New Imaging Modalities in the Evaluation of Patients With Ectopic Cushing's Syndrome
Phase: PHASE2
Conditions: Cushing Syndrome, Endocrine Disease
Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Clinical Protocol 99-CH-0055, p. 1
​Rev. 7-6-17
Project Number: 99-CH-0055
           
Drug/Device:
[18F]- L-3,4-dihydroxyphenylalanine (18F-DOPA), IND# 35513; 
IND Sponsor: Dr. Peter Herscovitch
mifepristone, IND#70795; IND Sponsor:  Laboratoire HRA-Pharma
 
Revision Date: July 6, 2017
 
Subject:   New Imaging Modalities in the Evaluation of Patients with Ectopic Cushing Syndrome
 
Identifying Words: PET,  [18F]-DOPA, Pentetreotide, Octreotide, ACTH
 
Principal Investigator and Accountable Investigator:
Lynnette K. Nieman, MD, Senior Investigator, DEOB, NIDDK; CRC/1-3140; 496-8935*
 
Associate Investigators:
Ahmed Gharib, MD, BMIB/NIDDK, 10/1C334
Clara C. Chen, MD, Nuclear Medicine Division, Radiology and Imaging Sciences Department, Clinical
Center; 10/1C459
Millie Whatley, Nuclear Medicine Department, CC; 10/1C423B
Susmeeta Sharma MD, NIH Volunteer
Raven McGlotten, RN, DEOB, NIDDK; CRC/1-3140*
Smita Jha, MD, NICHD/NIAMS; CRC/4-1341
Katherine Araque, MD,  NIDDK;CRC/1-3121
 
*Investigators with this designation will obtain informed consent for this protocol
 
Estimated Duration of Study: 15 years
 
Subjects of Study:
​  N
​Age Range
Cushing syndrome, for screening
​202
​18-90
Of these patients, for PET and Octreoscan
​100
​18-90
​
Project uses ionizing radiation?  Yes. Radiation use is indicated for research. NIH Radiation Safety
Committee has approved this use (rad authorization 1781C).
 
Project involves use of Durable Power of Attorney?  No
 
Off-Site Project?  No
 
Multi-Institutional Project?  No​PRECIS
 
Between 10% and 20% of patients with hypercortisolism (Cushing syndrome) have ectopic production of
adrenocorticotropin hormone (ACTH) that causes cortisol excess. In approximately 50% of these patients,
the source of ACTH cannot be found despite very detailed and extensive examination including imaging
studies such as computed tomography scanning, magnetic resonance imaging, and octreotide scan
(Octreoscan) using the standard dose of indium- 111 pentetreotide ([111In-DTPA-D-Phe]-pentetreotide).
The sensitivity and speciﬁcity of these imaging studies depends on anatomic alterations and/or the dose
and adequate uptake of radiopharmaceutical. In contrast, positron emission tomography (PET) has the
ability to detect pathologic tissue based on physiologic and biochemical processes within the abnormal
tissue. This protocol tests whether [18F]-L-3,4-dihydroxyphenylalanine (18F-DOPA) can be used to
localize successfully the source of ectopic ACTH production.  In addition the study examines whether
administration of the glucocorticoid antagonist mifepristone can improve the sensitivity of the standard
dose Octreocan. Eligible patients participating in this arm of the study will have a second standard dose

dose Oct eoca .
g b e pat e ts pa t c pat g
t s a
o t e study w
ave a seco d sta da d dose
scan.  Others will receive a higher dose octreoscan instead.
 
INTRODUCTION
 
Cushing’s syndrome is an endocrine disorder caused by excessive production of glucocorticoids. In
10%-20% of patients this syndrome results from ectopic production of ACTH and very rarely from
ectopic CRH production (1-6). Small cell carcinoma of the lung, islet cell tumor of the pancreas,
medullary thyroid cancer, pheochromocytoma, and foregut carcinoid tumors are the most common
sources of ACTH production (1,2,5,7). The mean age at diagnosis in patients with ectopic ACTH
production is 40 years and the male-female ratio is almost 1:1 (1,8). The ectopic source of ACTH
production cannot be found in 50% of patients despite aggressive, extensive, and expensive testing (9,10).
These patients are at high risk of death due to sepsis, hypertension, gastrointestinal pathology, and
metastatic dissemination (8,11). More than 50% of patients with ectopic ACTH production cannot be
treated surgically or fail medical therapy and therefore, they ﬁnally undergo adrenalectomy with life-long
hormone replacement therapy (8). However, if the source of ectopic ACTH production is found before the
tumor metastasizes, resection is usually curative. Thus, the ability to image primary and/or metastatic
lesions has proved to be the key to successful treatment. Conventional imaging is generally performed
with computerized tomography (CT) and magnetic resonance imaging (MRI) of the chest and abdomen.
123I-Metaiodobenzylguanidine (MIBG) is taken up by adrenal tissue and pheochromocytomas and may be
useful in identifying this source of ectopic ACTH secretion.  As discussed below, other modalities,
including somatostatin receptor scintigraphy and various positron emission tomography (PET) ligands,
also may be useful in the localization of these tumors.
 
Somatostatin receptor scintigraphy using [111In-DTPA-D-Phe]-pentetreotide (Octreoscan, OCT), an
analog of somatostatin, may identify gastroenteropancreatic tumors, carcinoids, and medullary thyroid
carcinomas, all of which express somatostatin receptors (12). The conventional 6 mCi dose of OCT has
been reported to localize ectopic ACTH production, at NIH and elsewhere (12-14). De Herder et al.
reported a sensitivity of 78% for Octreoscan in patients with ectopic ACTH production (15). However, at
NIH, our experience with somatostatin receptor scintigraphy using the conventional dose of 6 mCi of
[111In-DTPA-D-Phe]-pentetreotide has not been as promising. Detectability of lesions in scintigraphic
studies depends not only on the size of the lesion but also on the amount of radioactivity in that lesion.
 Thus, in the original version of this protocol, we investigated whether a higher dose of
radiopharmaceutical could lead to higher concentrations in a lesion and better visualization. In thyroid
cancer, it is known that higher doses of 131I can detect more lesions than lower doses. Furthermore,
investigators using high doses of [111In-DTPA-D-Phe]-pentetreotide for therapy (180 mCi) have seen
more lesions on patients’ post therapy scans as compared to their diagnostic scans (16). Analysis of 27
patients with surgically-proven ectopic ACTH-secreting tumors showed a 59% sensitivity for the “low
dose” (6 mCi, L-OCT).  In patients who had negative L-OCT, “high dose” (18 mCi, H-OCT) had an
additional 58% (7/12 patients) sensitivity (17).  As a result, the project was amended in 2006 to consider
the high dose Octreoscan a medically-indicated test.  
 
However, H-OCT delivers a substantial radiation dose, particularly when coupled with the L-OCT as is
done here.  In particular, the bladder receives high dose because these radiopharmaceuticals are excreted
by the kidneys.   (See later: concern about radiation).  
Thus, while the beneﬁt-to-risk ratio has been considered acceptable because of improved localization and
the high morbidity and mortality experienced by patients with this disease, a lower radiation dose would
be preferable.  To this end, we propose evaluation of whether the antiglucocorticoid mifepristone can
improve L-OCT sensitivity in patients with active hypercortisolism. 111In-DTPA-D-Phe]-pentetreotide
binds primarily to the somatostatin receptors subtypes (sst) 2 and 5.  There is a large variability in
functional sst2 receptor expression in these tumors (18), which may account for failure of OCT detection
of tumors.  One explanation for this variability is that glucocorticoids can directly down-regulate the
expression of sst2 in neuroendocrine cells in vitro (19-20).  If this is the case in vivo, antagonism of
glucocorticoid action would be expected to relieve this down-regulation, and possibly allow for
conversion of a negative OCT to a positive study. Two patients treated with mifepristone at the NIH and
in the Netherlands, who converted from a negative to a positive scan, generated this hypothesis (22).
 However, the interval between the scans was from 2 – 12 months. To test this hypothesis formally, we
will administer mifepristone to individuals whose initial L-OCT is negative, and will obtain a second L-
OCT after ten days of mifepristone 600 mg daily.  This dose is expected to antagonize most
glucocorticoid effect in patients with ectopic ACTH secretion.
 

PET is a method of imaging disease based on the uptake and metabolism of a speciﬁc
radiopharmaceutical by various tissues.  [18F]-Fluorodeoxyglucose (FDG) PET has been used for years in
evaluating brain anatomical and functional abnormalities and more recently, in tumor localization (22).
Several studies have shown that malignant lesions (e.g. lung, bone, and colorectal cancers, lymphoma)
demonstrate elevated glycolysis when compared to normal tissue (23). In our previous review of results
from this project (24) as well as in our recent analysis (17), the sensitivity of the test in patients with
found tumors is 64% (7/11) and 47% (7/15) when all patients were considered (including occult tumor
patients). However, FDG PET did not detect (or suggest) any tumors that were not identiﬁed by CT
and/or MRI.
 
Because of the inability of FDG PET to detect otherwise occult tumors, we explored the availability of
other ligands. Neuroendocrine tumors such as foregut carcinoids have been classiﬁed as APUDomas
based on demonstration of amine precursor uptake and decarboxylation (25).  In particular, tryptophan is
taken up and 5-hydroxylated to 5-hydroxy-tryptophan (5-HTP).  Carcinoid tumors that express the
enzyme aromatic amino acid decarboxylase (usually the mid-gut carcinoids) can decarboxylate 5-HTP to
serotonin (5-hydroxytryptamine or 5-HT). Sundin and colleagues demonstrated that these tumors take up
and retain [11C]-5-HTP, allowing visualization via PET  (26).  Similarly, the tumors take up and
decarboxylate L-3,4-dihydroxyphenylalanine (DOPA) (27).   The activity of L-DOPA decarboxylase is
increased in these tumors (28-30).  In a series of small studies, [18F]-DOPA PET (F-DOPA PET) or [11C]-
DOPA PET had a sensitivity for pancreatic neuroendocrine tumors, gastrointestinal carcinoids, other
carcinoids, melanoma, small cell lung cancer, pheochromocytoma, glomus tumor, and medullary thyroid
cancer of 50 to 85% (31-38).  Although 11C-5-HTP is not available as a ligand at the Clinical Center, F-
DOPA is available.  Since F-DOPA PET potentially has a better sensitivity than FDG PET, we
discontinued the research evaluation of FDG PET and substituted F-DOPA PET.
 
We found that F-DOPA PET substantiated a lesion seen on CT and/or MRI scan in 6 of 11 patients,
including some with questionable results on conventional imaging.  We amended the protocol in 2008 to
administer carbidopa, 200 mg, one hour before the study.  Dr. Pacak has found that this strategy improves
tumor detection of pheochromocytoma, presumably by inhibiting decarboxylation of the tracer.  This
amendment will now allow us to perform FDOPA PET/CT, which was not available previously.
 
The project was amended in 2004 regarding the routine chest MRI scans.  We initially obtained images on
a 0.5 T magnet using, using STIR, T1 and T2 images.  Subsequently a 1.5 T magnet replaced the lower
strength magnet and STIR images were not obtained.  Recently a 3.0 T magnet has become available with
image acquisition gated to the EKG R-R interval so that artifact from cardiac motion is reduced.  Our
collaborator Dr. Gharib has performed T1 and T2 sequences using this approach with excellent resolution
of mediastinal and chest structures. Increased strength of magnetic ﬁeld compared to conventional 1.5T
MRI allows for a stronger signal and therefore improved signal to noise ratio. Free breathing techniques
are used to avoid breath holding, which may be difﬁcult for those patients with volume overload. The
combination of higher signal and decreased motion artifacts should signiﬁcantly improve resolution
allowing for better delineation of small lesions that may be responsible for ectopic ACTH production. To
test this, we have added these sequences.
 
We wish to clarify the use of chest CT scans, as the available modalities have changed. A “surgical chest
protocol CT” (which involves thin (1-2mm) cuts throughout the thorax) will be obtained at each visit.
 For the initial imaging, gated “cardiac CT” will be obtained as well to look for retrocardiac lesions that
can be obscured by non-gated routine CT.   However, because of the amount of radiation, we will obtain
this scan only at the initial visit, unless there is a subsequent clinical suspicion of a retrocardiac lesion.  
 
OBJECTIVES
 
Speciﬁc questions to be addressed:
 
F-DOPA PET/CT
​(a) Compared to other imaging techniques, is the sensitivity and speciﬁcity of F-DOPA PET/CT
higher in detecting the source of ectopic ACTH production in patients with known and unknown tumor
localization?
​(b) Does a correlation exist between F-DOPA uptake and the type of tumor, its size and
proliferative activity?

 
Octreoscan
​(c) Can the administration of mifepristone, 600 mg daily for 10 days, convert a negative standard
6 mCi OCT (L-OCT) to a subsequent positive result?
 
MRI
​(d) Does gated chest MRI detect more lesions than routine MRI?
 
STUDY DESIGN AND METHODS
​
Standard Medical Evaluation of Cushing Syndrome
 
We will evaluate patients at the Clinical Center on an inpatient ward. Each subject will undergo a
complete medical history, physical examination, and chemical screening tests, including acute care panel,
liver function tests, thyroid function tests, complete blood count, plasma ACTH levels (30 ml of blood),
and urine free cortisol. Patients also undergo measurement of diurnal cortisol in blood and saliva to
conﬁrm the diagnosis of Cushing syndrome (20 ml of blood). This is followed by a CRH stimulation test
(30 ml of blood), inferior petrosal sinus sampling (IPSS; 90 ml of blood) and 8 mg overnight
dexamethasone suppression test (10 ml of blood).  Patients undergo MRI before IPSS: those with a mass
greater than 6 mm diameter may not need IPSS, if CRH and dexamethasone suppression tests are
compatible with Cushing’s disease.  All of these tests are performed as part of the standard evaluation of
Cushing syndrome.
​
The initial diagnostic evaluation lasts up to 14 days. Where not limited by medical or social concerns, and
where guesthouse accommodation is available, it may be performed in the outpatient/day hospital areas
except for overnight stays associated with diurnal sampling. Patients whose results are consistent with
Cushing’s disease will be referred for transsphenoidal surgery, and will not undergo the imaging studies
described below.
 
Patients whose evaluation indicates ectopic ACTH secretion (generally, lack of response to CRH,
dexamethasone and lack of central to peripheral ACTH gradient on IPSS) will undergo standard,
medically-indicated, imaging studies for localization of the tumor, including CT (neck, chest, abdomen,
and pelvis), 1.5 T MRI (neck, chest, abdomen, and pelvis), and 6 mCI standard Octreoscan (L-OCT).
Women will undergo a serum pregnancy test within 24 hrs before administration of any isotope.  
 
Patients without active hypercortisolism in whom the standard Octreoscan is negative (or those ineligible
for the mifepristone study) will undergo H-OCT. Because of interference we will wait at least one week
after dosing a low dose Octreoscan before doing a H-OCT. The IRB previously agreed that this would be
a medically indicated procedure in these patients. However, because it adds signiﬁcantly to the
cumulative radiation exposure, we have decided to limit this to three scans at intervals of at least one year.
 
The duration of standard imaging studies is about 10-15 minutes for either CT of the neck, chest,
abdomen, or pelvis and 1-2 hours for either MRI of the pituitary, chest, abdomen, or pelvis, and 1-3 hours
for Octreoscan (see below).
 
Research Procedures
 
Eligible patients with active hypercortisolism will receive the mifepristone-L-OCT combination as a
research study (see below). Patients will undergo F-DOPA PET/CT as a research study, up to two studies
with an interval of at least 12 months. Patients may undergo imaging before or after treatment of ectopic
Cushing syndrome (if they have evidence of active ectopic ACTH secretion). Because of interference and
to allow for administration of mifepristone, we will wait at least ten days after dosing a low dose
Octreoscan before doing a second L-OCT. A gated chest MRI will be obtained using a 3 Tesla magnet
with T1 and T2 sequences. Blood will be collected into one heparin and serum tube and an aliquot of
urine will be retained for additional clinical or future research studies related to hypercortisolism.  As an
example, we previously studied the utility of pro-calcitonin using research samples collected under
another protocol (39). Patients will be asked to consent to the future use of tumor samples.  If they
consent to such use, samples may be used in the future, with identiﬁers, for studies not described here,
without obtaining new informed consent.  Only studies related to Cushing’s syndrome or the biology of
tumors would be undertaken.

​
F-DOPA PET/CT procedures
 
The research team is responsible for ensuring that PET-speciﬁc regulations and procedures are followed.
 Patients are studied in the PET Department scanning facility at the Clinical Center after a minimum of 6
hours fasting. A plastic catheter is inserted into an arm vein.  Patients receive carbidopa, 200 mg, orally
60 minutes before the scheduled injection of F-DOPA.
 
The Pet Department's new PET/CT scanner has higher resolution and sensitivity than the older GE
Advance instruments and allows us to perform a low dose CT for attenuation correction and localization.  
 The F-DOPA dose (12 mCi) is injected intravenously over approximately 2 minutes. During the infusion,
the patient is instructed to rest quietly.  After a 30 min. uptake period, patients undergo a low dose
attenuation CT, followed by imaging of the pelvis through the pituitary.  
The F-DOPA PET scan lasts up to ~2 hours. Patients having problems controlling their urine may need to
use a Foley or condom catheter for approximately 12 hours after the injection of F-DOPA.
 
 
Octreoscan procedure
 
Patients are studied in the Nuclear Medicine scanning facility at the Clinical Center.  Patients are
ncouraged to hydrate themselves well before and after administration of [111In-DTPA-D-Phe]-
pentetreotide to aid in renal elimination of unbound material.
 
The patient is injected intravenously with approximately 6mCi (L-OCT) or 18 mCi [111In-DTPA-D-Phe]-
pentetreotide (H-OCT) in the Department of Nuclear Medicine and is imaged 4 and 24 hours later.
Whole body and SPECT/CT images are obtained.   For the clinical Octreoscans, additional delayed
images may be obtained if necessary.   Octreotide imaging takes 1-3 hours each day, depending on the
clinical situation. Patients having problems controlling their urine may need to use a Foley or condom
catheter for approximately 24 hours after the injection of Octreotide.  Some patients will be administered
a laxative after the ﬁrst day of imaging to clear bowel contents, as clinically indicated.
 
For the mifepristone study, mifepristone will be administered at a total daily dose of 600 mg (given as one
200 mg tablet tid, per os) starting 10 days before a second research L-OCT is performed.   It will be given
in the morning (before breakfast), middle of the day (either immediately before lunch for subjects who
have late lunch or 2 hours after lunch for subjects who have an early lunch), and evening (either
immediately before dinner for subjects who have late dinner or 2 hours after dinner for subjects who have
an early dinner). Blood (8 ml) will be drawn on the morning of the second scan, and will be stored for
possible measurement of mifepristone.  No other medical treatment for hypercortisolism will be given
during this time.  A research L-OCT will then be performed.  
 
The research L OCT scan will be performed in the same manner as the clinical study, except that
SPECT/CT of any one area will only be performed up to 2 times. All other SPECT studies of the area will
be performed without CT.  No clinical H-OCT study will be performed on these patients within one year
of the research L OCT study.
 
Evaluation and treatment at the conclusion of imaging episodes
​
The investigators will review the results of all imaging studies at the end of each admission. Imaging
results will be correlated; as is typical in standard medical care, we will not blind the reader of any
conventional images to other results. However, the F-DOPA PET/CT, studies will be read without
knowledge of the results of conventional MRI and CT studies. If the conventional imaging studies
localize a possible tumor, the patient will undergo surgical resection, probably during a subsequent
admission. If the conventional imaging studies are equivocal, or if only the research studies suggest a
tumor, additional studies will be performed as clinically indicated. These studies may include repeat CT
scan focused on the area of concern, venous sampling for ACTH measurement in chest or abdominal
vessels, ultrasound examination, bone scan, MIBG scan, ﬁne needle biopsy or other tests. The patient will
not undergo surgery unless additional studies reveal a mass. Thus, at the conclusion of each episode of
evaluation (and possible treatment), some patients with positive imaging will have surgical conﬁrmation
of the source of ectopic ACTH secretion. All others will be non-localized. These patients will receive
treatment for hypercortisolism (usually medical, but adrenalectomy may be chosen), and will return to the
Clinical Center to have repeated CT and MRI imaging (every 6 12 months) and repeated F DOPA

Clinical Center to have repeated CT and MRI imaging (every 6-12 months) and repeated F-DOPA
PET/CT and OCT (every 12 months).
 
If Cushing syndrome recurs or if patients are not cured by initial resection, patients are offered re-
evaluation to localize any residual tumor or recurrence. In that case, all clinical, biochemical, and imaging
tests may be repeated similar to the initial visit. Upon completion of the study, the patients are returned to
the care of their referring physician.
 
Concern about radiation dose
 
Patients receive radiation exposure with the medically indicated dedicated CT scans as well as with the
low-dose CT scans used for attenuation correction and co-registration with PET and Octreoscans.  The
low and high dose octreoscans and the PET scans also deliver radiation.  The kidneys excrete these
radiopharmaceuticals.   As a result, the bladder receives a higher dose of radiation than other tissues.  At
the doses potentially reached with the combination of L OCT plus H OCT, there may be a slight increased
risk of urinary bladder cancer. In patients receiving another radioisotope (I-131) in amounts that give
signiﬁcantly higher doses to the urinary bladder, results have been variable. One major study showed no
signiﬁcant increased risk whereas another showed a small increased risk of death from urinary bladder
cancer (44,45). This latter study showed that approximately 2 out of 1000 people will die from bladder
cancer over a 50 year lifetime after a dose of 100 rem to their urinary bladder. The dose to the urinary
bladder in from the combination of a clinical L OCT, clinical H OCT with their accompanying attenuation
CT scans is less than this.   The risk of fatal bladder cancer in the general population is 5 in 1,000.
Therefore, patients participating in this protocol and/or the alternative proposed clinical scans may have
an increased risk of a fatal bladder cancer.  
 
In consideration of these issues, exposure will be limited as follows:  F-DOPA or a larger dose of [111In-
DTPA-D-Phe]-pentetreotide can be repeated in patients with recurrent or persistent disease, but not until
twelve months after the last PET or Octreoscan. No patient will undergo a third F-DOPA. Patients who
previously received FDG PET may undergo two F-DOPA PET scans. A total of up to three H-OCT scans
will be performed in any ectopic ACTH patient followed at the NIH. Therefore, in those who undergo the
L-OCT with mifepristone on this protocol, only two H-OCT scans will be allowed.  
​
PATIENT SELECTION
 
Inclusions
 
All eligible patients are invited to participate in this protocol. Patients are adults with possible ectopic
Cushing syndrome. Since both men and women are affected with ectopic Cushing syndrome, both sexes
are studied. All ethnic and racial groups are at risk and will be included. Patients must be willing to return
to NIH for follow-up studies.
 
Exclusions 
​
• Pregnant or lactating women. A pregnancy test is performed in women of childbearing potential (up to
age 55) unless they have a history of  hysterectomy.
• Children (age less than 18) are excluded. Because ectopic ACTH secretion is rare in this age group, the
likelihood of beneﬁt is less and does not balance the risk of radiation.
• Patients taking medications that alter CYP3A4 activity will not be eligible for the mifepristone study,
since this P450 system metabolizes mifepristone.  Such participants would receive a clinical H-OCT
instead, if the L-OCT were negative.  Patients with hypokalemia (K < 3.5 mEq/L), despite medical
therapy with replacement or mineralocorticoid antagonists will also be excluded from the mifepristone
studies.
The presence of
• 
​severe active infection.
• clinically signiﬁcantly impaired cardiovascular (e.g. history of abnormally low ejection fraction, the
presence of moderate pulmonary ﬂuid overload, and blood pressure over 190/100), abnormal coagulation
in the absence of medically-indicated treatment (PT and PTT elevated by 30% above the normal values),
hematopoietic (hematocrit less than 30%, hemoglobin below 10 g/dl, white count below 3000 K/UL, and
platelets below 100,000 K/mm3), hepatic (liver enzymes elevated by 3-fold above normal values), or renal
function (plasma creatinine level over 2 0)

function (plasma creatinine level over 2.0).
• impaired mental capacity or markedly abnormal psychiatric evaluation that precludes informed consent.
• body weight over 136 kg, which is the limit for the tables used in the scanning areas.
• combined blood withdrawal during the six weeks preceding the study greater 450 ml.
• known allergy to [111In-DTPA-D-Phe]-pentetreotide or other somatostatin analogues.
• strong evidence for Cushing’s disease. This includes those with a central to peripheral ACTH gradient
during IPSS or a lesion on pituitary MRI. We anticipate that these exclusion criteria will increase the ratio
of patients with ectopic ACTH syndrome to those with Cushing’s disease from the usual 1: 8 to 1: 2, thus
we would accrue 3 patients to identify one with ectopic ACTH secretion.  
 
ANALYSIS OF THE STUDY
 
Justiﬁcation of the number of subjects
The IRB previously approved an accrual ceiling of 202 for the high dose octreoscan component.  That
component is no longer a part of the protocol.  Eighty-nine patients have enrolled in the protocol.  F-
DOPA PET was positive in 8 of 17 patients with known tumors and high dose Octreoscan was positive in
7 of 12.
 
Given these encouraging results, we propose performing F-DOPA in a total of at least 30 patients.  The
current results imply an estimated success rate of about 55% for each modality; the plausible range for the
true success rate ranges from about 26 to 80% using a 95% conﬁdence interval, a very broad range.
 Studying a total of 30 patients will allow us the possibility of precluding a true success rate of under 20%
(with 95% conﬁdence) if we were to see no additional successes.  If there are additional successes in the
additional patients the conﬁdence interval for what the true probability of success could be will still be
fairly broad. Since limited patients have been evaluated using F-DOPA, we ask that the overall accrual
ceiling remain intact and that it be altered based on annual reports of the results.  Additionally, we have
essentially no data on which to base a sample size calculation for the mifepristone study, and would re-
calculate accrual limits when such data are available.  
 
Data Collection and Evaluation
​
Staff in the Departments of Radiology will evaluate the conventional studies. Dr. Chen reviews the F-
DOPA PET/CT without knowledge of the results of other localization studies. Dr. Gharib reviews all
studies.  Data are maintained by the NICHD Clinical Trials DataBase.
 
The study will be analyzed in collaboration with Dr. Robert Wesley (Clinical Center Statistics Center).
Data are collected and analyzed with regard to the sensitivity, speciﬁcity, accuracy, and predictive value
for each scan being evaluated. The exploration and pathologic analysis is used as the reference standard.
McNemar’s test for evaluating paired data will be used (40).  In addition to McNemar’s test, other
approaches to evaluation of the four objectives are below:
​(a) Compared to other imaging techniques, is the sensitivity and speciﬁcity of F-DOPA PET/CT
higher in detecting the source of ectopic ACTH production in patients with known and unknown tumor
localization?  To determine this, we will calculate the sensitivity, speciﬁcity, positive and negative values
in patients with proven tumors and compare these with the results from the other modalities.  Conﬁdence
intervals will be calculated and overlapping results will indicate that the modalities are similar.  We
cannot perform these calculations for unknown tumors, but can compare the overall percentage of tumors
found of all imaged using each technique.
​(b) Does a correlation exist between F-DOPA uptake and the type of tumor, its size and
proliferative activity?  To do this, we will evaluate the percent of each type of tumor that has a positive F-
DOPA scan.  Conﬁdence intervals will be used to compare across tumor types. Univariate logistic
regression will be performed using size and mitotic index as the variables.
​(c) Can the administration of mifepristone, 600 mg daily for 10 days, convert a negative standard
6 mCi OCT (L-OCT) to a subsequent positive result?  This will be a descriptive analysis, indicating the
percentage of tumors that convert the test to a positive result.  A post-hoc analysis will compare this
percentage to the historical percentage of tumors that are positive on high but not low dose octreoscan.
​ (d) Does gated chest MRI detect more lesions than routine MRI?  A similar approach will be
used, to look at the percentage of known tumors that are detected by gated vs routine MRI and comparing
conﬁdence intervals around those values.

 
​
PHARMACEUTICAL AND RADIATION SAFETY
 
Pharmaceutical Information: F-DOPA
 
F-DOPA is a radiolabeled amino acid (18F has a 109 minute half-time). It is approved by the FDA for use
under IND # 35513. Dr. Peter Herscovitch, Chief, PET Department, holds the IND. F-DOPA is produced
as outlined in the IND.  F-DOPA has been used in many protocols at the NIH and at other centers
throughout the world. The formulation is prepared on the day of use and assayed in a dose calibrator. The
total amount of F-DOPA will typically be ~2.4 mg and will not exceed 6.5 mg.
 
Pharmaceutical Information: [111In-DTPA-D-Phe]-pentetreotide
 
Pentetreotide is an analogue of octreotide (Sandostatin), produced by the addition of DTPA, which allows
for the binding of metals such as Indium. Octreotide itself is an 8 amino acid cyclic peptide, biologically
active analogue of the native somatostatin and has a longer plasma half-life than somatostatin. [111In-
DTPA-D-Phe]-pentetreotide is an FDA-approved agent that is obtained on a unit dose basis or prepared
on-site in our radio pharmacy using commercial kits. Three 6 mCi standard low doses will be given for
the high dose (~18 mCi) scan. Each 18 mCi high dose contains ~30 mcg Pentetreotide.
 
Radiation toxicity and adverse events
 
The research radiation doses that the patient will receive as a result of participating in this study are from
the F-DOPA and its associated attenuation CT scan, and from the additional post-mifepristone L-OCT
scan and attenuation CT scans used in conjunction with SPECT. The maximum possible radiation dose
that patients will receive from these research studies is outlined in the 88-23a form.
​
F-DOPA
 
No toxicity has been associated with the administration of F-DOPA, although with increased use it is
possible, although unlikely, that unanticipated side effects or allergic reactions may be observed from this
DOPA analog. From 4/1/200 to 7/31/2004 128 F-DOPA scans were performed at the NIH using up to 17
mCi of F-DOPA. Any toxicity related to the F-DOPA-PET precludes repeat administration of the F-
DOPA.
​
[111In-DTPA-D-Phe]-pentetreotide (Octreoscan)  
​
[111In-DTPA-D-Phe]-pentetreotide is excreted almost exclusively by the kidneys, with hepatobiliary
excretion accounting for approximately 2% of excretion. After injection, plasma clearance is rapid such
that at 10 minutes, only approximately 33% of the injected dose remains in the blood pool. The physical
life of [111In-DTPA-D-Phe]-pentetreotide is approximately 2.8 days (67.3 hours). The biologic half-life of
[111In-DTPA-D-Phe]-pentetreotide is approximately 6 hours.
 
[111In-DTPA-D-Phe]-pentetreotide has been shown in nonclinical pharmacological studies to have 1/10
the hormonal effect of octreotide in vitro when 3 or 6 mCi dose was used (package insert). Because of
these decreased hormonal effects and the fact that the dose of pentetreotide administered during this study
is approximately 10 or 30 mcg, which is 2.5-10 times less than the usual dose of octreotide prescribed for
therapy, no hormonal effects are expected to result from the radiopharmaceutical administration. As stated
in the package, in clinical trials of 538 patients, less than 1% experienced the following: dizziness, fever,
hypotension, changes in liver enzymes, joint pain, nausea, sweating, and weakness. These were transient.
To date, no patients at NIH have reported any adverse side effects after receiving [111In-DTPA-D-Phe]-
pentetreotide (> 600 doses administered).
 
Mifepristone (HRA 052015; INN Mifepristone)
 
Mifepristone is a cortisol and progesterone analog with antiglucocorticoid and antiprogestin activity.
Healthy subjects receiving long-term mifepristone administration showed antiglucocorticoid effects at a
daily dose of 10 mg/kg, which is about 5 – 10 fold greater than that required to demonstrate antiprogestin
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effects (41).  The agent can effectively reverse the clinical and glucocorticoid-dependent biochemical
features of CS (42).
 
The dose (200 mg three times daily) is close to the median dose (732 mg daily) found effective in
improving diabetes in patients with Cushing’s syndrome (43).  The duration of dosing is arbitrary. There
are no data in animals regarding up-regulation of somatostatin receptors in vivo.  However, receptors are
restored in vitro within 24 hours (18).  Because octreoscans must be given at least one week apart
according to nuclear medicine a shorter dosing interval is not possible.  We have elected to give the agent
thrice daily to ensure constant levels.  Previous pharmacokinetic studies used an older formulation of the
agent; until new PK studies are done we think that this is a conservative approach.  In patients who have
UFC > 10-fold normal we will double the dose for 24 hours before and continuing until the 24-hour scan.
 
 
Mifepristone will be given under an active IND (70,795) sponsored by Laboratoire HRA Pharma,
NICHD’s collaborative research and development agreement (CRADA) partner, which is investigating
the utility of mifepristone for the treatment of ectopic ACTH secretion at the NIH and other sites. HRA
Pharma will provide mifepristone in 200 mg tablets packaged as 50 tablets in 5 blister packs.  
Mifepristone will be manufactured, controlled and released according to current GMP guidelines.
 
Adverse events and monitoring plan
All adverse reactions occurring during the study, either observed by the physicians or nurses or reported
by the patient, will be recorded.
 
Dr. Nieman is responsible for communication of events related to the IND. We will report to the Sponsor
those adverse events occurring within 24 hours of administration of F-DOPA (ten half-lives rounded up to
the nearest day), within 7 days if serious and 14 days if not serious. We will report similarly to
Laboratoire HRA Pharma (mifepristone sponsor) any event occurring during or within 10 days after the
last dose of mifepristone administration (about 24h half-life).  Speciﬁcally, report will be by telephone to
the NIDDK Clinical Director and NIDDK/NIAMS IRB and IND holders (Dr. Peter Herscovitch 301-451-
4248 for F-DOPA, Dr. Erin Gainer, Laboratoire HRA Pharma for mifepristone).
 
Unanticipated problems will be reported to the IRB within 7 days if serious, and 14 days if not serious.
 Minor deviations in the conduct of standard medical care and imaging, such as missing timepoints on a
test, or decisions not to schedule all possible imaging (for example, not scheduling pelvic imaging in a
patient with a possible lung mass) will not be reported to the IRB or sponsor. All other anticipated or
unanticipated adverse events related to the research studies will be reported in aggregate to the sponsor
and IRB at the time of annual reports.  Examples of expected adverse events include but are not limited to
those events detailed in the Investigators’ Brochure for mifepristone and in the protocol’s risk section, as
well as pulmonary embolism, other thromboembolic events, hypertension, worsening of pre-existing
conditions, infection, and the like, which are common in patients with Cushing’s syndrome.  These would
be reported to the IRB only if they become unanticipated problems.
 
In the unlikely event that any untoward or unexpected outcomes occur, the patients will be treated for all
immediate medical problems (e.g. anaphylactic reaction) in an appropriate setting (e.g. ICU). Any patient
withdrawn or discontinued from the present study is not reinstated. The occurrence of a serious adverse
reaction will prompt review and there will be no further subject accrual until a thorough investigation into
the cause has been completed and it is deemed safe to continue.  
 
There is no DSMB associated with this study.  We have revised the NICHD Clinical Protocol Monitoring
Plan to add that HRA Pharma will monitor the study for the use of mifepristone; we continue to request
NICHD monitoring of the F-DOPA portion of the study.
​
REGULATORY DOCUMENTATION
Source Documentation and Case Report Forms
The research staff documents data pertinent to eligibility and medical care during the admission.
 Research scans are reviewed at intervals with the study radiologist and recorded.  Biochemical data are
reviewed but not transcribed in toto from CRIS and eligibility is conﬁrmed at a meeting of the research
team.
 
IRB and DSMC Documentation  
The Principal Investigator Dr Nieman is responsible for maintaining IRB correspondence Documents

The Principal Investigator, Dr. Nieman, is responsible for maintaining IRB correspondence.  Documents
retained in the ﬁles include each submission to each committee, the committees’ ﬁndings, the
investigators’ responses and the ﬁnal approval sheets.
 
FDA Documentation  
Dr. Nieman is responsible for communications related to the IND.  Dr. Herscowitz is the sponsor of the
study.  Annual reports are sent to him regarding study progress.
 
Adverse Event Procedures and Documentation
Events are reported as described above.
 
Study Completion
Per the CRADA agreement, those study ﬁles and data will be maintained indeﬁnitely; however, this may
change depending on the circumstances surrounding closure of the study.  
 
HUMAN SUBJECTS PROTECTIONS
 
Rationale for Subjects Selection
 
Adults of any ethnic and racial group are invited to participate. Exclusion and inclusion criteria are listed
above. Since radiation is used, no pregnant or lactating women are studied.
 
Advertisement, Recruitment, and Payment
 
The study is posted on the Clinical Center www protocol site, which explains the characteristics of the
patients sought and the main purposes of the study. A phone number is listed, where inquirers can obtain
more information and enter a mailing list for receiving information packets, including consent forms. Any
other advertisement will be submitted to the IRB for approval.
 
NIH employees may participate in this protocol. Patients do not receive payments or compensation.
Travel costs may be provided after the initial visit, or including the initial visit if there is ﬁnancial need.
 
Beneﬁts, Risks, and Hazards
 
Beneﬁts
 
Patients beneﬁt from initial and follow-up general and endocrinologic evaluations, including imaging
studies. Patients in whom a tumor causing ectopic Cushing syndrome is found are offered surgery at the
NIH. Those with Cushing’s disease may undergo surgery at the NIH. Patients with hypercortisolemia due
to occult tumor will be offered medical treatment (i.e. administration of drugs blocking cortisol synthesis
or cortisol action) or bilateral adrenalectomy.
 
Since there is a possibility that patients may beneﬁt from detection of previously unrecognized tumor,
information gained from this study may affect future clinical management of patients with ectopic
Cushing syndrome.
 
This is an elective study. Thus, nonparticipation does not affect a patient's clinical care, but patients
electing not to participate in the research component will be returned to the care of their outside
physicians.
 
Risks and Hazards
​
1.  Risks related to radiation from the administration of radioactive drugs and attenuation CT scans. The
annual total effective research radiation dose to patients receiving both FDOPA PET/CT and L-OCT after
mifepristone, is 3.12 rem.  It will be correspondingly less for those who receive only one of these research
studies. (Please also see Concern About Radiation” above re: radiation from other studies).   To minimize
bladder exposure, FDOPA patients will be asked to void after approximately 30 min., and every 90
minutes for the 6 hours following completion of the PET scan.  Patients will be asked to void every 2 – 4
hours for 12 hours after the Octreoscans.
 

2.  Vein cannulation can cause pain, bleeding, thrombosis, or infection. Bleeding is prevented by local
pressure applied for 5-10 minutes after catheter removal. Infection is prevented by use of clean technique
and the relatively short time the catheter is in place. Fainting can occur during insertion of a vascular
catheter in subjects who are sitting; however, in this study, the subjects are supine. An indwelling line will
be placed to reduce the number of needle sticks needed for phlebotomy purposes.
 
3. Vein cannulation for IPSS may cause femoral hematoma, arteriovenous ﬁstula, bruising or discomfort
or transient arm anesthesia.  Femoral vein puncture is sometimes more difﬁcult in patients with Cushing
syndrome because of marked obesity. There is a slight, but deﬁnite risk of entering the femoral artery that
might result in bleeding, a groin hematoma or arteriovenous ﬁstula. However, we currently have available
a "smart" needle with an ultrasound transducer incorporated in the tip which enables us to puncture veins
even in the most difﬁcult subjects so that we anticipate < 1% rate of these complications.  Patients
experience mild discomfort and may have visible bruising in the groins after the procedure. Cannulation
of the internal jugular vein led to transient loss of sensation in the arm in one patient at the NIH,
presumably because of inﬁltration of the cervical nerves by the anesthetic.
 
4. CRH administration has minimal risk. Up to 20% of patients experience ﬂushing and a smaller
percentage experience a metallic taste. CRH has been given safely on multiple occasions to the same
patients, as proposed here, in the context of CRH stimulation test or dexamethasone test. CRH has been
given more than 1000 times at the NIH and many thousands of times world-wide. The commercially
available formulation is used (Ferring Corp.).
 
5. Contrast allergy to radiographic dye. There is a very small (< 0.5 %) risk of new contrast allergy.
 Patients with a known dye allergy will receive prophylactic treatment.
 
6. Anemia. The maximum total amount of blood drawn for the standard medical tests is about 265 ml. The
study is not to be performed if the patient's previous and predicted total blood withdrawal for the six
weeks prior to the study is more than 450 ml.
 
7. The use of Foley or condom catheters, if needed, may be associated with some local discomfort and an
increased risk of urinary tract infection.
 
8. Possible emotional responses during scans. A patient can develop nervousness, anxiety, and panic
attacks during any scanning procedure. In such a case, the study is discontinued and the patient evaluated
and treated if necessary.
 
9.  MRI evaluations may cause claustrophobia.  Should this occur the study will be stopped and re-
scheduled with administration of a sedative.
 
10. Risk of adrenal insufﬁciency due to mifepristone.  Subjects without Cushing syndrome who received
long-term mifepristone administration showed antiglucocorticoid effects at a daily dose of 10 mg/kg,
which is about 5 – 10 fold greater than that required to demonstrate antiprogestin effects (41).
Overtreatment with mifepristone may lead to adrenal insufﬁciency. In case of suspicion of adrenal
insufﬁciency (deﬁned as hypotension and the presence of severe symptoms of nausea, vomiting or
diarrhea), we will stop mifepristone and initiate glucocorticoid substitution with hydrocortisone or
dexamethasone. Therapy will take into account results from pharmacology studies demonstrating that 1
mg dexamethasone or 30 mg hydrocortisone antagonizes 400 mg mifepristone. These individuals will not
receive the second L-OCT.
 
Patients with isolated symptoms (nausea, vomiting, diarrhea, weight loss, anorexia or isolated fatigue)
will be monitored closely as an inpatient in the Clinical Center. Except for diarrhea, these symptoms are
expected possible effects of the study treatment and are not systematically indicative of adrenal
insufﬁciency. No modiﬁcation of treatment will be initiated unless symptoms worsen or patient develops
new symptoms. Hyponatremia and/or hyperkalemia can be indicative of adrenal insufﬁciency but also can
be explained by other causes and will require further investigation.
 
Less speciﬁc adverse events as maculopapular rash also have been observed.
 
11. Risks associated with use of gadolinium-based contrast agents(GBCAs) for magnetic resonance
imaging(MRI). The FDA has issued a warning that certain groups of patients are at risk for nephrogenic
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systemic ﬁbrosis after receiving gadolinium. In order to reduce unnecessary risks, serum creatinine and
GFR will be obtained prior to any gadolinium-based procedure. Gadolinium will be withheld in patients
with acute or chronic renal insufﬁciency (GFR<60ml/min), unless deemed necessary in order to verify CT
scan ﬁndings required for clinical management decisions. The vast majority of patients receiving
gadolinium-based contrast agents have no symptoms related to the injection of this medication.  Mild
symptoms that may occur include coldness in the arm at the time of injection, a metallic taste, headache,
and nausea.  In an extremely small number of patients, more severe symptoms have been reported
including shortness of breath, wheezing, hives, and lowering of blood pressure
 
Consent Process and Documents
 
When patients or physicians contact the research team to indicate an interest in participating in the study,
a consent form will be provided and any questions will be answered.  The study will be explained
verbally and all questions and concerns addressed at the ﬁrst NIH visit, at which time written informed
consent will be obtained. Members of the research team authorized to obtain consent are Dr. Nieman and
Ms. Raven McGlotten.  A record of communication of this information and of the consent to participate in
the study is placed in the medical record and the patient receives a copy of the document. The research
team retains a copy. The right of the subjects to withdraw from this study or to refuse any procedure is
made clear.
 
Three consent forms will be used to reﬂect the various options available to current patients (based on
number of previous scans) and for new patients. All returning patients will be consented again with the
appropriate consent.  These will include:
1.  Consent for previous patients who have had their maximum of two F-DOPA PET examinations and
three H-OCT examinations. On each admission they will get only standard clinical imaging (CT, MRI, 6
mCi OCT).
2.  Consent for (previous or new) patients who are hypercortisolemic.  On each admission they will get
standard clinical imaging (CT, MRI, 6 mCi L-OCT) as well as F-DOPA PET/CT and one octreoscans
with mifepristone.  Because most patients are hypercortisolemic at only one visit, we anticipate that they
would need a separate subsequent consent, unless they have recurrent disease.
3. Consent for (previous or new) patients who are hypercortisolemic and refuse or are not candidates for
mifepristone, or those who are not hypercortisolemic. On each admission they will get standard imaging
(CT, MRI, 6 mCi OCT) as well as F-DOPA PET and high dose octreoscan (if low dose is negative), up to
the maximum number of PET and high dose octreoscans.
We do not plan or anticipate the enrollment of non-English speaking subjects; however they are not
excluded from participation either. Should a non-English speaking subject be eligible for enrollment, IRB
approval will be obtained for use of the short form consent process in the absence of a fully translated
consent document as outlined in SOP 12.9.1, under the provisions of 45 CFR 46.117(b)(2). IRB approval
will be obtained according to IRB guidance prior to obtaining informed consent from the potential study
participant/s.
 
Employee enrollment is not anticipated in this protocol, but if an employee wants to be enrolled in the
study with the prospect of direct beneﬁt in accordance with the policy SOP 14F.3.1 the PI is not required
to amend the protocol. However the PI will take the following steps to ensure that there are adequate
protections in place to protect the conﬁdentiality of employee health information and minimize any
pressure or discomfort of the employee with consent process.
1. The PI or responsible AI will make the NIH Information Sheet on Employee Research Participation
available to employees who are considering enrolling in research to help them understand the possible
consequences. Also, the PI or AI will make a copy of the NIH policy 2300-630-3 available to employee.
2. If PI or AI is the supervisor of the employee-subject an independent person (i.e. bioethics staff) will
monitor consent process.
3. The PI will require that study staff who may have contact with sensitive data about a co-worker or
subordinate complete the Just-in-Take CITI course “Biomedical –Vulnerable Subjects-
Workers/Employees”.
 
Conﬁdentiality and use of retained tissue specimens
 
Conﬁdentiality of patients is assured according to the laws of the State of Maryland. When results of a
study such as this are reported at meetings or in medical journals, the identiﬁcation of those patients
taking part is withheld. Medical records of Clinical Center patients are maintained according to current
legal requirements and are made available for review as required by the FDA or other authorized users

legal requirements and are made available for review, as required by the FDA or other authorized users,
only under the guidelines established by the Federal Privacy Act. All data are kept in locked ﬁles.
 
Patients will be asked to consent to the future use of urine, blood and tumor samples.  If they consent to
such use, samples may be used in the future, with identiﬁers, for studies not described here, without
obtaining new informed consent.  Only studies related to Cushing’s syndrome or the biology of tumors
would be undertaken. Investigators who are not part of this protocol may procure tumor tissue in the
operating room only with authorization from Dr. Nieman. Tissue samples may be shared with
collaborators, without personal identiﬁers.  All samples will be coded without personal identiﬁers and will
be stored in accordance with NIH and NICHD biospecimen policies.
 
Other Interested Parties and Collaborators
 
The NIH has a Cooperative Research And Development Agreement (CRADA) with Laboratoire HRA-
Pharma, in Paris, France.  The intention of the CRADA is to develop mifepristone for the treatment of
Cushing’s syndrome, for use as an adjunctive agent for Octreoscan, and for use as a diagnostic agent.
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