study Design: 
 
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 DLT. Enrolled patients (sample size N=21 to 33) 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. 
 
Study Duration: 
 
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 


 
Page 6 of 36 
 
completing 6 cycles or in setting of disease progression or 
unacceptable toxicity). 
 
Study Agent/  
Intervention Description: 
Capecitabine, Temozolomide 
 
 
1) Capecitabine (oral 5-Fluorouracil) 1500mg/m2 orally per day 
(divided into two doses with maximum daily dose of 2500mg) on 
days 1 through 14.  
 
 
2) Temozolomide (second generation alkylating agent) 150 to 200 
mg/m2 orally on days 10 through 14. 
 
 
 
 
Primary Objective:  
To assess the radiographic response rate of capecitabine and 
temozolomide in patients with recurrent pituitary adenomas.  
 
Secondary Objectives: 
To assess the effect of capecitabine and temozolomide on pituitary 
adenoma hormone secretion in patients with residual or recurrent 
functioning pituitary adenomas; To assess the effect of 
capecitabine and temozolomide on pituitary function in these 
patient; To assess the overall safety and tolerability of combination 
treatment with capecitabine and temozlomide. 
 
 
 
Exploratory Objectives: 
Further clarify the role of Ki67 nuclear labelling index, p53 
expression, MGMT expression/methylation status, and additional 
molecular profiling as indicators of tumor aggressiveness and 
invasiveness.  
 
Endpoints: 
 
Primary endpoints is tumor response assessed by the RECIST 
criteria. 
 
 
 
Secondary endpoints include biochemical control as assessed by 
measurement of hormones secreted in excess by the pituitary at 
baseline, pituitary function (assessed by standard pituitary function 
tests), and any change in tumor invasiveness (graded by Knosp 
classification system to quantify cavernous sinus invasion), and 
safety and tolerability of the combined CAP and TMZ regimen (as 
assessed by NCI CTCAE v4.0). 


 
Page 7 of 36 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Labs 
and 
Registration 
Study Treatment (with 28-day Cycles) 
CAP Days 1-14 
TMZ Days 10-14 
 
6 cycles 
completed 
Disease 
Progression 
Unacceptable 
Toxicity 
CONTINUE UNTIL 
MRI Brain/Pituitary x8 weeks 
Disease Assessment labs x8 weeks 
Physician Assessment x4 weeks 
Serum Chemistry x2 weeks 
CBC w/ Diff. x1 week 


 
Page 8 of 36 
 
 
 
Page 
Contents 
1. 
STUDY OBJECTIVES ......................................................................................................... 11 
1.1. 
Primary Objectives ......................................................................................................... 11 
1.2  Secondary Objectives......................................................................................................... 11 
1.3 
Exploratory Objectives ................................................................................................... 11 
2.0 
BACKGROUND ............................................................................................................... 11 
2.1 
Disease ........................................................................................................................... 11 
2.2 
Investigational Agent or Device ..................................................................................... 12 
2.2.1 
Capecitabine (Xeloda) ............................................................................................ 12 
2.2.2 
Temozolomide (Temodar) ...................................................................................... 14 
2.3 
Rationale for combination of CAP and TMZ ................................................................. 16 
2.4 
Risk/Benefit Assessment ................................................................................................ 16 
2.5 
Correlative Studies Background..................................................................................... 16 
3.0 
SUBJECT SELECTION .................................................................................................... 16 
3.1 
Study Population ............................................................................................................ 17 
3.2 
Inclusion Criteria ............................................................................................................ 17 
3.3 
Exclusion Criteria ........................................................................................................... 18 
4.0 
REGISTRATION PROCEDURES ................................................................................... 18 
4.1 
Patient Registration ........................................................................................................ 18 
5.0 
STUDY PROCEDURES ................................................................................................... 19 
5.1 
Overview ........................................................................................................................ 19 
5.2 
Table of Assessments ..................................................................................................... 19 
5.3 
SCREENING VISIT .......................................................................................................... 20 
5.4 
Treatment Phase ............................................................................................................. 20 
5.5 
End of Study Visit .......................................................................................................... 21 
6.0 
TREATMENT ADMINISTRATION ................................................................................ 21 
6.1 
Dose De-escalation Schema (for Safety Run-in component in case of DLT) ............... 22 
6.1.1 
Inter-patient De-escalation ...................................................................................... 22 
6.1.2 
Criteria for Dose De-escalation .................................................................................. 22 
6.2 
Definition of Dose Limiting Toxicity (DLT) (Criteria for entire study) ........................ 23 


 
Page 9 of 36 
 
6.3 
General Concomitant Medication and Supportive Care Guidelines .............................. 23 
6.4 
DURATION OF THERAPY AND CRITERIA FOR REMOVAL FROM STUDY ........ 23 
7.0 
DOSING DELAYS/DOSE MODIFICATIONS................................................................ 24 
8.0 
ADVERSE EVENT REPORTING REQUIREMENTS .................................................... 25 
8.1 
 Adverse Event Definition .............................................................................................. 25 
8.1.1 
Investigational Agent or Device Risks ................................................................... 25 
8.1.2 
Adverse Event Characteristics and Related Attributions ........................................ 26 
8.1.3 
Recording of Adverse Events ................................................................................. 26 
8.1.4  
Reporting of AE to WCMC IRB ............................................................................ 26 
8.2 
  Definition of SAE ......................................................................................................... 26 
8.2.1 
Reporting of SAE to IRB ........................................................................................ 27 
8.2.2 
Reporting of SAE to FDA ....................................................................................... 27 
8.2.3 
AE/SAE Follow Up ................................................................................................ 27 
9.  PHARMACEUTICAL INFORMATION ............................................................................. 27 
9.1 
Investigational Agent ..................................................................................................... 27 
9.2 
Availability ..................................................................................................................... 28 
9.3 
Agent Ordering ............................................................................................................... 28 
9.4 
Agent Accountability ..................................................................................................... 28 
10. 
CORRELATIVE/SPECIAL STUDIES ............................................................................. 28 
10.1 
Pathology Evaluation/Molecular Profiling ................................................................. 28 
11 MEASUREMENT OF EFFECT........................................................................................... 28 
11.1 
Definitions .................................................................................................................. 29 
11.1.1 Measurable ................................................................................................................. 29 
11.1.2 Non-measurable ......................................................................................................... 29 
11.1.3 Special considerations regarding lesion measurability .............................................. 29 
11.2 
Response Criteria ........................................................................................................ 29 
11.3 
Other Response Parameters ........................................................................................ 30 
11.3.1 Knosp Classification3 .............................................................................................. 30 
11.3.2 Pituitary function testing ......................................................................................... 31 
12 DATA REPORTING / REGULATORY CONSIDERATIONS .......................................... 31 
12.1 
Data Collection ........................................................................................................... 31 


 
Page 10 of 36 
 
12.1.1 REDCap ..................................................................................................................... 31 
12.2  Regulatory Considerations ............................................................................................... 32 
13 STATISTICAL CONSIDERATIONS.................................................................................. 32 
13.1 
Analysis for Primary endpoint:................................................................................... 32 
13.2 
Sample Size/Accrual Rate .......................................................................................... 33 
13.3 
Analysis for Secondary endpoints: ............................................................................. 33 
13.4   
Exploratory analysis ................................................................................................... 33 
14 DATA AND SAFETY MONITORING PLAN (DSMP) ..................................................... 34 
14.1 
Stopping Rules ............................................................................................................ 34 
REFERENCES ............................................................................................................................. 35 
 


 
Page 11 of 36 
 
1. STUDY OBJECTIVES 
1.1. Primary Objectives 
• To assess the radiographic response rate of capecitabine and temozolomide in 
patients with residual or recurrent pituitary adenomas.  
1.2  Secondary Objectives 
• To assess the effect of capecitabine and temozolomide on pituitary adenoma 
hormone secretion in patients with residual or recurrent functioning pituitary 
adenomas 
• To assess the effect of capecitabine and temozolomide on pituitary function in 
these patients. 
• To assess the overall safety and tolerability of combination treatment with 
capecitabine 
     1.3 Exploratory Objectives 
• To clarify the role of Ki67 nuclear labelling index, p53 expression, MGMT 
expression/methylation status, and additional tumor genetic profiling as indicators 
of tumor aggressiveness and invasiveness. 
 
2.0 BACKGROUND  
 
2.1 Disease 
 
Pituitary adenomas are relatively common, representing 10-15% of all intracranial 
tumors 1-3. Although generally considered benign, these tumors can have significant 
morbidity due to their sensitive location. Symptoms may be related to compression of 
cranial nerves and adjacent structures, particularly loss of vision and headaches. In 
addition to mass effect, some of these adenomas are invasive. A reported 25-55% of 
pituitary adenomas invade surrounding structures including the cavernous sinus and 
sphenoid sinus3-6. Criteria such as the Hardy and Knosp classification systems have 
been used to quantify the extent of tumor invastion (Hardy system focusing on bony 
invasion, while the Knosp system evaluates cavernous sinus invasion).  
 
Unfortunately, a subset of pituitary adenomas are also pathologically aggressive, 
which is distinct from their potential invasiveness. Several factors including high 
mitotic activity, elevated MIB-1/Ki67, and increased p53 expression have been used 
to assess aggressiveness on pathology evaluation. Although not fully standardized, it 
has been shown that a Ki67 index of ≥3% is a predictor of tumor aggressiveness and 
may also indicate probable invasiveness6. Similarly, strong p53 immunoreactivity has 
been found in large, aggressive pituitary adenomas7,8. Further, elevated levels of 
EGFR, VEGFR, and FGFR have been associated with more aggressive tumors9,10. 
Unfortunately, there is still limited knowledge regarding the genetic causes of 
pituitary tumorigenesis and/or transition to more aggressive phenotypes.  
 
Another complication is that a subset of these tumors may be functional and secrete 


 
Page 12 of 36 
 
excess levels of pituitary hormones such as prolactin, adrenocorticotrophic hormone 
(ACTH), and growth hormone (GH) as well as less commonly thyroid stimulating 
hormone (TSH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) 1. 
This hormonal dysfunction can contribute to significant systemic medical illness, 
including Cushing’s disease and acromegaly with ACTH and GH-secreting tumors, 
respectively. Initial treatment of pituitary adenomas is specific for each type.  
 
Initial treatment is variable and can be dependent on the specific tumor type (and 
whether it is functioning or non-functioning). Prolactinomas are typically first treated 
with dopamine agonist therapy, while surgery is usually preferred for adenomas that 
are non-functioning or produce GH or ACTH. Full resection may be limited by 
neoplastic invasion into surrounding structures. Radiotherapy is also considered for 
residual tumor present after surgery as well as on occurrence. Occasionally, pituitary 
adenomas behave aggressively and progress even after multiple treatment approaches 
including surgery, proton beam radiation therapy, stereotactic radiosurgery (SRS) and 
pharmacologic treatment11,12. As the goal of these treatments is often palliative, 
chemotherapy has been trialed in hopes of shrinking or stabilizing these tumors.  
 
 
2.2 Investigational Agent or Device 
2.2.1 Capecitabine (Xeloda) 
Capecitabine (CAP) is an antimetabolite that is enzymatically converted to 5-
fluorouracil (5-FU) which is then converted to active metabolites 5-fluoro-2-
deoxyuridinemonophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). 
Cytoxicity is mediated by two mechanisms. With folate cofactor N 5-10-
methylenetetrahydrofolate, FdUMP binds to thymidylate synthase, forming a 
complex that inhibits thymidylate formation, which is necessary for DNA 
synthesis. Lack of thymidylate leads to blocking of cell division. Secondly, FUTP 
can be incorporated in place of uridine triphosphate during RNA synthesis, which 
causes an error that prevents proper RNA processing and protein synthesis.  
 
CAP has been shown to be effective in several malignancies, and is often used for 
treatment of metastatic breast and colorectal cancers13,14 as well as neuroendocrine 
tumors in combination with temozolomide (discussed below). FDA-approved 
dosage, based on several studies, is 1250mg/m2 orally twice daily (total daily 
dose: 2500 mg/m2) at the end of meal for two weeks followed by one to two week 
rest period.  
 
 
Significant adverse affects:  
 
• Bone marrow suppression: Bone marrow suppression may occur, hematologic 
toxicity is more common when used in combination therapy.  
 


 
Page 13 of 36 
 
• Cardiotoxicity: Cardiotoxicity has been observed with capecitabine, including 
myocardial infarction, ischemia, angina, dysrhythmias, cardiac arrest, cardiac 
failure, sudden death, ECG changes, and cardiomyopathy. These adverse events 
may be more common in patients with a history of coronary artery disease. 
 
• Dermatologic toxicity: Stevens-Johnson syndrome and toxic epidermal 
necrolysis (TEN) have been reported. 
 
• Gastrointestinal toxicity: May cause diarrhea (may be severe); median time to 
first occurrence of grade 2 to 4 diarrhea was 34 days and median duration of 
grades 3 or 4 diarrhea was 5 days. Necrotizing enterocolitis (typhlitis) has been 
reported. 
 
• Hand-and-foot syndrome: May cause hand-and-foot syndrome (palmar-plantar 
erythrodysesthesia or chemotherapy-induced acral erythema); characterized by 
numbness, dysesthesia/paresthesia, tingling, painless or painful swelling, 
erythema, desquamation, blistering, and severe pain. The median onset is 79 days 
(range: 11 to 360 days).  
 
• Hepatotoxicity: Grade 3 and 4 hyperbilirubinemia have been observed (median 
onset: 64 days). Transaminase and alkaline phosphatase elevations have also been 
reported.  
 
 
Pharmacokinetics: 
 
Absorption 
• Bioavailability: readily absorbed (bioavailability data lacking)  
• Effect of food: reduces rate and extent of absorption  
 
Distribution 
• Protein binding: less than 60% (35% bound to human albumin)  
 
Metabolism 
• Hepatic: extensive  
• 5-fluorouracil: active  
• 5'-deoxy-5-fluorocytidine (5-DFCR): active  
• 5'-deoxy-5-fluorouridine (5-DFUR): active  
• 5-fluoro-2'-deoxyuridine monophosphate (FdUMP): active  
• 5-fluorouridine triphosphate (FUTP): active  
 
Excretion 
• Renal: 95.5% (3% as unchanged drug)  
• Fecal: 2.6%  


 
Page 14 of 36 
 
 
Elimination Half Life 
• Capecitabine: 38 to 45 minutes  
 
 
 
 
 
 
 
(from Micromedex) 
 
2.2.2 Temozolomide (Temodar) 
 
TMZ is an alkylating agent which interferes with cell division. It is rapidly 
converted to its active form MTIC, which alkylates DNA (at the O6 and N7 
positions of guanine) causing DNA double strand breaks and subsequent 
apoptosis.  
 
TMZ has become standard-of-care for treatment of glioblastoma based on the 
landmark trial by Stupp et al15. In glioblastoma, a dose of 75 mg/m2 orally is 
given daily concurrent with radiation. In the adjuvant setting, the first cycle 
150mg/m2 daily x 5 days followed by 23 days without treatment (starting 4 weeks 
after the TMZ + RT phase). The dose is escalated to 200mg/m2 per day for five 
days, again followed by 23 days off treatment, if there is not significant 
hematologic toxicity.  
 
 
Significant adverse affects: 
  
• 
Bone marrow suppression: Myelosuppression may occur; may require 
treatment interruption, dose reduction and/or discontinuation; monitor blood 
counts. An increased incidence has been reported in geriatric and female 
patients. Prolonged pancytopenia resulting in aplastic anemia has been 
reported (may be fatal); concurrent use of temozolomide with medications 
associated with aplastic anemia (eg, carbamazepine, co-trimoxazole, 
phenytoin) may obscure assessment for development of aplastic anemia.  
 
• 
Gastrointestinal toxicity: Temozolomide is associated with a moderate emetic 
potential (Dupuis 2011; Roila 2010); antiemetics are recommended to prevent 
nausea and vomiting. 
 
• 
Hepatotoxicity: Hepatotoxicity has been reported; may be severe or fatal. 
Postmarketing reports of hepatotoxicity have included liver function 
abnormalities, hepatitis, hepatic failure, cholestasis, hepatitis cholestasis, 
jaundice, cholelithiasis, hepatic steatosis , hepatic necrosis, hepatic lesion, and 
hepatic encephalopathy (Sarganas 2012). 
 


 
Page 15 of 36 
 
• 
Pneumonia: Pneumocystis jirovecii pneumonia (PCP) may occur; risk is 
increased in those receiving steroids or longer dosing regimens. Monitor all 
patients for development of PCP (particularly if also receiving 
corticosteroids).  
 
• 
Secondary malignancies: Rare cases of myelodysplastic syndrome and 
secondary malignancies, including myeloid leukemia, have been reported. 
 
 
Pharmacokinetics: 
     Absorption 
• Oral: Rapid and complete 
 
Distribution  
• Vd: Parent drug: 0.4 L/kg; penetrates blood-brain barrier; CSF levels are 
~35% to 39% of plasma levels (Yung 1999)Protein binding:15%  
 
Metabolism  
• Prodrug, hydrolyzed to the active form, MTIC; MTIC is eventually 
eliminated as CO2 and 5-aminoimidazole-4-carboxamide (AIC), a natural 
constituent in urine; CYP isoenzymes play only a minor role in 
metabolism (of temozolomide and MTIC) 
 
Bioavailability  
• Oral: 100%  
 
Half-life elimination 
• Mean: Parent drug: Adults: 1.6-1.8 hours 
 
Time to peak 
• Oral:  
 Empty stomach: 1 hour 
 With food (high-fat meal): 2.25 hours 
 
Excretion:  
• Urine (~38%; parent drug 6%)  
• Feces <1% 
 
Clearance 
• 5.5 L/hour/m2; women have a ∼5% lower clearance than men (adjusted 
for body surface area) 
 
 
 
 
(from Micromedex) 
 


 
Page 16 of 36 
 
2.3 Rationale for combination of CAP and TMZ 
 
Temozolomide, a second-generation alkylating agent, has emerged as a promising 
treatment for aggressive pituitary adenomas. It kills tumor cells through methylation 
of DNA at the O6 position of guanine, which mispairs with thymine during the 
subsequent cycle of DNA replication16. Based on several case series, the overall 
clinical and radiological response rate with temozolomide is about 60% in aggressive 
pituitary adenomas3,11,17-19.Losa et al. completed a one-year prospective study of TMZ 
in atypical pituitary adenoma. Five patients were treated with TMZ treatment, with 
two demonstrating response, two with stable disease, and two stopping treatment at 3 
and 6 months, respectively, due to disease progression20. Low expression of 6-O-
methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme that reverses 
the effects of temozolomide, may correlate with better outcomes with chemotherapy.  
 
Both temozolomide and capecitabine penetrate the blood-brain barrier. Several 
studies have shown the efficacy of combination treatment with capecitabine and 
temozolomide in neuroendocrine tumors21-23. Based on this literature, Robert Fine et 
al. utilized this regimen in four patients with aggressive refractory ACTH-producing 
adenomas, and reported prolonged antitumor response24. The capecitabine (oral 5-
fluorouracil) may have synergistic antitumor effects with the temozolomide, by 
contributing to thymidine depletion which may increase temozolomide-induced 
toxicity on tumor cells. To our knowledge, the efficacy of temozolomide and/or 
capecitabine in recurrent pituitary adenomas has not been assessed in a controlled 
clinical trial, and with the encouraging anecdotal data this deserves further 
investigation. 
 
2.4 Risk/Benefit Assessment  
 
 
Unfortunately, treatment for recurrent/residual pituitary adenomas is limited, and for 
some patients the tumors remain or progress even after multimodality treatment. 
Chemotherapy is not often used in these type of tumors due to limited clinical 
evidence, but it may play a key role in treatment. This study would clarify, in a 
standardized fashion, whether chemotherapy with temozolomide and capecitabine 
demonstrates activity in recurrent pituitary adenomas. Additionally, it will provide 
significant information regarding tolerability of chemotherapy in these patients.  
 
2.5 Correlative Studies Background 
 
No correlative studies are planned. 
 
 
3.0 SUBJECT SELECTION 
 


 
Page 17 of 36 
 
3.1 Study Population 
 
The study population will include patients 18 years of age and older with relatively 
good functional status who have a diagnosis of pituitary adenoma (both secreting and 
non-functioning) that has recurred (or with residual disease) after at least one prior 
treatment (such as with surgery, radiation and/or medical therapy).  
 
3.2 Inclusion Criteria 
 
1. Male or female ≥ 18 years of age.  
 
2. 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.   
 
 
3. Karnofsky performance status ≥ 70%. 
 
4. Life expectancy of greater than six months. 
 
5. 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.  
 
6. 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): 
 
a. Platelet count ≥ 100 × 109/L. 
b. Hemoglobin ≥ 9 g/dL. 
c. WBC ≥ 3 × 109/L  
d. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L. 
e. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 x ULN if 
Gilbert’s disease is documented. 
f. Aspartate transaminase (AST) ≤ 2.5 ULN. 
g. Alanine transaminase (ALT) ≤ 2.5 ULN. 
h. Serum creatinine ≤ 1.5 × ULN OR creatinine clearance≥60mL/min/1.73 
m2 for patients with creatinine levels above institutional normal. 
 
7. Patients must be able to undergo a MRI Brain/Pituitary 
 


 
Page 18 of 36 
 
8.  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. 
 
9. Patients must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
3.3 Exclusion Criteria  
 
 
 
1. Prior temozolomide and/or capecitabine therapy for treatment of the pituitary 
tumor. 
 
2. 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). 
 
3. Clinically significant renal, hematologic or hepatic abnormalities. 
 
4. Use of Vitamin K antagonists such as warfarin (concentrations may be altered by 
concomitant use of capecitabine) 
 
5. 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 
 
6. History of deficient dihydropyrimidine dehydrogenase activity. 
 
7. History of immunodeficiency. 
 
8. Patients who are taking any other concurrent investigational therapy.  
 
9. Patients who are pregnant or breastfeeding. 
 
10. Patients who have had prior radiation treatment in the last six months  
 
11. Patients who have had prior pituitary surgery within the last two months  
 
 
4.0  REGISTRATION PROCEDURES 
 
4.1 Patient Registration 
Patients will be centrally registered with Weill Cornell Medicine, Joint Clinical Trials 
Office, Cancer Clinical Trials Operations. To register a patient, completed the web-based 


 
Page 19 of 36 
 
demographic, enrollment pages and the following documents and email to the Joint 
Clinical Trials Office.  
• 
WCMC Patient Registration Form  
• 
First and last page of the fully executed informed consent form, plus additional pages 
if with subject’s markings  
• 
Fully executed HIPAA research authorization form (if separate from the consent 
document)  
• 
Eligibility checklist signed and dated by investigator and second study team member  
• 
Documentation of any eligibility waivers granted 
 
5.0 STUDY PROCEDURES 
 
5.1 Overview 
 
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 DLT. Enrolled patients (sample size N=21 to 33) 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.  
 
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). 
 
5.2 Table of Assessments 
 
 
Screening 
Each Treatment Cycle 
EOT 
Follow 
Up 
Day 1 
Day 8 
Day 15 
Day 22 
Agent Administration 
 
X 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical exam 
X 
X 
 
 
 
X 
 
Karnofsky Performance 
Status 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
CBC w/diff 
X 
X 
X 
X 
X 
X 
 
Serum chemistry (including 
LFTs)a 
X 
X 
 
X 
 
X 
 
B-HCG 
Xb 
 
 
 
 
 
 


 
Page 20 of 36 
 
Serum prolactin, GH, IGF-1, 
ACTH, cortisol +/- 
Dexamethasone level, FSH, 
LH, testosterone/estradiol, 
TSH, free T4, free T3, 24h 
urine free cortisol, creatinine, 
midnight salivary cortisol 
X 
Xc 
 
 
 
X 
 
EKG 
X 
 
 
 
 
 
 
MRI Brain/Pituitary 
Xd 
To be performed every 8 weeks 
according to institutional standards 
 
 
Adverse Event Review 
 
X 
X 
X 
X 
X 
 
Conmed Review 
 
X 
X 
X 
X 
X 
 
Survival Phone Call 
 
 
 
 
 
 
X 
a: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
LDH, phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], sodium, ALK, and Liver 
Function Tests. 
b: Serum pregnancy test (women of childbearing potential). 
c:  Only labs that are abnormal at baseline need to be checked every 8 weeks (on Day 1 of even cycles) 
d: to be completed within 6 weeks of enrollment on trial, according to institutional standards 
 
5.3 Screening Visit  
 
 
 
Labs must be completed within three weeks of study consent 
• Informed consent 
• Medical history 
• Medication history 
• Physical exam 
• KPS 
• Vital Signs 
• Height 
• Weight 
• CBC w/diff, platelets 
• Serum chemistry with liver function tests 
• Serum prolactin, GH, IGF-1, ACTH, cortisol +/- Dexamethasone 
level, FSH, LH, testosterone/estradiol, TSH, free T4, free T3, 24h 
urine free cortisol, creatinine, midnight salivary cortisol 
• B-HCG if woman of childbearing age 
• EKG 
• Radiologic evaluation with MRI Brain or MRI Pituitary for baseline 
tumor measurements and Knosp classification grading (to be 
completed within 14 days of study enrollment) 
 
5.4 Treatment Phase 
 (1 cycle=28 days) 
CAP will be taken twice daily Days 1-14 with the addition of TMZ Days 10-
14 followed by 14 days off treatment. Prior to each cycle, ANC must be 
≥1,500/mm3 and platelets ≥100,000/mm3 or treatment will be held.  
 
 
 
 
 
 
 
 
 
 
 
Days 1, 8, 15, and 22 of Every Cycle (± 3 days): 
• CBC w/diff, platelets 


 
Page 21 of 36 
 
 
 
 
 
 
 
Days 1 and 15 of every cycle (± 3 days): 
• Serum chemistry with liver function tests 
 
 
 
 
 
 
 
Day 1 of every cycle  (± 5 days): 
• Physical exam 
• Vital Signs 
• Adverse Event and Conmed Review 
• Physical Exam 
• Vital Signs 
 
 
 
 
 
 
Day 1 of every even cycle (± 5 days)  
• Serum prolactin, GH, IGF-1, ACTH, cortisol +/- Dexamethasone 
level, FSH, LH, testosterone/estradiol, TSH, free T4, free T3, 24h 
urine free cortisol, creatinine, midnight salivary cortisol (*only labs 
that are abnormal at baseline need to be checked every eight weeks) 
• MRI Brain/Pituitary with tumor measurements and Knosp 
classification grading 
*Continue as above with imaging and pituitary function tests after completion 
of every even chemotherapy cycle (i.e. 2, 4, 6, 8, 10, 12) unless toxicity 
preventing further chemotherapy and/or progression on imaging. 
 
5.5 End of Study Visit 
• Physical exam 
• Vital Signs 
• CBC w/diff, platelets 
• Serum chemistry with liver function tests 
• Serum prolactin, GH, IGF-1, ACTH, cortisol +/- Dexamethasone 
level, FSH, LH, testosterone/estradiol, TSH, free T4, free T3, 24h 
urine free cortisol, creatinine, midnight salivary cortisol (*only labs 
that are abnormal at baseline need to be checked again at end of study) 
• Radiologic evaluation with MRI Brain or MRI Pituitary  
 
6.0 TREATMENT ADMINISTRATION 
 
Treatment will be administered on an outpatient basis. Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications for 
Investigational Agent or Device are described in Section 6.   
 
1) Capecitabine 1500mg/m2 orally per day (divided into two doses with maximum 
daily dose of 2500mg) on days 1 through 14.  
 
Doses should be taken with water within 30 minutes after a meal. The tablets 
should be swallowed whole (should not be cut or crushed). 


 
Page 22 of 36 
 
 
2) Temozolomide 150mg/m2 orally per day on days 10 through 14 (dose will be 
escalated to 200mg/m2 on Cycle #2 if well-tolerated without significant 
hematologic toxicity on first cycle).  
 
Patient will take odansetron 4mg on empty stomach, and 20 minutes later take the 
temozolomide dose. The capsules should be swallowed whole with a glass of 
water. Capsules should not be opened or chewed, and patients should avoid 
contact with skin or mucous membranes if capsules are accidentally opened or 
damaged. 
 
 
6.1 Dose De-escalation Schema (for Safety Run-in component in case of DLT) 
 
6.1.1 Inter-patient De-escalation 
 
Dose level  
Capecitabine 
Temozolomide 
-2 
750mg/m2 orally per day 
in two divided doses on 
Days 1-14 
100mg/m2 once daily on 
Days 10-14 for all 
subsequent cycles 
-1 
1000mg/m2 orally per day 
in two divided doses on 
Days 1-14 
150mg/m2 once daily on 
Days 10-14 for all 
subsequent cycles 
0 
1500mg/m2 orally per day 
in two divided doses on 
Days 1-14  
150mg/m2 once daily on 
Days 10-14 for cycle 1, 
200mg/m2 once daily on 
Days 10-14 (for cycles 2-
12 if no significant toxicity 
on first cycle) 
 
6.1.2 Criteria for Dose De-escalation 
 
Cohorts of 3 to 6 patients will be treated with capecitabine and temozolomide at dose 
level 0. If a minimum of three patients who are evaluable for toxicity have completed 
first cycle of treatment at this dose level without evidence of dose-limiting toxicity 
(DLT) (section 5.3.3), the study may be proceeded to the phase II component with 
subsequent patients being enrolled at the same dose level.  
 
If DLT is observed in 1 patient from the initial cohort of 3 patients at dose level 0 
(1/3 with DLT), an additional 3 patients will be enrolled at dose level 0.  
 


 
Page 23 of 36 
 
If DLT is observed in 1 patient from the 6 patients at dose level 0 (1/6 with DLT), 
then dose level 0 will be the dose level for phase II component, and we may proceed 
to the phase II component with subsequent patients being enrolled at dose level 0. 
 
If 2 or more patients have DLT at dose level 0 from the first 3 patients (>= 2/3 with 
DLT) or 2 or more patients with DLTs are observed in 6 patients (>= 2/6 with DLT), 
three more patients will be enrolled at one lower dose level. 
 
The dose level for the phase 2 component will be the dose below the one where two 
or more patients in a group of 6 experience a DLT. 
 
6.2 Definition of Dose Limiting Toxicity (DLT) (Criteria for entire study) 
 
Dose-limiting toxicity (DLT) is defined as the occurrence of any of the following 
AEs using NCI-CTCAE (v 4.03) that are possibly, probably or definitely attributed to 
capecitabine or temozolomide during the FIRST CYCLE of treatment: 
 
1) Any Grade 4 non-hematologic toxicity (excluding alopecia, nausea/vomiting) 
including palmar-plantar erythrodysesthesia (Hand-Foot Syndrome).  
2) Any >= Grade 3 neurologic toxicity 
3) Grade 4 thrombocytopenia 
4) Grade 4 neutropenia 
 
6.3 General Concomitant Medication and Supportive Care Guidelines 
 
Capecitabine: CAP is a strong inhibitor of CYP2C9. It may increase the anticoagulant 
effects of warfarin leading to bleeding events, including death. Use of Vitamin K 
antagonists is contraindicated with CAP. It may also interfere with the concentrations 
of other drugs metabolized by CYP2C9.  
 
Temozolomide: Due to moderate risk of nausea/vomiting, preventative anti-emetic is 
taken before every dose of TMZ (Odansetron 4mg orally 20 minutes before 
administration of TMZ capsules). 
 
6.4 Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse event(s), treatment may continue 
for 12 cycles or until one of the following criteria applies: 
 
o Disease progression, 
 
o Intercurrent illness that prevents further administration of treatment, 
 


 
Page 24 of 36 
 
o Unacceptable adverse event(s), 
 
o Patient decides to withdraw from the study, or 
 
o General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator,. 
 
6.6 Duration of Follow Up 
 
Patients will be followed every two months for six months after removal from study.  
If possible, MRI imaging will be completed every two months to continue monitoring 
of the pituitary adenoma (according to institutional practice). Patients removed from 
study for unacceptable adverse events will be followed until resolution or stabilization 
of the adverse event. 
 
7.0 DOSING DELAYS/DOSE MODIFICATIONS 
 
*Prior to treatment for each cycle, ANC must be ≥1,500/mm3 and platelets ≥100,000/mm3. 
If those values are not met, treatment will be held until they reach the respective threshold.  
 
Capecitabine: 
Normal Dosage: 1500mg/m2 orally per day (divided into two doses with maximum daily 
dose of 2500mg) on Days 1-14 of a 28-day treatment cycle. 
 
Dose modification for CAP-related toxicity (including renal, hematologic, hepatic): 
Toxicity Grades 
During course of therapy 
Dose adjustment for NEXT cycle 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
 
 
1st appearance Interrupt until resolved to grade 0 to 1 
No change 
2nd appearance Interrupt until resolved to grade 0 to 1 
750mg/m2 daily dose (max 1250mg 
daily dose) 
3rd appearance Discontinue CAP 
(may still continue with TMZ 
monotherapy if toxicity presumed 
fully related to CAP) 
Grade 3 or 4 
 
 
1st appearance Discontinue CAP 
(may still continue with TMZ 
monotherapy if toxicity presumed 
fully related to CAP) 
 
Temozolomide Normal Dosage: 
Cycle 1: 150 mg/m2 once daily on Day 10-14 of 28-day treatment cycle 
 


 
Page 25 of 36 
 
Cycles 2 to 12: Increase to 200 mg/m2 once daily on Day 10-14 of 28 day treatment cycle, IF 
ANC ≥1,500/mm3, platelets ≥100,000/mm3, and non-hematologic toxicities for Cycle 1 are 
≤grade 2 (excludes alopecia, nausea/vomiting) 
 
Dosage modification for TMZ-related toxicity: 
 
If patient experiences ANC <1,000/mm3, platelet count <50,000/mm3, or grade 3 non-
hematologic toxicity (excluding alopecia, nausea/vomiting) during previous cycle:  
- 
Decrease dose by 1 dose level (by 50 mg/m2/day) 
- 
If dose has already been lowered to 100 mg/m2/day, then discontinue 
therapy. 
 
Patients should come off trial if any of the following conditions are met: 
- 
If dose reduction <100 mg/m2/day is required 
- 
Patient experiences a  grade 4 nonhematologic toxicity (excluding 
alopecia, nausea/vomiting)  
- 
Patient previously had a dose reduction, but  the same grade 3 non-
hematologic toxicity occurs after dose reduction 
 
8.0 ADVERSE EVENT REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the 
safe use of the drug or device under investigation.  Safety will be monitored by evaluation of 
adverse events reported by patients or observed by investigators or research staff, as well as 
by other investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc. 
 
8.1  
Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, and does not imply any judgment about 
causality. An adverse event can arise with any use of the drug (e.g., off-label use, use 
in combination with another drug) and with any route of administration, formulation, 
or dose, including an overdose.  
 
 
8.1.1 Investigational Agent or Device Risks  
 
 Capecitabine: Potential adverse reactions related to capecitabine include 
(but are not limited to) myelosuppression, fatigue/weakness, hand and foot 
syndrome, dermatitis, diarrhea, mucositis, abdominal pain, anorexia, 
hyperbilirubinemia, paresthesias, and peripheral sensory neuropathy. 


 
Page 26 of 36 
 
 
 
 
 
Temozolomide: Generally well-tolerated but side effects include 
myelosuppression, moderate nausea/vomiting (reduced by taking on 
empty stomach), anorexia, constipation, headache, fatigue and alopecia. 
MDS and secondary malignancies have been reported but are extremely 
rare. 
 
8.1.2 Adverse Event Characteristics and Related Attributions 
 
 CTCAE term (AE description) and grade:  The descriptions and 
grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). 
 
• 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
8.1.3 Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific AE log. The AE 
log will be maintained by the research staff and kept in the patient’s 
research chart and Redcap database.    
 
 
8.1.4  Reporting of AE to WCMC IRB 
 
All AEs occurring on this study will be reported to the IRB according to 
the IRB policy, which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immed
iate_Reporting_Policy.pdf.  
 
8.2  
 
Definition of SAE 
 
SAE’s include death, life threatening adverse experiences, hospitalization or 
prolongation of hospitalization, disability or incapacitation, overdose, 
congenital anomalies and any other serious events that may jeopardize the 
subject or require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  
 


 
Page 27 of 36 
 
8.2.1 
Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to 
the IRB policy, which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immed
iate_Reporting_Policy.pdf.  
  
8.2.2 
 Reporting of SAE to FDA   
 
If an SAE occurs on this study, the event will be filed on a MedWatch 
form with the FDA. The investigator must notify the FDA of any SAE’s as 
soon as possible but no later than 7 calendar days after the initial receipt of 
the information 
 
CDER-only Biologic INDs:  
Food and Drug Administration  
Center for Drug Evaluation and Research  
Therapeutic Biologic Products Document Room  
5901-B Ammendale Road  
Beltsville, MD 20705-1266  
 
8.2.3 AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or 
until the investigator confirms that the AE/SAE has stabilized and no more 
follow-up is required. This requirement indicates that follow-up may be required 
for some events after the patient discontinues participation from the study.  
 
 
9.  
PHARMACEUTICAL INFORMATION 
 
 
9.1 
Investigational Agent   
 
Capecitabine: CAP is an antimetabolite that is enzymatically converted to 5-FU in tumors 
which induces cytotoxicity. It is a commonly used chemotherapy in breast cancer, 
colorectal cancer and neuroendrocrine tumors. It undergoes extensive hepatic metabolism 
and is mostly excreted by the kidney with elimination half life of 38-45 minutes. It is 
available in 150mg and 500mg tablets. It is considered a hazardous neoplastic agent, and 
NIOSH recommends single gloving for administration of intact tablets. 
 
Temozolomide: Temozolomide is a second generation alkylating agent that inhibits DNA 
replication and cell division. It is used as standard-of-care chemotherapy for 


 
Page 28 of 36 
 
glioblastoma. About 38% is eliminated in the urine with an elimination half-life of 1.6-
1.8 hours. It is available in 5, 20, 100, 140, 180 and 250mg capsules. It is considered a 
hazardous neoplastic agent, and NIOSH recommends single gloving for administration of 
intact capsules. 
 
9.2 
Availability 
 
Both Capecitabine and Temozolomide are available through any specialty pharmacy that 
provides chemotherapy. 
 
9.3 
Agent Ordering 
 
 
 
Not applicable. 
 
9.4 
Agent Accountability 
 
Not applicable. 
 
10.  CORRELATIVE/SPECIAL STUDIES 
 
10.1 Pathology Evaluation/Molecular Profiling  
 
To be performed if tissue sample available; this will not be necessary for enrollment. 
 
The exact mechanisms for pituitary tumorigenesis and transformation to a more 
aggressive phenotype are still not known. Both Ki67 nuclear labelling index and p53 
expression are possible indicators of pituitary tumor invasiveness and aggressiveness. 
Further, low expression of 6-O-methylguanine-DNA methyltransferase (MGMT), a 
DNA repair enzyme that reverses the effects of temozolomide, may correlate with 
better outcomes with chemotherapy.  
 
On enrollment, we will request 20 unstained tumor tissue slides from the institution 
where surgery was performed (if available) for evaluation of MGMT expression, 
MGMT methylation status, p53 expression, and Ki67 nuclear labelling index. In 
addition, we will attempt to acquire extended genetic profiling of these pituitary 
tumors via testing with Foundation Medicine. Specific somatic mutations within the 
tumor may contribute to tumorigenesis, aggressiveness and invasiveness. These tumor 
samples will be encouraged but are NOT necessary for enrollment in the trial.  
 
11 MEASUREMENT OF EFFECT 
 
Although not fully validated for pituitary tumors, the RECIST criteria 25 will be used to 
assess response of pituitary adenoma to the chemotherapy regimen of CAP and TMZ.  


 
Page 29 of 36 
 
 
11.1 Definitions 
11.1.1 Measurable 
Pituitary tumor: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of 10mm 
by MRI scan.  
 
11.1.2 Non-measurable  
This may be irrelevant for the pituitary tumors, if metastatic probably carcinomas. 
 
All other lesions, including small lesions (longest diameter <10 mm) as well as truly non-
measurable lesions (such as leptomeningeal disease).  
 
11.1.3 Special considerations regarding lesion measurability 
Cystic lesions: 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
 
Lesions with prior local treatment: 
Lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
 
11.2  Response Criteria 
 
 
 
11.2.1 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 on study (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): 


 
Page 30 of 36 
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
 
11.2.2 Evaluation of non-target lesions 
 
This section provides the definitions of the criteria used to determine the tumor 
response for the group of non-target lesions. While some non-target lesions may 
actually be measurable, they need not be measured and instead should be assessed 
only qualitatively at the time points specified in the protocol. 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor marker level.  
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s)  
 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions. (Note: the appearance of one 
or more new lesions is also considered progression). 
 
11.2.3 Duration of Response  
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
 
 
 
 
11.3 Other Response Parameters 
11.3.1 Knosp Classification3 
 


 
Page 31 of 36 
 
We will use the Knosp classification system to quantify invasion of pituitary 
tumor into the cavernous sinus, which is clinically relevant and cannot be fully 
assessed by the measurements described under the RECIST criteria.  
 
Grade 0: No cavernous sinus involvement 
Grade 1: Pushes into medial wall of the cavernous sinus but not past hypothetical 
line extending between the centers of the two segments of the internal carotid 
artery 
Grade 2: Extends past hypothetical line extending between the centers of the two 
segments of the internal carotid artery, but without passing a line tangent to the 
lateral margins of the artery itself 
Grade 3: Tumor extends laterally to the internal carotid artery within the 
cavernous sinus 
Grade 4: Total encasement of the intracavernous carotid artery 
 
 
 
 
 
(from Di leva, A. et al. Nat. Rev. Endrocrinol. 10, 423-435 (2014) 
 
 
11.3.2 Pituitary function testing 
 
Will measure baseline serum prolactin, IGF-1, ACTH, FSH, LH and TSH and re-
check every 8 weeks while patients are on study. Will assess any interval change 
in these levels after initiation of chemotherapy.   
 
 
 
12 DATA REPORTING / REGULATORY CONSIDERATIONS 
 
12.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, efficacy, and adverse event data for all enrolled patients.  
 
            12.1.1 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software 
system that is fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool 


 
Page 32 of 36 
 
for the creation of customized, secure data management systems that include Web-
based data-entry forms, reporting tools, and a full array of security features including 
user and group based privileges, authentication using institution LDAP system, with a 
full audit trail of data manipulation and export procedures.  REDCap is maintained on 
CTSC-owned servers that are backed up nightly and support encrypted (SSL-based) 
connections.  Nationally, the software is developed, enhanced and supported through 
a multi-institutional consortium led by the Vanderbilt University CTSA. 
 
12.2  Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the 
Principal Investigator.   
 
 
13 STATISTICAL CONSIDERATIONS 
 
13.1 
Analysis for Primary endpoint: 
 
This is a single-stage phase II clinical trial with safety run-in. The primary endpoint of the 
study is the response rate in patients with recurrent pituitary adenoma treated with 
temozolomide and capecitabine, assessed by the RECIST criteria.  
 
Safety run-in 
In the safety run-in portion, a conventional 3+3 design is used. The initial starting dose of 
capecitabine and temozolomide will be dose level 0 in table 5.3.1. The total dose level will 
likely only be 1, with the possibility of 2 dose de-escalations. Cohorts of 3 to 6 patients will 
be treated per dose level.  The recommended dose for the phase II part will be defined as the 
dose level immediately below the level at which 2 or more patients in a group of 6 
experience a DLT. The safety run-in patients at the final recommended dose for the phase II 
part will be counted in the total accrual for Phase II part. 
 
Phase II  
Patients will be treated at the recommended dose for the phase II portion based on the safety 
run-in.  
 
We consider that the effect of temozolomide and capecitabine on patients with recurrent 
pituitary adenomas to be clinically meaningful if the response rate is at least 20%, with the 
null hypothesis that a 5% response rate is seen with standard treatment. A total of 21 patients 
will be enrolled for the phase II part, including those in the safety run-in group who are 
treated at the recommended dose for the phase II part. The null hypothesis will be rejected if 
3 or more responders are observed out of 21 evaluable patients. We assume that responses 
are binomially distributed. With a sample size of 21 patients, the power to detect a response 
rate of 0.2 is 82.1%, with a one-sided alpha of 8.5%. 


 
Page 33 of 36 
 
 
 
(Sample size, accrual rate and enrollment time will be addressed later after the design, 
alternative and null hypothesis for the study have been decided.) 
 
 
 
  
13.2 
Sample Size/Accrual Rate 
 
If none of the first 3 patients, or 1 out of the first 6 patients, at dose level 0 experience a DLT, 
the total sample size will be 21 patients.  
 
If the toxicity is worse than expected, 3 patients will have de-escalated to dose level -1 prior 
to the decision to proceed to the phase II. If none of the first 3 patients or 1 out of the first 6 
patients at dose level -1 experience a DLT, the sample size will be 24-27 patients. 
 
If 2 or more of the first 6 patients at dose level -1 experiencing DLT, the dose level will be 
de-escalated to dose level -2, and the sample size will be 27 – 33 patients. 
 
Hence, the minimum sample size is 21 patients, and the maximum could be 33. 
 
13.3 
Analysis for Secondary endpoints: 
 
1. Assess the effect of temozolomide on pituitary adenoma hormone secretion and on 
pituitary function in these patients.  
 
Any change in pituitary hormone secretion during the study will be assessed by endocrine 
laboratory work-up (including serum prolactin, IGF-1, ACTH, FSH, LH and TSH levels) 
at baseline, every two months while receiving treatment, and at the end of study. 
Descriptive statistics will be provided, including any change from baseline. Linear mixed 
model will be utilized, as appropriate, to assess the effect of chemotherapy on pituitary 
adenoma hormone secretion over time. Statistical analysis for these endpoints will be 
considered exploratory. 
 
2. To assess the overall safety and tolerability of temozolomide and capecitabine in patients 
with recurrent pituitary adenomas. 
 
The number and severity of all adverse events will be tabulated and summarized. The 
grade 3 or higher adverse events will also be summarized in a similar way. Summary 
tables of number and percentage of patients who experienced AEs as well as SAEs by 
severity (graded according to CTCAE version 4.0) and by relationship to temozolomide 
and/or capecitabine will also be provided. This will be based on the maximum grade of 
the specific AE experienced by a patient.  
 
13.4   
Exploratory analysis 
 
1. To clarify the role of Ki67 nuclear labelling index, p53 expression, MGMT 


 
Page 34 of 36 
 
expression/methylation status, and additional tumor genetic profiling as indicators of 
tumor aggressiveness and invasiveness. 
 
On enrollment, unstained tumor slides will be requested from the institution where 
surgery was completed, and below studies will be used for the exploratory analysis. 
These are NOT necessary for enrollment in the trial. We will evaluate Ki67 nuclear 
labelling index, p53 expression, MGMT expression/methylation status, and additional 
tumor genetic profiling. Descriptive statistics of Ki67 nuclear labelling index, p53 
expression, MGMT expression/methylation status, and tumor genetic profiling of 
enrolled patients will be provided separately. Statistic modelling methods, if appropriate, 
such as Cox proportional hazard model, will be used to explore the relationship between 
these indicators and response to chemotherapy, time to progression, and tumor 
invasiveness (based on the Knosp criteria). Statistical analysis for these endpoints will be 
considered exploratory. 
 
14   Data and Safety Monitoring Plan (DSMP)  
 
This study will utilize the Weill Cornell Medical College (WCMC) Institutional Data 
Safety Monitoring Board (DSMB) and follow its policies and procedures for 
monitoring this study for safety concerns, with ongoing updates from the Study Chair 
on an ongoing basis.   
 
Reports to the DSMB will include the following items for review: 
1.  Completed DSMB Periodic Review Form. 
2.  Synopsis of the study to date. 
3.  IRB approved consent form. 
4.  IRB current protocol. 
5.  Summary table of study results. 
6.  Adverse event table. 
7.  Data safety monitoring plan. 
 
14.1 Stopping Rules 
 
If at any time 5 or more patients have a grade 4+ event attributable to treatment then 
trial accrual will be halted to determine the safety of the regimen. A decision will be 
made with input from DSMB whether to (1) continue the trial as planned, (2) 
permanently halt the trial or, (3) modify the treatment protocol. 
 
 
 
 


 
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