Treatment of Pituitary Cushing Disease With a Selective CDK Inhibitor, R-roscovitine
Phase: PHASE2
Conditions: Cushings Disease
Sponsor: Shlomo Melmed, MD

Melmed, S 
 
 
 
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Treatment of pituitary Cushing disease with a selective CDK inhibitor, R-roscovitine 
 
PI: Shlomo Melmed MD 
Co-investigators: Ning-Ai Liu MD PhD 
NCT: NCT02160730 
Version: 6.0 
Date: 18SEP2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Melmed, S 
 
 
 
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Section 1.0 General Information  
Treatment of pituitary Cushing disease with a selective CDK inhibitor, R-roscovitine 
PI: Shlomo Melmed MD  
Co-investigators: Ning-Ai Liu MD PhD 
Study staff: Billy Gellepis 
Version: 6.0 
 
Section 2.0 
Background information 
A1. Clinical features of pituitary corticotroph tumors (Cushing disease) 
Pituitary 
adenomas comprise ~15 % of intracranial neoplasms with an overall incidence at 15 to 20 per 
million per year.  Although pituitary tumors are generally benign, tumor compression of critical 
structures can lead to headaches, visual disorders, cranial nerve dysfunction and failure of 
pituitary hormone production. Pituitary adenomas also result in clinical features based on their 
specific cell type. Adrenocorticotropin (ACTH) -producing tumors of the corticotroph lineage 
(Cushing disease, CD) comprise 10 % of pituitary adenomas.  
CD is rare, but it is the most common cause of endogenous hypercortisolism, which 
predisposes patients to central obesity, diabetes, hypertension, osteoporosis and substantially 
increases their risk of infection, thrombosis and psychiatric disorders.  If inadequately controlled, 
CD is fatal with mortality rate 4-fold-higher than that of age- and sex-matched controls and a 
median survival of 4.6 years. Cardiovascular disease is the leading cause of death in CD (1).  
The standard of care for Cushing disease is multimodal, as no single approach is 
uniformly effective: although transsphenoidal ACTH-secreting tumor resection yields 30% to 
70% surgical cure rates, adenoma recurrence rates are high. Furthermore, over half of all such 
adenomas are not visible on MRI, further challenging a surgical approach. Often, total 
hypophysectomy, with all its attendant complications, may be blindly performed in an attempt to 
resolve excess ACTH secretion. Efficacies of other therapeutic modalities, such as pituitary-
directed radiation, adrenalectomy, and/or medical suppression of adrenal gland cortisol 
production, are limited by serous side effects, slow therapeutic responses, development of 
pituitary insufficiency, and/or uncontrolled pituitary tumor growth (Nelson syndrome) in the 
setting of adrenal gland resection or inhibition. Currently, there is no safe and effective 
pharmacotherapy directly targeting corticotroph tumor growth and/or ACTH production(2). 
Recently, pasireotide, a somatostatin analogue, has shown benefits as the first 
therapeutic agent targeted to pituitary corticotrophs in a Phase III trial of patients with CD. 
However pasireotide has a modest overall disease control rate of 25% (limited to patients with 
mild disease) and very significant metabolic side effects, including invariable hyperglycemia, 
and subsequent insulin-requiring diabetes, since the polypeptide is a potent suppressor of 
insulin synthesis/secretion(3). Peripheral glucocorticoid receptor antagonist is approved for 
hypercortisolism of CD, but it also has multiple side effects and does not target the pituitary 
adenoma(4). Other investigational agents, including peroxisome proliferator-activated receptor-γ 
agonists, retinoic acid, dopamine D2 receptor angonists and EGFR inhibitors have yet to yield 
therapeutic efficacy in human CD. Therefore, there is a clearly unmet need for effective and 
safe pituitary-targeted pharmacotherapy that can normalize ACTH and cortisol levels, control 
tumor growth, improve clinical signs and symptoms and ultimately leading to reversal of co-
morbidities and normalize mortality. 
A2. Pituitary corticotroph tumorigenesis and cell cycle regulators 
Based on our own 
work, and that of others, cell cycle deregulation is implicated in pituitary tumorigenesis. Pituitary 
tumors acquire oncogene and tumor suppressor genetic and epigenetic alterations,  which 

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result in unrestrained proliferation, aberrant neuroendocrine regulatory signals and disrupted 
humoral milieu, mediated directly or indirectly by dysregulated cyclin-dependent kinases 
(CDKs)(5).  Although CDK gene mutations have not been identified in human pituitary tumors, 
overexpression of cyclins and dysregulation of CDK inhibitors are frequently encountered in 
pituitary adenomas, indicating the importance of CDK activation for potential therapeutic 
targeting(6).  
Corticotroph tumors exhibit up-regulated levels of cyclin E, which is undetectable in normal cells 
or tumors arising from other lineages of the pituitary (7). During the normal cell cycle, cyclin E is 
transcriptionally activated from late G1 till end of S phase, binds and activates the 
serine/threonine protein kinase cdk2 to promote G1-S phase transition. Cyclin E activity and 
expression are regulated by members of the E2F family of transcription factors and the 
corepressors pRb and HDACs(8). Cyclin E stimulates its own transcription through a positive 
feedback mechanism involving E2F activation, and also phosphorylate Cdk2-bound p27 and 
p21, triggering their degradation by the ubiquitin-proteasome pathway(9, 10). Dysregulated 
cyclin E activity causes critical disruptions of the G1-S transition, affecting cell proliferation, 
differentiation, survival and senescence, and contributing to tumor development (11-14). For 
pituitary corticotroph tumors, mechanisms underlying lineage-specific cyclin E up-regulation 
remain to be defined. In mouse corticotroph tumor AtT-20 cells, cyclin E expression is repressed 
by brahma related-gene 1 (Brg1). Brg1 was implicated in cell cycle control as a repressor of 
cyclin E, and is mis-expressed in about 30% of human corticotroph tumors(15) (16). We recently 
showed that corticotroph overexpression of pituitary tumor transforming gene (PTTG) induces 
cyclin E, whereas PTTG siRNA suppresses cyclin E expression(17). As a cell cycle regulator 
and global transcription factor modulating G1/S and G2/M phase transition, PTTG is 
overexpressed in more than 90% of all type of pituitary tumors, including corticotroph adenomas 
(18). PTTG encodes a securin that binds separase in the APC complex, and governs faithful 
chromosome segregation during mitosis. PTTG was originally isolated from rat pituitary tumor 
cells(19). Dysequilibrium of intracellular PTTG abundance leads to cell cycle disruption and 
neoplastic formation, causing chromosomal instability and aneuploidy, and also aberrant G1/S 
and G2/M transition by transcriptional dysregulation of cyclin expression. On the other hand, 
PTTG overexpession also activates lineage-specific senescence pathways in pituitary growth 
hormone (GH)- and gonadotropin (LH, FSH)-expressing tumors, contributing to the benign 
propensity of pituitary tumors(20, 21). Our study indicates that corticotroph cyclin E up-
regulation may represent another pathway for PTTG-induced pituitary lineage-specific effects, 
contributing to corticotroph tumor development (17).  
A3. Targeting corticotroph tumors with CDK inhibitor    CDK inhibitors have been 
considered relevant drug candidates for cancer therapy because of their potential role in 
restoring cell cycle control and a growing number of CDK inhibitors classes are currently in 
clinical trials for cancer therapy(22). However, clinical development of CDK inhibitors has 
encountered numerous failures in more than a decade with narrow therapeutic window being 
one of the major obstacles, complicating the lack of efficacy and increased toxicity issues. CDKs 
are important for both normal and tumor cells. Although genetic spectrum of tumor-associated 
mutations and/or their cellular context may dictate specific CDK dependence, it is difficult to 
predict which CDK inhibitor(s) may be effective against particular tumor types in vivo. The key is 
to identify which regulator(s) is responsible for cell division down stream of a tumorigenic event, 
so that a proper inhibitor can be selected for a specific tumor type and/or event.  
As a rare disease with an annual incidence of 0.7-2.4 per million populations and a US 
prevalence of 11,000 to 15,000, development of drugs to treat CD presents multiple challenges, 
leading to sparse basic and translational science research, poorly understood disease 

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pathophysiology, as well as difficulties in setting up effective clinical evaluations. To overcome 
these obstacles, animal models that faithfully recapitulate pathological phenotypes of CD are 
needed. Selection and prioritization of agents for clinical trials is a key challenge in drug 
development for CD as only a very few agents can be tested in the clinical setting due to small 
patient numbers, extensive treatment time required, and cost.  In the past, a lack of relevant 
models has precluded preclinical testing.   
Through collaborative studies over the past 10 years, we have developed a transgenic 
zebrafish Cushing disease model that have utility in the rational preclinical development of 
drugs for CD(17). Combining the CD zebrafish with a transgenic fluorescent reporter line that 
specifically labels the pituitary proopiomelanocortine (POMC, encoding an ACTH precursor) 
lineage in live transparent larvae, we tested small-molecule CDK inhibitors, which lead to the 
identification of a selective CDK inhibitor, R-roscovitine (CYC202 or Seliciclib), directed against 
neoplastic corticotrophs(17). R-roscovitine is a 2,6,9-trisubstituted purine analogue that 
competes with ATP for its binding site on CDKs.  R-roscovitine is a 2,6,9-trisubstituted purine 
analogue, which competes with ATP binding site on CDKs, and preferentially inhibits the activity 
of CDK2/cyclin E complex with an IC50 < 0.1 µM(23). We subsequently confirmed in mouse 
corticotroph tumor models and in primary human pituitary corticotroph tumor cell cultures that 
down-regulated CDK2/cyclin E activity and dephosphorylation of their natural substrate, pRb 
(and possibly p27) by R-roscovitine lead to direct cell cycle arrest and apoptosis [(17) and 
unpublished data].  
Unexpectedly, R-roscovitine also induces a rapid suppression of POMC gene 
expression and ACTH production independent of its cell cycle inhibitory effect, suggesting a 
previously unappreciated negative regulatory role of a selective CDKI on POMC gene that 
encodes the precursor hormone of ACTH in corticotrophs. The POMC gene encodes the 
precursor hormone of ACTH in corticotrophs. Pituitary POMC gene expression depends on the 
combination of tissue- and cell-restricted transcription activators such as Pitx1, NeuroD1 and 
Tpit/Tbx19(24). These factors act on the proximal POMC promoter and integrate inputs from 
different signaling pathways to regulate POMC and ACTH production. Suppressed POMC gene 
expression by R-roscovitine may result from inhibition of CDK2/cyclinE that maintains pRB in an 
inactive hypophosphorylated state, thereby affecting downstream transcriptional pathways. If 
this is true, amplified cyclin E expression in corticotroph tumors serves as a therapeutic target 
for the dual inhibition of both tumor cell growth and ACTH expression. On the other hand, in 
addition to targeting the cell cycle CDKs (CDK1 and CDK2), R-roscovitine can also inhibit 
transcriptional CDKs (CDK7, 8 and 9) that activate mRNA transcription by phosphorylating the 
C-terminal domain (CTD) of RNA polymerase II, which leads to complex changes in mRNA 
levels rather than blocking global mRNA transcription(25). 
R-roscovitine is currently undergoing phase I and II clinical trials for several 
malignancies, and is a proven safe oral molecule in humans [IND No. 71,011-CYC202(R-
roscovitine or Seliciclib)]. Here, we propose to perform a phase II clinical trial on the safety and 
efficacy of R-roscovitine for treatment of patients with CD. 
 
B. Preliminary Data:  
R-Roscovitine inhibits ACTH production from human corticotroph tumor cells by 
targeting hPOMC gene regulatory sequences  

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To further explore the therapeutic potential of R-roscovitine directly targeting human ACTH 
production, we treated 6 consecutive human pituitary corticotroph tumors in primary cultures 
with R-roscovitine for 48 hours, which led to significant reduction of ACTH levels in the culture 
medium (Fig 1A). Among the 6 corticotroph tumors, tumors No. 4 – 6 had sufficient yield of cells 
in primary culture that allowed further RT-PCR analysis, demonstrating suppressed Tpit/Tbx19 
expression (Fig 1A), as well as reduced cyclin E (Fig 1A). Western blot analysis of protein 
extracts derived from R-roscovitine–treated human corticotroph tumor cells also showed 
decreased ACTH protein expression (Fig 1B). In mouse AtT20 cells, R-roscovitine inhibited 
expression of NeuroD1 and Tpit protein in a dose-dependent pattern, without affecting that of 
Pitx1 (Fig 1C), suggesting that R-roscovitine may target unique corticotroph lineage-specific 
transcription factors leading to inhibition of POMC expression. As R-roscovitine suppresses 
corticotroph cyclin E expression and dephosphorylates pRb(17), which maintains E2F in an 
inactive state thereby affecting down stream transcriptional pathways, we also assessed the 
role of E2F1 in POMC gene regulation. R-roscovitine treatment of human ACTH-producing DMS 
79 cells caused E2F1 dephophorylation (Fig 1 D), and suppressing E2F1 expression with siRNA 
Figure 1. Inhibition of ACTH production by R-roscovitine. (A) Primary culture of human corticotroph tumor cells treated with 
vehicle or R-roscovitine. Top, ACTH concentration in primary culture medium measured by radioimmunoassay (n=6 tumors, 
mean ± SE; *P < 0.05). Middle and Bottom, Tpit and cyclin E expression measured by RT-PCR of cDNA derived from 
tumors No. 4-6. No sufficient cDNA were available from tumors No.1-3. #, level of PCR product was too low to detect. (B) 
Western blot analysis of ACTH expression in human corticotroph tumor primary culture cells treated with vehicle or R-
roscovitine. (C) Western blot analysis of protein extract derived from AtT20 cells treated with vehicle or R-roscovitine. (D) R-
roscovitine treatment of human ACTH producing DMS79 cells result in E2F1 dephosphorylation. (E) E2F1 siRNA 
overexpression in AtT20 cells suppresses POMC and Tpit expression. (F) Schematic representation of hPOMC 5’ proximal 
promoter DNA sequence from -39 to +66. 7 mini-promoter fragments (#1 - #7) were generated for luciferase reporter assay 
and EMSA. (G) Luciferase activity of mini-promoter #5 and #6 are inhibited by R-roscovitine treatment. (H and I) Protein-
DNA mini-promoter #5 complex (red arrow) is interrupted by R-roscovitine (H) and E2F1 antibody (I) treatment.  

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resulted in decreased Tpit and POMC expression in AtT20 cells (Fig 1E). Further hPOMC gene 
promoter driven luciferase reporter assays revealed a R-roscovitine-responsive element within 
the 5’ hPOMC promoter (Fig 1 F and G). Electrophoretic mobility shift assay (EMSA) 
demonstrated that the protein-DNA complex with mini-promoter #5 (+22 - +34) of the hPOMC 
gene is disrupted by either R-roscovitine or specific E2F1 antibody treatment (Fig 1H and I). In 
summary, R-roscovitine suppresses corticotroph cyclin E expression and dephosphorylates 
pRb, thereby inhibiting E2F1 activity, which both directly and indirectly down-regulates POMC 
gene transcription. These preliminary results, combined with our published preclinical data 
provide a strong rationale to translate our laboratory research to the proposed clinical study of 
pharmacotherapy directly targeting corticotroph tumors. 
 
Summary: 
Taking advantage of a zebrafish transgenic model with early-onset, characteristic 
pathology of human Cushing disease including corticotroph expansion and partial Gc 
resistance, combined with pituitary POMC lineage-specific expression of a fluorescent reporter 
in live transparent larvae, we tested small-molecule CDK inhibitors. Our study identified R-
roscovitine as being effective against PTTG-overexpressing corticotroph tumors. Inhibitory 
effects of R-roscovitine on corticotroph tumor cell expansion and ACTH production were 
subsequently validated in an in vivo and in vitro mouse model. Our most recent data on in vitro 
treatment of human corticotroph tumor cells with R-roscovitine also show consistent 
suppression of ACTH production. Further study demonstrated that R-roscovitine inhibits human 
corticotroph ACTH production by targeting E2F1 regulated hPOMC gene activation, providing a 
strong rationale for use of R-roscovitine as an effective pituitary-targeted therapy for Cushing 
disease. 
 
  
 
Section 3.0 
Trial objectives and purpose 
 
Aim: Evaluate the efficacy and safety of R-roscovitine for treatment of pituitary 
corticotroph tumors (Cushing disease).  
Hypothesis: We hypothesize that R-roscovitine will suppress pituitary corticotroph tumor 
ACTH production and normalize urinary free cortisol levels in patients with Cushing 
disease. To date, R-roscovitine has been evaluated in several Phase I and II studies and has 
shown early signs of anti-cancer activity in approximately 240 patients. Studies included a 
Phase I study in which single agent seliciclib was administered to patients with advanced non-
small cell lung cancer (NSCLC) and two Phase IIa studies in which seliciclib was administered 
in combination with gemcitabine and cisplatin as first-line treatment and with docetaxel as 
second-line treatment in NSCLC(26). Seliciclib was also evaluated in a Phase I study in patients 
with nasopharyngeal cancer (NPC) with evidence of tumor shrinkage and concomitant reduction 
in copy counts of the EBV virus that is causally associated with the pathogenesis of NPC [IND 
No. 71,011-CYC202(R-roscovitine or Seliciclib)](27). Results from APPRAISE, a randomized 
discontinuation, double-blinded, placebo-controlled, Phase IIb study of oral seliciclib capsules 
as a monotherapy in heavily pretreated patients with NSCLC, demonstrated no difference 
between the seliciclib and placebo arms in progression free survival but a substantial increase 
in overall survival was observed (388 versus 218 days respectively (Cyclacel press release Dec 
21, 2010). Here, we propose an exploratory, proof of concept clinical trial to determine if 
seliciclib can safely normalize urinary free cortisol levels by reducing pituitary corticotroph tumor 
ACTH production in patients with Cushing disease. 
  

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Section 4.0 
Trial Design 
 
 
Study Type: 
• Interventional 
 
Study Design: 
• Phase II, proof-of-concept, open-label and single arm study to assess the safety and 
efficacy of seliciclib in patients with Cushing disease 
• Rationale for study design: due to the rarity of Cushing disease in the general 
population, it is difficult to do a randomized placebo controlled trial with sufficient sample 
size numbers to achieve adequate power. By using the subjects as their own controls, 
we alleviate the issues with recruitment. This is a safety and activity trial to look for a 
sufficient effect of the drug on normalizing urinary free cortisol before proceeding to a 
larger, randomized placebo controlled trial.  
 
Study population: 
 
• Patients with de novo, persistent, or recurrent Cushing disease will be recruited from the 
Pituitary Center at Cedars-Sinai Medical Center. 
 
Intervention: 
• R-roscovitine 400 mg oral administration twice daily for 4 days every week for total of 4 
weeks. The dose of R-roscovitine could be reduced by 25% at any time if patients are 
unable to tolerate the protocol-specified dosage, and/or investigator believes that an 
ongoing drug-related adverse effect is present. Cyclacel Pharmaceuticals, Inc. (UK) will 
provide the drug in 200 mg strength capsules.  
 
• Rationale for dose and regimen selection: transsphenoidal pituitary tumor resection is 
the primary therapy for Cushing disease, and in the best hands, yields 30-70% surgical 
cure rates. Patients with recurrent or residual tumors, and/or those not deemed surgical 
candidates typically undergo pituitary-directed radiation, adrenalectomy, treated with 
pasireotide, and/or medical suppression of adrenal gland cortisol production(2). In this 
study, we will treat patients with de novo, persistent, or recurrent pituitary ACTH-
dependent hypercortisolism with R-roscovitine for 4 weeks before the standard care of 
pituitary surgery, radiation, surgical or medical adrenalectomy are offered. The dose 
selected is based on data from the CYC202-07-15 study in patients with nasopharyngeal 
cancer [IND No. 71,011-CYC202(R-roscovitine or Seliciclib)]. As the pre-op evaluation 
and preparation time at our center usually takes about 4 weeks, patients can be treated 
with R-roscovitine during this period without compromising standard of care. As Cushing 
disease is a chronic longstanding disorder, the risks of experimental treatment prior to 
surgery or other standard management are deemed to be acceptable by our IRB. After 
completion of the study, subjects will be ready to start standard care.  If a given patient 
responds to the study drug and chooses to stay on the drug after cessation of the trial, 
clinical data will continue to be collected for further analysis of drug response and safety 
monitoring. 
 
Primary objectives: 
 
• To evaluate the efficacy of seliciclib 400 mg oral administration twice daily for 4 days 
every week for total of 4 weeks on normalizing 24 hour urinary free cortisol (24 h UFC) 
levels in CD patients. 
 

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Secondary objectives: 
• To evaluate changes in levels of pituitary hormones and metabolic abnormality; changes 
in clinical signs and symptoms; changes in tumor size; and safety of seliciclib 400 mg 
oral administration twice daily for 4 days every week for total of 4 weeks in CD patients. 
 
Primary endpoint:  
• A normalized urinary free cortisol level at week 4 
  
Secondary endpoint: 
• A urinary free cortisol level above the upper limit of the normal range but reduced by 
≥50% from baseline at week 4  
• Plasma ACTH, 24 hour urinary free cortisol, serum and salivary cortisol levels over time 
• Hemoglobin A1C (HbA1C), fasting blood glucose and blood electrolytes, e.g. K+ 
• Cushing's syndrome clinical signs and symptoms, e.g. weight, body mass index, blood 
pressure 
• Changes in tumor size 
• Safety end points: hematologic and blood chemistry including total sodium, potassium, 
urea, serum creatinine, creatinine clearance, total protein; LFT (ALT, AST, total bilirubin, 
albumin, ALP, ); total cholesterol (TC), LDL-cholesterol, triglycerides: coagulation (PT, 
INR) and ECG 
 
Section 5.0. Selection and Withdrawal of Subjects 
 
Estimated enrollment:  
• 16 subjects 
 
Inclusion criteria: 
 
• Male and female patients at least 18 years old 
• Patients with confirmed pituitary origin of excess adrenocorticotropic hormone (ACTH) 
production: 
o 
Persistent hypercortisolemia established by two consecutive 24 hr UFC levels at 
least 1.5x the upper limit of normal 
o 
Normal or elevated ACTH levels 
o 
Pituitary macroadenoma (>1 cm) on MRI OR 
o 
Inferior Petrosal Sinus Sampling (IPSS) central to peripheral ACTH gradient >2 
at baseline and >3 after CRH stimulation 
o 
Recurrent or persistent Cushing disease is defined as pathologically confirmed 
resected pituitary ACTH-secreting tumor, and 24 hour UFC above the upper limit 
of normal reference range beyond post-surgical week 6 
o 
Patients on medical treatment for Cushing’s disease the following washout 
periods must be completed before screening assessments are performed : 
 
Inhibitors of steroidogenesis (metyrapone, ketoconazole): 2 weeks  
 
Somatostatin analogs (pasireotide): 2 weeks 
 
Progesterone receptor antagonist (mifepristone): 2 weeks 

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 
Dopamine agonists (cabergoline): 4 weeks  
 
CYP3A4 strong inducers or inhibitors: varies between drugs; minimum 5-
6 times the half-life of drug 
 
Exclusion criteria: 
• Patients with compromised visual fields, and not stable for at least 6 months 
• Patients with abutment or compression of the optic chiasm on MRI and normal visual 
fields 
• Patients with Cushing’s syndrome due to non-pituitary ACTH secretion 
• Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral 
adrenal hyperplasia 
• Patients who have a known inherited syndrome as the cause for hormone over secretion 
(i.e. Carney Complex, McCune-Albright syndrome, MEN-1) 
• Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA) 
• Patients with cyclic Cushing’s syndrome defined by any measurement of UFC over the 
previous 1 months within normal range 
• Patients with pseudo-Cushing’s syndrome, i.e. non-autonomous hypercortisolism due to 
overactivation of the HPA axis in uncontrolled depression, anxiety, obsessive 
compulsive disorder, morbid obesity, alcoholism, and uncontrolled diabetes mellitus  
• Patients who have undergone major surgery within 1 month prior to screening 
• Patients with serum K+< 3.5 while on replacement treatment 
• Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8% 
• Patients who have clinically significant impairment in cardiovascular function or are at 
risk thereof, as evidenced by 
o 
Congestive heart failure (NYHA Class III or IV), unstable angina, sustained 
ventricular tachycardia, clinically significant bradycardia, high grade AV block, 
history of acute MI less than one year prior to study entry 
• Patients with liver disease or history of liver disease such as cirrhosis, chronic active 
hepatitis B and C, or chronic persistent hepatitis, or patients with ALT or AST more than 
1.5 x ULN, serum total bilirubin more than ULN, serum albumin less than 0.67 x LLN at 
screening 
• Serum creatinine > 2 x ULN 
• Patients not biochemically euthyroid 
• Patients who have any current or prior medical condition that can interfere with the 
conduct of the study or the evaluation of its results, such as 
o History of immunocompromise, including a positive HIV test result (Elisa and 
Western blot). An HIV test will not be required, however, previous medical history 
will be reviewed 
o Presence of active or suspected acute or chronic uncontrolled infection 

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o History of, or current alcohol misuse/abuse in the 12 month period prior to 
screening 
• Female patients who are pregnant or lactating, or are of childbearing potential and not 
practicing a medically acceptable method of birth control. If a woman is participating in 
the trial then one form of contraception is sufficient (pill or diaphragm) and the partner 
should use a condom. If oral contraception is used in addition to condoms, the patient 
must have been practicing this method for at least two months prior to screening and 
must agree to continue the oral contraceptive throughout the course of the study and for 
3 months after the study has ended. Male patients who are sexually active are required 
to use condoms during the study and for three month afterwards as a precautionary 
measure (available data do not suggest any increased reproductive risk with the study 
drugs) 
• Patients who have participated in any clinical investigation with an investigational drug 
within 1 month prior to screening or patients who have previously been treated with 
seliciclib 
• Patients with any ongoing or likely to require additional concomitant medical treatment to 
seliciclib for the tumor  
• Patients with concomitant treatment of strong CYP3A4 inducers or inhibitors. 
• Patients who were receiving mitotane and/or long-acting somatostatin analogs 
(octreotide LAR or lanreotide) 
• Patients who were receiving  pasireotide or ketoconazole before study entry must 
complete a 2 week washout period prior to receiving seliciclib 
• Patients who have received pituitary irradiation within the last 5 years prior to the 
baseline visit 
• Patients who have been treated with radionuclide at any time prior to study entry 
• Patients with known hypersensitivity to seliciclib 
• Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will be unable to complete the entire study 
• Patients with presence of Hepatitis B surface antigen (HbsAg) 
• Patients with presence of Hepatitis C antibody test (anti-HCV) 
 
 
Withdrawal of Subjects: 
• Monitoring for adverse effects: Patients will be evaluated for adverse effects weekly with 
physical examinations, chemistry and hematology panels.  Adverse events will be 
graded by the NCI-CTCAE and include: fatigue, fever, nausea, vomiting, anorexia, 
hepatic dysfunction (increased ALT/SGPT, AST/SGOT and AP), hypokalemia, 
hyponatremia and insomnia [IND No. 71,011-CYC202(R-roscovitine or Seliciclib)]. 
Seliciclib will be discontinued in those who developed worsening of visual fields, and 
those with toxicity greater than or equal to Grade 4 on the NCI-CTCAE.  Demonstration 
of compromised visual fields at any time will lead to withdrawal from the study and 
surgical referral. 

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Section 6.0 
Treatment of Subjects 
Transsphenoidal pituitary tumor resection is the primary therapy for Cushing disease, and yields 
30-70% surgical cure rates. Patients with recurrent or residual tumors, and/or are not surgical 
candidates typically undergo pituitary-directed radiation, adrenalectomy, treated with 
pasireotide, and/or medical suppression of adrenal gland cortisol production. In this study, we 
will treat patients with de novo, persistent, or recurrent Cushing disease with seliciclib during the 
period of evaluation and preparation for standard care, which usually takes 4 weeks at our 
center. We are excluding any subjects who need immediate surgical intervention, i.e. unstable 
visual field deficit, tumor compression of optic chiasm, or sever metabolic complications. We 
only will recruit those whom we would recommend for routine evaluation process for standard 
care.  After completion of their participation in the study, subjects will be ready to start standard 
care.  If a given patient responds to the study drug and chooses to stay on the drug after 
cessation of the trial, clinical data will continue to be collected for further analysis of drug 
response and monitoring safety.  
 
Study calendar: baseline physical exam, vital signs, weight and laboratory evaluations will be 
conducted within 7 days prior to the start of therapy. Pituitary imaging and ECG will be 
performed within 60 days prior to the start of therapy. All procedures and evaluations may be 
performed within 3 calendar days of that specified in the protocol to accommodate patient 
convenience and scheduling. Patient informed consent will be obtained prior to any protocol-
specific procedures. The schedule of study events is provided in Table 1. 
Patients will be administered a dose of oral seliciclib 400 mg twice daily for 4 days every week 
for total of 4 weeks. Patients will be seen on days 1, 8, 15, 22 and 29 for repeat laboratory 
testing, assessment of treatment compliance, and toxicity according to National Cancer Institute 
Common Toxicity Criteria version 3.  
 
The following tests will be performed: 
 
Screening visit: Day -60 to -1 
• History and physical exam 
• Dexamethasone dispensed 
o 
Dexamethasone will be dispensed during the screening visit. Study doctor will 
explain when the subject should take it. During an overnight dexamethasone 
suppression test, 8mg of dexamethasone will be taken orally the night before at 
11:00 PM. Subjects will go to the local Quest laboratory the next morning and will 
have their blood drawn between 8:00 AM - 9:00 AM to test their serum cortisol 
levels. Dexamethasone, which acts like a cortisol, decreases the amount of 
ACTH released by the pituitary gland, which then decreases the amount of 
cortisol released by the adrenal glands. More than 50% suppression of morning 
cortisol level after dexamethasone administration will confirm the diagnosis of 
Cushing's disease. Patients who had previously undergone dexamethasone 
suppression test at Cedars-Sinai Medical Center or if the patient has been 
confirmed with diagnosis such as a previous surgery or IPSS a repeat exam is 
not required.  
• 24 hour urinary free cortisol x 2  
o 
Subjects will be given 2 containers to collect 2 - 24 hour UFC 
o 
The 2 - 24 hour UFC can be collected anytime between one week after taking 
dexamethasone and the baseline visit 
o 
Subjects will drop off the 2 - 24 hour UFC at their local Quest laboratory 

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• ECG 
• Visual fields 
• Pituitary MRI 
• HbA1C 
• CBC with differential, CMP (including fasting blood glucose), LFTs 
• Hormone profile: PRL, TSH, thyroid panel, free T4, IGF-1, LH, FSH, estradiol for 
females, testosterone (total and free) for males 
• PT/INR 
• Serum Pregnancy Test (for females of childbearing potential) 
• Serum cortisol level at 8:00-9:00 AM on the day of screening visit, then at 8:00-9:00 AM 
the next day after an overnight 8 mg dexamethasone 
  
 
Baseline visit 1: Day -7 
• CBC with differential, CMP (including fasting blood glucose), PT/INR 
Fasting lipid profile, HbA1C, Hormone profile: PRL, TSH, adjusted T4, free T4, IGF-1, LH, FSH, 
estradiol for females, testosterone (total and free) for males,  
• Plasma ACTH and serum cortisol levels (every three hours from 9:00 – 15:00) 
o 
Blood draws will be done via intravenous catheter every 3 hours from 9AM to 
3PM. 
 
In the case that an intravenous catheter cannot be placed, one blood 
draw will be performed at every 3 hour interval.  
• Serum Pregnancy Test (for females of childbearing potential) 
• ECG 
• Visual fields 
o 
2 x late night salivary cortisol collection at 23:00-24:00 PM on any nights 
between baseline visit 1 and visit 2.The subject will rinse their mouth thoroughly 
with water and discard (do not swallow). The subject will hold the Salivette(R) at 
the rim of the suspended insert and remove the stopper and remove the swab. 
The swab will be placed under the tongue until well saturated (approximately one 
minute). The subject will then return the saturated swab to the suspended insert 
and close the Salivette(R) firmly with the stopper.  
• 24 hour urinary free cortisol x 3  
o 
Subjects will be given 3 containers to collect 3 - 24 hour UFC 
o 
The 3 - 24 hour UFC can be collected anytime between the baseline visit 1 and 
visit 2. 
o 
Subjects will drop off the 3 - 24 hour UFC at their local Quest laboratory 
 
 
Visit 2: Day #1 
• History and physical exam 
• Serum Pregnancy Test (for females of childbearing potential) 
• Plasma ACTH and serum cortisol levels (every three hours from 9:00 – 15:00) 
o 
Blood draws will be done via intravenous catheter every 3 hours from 9AM to 
3PM. 
 
In the case that an intravenous catheter cannot be placed, one blood 
draw will be performed at every 3 hour interval.  
• 24 hour urinary free cortisol any time between days 3-7 
o 
Subjects will collect 3 - 24 hour UFC any time between days 3-7 prior to coming 
in for study visit 3   

Melmed, S 
 
 
 
13
• 2 - late night salivary cortisol at 23:00-24:00 between days 3-7 
 
 
Visit 3: Day #8 
• History and physical exam 
• Adverse events assessment 
• CBC with differential, CMP (including fasting blood glucose), PT/INR  
• Thyroid panel: TSH, adjusted T4, free T4  
• Serum Pregnancy Test (for females of childbearing potential) 
• Plasma ACTH and serum cortisol levels (every three hours from 9:00 – 15:00) 
o 
Blood draw will be done via intravenous catheter every 3 hours from 9AM to 
3PM. 
 
In the case that an intravenous catheter cannot be placed, one blood 
draw will be performed at every 3 hour interval.  
•  
• ECG 
• 24 hour urinary free cortisol any time between days 10-14 
o 
Subjects will collect 3 - 24 hour UFC any time between days 10-14 prior to 
coming in for study visit 4   
• 2 - late night salivary cortisol at 23:00-24:00 between days 10-14 
•  
 
Visit 4: Day #15 
• History and physical exam 
• Adverse events assessment 
• CBC with differential, CMP (including fasting blood glucose), PT/INR  
• Thyroid panel: TSH, adjusted T4, free T4  
• Serum Pregnancy Test (for females of childbearing potential) 
• Plasma ACTH and serum cortisol levels (every three hours from 9:00 – 15:00) 
o 
Blood draw will be done via intravenous catheter every 3 hours from 9AM to 
3PM. 
 In the case that an intravenous catheter cannot be placed, one blood draw 
will be performed at every 3 hour interval.  
• ECG 
• 24 hour urinary free cortisol any time between days 17-21 
o 
Subjects will collect 3 - 24 hour UFC any time between days 17-21 prior to 
coming in for study visit 5  
• 2 - late night salivary cortisol at 23:00-24:00 between days 17-21 
 
Visit 5: Day #22 
• History and physical exam 
• Adverse events assessment 
• CBC with differential, CMP (including fasting blood glucose), PT/INR  
• Thyroid panel: TSH, adjusted T4, free T4  
• Serum Pregnancy Test (for females of childbearing potential) 
• Plasma ACTH and serum cortisol levels (every three hours from 9:00 – 15:00) 
o 
Blood draw will be done via intravenous catheter every 3 hours from 9AM to 
3PM. 
 
In the case that an intravenous catheter cannot be placed, one blood 
draw will be performed at every 3 hour interval.  

Melmed, S 
 
 
 
14
• ECG 
• 24 hour urinary free cortisol any time between days 24-28 
o 
Subjects will collect 3 - 24 hour UFC any time between days 24-28 prior to 
coming in for study visit 6   
• 2 - late night salivary cortisol at 23:00-24:00 between days 24-28 
 
 
Visit 6: Day #29 
• History and physical exam 
• Adverse events assessment 
• CBC with differential, CMP (including fasting blood glucose), , PT/INR 
• Fasting lipid profile, HbA1C 
• Hormone profile: PRL, TSH, adjusted T4, free T4, IGF-1, LH, FSH, estradiol for females, 
testosterone (total and free) for males 
• Serum Pregnancy Test (for females of childbearing potential) 
• Plasma ACTH and serum cortisol levels (every three hours from 9:00 – 15:00) 
o 
Blood draw will be done via intravenous catheter every 3 hours from 9AM to 
3PM. 
 
In the case that an intravenous catheter cannot be placed, one blood 
draw will be performed at every 3 hour interval. 
• ECG 
• Visual Fields 
• Pituitary MRI 
• 24 hour urinary free cortisol on days any time between 30-35  
o 
Subjects will collect 3 - 24 hour UFC any time between days 30-35 prior to 
coming in for study completion visit  
• 2 - late night salivary cortisol at 23:00-24:00 between days 30-35 
 
Study Completion Visit: Day 36 
• History and physical exam 
• Adverse events assessment 
 
 
 
 
 
 
 
 
 

Melmed, S 
 
 
 
15
Table 1. Study procedure flow sheet 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedures 
Screening Visit 
-60 to -1 
Visit 1 
Baseline 
Visit 2 
Day 1 
Visit 3 
Day 8 
Visit 4 
Day 15 
Visit 5 
Day 22 
Visit 6 
Day 29 
Study 
Completion 
Visit 
Standard of Care Procedures: Items, drugs and services that are part of regular care and would be done even if you did not take part in this research study.  These will 
be billed to you and/or your insurance company. 
Visual Field Exam 
X1 
 
 
 
 
 
 
 
MRI of the Pituitary 
X2 
 
 
 
 
 
 
 
Research Related Procedures: Items, drugs and services done for research purposes only. 
These  will be covered by the sponsor of the study and will NOT be billed to your insurance company. 
Review of medical records 
X 
 
 
 
 
 
 
 
History and Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Test (for female of childbearing 
potential) 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Draw for blood count with differential, 
comprehensive metabolic panel (CMP),  and 
prothrombin time/INR 
X 
X 
 
X 
X 
X 
X 
 
Thyroid panel (TSH, adjusted T4, free T4) 
 
 
 
X 
X 
X 
 
 
Hormone profile (Prolactin, FSH, LH, estradiol 
for female, total and free testosterone for male, 
IGF-1, TSH, adjusted T4, free T4) 
X 
X 
 
 
 
 
X 
 
Fasting lipid profile 
 
X 
 
 
 
 
X 
 
HbA1C 
X 
X 
 
 
 
 
X 
 
Dexamethasone dispensed3 
X 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
X 
X 
 
X 
X 
X 
X 
 
24 hour Urine Collection for free cortisol 
         X4 
X5 
X5 
X5 
X5 
X5 
X5 
 
Visual Field Exam 
 
X 
 
 
 
 
X 
 
Insertion of IV catheter peripherally for repeated 
blood draws 
 
X 
X 
X 
X 
X 
X 
 
Plasma ACTH and serum cortisol (every 3 hours 
from 9AM to 3PM) 
X6 
X7 
X7 
X7 
X7 
X7 
X7 
 
MRI of the Pituitary 
 
 
 
 
 
 
X 
 
Saliva sample for salivary cortisol 
 
X 
X 
X 
X 
X 
X 
 
Study drug dispensed8 
 
 
X 
X 
X 
X 
 
 
Adverse events assessment 
 
 
X 
X 
X 
X 
X 
X 

Melmed, S 
 
 
 
16
1.  If previously performed greater than 28 days from start of therapy, repeat exam will be RES. 
2.  If previously performed greater than 28 days from start of therapy, repeat exam will be RES. 
3.  Dexamethasone is taken one time the night of the screening visit. If previously performed at Cedars-Sinai Medical Center, or if the 
subject has been confirmed with diagnosis such as previous surgery or IPSS repeat exam is not required.  
  
4.  2 - 24 hour UFC can be collected anytime between one week after taking dexamethasone and the baseline visit. 
5.  3 - 24 hour UFC will be collected for 3 days prior to coming in for study visit.  
6.  Blood draws will be done only for cortisol level between 8:00-9:00 AM on the day of screening visit, and 8:00-9:00 AM the next 
day after 8 mg dexamethasone 
7.  Blood draws will be done via intravenous catheter every 3 hours from 9AM to 3PM. In the case that an intravenous catheter cannot 
be placed, one blood draw will be performed at every 3 hour interval.   
8. Study drug is taken orally twice per day for 4 days each week. 
 

Melmed, S 
 
 
 
17
 
 
 
Section 7.0 
Assessment of Efficacy 
The primary efficacy population will include patients who had baseline mean UFC levels 1.5x 
above the upper normal range, and who completed the 4-cycle, 4-week treatment period with no 
more than 2 weeks of interrupted drug doses. Baseline UFC levels are defined as the mean of 
three 24-hour urine specimens collected within one week of baseline visit.  
 
Primary outcome:  
• The primary efficacy outcome will be normalization of mean UFC levels after 4-weeks 
treatment. This will be measured as the mean of three 24-hour urine specimens 
collected at baseline and within 5 days before completion of the study. Patients who 
achieve a mean post-treatment UFC level within the normal range are considered 
responders.  
 
 
Secondary outcome:  
• Plasma ACTH, serum cortisol levels will be measured at baseline, day 1, 8, 15, 22 and 
29 every 3 hours from 9:00–15:00. The areas under the concentration-time curve (AUC0–
8h) for ACTH and cortisol will be calculated using a trapezoidal method from 0–6 h (the 
last sampling time point) by WinNonlin software (Pharsight, Mountain View, CA). Visual 
field will be measured at baseline and end of the study. 
 
Section 8.0 
Assessment of Safety  
Cross reference: [IND No. 71,011-CYC202(R-roscovitine or Seliciclib)].  
 
Monitoring for adverse effects (further detailed below): 
 
• Patients will be seen in clinic every week and evaluated for adverse effects with physical 
exam, ECG, chemistry, hematology panels, as listed in Table 1. Adverse events will be 
graded according to NCI Common Terminology Criteria (NCI-CTCAE).  Known common 
adverse events of R-roscovitine at 400mg oral dose twice daily include fatigue, fever, 
nausea, vomiting, anorexia, hepatic dysfunction (increased ALT/SGPT, AST/SGOT and 
AP), hypokalemia, hyponatremia, anemia and insomnia (cross reference: IND No. 
71,011-CYC202(R-roscovitine or Seliciclib)).  
•   
• If at any time a patient demonstrates a worsening of their visual fields or tumor growth 
on MRI, they will be withdrawn from the study and referred for surgery.  
• All patients will be followed regularly until the resolution or stabilization of drug-related 
toxicity. A post-treatment follow-up visit will be conducted within 4 weeks after the last 
dose of the study drug or prior to the initiation of new treatment.  This post-treatment 
evaluation may be conducted over the telephone if the patient is unable to return to the 
clinic.  
• In all cases where the subject is withdrawn due to unusual or unusually severe adverse 
event considered related to R-roscovitine, the withdrawal will be reported as an SAE and 
on the CRFs. 
 
Dose delays and dose reductions: 

Melmed, S 
 
 
 
18
 
• Dose delay or reduction for drug-related toxicity is permitted; however the DSMB will be 
consulted prior to implementing any change in dosing. Dose delay or reduction will only 
be implemented when all supportive care measures have been exhausted without an 
improvement of patient status. 
• Those subjects with toxicity less than or equal to NCI-CTCAE Grade 2 will continue their 
full dose, unless the investigator, based on clinical judgment, feels it is necessary to 
have their dose reduced or held. 
• Patients experiencing unacceptable toxicity (Grade 3 or higher) that the investigator 
considers directly attributable to R-roscovitine should have their dose held, reduced, or 
should be withdrawn from the study (Table 2 and 3).  
• Treatment may be delayed, up to 2 weeks, until the patient recovers completely or the 
adverse event reverts to Grade 1 or to baseline grade. 
• A maximum two dose reductions are permitted per subject and subjects will not be re-
challenged to a higher dose level. 
• The Investigator will consult the DSMB prior to continuing therapy for any subject 
requiring a delay of more than 2 weeks for unresolved toxicity, but in general, such 
subjects should be withdrawn from the study.  
 
 
Table 2. Guideline for Dose Modifications 
 
Patients 
Adverse event 
Action 
All 
Grade ≤ 2 (mild to moderate) 
No drug dose adjustments* 
 
Grade 3 (severe) 
Hold the dose for a maximum of 14 days until the 
patient recovers completely or the adverse event 
reverts to < Grade 1 or to baseline grade. Resume 
at one dose level lower (Table 3). If AE recurs at 
grade 3, reduce dose by 200 mg q.d. again and 
maintain at lower dose. If AE does not improve to 
grade < 2 within 1 week on 200 mg b.i.d., patient is 
to discontinue treatment. 
 
Grade 4 (life-threatening) 
Discontinue study drug 
*Unless the investigator, based on clinical judgment, feels it is necessary to have dose reduced or 
held. 
Note: for hepatic safety management follow Liver Chemistry Stopping and Follow up Criteria 
 
 
 
Table 3. Dose Reduction Table 
Dose Level 
Weekly R-roscovitine Dose and 
schedule 
-2 
200mg, two times daily x 4 days 
-1 
200mg, three times daily x 4 days 
0 
400mg, twice daily x 4 days 
 
• If treatment is delayed for reasons other than toxicity (i.e., unplanned travel or vacation, 
or lack of transportation to the site) and the subject has insufficient investigational 

Melmed, S 
 
 
 
19
product available, the subject should resume the usual dosing schedule once drug 
supply has been made available. However, if the subject has been off therapy for more 
than 2 weeks, the Investigator will consult the DSMB prior to continuing therapy. 
 
• If a patient permanently discontinues study treatment, the patients will be considered as 
prematurely discontinued from the study. Patients will have to perform a study phase 
completion evaluation on the day of the last study drug administration. 
 
Hepatic adverse events 
Hepatobiliary events have been seen in subjects taking seliciclib.  As a precaution, the following 
will be reported as an SAE: 
• ALT or AST >3 × ULN and total bilirubin >2.0 × ULNOther hepatic events should be 
documented as an AE or an SAE as appropriate. 
 
Liver chemistry stopping and follow up criteria have been designed to assure subject safety and 
evaluate liver event etiology.  All subjects who meet liver chemistry criteria requiring permanent 
discontinuation of investigational product (IP) must continue to be followed for the study 
assessments and procedures as defined in Table 4.  
 
Table 4. Liver Chemistry Stopping Criteria 
Hepatic AE 
Management/Next Dose for R-roscovitine 
• ALT or AST >3 × ULN and <5 × 
ULN and total bilirubin ≤2 × ULN, 
without signs or symptoms of 
hepatitis or hypersensitivity, and 
who can be monitored weekly 
• Hold IP for maximum 2 weeks, repeat liver chemistry 
testing weekly 
• Discuss with DSMB for possible re-challenge with IP 
and define dose reduction 
• If the treatment is exhibiting efficacy and the subject 
wants to continue after being informed of the liver 
chemistry results, then the IP may be re-started at 
the DSMB defined dose reduction. 
• Liver chemistries and aforementioned signs and 
symptoms should be monitored at a minimum of 
every week until resolution, stabilization, or a return 
to baseline values, at which point monitoring should 
be continued per protocol. 
• ALT or AST >8 × ULN; or 
 
• ALT or AST >5 × ULN persisting for 
≥2 weeks; or 
 
• ALT or AST >3 × ULN and (total 
bilirubin >2.0 × ULN or INR >1.5); or 
 
• ALT or AST>3 × ULN with signs or 
symptoms of hepatitis or 
hypersensitivity* 
• Immediately and permanently discontinue IP;  
• Complete the SAE data collection tool, the liver 
event CRF, and the liver imaging and/or liver biopsy 
CRFs, if these tests are performed; 
• In addition to the liver event follow up assessments 
defined 
below, 
the 
following 
are 
suggested: 
specialist or hepatology consultation; anti-nuclear 
antibody, anti-smooth muscle antibody, and Type 1 
anti-liver kidney microsomal antibodies; and liver 
imaging and/or liver biopsy to evaluate liver disease; 
• Promptly report the event to Cyclacel within 24 hours 
of learning its occurrence 
• Monitor every week until liver chemistries resolve, 
stabilize or return to within baseline values; 
• Do not re-challenge with investigational product. 

Melmed, S 
 
 
 
20
Hepatic AE 
Management/Next Dose for R-roscovitine 
• If ALT or AST>3 and < 5 × ULN for 
> 4 weeks 
 
Discontinue study drug 
*Includes: worsening of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia 
 
Liver Chemistry Follow up Criteria 
For all subjects who meet any of the liver chemistry criteria described above, make every 
attempt to carry out the liver event follow up assessments described below: 
 
• Viral hepatitis serology including: 
o Hepatitis A IgM antibody; 
o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
o Hepatitis C RNA; 
o Cytomegalovirus IgM antibody; 
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); 
o Hepatitis E IgM antibody (if subject resides or has traveled outside USA 
or Canada in past 3 months); 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
• Complete blood count with differential to assess eosinophilia; 
• Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, 
jaundice, fever, or rash as relevant on an AE report form; 
• Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form; 
• Record alcohol use on the liver event alcohol intake case report form. 
 
Adrenal adverse events 
If at any time this subject meets any of the adrenal suppression stopping criteria, then proceed 
as described below. 
Table 5. Adrenal Suppression Stopping Criteria 
Adrenal AE 
Management/Next Dose for R-roscovitine 
24 hr UFC < LLN with signs or 
symptoms of adrenal insufficiency 
(fatigue, nausea, vomiting, abdominal 
pain and hypotension) 
• Hold IP for maximum 2 weeks 
• Repeat 24 hr UFC in 1 week 
• Discuss with DSMB the possibility of re-challenge 
with IP 
24 hr UFC <LLN without signs or 
symptoms of adrenal insufficiency, 
and who can be monitored weekly 
• Continue IP 
• Monitor weekly until 24 hr UFC stabilize, then 
monitor 24 hr UFC as per protocol assessment 
schedule 
If the subject wants to continue for potential benefit of R-roscovitine therapy after being informed 
of the results of 24 hr UFC testing, then the IP may be re-started at the reduced dose 
agreed upon by the investigator. 24 hr UFC and aforementioned signs and symptoms 

Melmed, S 
 
 
 
21
should be monitored at a minimum of every week until resolution, stabilization, or a return to 
baseline values, at which point monitoring should be continued per protocol. 
 
Glucose metabolism adverse events 
The principal investigator is to evaluate the risks for hyperglycemia in all patients, following 
established guidelines by the American Diabetes Association (ADA) and European Association 
for the Study of Diabetes (EASD). The principal investigator is to educate the patient on the 
signs and symptoms of hyperglycemia.  
Patients with a prior history or new diagnosis of impaired fasting glucose, impaired glucose 
tolerance or diabetes mellitus, or at risk of developing these conditions should monitor their 
blood glucose by fingerstick twice daily (fasting and 2-hours post-prandial). The patients will be 
encouraged to keep a diary for their blood glucose for appropriate management of the disease 
throughout the trial and present the collected data to their physician/diabetes specialist for 
evaluation.  
Any patient showing a fasting plasma glucose > 130 mg/dL (7.2 mmol/L), or 2-hour post-
prandial capillary glucose (PPG) ≥ 180 mg/dl (10 mmol/L) on two consecutive measurements 
that are approximately 14 days apart, and/or HbA1c > 7% is evaluated by a diabetes specialist 
for appropriate treatment. In addition, these patients are given information regarding diabetes 
disease management. Initiation or adjustment of hypoglycemic treatment is considered as early 
as possible at the discretion of the diabetes specialist. The above instructions regarding glucose 
monitoring by fingerstick and collection of blood level in a diary are given to the patients. 
Patients who develop symptoms of diabetes mellitus out of control and/or fasting blood glucose 
values consistently as high as or above 240 mg/dL in spite of appropriate therapeutic 
interventions are discontinued from the study, as are those patients whose HbA1c is greater than 
or equal to 8% in spite of appropriate therapeutic intervention. 
 
Electrolyte metabolism adverse events 
High levels of cortisol also exert mineralcorticoid (aldosterone) activity, stimulating absorption of 
sodium and excretion of potassium at the renal collecting tubules. Hypokalemia is most often 
associated with Cushing’s syndrome due to ectopic ACTH production. Patients with pituitary 
corticotroph tumors may present with mild hypokalemia (3.0-3.5 mmol/L). Hypokalemia 
associated with seliciclib appeared to be dose dependent, occurring only in doses higher than 
1200 mg b.i.d. 3 days per every 2 weeks. Patients who develop serum potassium values 
consistently <3.0 mmol/L in spite of appropriate therapeutic interventions are discontinued from 
the study. 
 
Dermatologic (skin) adverse events 
Significant skin adverse events (Grade 3 or more) resulting from seliciclib are rare (<1%). For 
NCI-CTCAE v3.0 Grade 4 rash manifested as toxic epidermal necrolysis (i.e. Stevens-
Johnson’s Syndrome etc) seliciclib must be permanently discontinued. Subjects with poorly 
tolerated skin adverse events may be successfully managed by providing a brief (up to 14 days) 
therapy interruption; the daily dose of seliciclib should then be reinstated. However, the rash 
may improve without the need for interrupting therapy with seliciclib. A variety of agents can be 
used to manage skin rashes. These include mild-to-moderate strength steroid creams, topical or 
systemic antibiotics, topical or systemic antihistamines, and occasionally, retinoid creams. 
There is no standard, known, or established treatment proven effective for drug-related skin 
rashes or changes due to seliciclib. The need for oral or topical antibiotics will be a clinical 
decision of the investigator and should be preceded by a culture of affected areas and, if 

Melmed, S 
 
 
 
22
indicated, a dermatology consultation. Oral steroids will be strongly discouraged. Other options 
for treatment of significant rashes may be determined upon consultation with dermatologist. 
 
Gastrointestinal adverse events 
If GI adverse events are not appropriately managed, they may be associated with the 
development of dehydration. Management of gastrointestinal adverse events is discussed in 
detail in below. 
Nausea, vomiting, or both 
In subjects who have emesis and are unable to retain seliciclib, every attempt should be made 
to obtain control of nausea and vomiting. A dose may be repeated if tablets can be visually 
found after the vomiting episode. 
 
 
 
 
 
PHARMACEUTICAL INFORMATION 
 
Seliciclib (NSC # ) 
 
Chemical Name: 2-(R)-(1-Ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine 
 
Other Names: CYC202 
 
Mode of Action: Selective CDK inhibitor 
 
How Supplied: 200 mg/capsule 
Storage: Cross reference [IND No. 71,011-CYC202(R-roscovitine or Seliciclib)].  
 
Stability: Cross reference [IND No. 71,011-CYC202(R-roscovitine or Seliciclib)].  
 
Route of Administration: Oral  
 
REGULATORY AND REPORTING REQUIREMENTS 
 
It is the responsibility of the investigator to document all adverse events, which occur during the 
investigation.  An adverse event is any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use of the medicinal product, whether or 
not considered related to the medicinal product.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a medicinal product.  Anticipated day-to-day 
fluctuations of the disease under study that do not represent a clinically significant exacerbation 
or worsening need not be considered an adverse event. 
 
All adverse events occurring from the first dose of investigational product until five days after the 
last dose will be recorded REGARDLESS OF WHETHER OR NOT THEY ARE CONSIDERED 
DRUG RELATED.  In addition, any SAEs, which occur as a result of protocol specific diagnostic 
procedures or interventions will also be reported. 
 

Melmed, S 
 
 
 
23
Assessment of Causality 
Every effort will be made by the investigator to explain each adverse event and assess its 
relationship, if any, to study drug treatment.  Causality will be assessed using the following 
categories: no (not related), or yes (reasonable possibility). 
 
The degree of certainty with which an adverse experience is attributed to drug treatment (or 
alternative causes, e.g. natural history of the underlying diseases, concomitant therapy, etc.) will 
be determined by how well the experience can be understood in terms of the following: 
 
• Known pharmacology of the drug 
• Reaction of similar nature being previously observed with this drug or class of 
drug 
• The event having often been reported in literature for similar drugs as drug 
related (e.g. skin rashes, blood dyscrasia) 
• The event being related by time to drug administration terminating with drug 
withdrawal (dechallenge) or reproduced on rechallenge. 
 
The investigator may change his/her opinion of causality in light of follow-up information, 
amending the SAE form.  The causality assessment is one of the criteria used when 
determining regulatory reporting requirements. 
 
Following-up of Adverse Events 
Investigators should follow-up subjects with adverse events until the event has subsided 
(disappeared) or until the condition has stabilized. 
 
Definition of Serious Adverse Events: 
A serious adverse experience is any event, which is fatal, life threatening, disabling or 
incapacitating or results in hospitalization, prolongs a hospital stay or is associated with 
congenital abnormality.  In addition, any experience which the investigator regards as serious or 
which would suggest any significant hazard, contraindication, side effect or precaution that may 
be associated with the use of the drug should be reported as a serious adverse event. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
 
Abnormal laboratory findings (e.g., clinical chemistry, hematology) or other abnormal 
assessments (e.g., x-rays, scans, vital signs, etc.) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE or 
SAE. 
 
Life threatening definition: 
An adverse event is life threatening if the patient was at immediate risk of death from the event 
as it occurred (i.e. it does not include a reaction that if it had occurred in a more serious form 
might have caused death).  For example, drug-induced hepatitis that resolved without evidence 
of hepatic failure would not be considered life threatening even though drug-induced hepatitis 
could be fatal. 
 
Disability/incapacitating definition: 
An adverse experience is incapacitating or disabling if the experience results in a substantial 
and/or permanent disruption of the patient's ability to carry out normal life functions. 

Melmed, S 
 
 
 
24
 
Hospitalization definition: 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
 
Additional SAE definitions 
- All Grade 4 laboratory abnormalities 
- Hepatobiliary events have been seen in subjects taking seliciclib.  As a precaution, the 
following will be reported as an SAE: 
• ALT >3 × ULN and total bilirubin >2.0 × ULN (>35% direct; bilirubin fractionation 
required). 
• Other hepatic events should be documented as an AE or an SAE as 
appropriate.SAEs, pregnancies, and liver function abnormalities meeting pre-
defined stopping criteria will be reported promptly to Cedars-Sinai Office of 
Research Compliance as described in the following table once the investigator 
determines that the event meets the protocol definition for that event. 
 
Reporting Serious Adverse Events 
Any serious adverse events, which occur during the clinical study or within 5 days of receiving 
the last dose of study medication, whether or not related to the study drug, will be reported by 
the investigator. In addition, any SAEs, which occur as a result of protocol specific diagnostic 
procedures or interventions will also be reported. 
 
Lack of Efficacy 
“Lack of efficacy” per se will not be reported as an AE.  The signs and symptoms or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfill the AE or SAE definition. 
 
All serious adverse events will be reported to the FDA,  Cedars-Sinai Office of Research 
Compliance and Cyclacel Pharmaceutical, Inc. by the investigator. 
The SAE report will comprise a full written summary, detailing relevant aspects of the adverse 
events in question.  Where applicable, information from relevant hospital case records and 
autopsy reports will be included.  Follow-up information will also be forwarded within 24 hours. 
 
SAEs brought to the attention of the investigator at any time after cessation of seliciclib and 
considered by the investigator to be related or possibly related to seliciclib will be reported if and 
when they occur. Additionally, SAEs that are related to study participation (e.g., procedures, 
invasive tests, change from existing therapy) or are related to a concurrent medication will be 
collected and recorded from the time the subject consents to participate in the study until he/she 
is discharged. 
 
Pregnancy 
Patients who become pregnant during the study should discontinue the study immediately. 
Patients should be instructed to notify the investigator if it is determined after completion of the 
study that they become pregnant either during the treatment phase of the study or within five 
days after the treatment period. Whenever possible a pregnancy should be followed to term, 
any premature termination reported, and the status of the mother and child after delivery 
reported. 
 

Melmed, S 
 
 
 
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Section 9.0 
Statistics 
Due to the rarity of Cushing disease in the general population, it is difficult to do a randomized 
placebo controlled trial with sufficient sample size numbers to achieve adequate power. By 
using subjects as their own controls, we measure pre- and post-treatment changes on the same 
population, therefore alleviate the issues with recruitment.   
We used a Simon exact single-stage phase II design (8) to determine the sample size for 80% 
power and a one-sided 0.05 significance level.  The trial tests the null hypothesis that the 
seliciclib (response rate) ≤ 5% (unacceptable response rate) versus the alternative hypothesis 
that RR ≥ 25% (promising response rate).  We enroll 16 patients.  If at least 3 of the 16 respond, 
we conclude that seliciclib is promising in the treatment of ACTH-producing pituitary tumors. 
A regression model will be used to investigate the relationship between end-of-study UFC and 
baseline UFC. The comparison between serum cortisol or plasma ACTH in patients who 
responded to seliciclib and in those who did not respond will be performed by a Student’s t test. 
Categorical variables, i.e. normalization of 24 hour UFC, development of new pituitary deficits, 
and visual field deficits will be compared in the pre- and post- treatment time points using 
fisher’s exact test.  
 
Section 10.0 Quality Control and Quality Assurance 
Only samples and data collected with appropriate consent will be used for the proposed 
analysis.  Specimens and data collected under the proof of concept clinical trial of seliciclib will 
be coded in such a way so that other members of the research team will be unable to ascertain 
the identity of specific patients.  All of our data will be maintained confidentially.  Data will be 
kept in locked file cabinets and in password protected files on computer systems. 
 
Section 11.0 Ethical considerations relating to the trial 
Subjects will be recruited from Cedars-Sinai Pituitary Center.  They will be patients followed 
clinically. Patients will be approached regarding participation in the study and given consent 
forms to review at home.  They will be reassured that their clinical care will not be affected if 
they choose not to participate.  Patients will be given opportunities to ask questions and review 
the consent process.  Once they consent and enroll in the study, their data will be de-identified 
for the duration of the study.  All patients entering the trial will be given the study drug.  There is 
no placebo arm.  The risks of the study are related to the side effects of the study drug and 
patients will be monitored for this and informed on the effects.  The benefits of the study are 
normalization of urinary free cortisol. There are potential conflicts of interest between the 
patient’s need for surgical referral and participation in the research study.  However, by limiting 
the study period to 4 weeks, which is the average pre-op preparation time for our pituitary 
surgery patients, we will minimize the conflict of interest. 
 
Section 12.0 Data Handling and Recordkeeping 
Data will be maintained in separate research charts in a locked cabinet in a locked office. The 
data will be entered as well into an electronic database on a password- protected computer. 
Only study staff and the investigators will have access to these records. 
 
Section 13.0 Financing and Insurance 
Funding for this study will be through a Cedars-Sinai institutional grant. Patients will only be 
charged for the initial MRI and visual field test. 
 
Section 14.0 Publication Policy 
We intend to submit our research findings to relevant peer-reviewed journals for publication.  
We will submit data for presentation at international meetings.  We will adhere to the NIH Grants 

Melmed, S 
 
 
 
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Policy Statement on Sharing of Biomedical Research Resources, including the “Principles and 
Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and 
Disseminating Biomedical Research Resources: Final Notice” (64FR 72090, December 23, 
1999; and described at http://ott.od.nih.gov/NewPages/RTguide/final.html.  

Melmed, S 
 
 
 
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