Phase IB/II Study of Enzalutamide With Ribociclib in Patients With Metastatic Castrate Resistant, Chemotherapy Naïve Prostate Cancer That Retains RB Expression
Phase: PHASE1
Conditions: Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Prostate Carcinoma Metastatic in the Bone, Stage IV Prostate Cancer AJCC v7
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University

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Phase IB/II study of enzalutamide with ribociclib in  
patients with metastatic castrate resistant, chemotherapy naïve prostate cancer that retains RB 
expression 
 
Prostate Cancer Clinical Trials Consortium, LLC (PCCTC) 
Novartis # : CLEE011XUS12T 
PCCTC LOI #: c15-153 
IND #: 127,016 
Thomas Jefferson University 
Sponsor Investigator/Principal Investigator 
Statistician 
William Kevin Kelly, DO 
Benjamin Leiby, PhD 
Thomas Jefferson University 
Department of Medical Oncology 
1025 Walnut Street 
College Bldg., Suite 700 
Philadelphia, PA 19107 
Thomas Jefferson University 
Division of Biostatistics 
1015 Chestnut St., Suite M100 
Philadelphia, PA 19107 
email: benjamin.leiby@jefferson.edu 
email: William.kelly@jefferson.edu 
 
Co-Investigator 
Protocol Manager 
Robert Den, MD 
Prostate Cancer Clinical Trials Consortium 
Thomas Jefferson University 
Department of Radiation Oncology 
111 South 11th Street 
Philadelphia, PA 19107 
email: Robert.den@jefferson.edu 
55 Fifth Avenue, 13th Floor 
New York, NY 10003 
email: pcctc@mskcc.org  
 
 
Correlative Science Chair 
Karen Knudsen, PhD 
 
Thomas Jefferson University 
233 10th Street, BLSB 1008 
Philadelphia, PA 19107 
email: Karen.knudsen@jefferson.edu 
 
 
Protocol Date: June 11, 2015 
Amended Version Date: January 17, 2020
 
 
 

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SPONSOR INVESTIGATOR’S APPROVAL OF PROTOCOL 
 
Title: Phase IB/II study of enzalutamide with ribociclib in patients with metastatic castrate resistant, 
chemotherapy naïve prostate cancer that retains RB expression 
 
Sponsor Investigator Signature:  
_______________________________________________________ 
Sponsor Investigator Print:   
_______________________________________________________ 
Date:   
 
 
 
_______________________________________________________ 
 
PCCTC, LLC CEO Signature:   ________________________________________________________ 
PCCTC, LLC CEO Print:   
 
________________________________________________________ 
Date:   
 
 
 
 _______________________________________________________ 
 
 
 
 
 
 
 
 

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PROTOCOL AGREEMENT 
INVESTIGATOR’S APPROVAL OF PROTOCOL 
 
Title: Phase IB/II study of enzalutamide with ribociclib in patients with metastatic castrate 
resistant, chemotherapy naïve prostate cancer that retains RB expression  
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing Thomas 
Jefferson University with complete and timely information, as outlined in the protocol. It is 
understood that all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of the study 
staff and myself, I agree to maintain the procedures required to carry out the study in accordance 
with accepted Good Clinical Practice (GCP) principles and to abide by the terms of this protocol 
 
 
 
 
Investigator Signature:  
_______________________________________________________ 
Investigator Print:  
 
_______________________________________________________ 
Date:   
 
 
______________________________________________________ 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1.  
INTRODUCTION .......................................................................................................................................................... 6 
1.1 
Disease Background .............................................................................................................................................................6 
1.2 
Treatment Background .......................................................................................................................................................6 
1.3 
Rationale ................................................................................................................................................................................. 15 
2.  
OBJECTIVES .............................................................................................................................................................. 16 
2.1 
Primary Objective ............................................................................................................................................................... 16 
2.2 
Secondary Objectives ........................................................................................................................................................ 16 
2.3 
Correlative/Exploratory/Tertiary Objectives ....................................................................................................... 16 
3. 
PATIENT SELECTION ............................................................................................................................................. 17 
3.1 
Inclusion Criteria ................................................................................................................................................................ 17 
3.2 
Exclusion Criteria ............................................................................................................................................................... 18 
4. 
ENROLLMENT PLAN AND SUBJECT REGISTRATION .................................................................................... 21 
4.1 
Enrollment Plan ................................................................................................................................................................... 21 
4.2 
Registration Procedure .................................................................................................................................................... 21 
5. 
TREATMENT PLAN ................................................................................................................................................. 22 
5.1 
Screening/Pretreatment Assessment (Day -28 to Day 0) ................................................................................ 27 
5.2 
Treatment Period (Day 1 to POD/EOT ± 2 days) ................................................................................................. 28 
5.3 
End of Treatment/Treatment Discontinuation Visit (28  days from last dose ± 7 days) ................... 28 
5.4 
Post Treatment Follow-up (EOT – 24 months from last dose ± 7 days) .................................................... 28 
5.5 
Safety Assessments ............................................................................................................................................................ 28 
5.6 
Correlative/Special Studies ............................................................................................................................................ 29 
5.7 
Dose Modifications ............................................................................................................................................................. 31 
5.8 
Removing Subjects from the Protocol ....................................................................................................................... 38 
6. 
THERAPEUTIC/DIAGNOSTIC AGENT(S) .......................................................................................................... 38 
6.1 
Ribociclib ................................................................................................................................................................................ 38 
6.2 
Enzalutamide ........................................................................................................................................................................ 40 
6.3 
Concomitant Medications ............................................................................................................................................... 41 
7.0 
ADVERSE EVENTS ................................................................................................................................................... 42 
7.1 
Definitions .............................................................................................................................................................................. 42 
7.2 
Recording and Grading of Adverse Events .............................................................................................................. 44 
7.3 
Reporting Adverse Events .............................................................................................................................................. 45 
7.4  
Safety Reports ...................................................................................................................................................................... 47 
8. 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE ...................................................... 47 
8.1 
Outcome Assessment ........................................................................................................................................................ 47 
8.2 
Therapeutic Response ...................................................................................................................................................... 48 
8.3 
Response Criteria for Control/Relieve/Eliminate Endpoints ......................................................................... 50 
8.4 
Confirmatory Measures/Duration of Response .................................................................................................... 52 
8.5 
Progressive Disease (PD) ................................................................................................................................................ 54 
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS ............................................................................ 54 
9.1 
Data Collection and Management ................................................................................................................................ 54 
9.2 
Data and Safety Monitoring ............................................................................................................................................ 55 
10. 
STATISTICAL CONSIDERATIONS ........................................................................................................................ 56 
10.1 Study Endpoints .................................................................................................................................................................. 56 
10.2 Analysis Populations ......................................................................................................................................................... 57 
10.3 Safety Analysis ..................................................................................................................................................................... 57 
10.4 Statistical Procedures ....................................................................................................................................................... 58 
11. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS ............................................................................ 58 
11.1 Role and Responsibilities ................................................................................................................................................ 58 
11.2 Ethical Considerations ...................................................................................................................................................... 59 

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11.3 Protocol Amendments ...................................................................................................................................................... 59 
11.4 Written Informed Consent .............................................................................................................................................. 60 
11.5 Protection of Privacy ......................................................................................................................................................... 60 
11.6 Terminating or Modifying the Study .......................................................................................................................... 60 
12. 
REFERENCES ............................................................................................................................................................. 62 
Appendix A: Performance Status Criteria ............................................................................................................................. 65 
Appendix B: Medications with the Potential for Drug-Drug Interactions .............................................................. 66 
Appendix C: Laboratory Manual ............................................................................................................................................... 71 
Appendix D: Glossary of Abbreviations and Acronyms .................................................................................................. 72 
Appendix E. Pill Diary (PHASE I) .............................................................................................................................................. 75 
Appendix F. Pill Diary (PHASE II) ............................................................................................................................................. 77 
Appendix G. Novartis SAE Coversheet .................................................................................................................................... 80 
Appendix H. PCCTC SAE Report Form .................................................................................................................................... 83 
  
 

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1.  
INTRODUCTION 
1.1 
Disease Background 
Prostate cancer is the second leading cause of cancer deaths in men. According to American 
Cancer Society estimates in 2014, as many as 233,000 American men will be diagnosed with 
prostate cancer, and nearly 29,480 will die of the disease.1 The course of prostate cancer from 
diagnosis to death is best categorized as a series of clinical states (Figure 1). These clinical 
states involve the complex interplay of a network of signaling molecules that collectively 
promote net cell proliferation relative to cell death.  
Figure 1. Clinical states of prostate cancer 
 
Treatment options for patients with castrate resistant prostate cancer (CRPC) are limited and 
until recently only docetaxel was shown to improve survival. In the last several years we had 
five new agents; abiraterone acetate, cabazitaxel, enzalutamide, radium-223 and sipuleucel-
T approved for use in this clinical state.2-6 However the optimal sequencing of these agents is 
unknown. Moreover, all patients with CRPC are treated identically and there is no means of 
identifying which patient population would benefit from a particular agent. 
1.2 
Treatment Background 
Standard treatment approach for patients with progression after primary androgen 
ablation therapy 
Enzalutamide inhibits androgen receptor (AR) signaling in three distinct ways: it inhibits 1) 
testosterone binding to ARs; 2) nuclear translocation of ARs; and 3) DNA binding and 
activation by ARs. Based on the AFFIRM trial, enzalutamide was approved by the FDA in 2012, 
and by the EMA in 2013, for the treatment of men with mCRPC who have progressed on or 
after first-line docetaxel chemotherapy.7 Currently the NCCN guidelines recommend 
enzalutamide in this setting as well as for men with mCRPC who are not candidates for 
docetaxel. Recently, Beer and colleagues (PREVAIL phase III trial) have shown that 
enzalutamide significantly reduced the risk for radiographic progression, delayed initiation 
of chemotherapy and improved overall survival (OS) in men with CRPC that have not received 
prior chemotherapy.8 In September 2014, the U.S. Food and Drug Administration (FDA) 
expanded the use of enzalutamide to include men with CRPC that have not received prior 
chemotherapy. Thus, enzalutamide has become a standard of care as systemic therapy for 
men with mCRPC and since there is no need for systemic steroids, it is expected to be the 
predominant agent to be used in this pre-chemotherapy setting.  
 

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Development of CRPC 
Extensive work has been performed to increase the understanding of the major mechanism 
driving resistance to castration (including after treatment with abiraterone acetate).  
Preclinical and clinical studies have demonstrated that alterations, specifically, up-regulation 
of the AR is central to the progression to CRPC.9 Preclinical modeling of AR up-regulation 
showed that this event alone is sufficient to drive progression to CRPC. Recently reported 
findings identified perturbations of the RB tumor suppressor as a major mechanism by which 
AR deregulation occurs and induction of CRPC formation. Principle findings were: a) RB loss 
is infrequently observed in primary disease, but is predominantly associated with the 
mCRPC; b) loss of RB function is associated with poor outcome; c) modeling of RB dysfunction 
in vitro and in vivo revealed that RB controls AR expression and output via transcriptional 
regulation of the AR locus; d) disruption of the newly identified RB-E2F/AR axis was 
frequently observed in the transition to castrate  resistance in human disease.10-16 These data 
suggest that a new paradigm for RB function in controlling prostate tumor progression and 
lethal tumor phenotypes.  
Accessing RB Status in Tumors 
Using multiple methods to assess RB expression and activity, it was noted that RB loss of 
function is highly overrepresented in CRPC. A representative example of the data are shown 
in Figure 2 and in the study by Sharma et al.17 Using the combined analyses of RB expression 
and the RB signature, up to 60% of CRPCs show loss of RB activity.  While the initial study 
examined over 150 CRPC specimens, enrichment of RB loss in the CRPC setting has been 
further confirmed by the work of Gerald and Sawyers, and in subsequent analyses of cohorts 
from Dr. Tapio Visakorpi (data not shown). Moreover, recent mouse models confirm the 
importance of RB function in prostate cancer.15  
 
Figure 2. RB function is perturbed in the transition to CRPC. These data are taken from a recent 
comprehensive study (Sharma et al., J Clin Invest 2010) which assesses RB functional status in 
multiple tumor sets.  As shown, the RB loss signature is highly overrepresented in CRPC (left). 
Quantification and statistical analyses (right) demonstrate that there is little evidence for loss 
of RB function in primary disease, whereas this event is frequent in CRPC.  Based on this 
published (Sharma et al., 2010) and new preliminary data, analyses of over 150 CRPCs 
demonstrate that RB loss of function occurs in up to 60% of CRPCs. 
We estimate in the current proposed study populations approximately 50% of the 
patients will have intact RB function (RB+).  

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Contemporary means to activate RB function in the clinical setting:   
Our new data identify pharmacological means to hyperactivate RB function in tumors that 
retain the RB protein (RB+). RB function is often downregulated in tumors through 
hyperphosphorylation of the protein – thus, agents that target the kinases that phosphorylate 
RB (e.g., Cyclin dependent kinase 4, CDK4) are attractive therapeutic agents.11 CDK4 initiates 
RB phosphorylation, thus ‘priming’ RB for further phosphorylation and resultant diminution 
of tumor suppressor activity.18  While first generation CDK inhibitors were both non-specific 
and toxic, second generation inhibitors are specific, effective, and well tolerated (patients 
treated for >1 year showed minimal toxicity and stabilization of therapy-refractory 
disease).19-21 We utilized cell culture, xenograft, and primary tumor explant strategies to 
assess the impact of a second generation CDK4 inhibitor on prostate cancer (Figure 3 and 
data not shown). The explant studies utilize cutting-edge technology wherein tissue obtained 
from radical prostatectomy are sampled and therapeutically interrogated in a novel explant 
assay. In this assay, primary tumor tissue can be cultured for up to 7 days; importantly, the 
sections retain histology and tumor phenotypes identical to that of the specimen at resection. 
Moreover, these studies allow for examination of drug effects on the surrounding stroma and 
normal tissue. As would be expected, the tumors obtained to date from radical prostatectomy 
retain RB (not shown), and are exquisitely responsive to the CDK4 inhibitor. Investigation to 
date reveals both cytostatic and cytotoxic effects of the drug that are specific to tumor cells. 
Moreover, RB was hyperactivated in cells treated with the CDK4 inhibitor. These data 
strongly support the contention that CDK4 inhibitors can be used to activate RB, and therein 
suppress tumor growth, survival, and progression.  
 
Figure 3. Novel human explant protocol allows for rapid validation of drug efficacy; clinically 
attainable doses of PD-0332991 effectively suppress tumor growth and survival in RB+ tumors. 
A brief schematic of the explant protocol is shown on the left. To the right of the arrow, 
examples of Ki67 staining in the portion of tumor treated without PD-0332991 (0μM) or 
treated with doses known to be clinically achievable (0.5-1.0 μM) are shown. Data 
quantification from multiple explant studies is also shown. 
 
Summary 
The current data suggests RB function is often attenuated in tumors through 
hyperphosphorylation-- thus, RB activity can be “re-awakened” in RB+ tumors by 
suppressing the key kinases that phosphorylate RB (CDK4/6). Indeed, promising clinical data 

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using next-generation CDK4/6 inhibitors in multiple cancers have shown significant anti-
tumor effects, giving further encouragement for this new line of therapeutic intervention.   
Hypothesis 
Therefore, we hypothesize that the addition of ribociclib in combination with 
enzalutamide in patients with progressive metastatic prostate cancer despite castrate 
levels of testosterone that retains RB expression will significantly increase the efficacy of 
enzalutamide.   
1.2.1 
Description and mechanism of action 
1.2.1.1 Nonclinical activity 
Overview of the G1 to S phase transition in mammalian cells  
Normal mammalian cells proliferate in response to extracellular signals by transitioning 
through a series of tightly controlled phases that culminate in cell division. The commitment 
to transition from G1 to S phase and the initiation of cell cycle progression is regulated by the 
retinoblastoma protein (pRb). In the absence of appropriate growth stimuli, pRb, in its 
unphosphorylated state, binds and inhibits the activity of the E2F family of transcription 
factors, preventing these proteins from activating the genes required for S phase 
transition.22,23 Upon mitogen stimulation, signaling through pathways such as the MAPK and 
PI3K pathways increases the abundance of  D-cyclins, which bind and activate CDK4/6. Cyclin 
D-bound CDK4/6 then phosphorylates the pRb protein to deactivate it and release bound 
E2F. Once freed, E2F activates S phase-specific genes in order to start cell cycle progression. 
Full deactivation of pRb requires its sequential phosphorylation at different sites by both 
cyclin D-CDK4/6 and cyclin E-CDK2.  The phosphorylation events mediated by CDK4/6 are 
prerequisites for those catalyzed by CDK2.24 The kinase activity of CDK4/6 is in turn inhibited 
by p16, encoded by the INK4a gene.25,22 The CIP/KIP proteins, inhibitors of cyclin E-CDK2, 
also bind to the cyclin D-CDK4/6 complex, and this results in further activation of CDK2 by 
sequestering CIP/KIP proteins from their target.26 Cyclin D-CDK4/6 is therefore a key 
enzyme complex that regulates the G1 to S phase transition.  
Alterations in the D-cyclin-CDK4/6-INK4a-pRb pathway in human malignancies 
The D-cyclin-CDK4/6-INK4a-pRb pathway is universally disrupted in cancer to favor cell 
proliferation. Eighty percent of human neoplasms maintain functional pRb but harbor 
aberrations that increase the activity of CDK4/6 to effectively inactivate pRb function.  These 
aberrations include genetic or epigenetic changes that directly increase the kinase activity of 
CDK4/6 or defects that activate the upstream.22,23 One of the most common events is the 
inactivation of p16 via mutations, deletion and epigenetic silencing. p16 inactivation is 
frequently observed in a significant portion of non-small cell lung cancer (NSCLC), melanoma, 
pancreatic cancer and mesothelioma.27-30 Moreover, a specific mutation of the CDK4 gene 
(CDKR24C), that confers resistance to p16 binding, has been shown to play a causal role in 
rare cases of familial melanoma, suggesting that unchecked CDK4 activity is a key event in 
these cancers.31 
Translocations of the genes encoding D-cyclins to the immunoglobulin heavy chain locus are 
found in a majority of mantle cell lymphomas (MCLs) and in many cases of multiple 
myeloma.32 These translocations lead to constitutive expression of D-cyclins, which result in 
enhanced CDK4/6 kinase activity and unchecked cell proliferation.33 Amplification of  cyclin 
D1 and overexpression of the protein have also been reported in approximately 50% of 

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squamous cell esophageal cancers  and  in 20-30% of breast cancers, suggesting that 
activation of this pathway may play a role in the growth of these tumors.34-36 Furthermore, 
many of the receptor-mediated growth pathways that are activated in human cancers 
increase D-cyclin transcription and expression to drive cell proliferation. In mouse breast 
cancers driven by activated Ras or Her2/Neu oncogenes, cyclin D1 and CDK4 have been 
shown to be necessary for the tumorigenic phenotype in both initiation and maintenance 
phases, demonstrating that Cyclin-D1/CDK4 is the key effector enzyme complex for Ras- or 
Her2/Neu-driven cancers.37,38 Other activating aberrations of mitogen pathways such as 
V600E B-Raf in the MAPK pathway and PTEN deletions in the PI3K pathway also increase D-
cyclins to achieve unchecked proliferation, suggesting that CDK4/6 may also be crucial for 
the cancers bearing these alterations.39,40 Finally, the genes encoding CDK4 and CDK6 are 
amplified in a subset of human neoplasms. The CDK4 gene is amplified in 100% of 
liposarcomas along with the MDM2 gene, while CDK6 is frequently amplified in T-
lymphoblastic lymphoma and/or acute lymphoblastic leukemia.41,42 
1.2.1.2 Preclinical studies 
Nonclinical pharmacokinetics and metabolism of ribociclib  
Ribociclib showed high clearance (CL) in the mouse, rat, dog and monkey. The volume of 
distribution was large across species and the terminal elimination half-life (T1/2) was 
moderate in rodents and monkey (~2 to 5 h) and longer in dog (18 h). 
Bioavailability was low to moderate in rat (37%) and cynomolgus monkey (17%), and 
moderate in mouse (65%) and dog (64%). Following oral administration, time to reach 
maximal plasma concentrations (Tmax) occurred between 2 to 4 h across species. Gender-
dependent toxicokinetics were observed in rats with higher exposure to ribociclib in males 
as compared to females and with higher exposure to the metabolite, LEQ803. 
Plasma protein binding was moderate in all species (unbound fraction (fu) in human: 30%). 
In a rat ADME (absorption, distribution, metabolism and excretion) study, extensive 
distribution of [3H] ribociclib and its metabolites was seen. In pigmented rats, radioactivity 
was specifically found in melanin-containing structures, and the highest exposure to total 
radiolabeled components was observed in eye ciliary body, eye choroid, meninges, tactile 
hair and hair follicles. Radioactivity was not detected in the brain. Tlast (last observation 
timepoint) was ≤ 48h for most tissues, but long (168 to 840h) for lymph nodes, preputial 
gland, testis, eye and meninges. At one week ≤ 0.04% of the dose was retained in the carcass. 
LEQ803 (N-demethylation) was a prominent metabolite found in mouse, rat, dog, monkey 
and human hepatocytes. This metabolite retains some pharmacologic activity and interacts 
with human Ether-a-go-go Related Gene (hERG) channels in vitro. In male rats, unchanged 
ribociclib (24.7% of [3H]AUC0-24h) and its metabolite M11 (26.3% of [3H]AUC0-24h) were 
the major components in plasma. In rats, ribociclib was eliminated mainly by metabolism. 
The major metabolism pathway was direct sulfation of ribociclib to M8 and its excretion into 
the bile. Direct ribociclib secretion accounted for 18.2% of the total plasma clearance. 
Results from the ADME (male rats) study showed that 3H-components were predominantly 
excreted with bile (61.4% of dose). Minor urinary excretion was observed (5.9% of dose after 
p.o.). The majority of the administered dose (87.3%) was excreted within 24 h via urine, feces 
(enteric secretion) and bile. 

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In vitro, ribociclib was a reversible inhibitor of cytochrome P450 (CYP) enzymes CYP1A2, 
CYP2E1 and CYP3A4 and a time-dependent inhibitor of CYP3A4. ribociclib may inhibit these 
enzymes under therapeutic conditions. No pregnane X-receptor (PXR)-mediated CYP3A4 
induction was observed. The in vitro inhibitory potency of ribociclib observed for the 
transporters OATP1B1 (organic anion transporting polypeptide 1B1), BCRP (breast cancer 
resistance protein), OCT1 (organic cation transporter 1), OCT2, MATE1 (multidrug and toxin 
extrusion protein 1), MATE2K and BSEP (bile salt export pump) may translate into clinically 
relevant inhibition at therapeutic doses. 
Elimination of ribociclib is dominated by oxidative metabolism mainly via CYP3A4 with a 
minor contribution by flavin-containing monooxygenase 3 (FMO3). The elimination of 
ribociclib may be affected by co-administered drugs that inhibit or induce CYP3A4. Although 
ribociclib is a substrate of the P-glycoprotein (P-gp) efflux transporter and subject to active 
uptake into hepatocytes, these processes are likely not clinically relevant due to the high 
passive permeability of ribociclib. 
Safety pharmacology and toxicology of ribociclib 
In vivo cardiac safety studies demonstrated a signal for QT prolongation with the potential to 
induce incidences of premature ventricular contractions (PVCs) at higher exposure levels. 
The effects of ribociclib on the bone marrow (hypocellularity), lymphoid system (lymphoid 
depletion), intestinal mucosa (atrophy), skin (atrophy), bone (decreased bone formation) 
and testes (atrophy) are considered to be related to the pharmacological inhibition of cell 
replication in these tissues due to CDK4/6 inhibition. An increased number of ovarian 
corpora lutea was observed in a single female dog in the 4-week toxicity study at the highest 
dose tested (20 mg/kg/day) and this effect could also be related to the pharmacology of 
ribociclib (arrest of estrous cycle). The liver, bile system and gall bladder (proliferative 
changes, cholestasis, sand-like gallbladder calculi and inspissated bile) and the kidney 
(concurrent degeneration and regeneration of tubular epithelial cells) were identified as 
additional target organs of toxicity which are not likely related to the primary pharmacology 
of ribociclib. Inflammatory changes in the lungs of dogs were considered secondary to 
aspiration of test-article and are indicative of the irritant potential of the formulated test-
article in the respiratory tract. Correlating hematological and/or biochemistry changes were 
seen for the effects described in the bone marrow, lymphoid system and liver. Generally all 
changes demonstrated either reversibility or a clear tendency towards reversibility. 
Reproductive studies have demonstrated ribociclib induced embryotoxicity and fetotoxicity 
in rats and rabbits and teratogenicity in rabbits. 
1.2.1.3 Clinical studies 
Clinical Study with ribociclib 
As of 24 April 2014, 132 patients have been treated with single agent ribociclib in the FIH 
phase I study; 85 patients have been treated in the dose escalation part and 47 patients in the 
dose expansion part of the study. 
 
Patients with advanced solid tumors or lymphomas were treated with increasing doses of 
ribociclib orally, once daily (qd) for 21 days followed by a 1-week rest (28-day cycle). Doses 
ranging from 50 mg to 1200 mg were evaluated on this schedule. In addition, continuous 

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dosing of ribociclib at 600 mg was evaluated (qd for 28 days of a 28-day cycle). Doses tested 
include, 50 mg (n=4), 70 mg (n=2), 140 mg (n=4), 260 mg (n=4), 280 mg (n=4), 350 mg 
(n=5), 400 mg (n=5), 600 mg (n=67), 600 mg continuous (n=7), 750 mg (n=14), 900 mg 
(n=13), and 1200 mg (n=3). The median age of patients was 60 years (22 to 84), the 
male/female ratio was 1, and the distribution of Eastern Cooperative Oncology Group (ECOG) 
performance status of 0/1 at baseline was 47/84 patients, respectively. The most common 
cancer types were liposarcoma (33), ER+ breast cancer (20), head and neck (including 
salivary gland) cancer (16), colon cancer (14), lung cancer (8), and lymphoma (8). Treatment 
has been discontinued in 111 (84%) patients; the primary reasons for treatment 
discontinuation were: disease progression (96 [72%] patients); adverse events (AEs) (8 [6%] 
patients); withdrawal of consent (3 [2%] patient); and loss to follow up (1 [1%] patient). 
A total of 10 events meeting dose limited toxicity (DLT) criteria were observed at the 
indicated doses in the 70 patients evaluable for dose determination and include Grade 3 
mucositis/stomatitis (later determined to be due to herpes simplex virus infection) (n=1) at 
50 mg, Grade 3 pulmonary embolism (n=1) at 280 mg, Grade 3 hyponatremia (asymptomatic 
and corrected with saline infusion) (n=1) and prolonged Grade 3/4 neutropenia (n=1) at 400 
mg, prolonged Grade 2 elevated creatinine (n=1) at 600 mg, Grade 4 thrombocytopenia (n=1) 
at 750 mg, Grade 3 asymptomatic QTcF prolongation with Grade 3 neutropenia (n=1) at 900 
mg and Grade 4 febrile neutropenia (n=1) and Grade 4 thrombocytopenia (n=1) at 1200 mg. 
There was also one DLT, prolonged Grade 3 neutropenia (n=1) at 600 mg on the continuous 
dosing schedule. 
The most frequently reported AEs (≥10%), regardless of grade, causality and ribociclib dose 
were: fatigue (53.8%); nausea (50.8%); neutropenia (47.7%); leukopenia (46.2%); anemia 
(37.1%); vomiting (34.8%); thrombocytopenia (34.1%); diarrhea (32.6%); lymphopenia 
(30.3%); decreased appetite, hyperglycemia (21.2% each); constipation (19.7%); 
hypoalbuminemia 
(18.9%); 
dyspnea 
(18.2%); 
cough 
(16.7%); 
fever, 
increased 
creatinine(15.9% each); abdominal pain, AST increase, edema, headache (15.2% each); back 
pain (14.4%); dizziness (13.6%); ECG QT prolonged (11.4%); blood alkaline phosphatase 
increased and hypocalcemia (10.6% each). 
For either continuous or intermittent dosing, the onset of neutropenia (most frequently 
Grade 2) occurs by Day 15, reaching a nadir in the third or fourth week with recovery during 
the week of drug holiday. Some patients require additional time for recovery (7 to 14 days). 
QT changes become evident in the first cycle by Day 8 and later (once steady state is reached), 
are associated with the maximum drug levels between 1 to 8 h post-dose, and remain stable 
or improve in subsequent cycles. 
As of 24 April 2014, asymptomatic Grade 2 QTcF prolongation was observed with increasing 
frequency when increasing the dose starting at 600 mg: twelve patients (18%) in the 600 mg 
cohort, three patients (21%) in the 750 mg cohort, four patients (31%) in the 900 mg cohort, 
and two patients (67%) in the 1200 mg cohort. Two patients (3%) at 600 mg and two patients 
(15%) at 900 mg had asymptomatic QTcF prolongation that resulted in a QTcF interval of 
500 ms or more. As compared to baseline value, QTcF prolongation was at least 30 msec in 2 
patients (50%) at 250mg, 2 (40%) at 350 mg and 400 mg, 46 (73%) at 600 mg, 10 (71%) at 
750 mg, 11 (85%) at 900 mg and 2 (67%) at 1200 mg; and at least 60 msec as compared to 
baseline in respectively 16%, 0%, 39% and 67% of patients at 600 mg, 750 mg, 900 mg and 
1200 mg. One grade 1 atrioventricular block of first degree was reported as related to 

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ribociclib given at the dose of 140 mg. No other cardiac abnormalities were observed as 
related adverse events in any patient. 
Paired skin biopsies from 55 patients treated with ribociclib at doses ranging from 50 to 900 
mg and paired tumor biopsies from 20 patients (16 patients at 600 mg, 2 patients at 900 mg, 
and 1 patient each at 70 and 750 mg) were assessed for changes in Ki67 and pRb levels. 
Preliminary results indicate the following: in skin biopsies, reductions in Ki67 from baseline 
were observed across all dose levels with a more consistent trend from 400 mg onwards; in 
tumor biopsies, reductions in Ki67 from baseline were observed in 18/20 patients; however, 
limited samples and varied tumor types prevent conclusions about any dose-response 
relationship from being drawn. Changes in pRb were not significant or consistent in either 
skin or tumor samples, possibly due to varied tumor types. 
Out of the 114 evaluable patients, 3 partial responses were observed at the 600 mg dose level; 
one each in BRAF/NRAS wild type with CCND1 amplified melanoma, and head and neck 
acinar carcinoma with CDKN2A loss (both on the 3 weeks on/1 week off regimen), and 
ER+/HER2-, PIK3CA mutant, CCND1 amplified b reast cancer (on the continuous daily dosing 
regimen). 
This study is currently evaluating a dosing schedule with ribociclib 400 mg continuous 
dosing, as well as the safety and PK of the oral solution formulation. 
The maximum tolerated dose (MTD) of ribociclib is 900 mg qd with a 3 weeks on/1 week off 
schedule. The RP2D for future development is 600 mg qd with a 3 weeks on/1 week off 
schedule which has an acceptable safety profile, lower risk for QT prolongation, adequate 
exposures, and preliminary evidence of clinical activity. 
For additional information, please refer to the [ribociclib Investigator’s Brochure].  
Clinical pharmacokinetics of ribociclib 
The pharmacokinetics (PK) of ribociclib have been evaluated following single and repeat 
daily doses in the ongoing single agent, phase I study in patients with advanced solid tumors 
or lymphomas CLEE011X2101. Patients in all but one cohort received escalating doses of 
ribociclib once daily for 3 weeks followed by 1 week off schedule. In one cohort, patients 
received once daily continuous dosing of 600 mg ribociclib. PK sampling (pre-dose and 0.5, 
1, 2, 4, 6, 8, and 24 h post-dose) was conducted on Days 1 and 18 or 21 of Cycle 1. Additional 
PK sampling (predose and 1, 2, and 4 h post-dose) was conducted on Days 8 and 15 of Cycle 
1. Sparse samples were collected in Cycle 2 and subsequent cycles. The PK parameters from 
noncompartmental analysis of plasma concentration-time profiles on Day 1 and Day 18 or 21 
of Cycle 1 are summarized in the Investigator’s Brochure. Following oral dosing, ribociclib 
was rapidly absorbed with median Tmax ranging from 1 to 4 h. ribociclib exhibited slightly 
over-proportional increases in exposure (Cmax and AUC) across the dose range tested (50 to 
1200 mg), with no clear evidence of time-dependent auto-inhibition of its clearance mediated 
by CYP3A4. Steadystate was generally reached by Day 8 and mean T1/2,acc ranged from 15.9 
to 32.6 h across the dose range (50 to 1200 mg). Mean Racc across the studied doses ranged 
from 1.55 to 2.52. At the 600 mg dose level, LEQ803, an active metabolite of ribociclib, 
accounted for approximately 8% (geometric mean) of the ribociclib AUC0-24h after a single 
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1.2.2 
Other agents or interventions 
 
Enzalutamide 
Enzalutamide (MDV3100) is an AR signaling inhibitor that targets several steps in the AR 
signaling pathway. Enzalutamide competitively inhibits binding of androgens to ARs, inhibits 
nuclear translocation of receptors and inhibits the association of the AR with DNA, even in 
the setting of AR overexpression and in prostate cancer cells resistant to anti-androgens. 
The efficacy of enzalutamide in patients with metastatic prostate cancer who progressed on 
androgen deprivation therapy has been demonstrated in two randomized controlled phase 
III studies including MDV3100-03 in asymptomatic or mildly symptomatic patients and 
CRPC8 in patients with more advanced disease who previously received docetaxel. Both 
studies showed a statistically significant advantage of enzalutamide treatment over placebo 
across multiple clinically relevant endpoints such as OS, rPFS, time to first skeletal-related 
event, time to PSA progression, PSA response rate, best overall soft tissue response, and 
quality of life as measured by the FACT-P. Notably, Study MDV3100-03 showed a significant 
benefit of enzalutamide in time to initiation of cytotoxic chemotherapy. Additional efficacy 
data from open-label Studies S-3100-1-01, CRPC-MDA-1, and 9785-CL-0111 in patients with 
mCRPC provided supportive data on PSA response rate, time to PSA progression, and/or best 
overall soft tissue response, although the magnitude of these treatment effects varied based 
on the characteristics of the enrolled populations. In general, the treatment effect across 
these endpoints was larger in patients with mCRPC who had not yet received chemotherapy 
compared with patients who previously received docetaxel, but the benefit was consistently 
demonstrated across endpoints within a patient population. 
In both phase III studies of patients with mCRPC, the benefit of enzalutamide treatment on 
OS as measured by the estimated hazard ratio was observed across all prespecified 
subgroups. The statistically significant benefit on OS was also observed despite substantially 
higher and earlier use in the placebo groups compared with the enzalutamide groups of 
subsequent therapies that have demonstrated a survival benefit in patients with prostate 
cancer. These findings limit the ability to observe the isolated treatment effect of 
enzalutamide on this endpoint. This is especially true for MDV3100-03, based on the wider 
availability during this study of subsequent therapies demonstrated to prolong survival in 
patients with mCRPC. 
In Study MDV3100-03, rPFS was a coprimary endpoint and was rigorously evaluated through 
use of blinded central reviewers as well as through a variety of sensitivity analyses of this 
endpoint. The magnitude of the relative treatment benefit (unstratified hazard ratio 0.186 
[95% CI: 0.149, 0.231]) was coupled with a statistically greater best overall radiographic soft 
tissue response of 58.8% in the enzalutamide group versus 5.0% in the placebo group 
(difference of 53.9% [95% CI: 48.53, 59.17%]). Another clinically important finding in this 
patient population with earlier-stage disease included a 17.2 month delay in the median time 
to initiation of cytotoxic chemotherapy, which also delays treatment-associated morbidities. 
The decrease in risk of a skeletal-related event and PSA progression, and improvement in 
radiographic response in enzalutamide-treated patients provide additional evidence of 
clinical benefit. Furthermore, the benefit on time to degradation of FACT-P scores suggests 
that treatment with enzalutamide may prolong quality of life. 
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The benefit of enzalutamide for men with prostate cancer is consistently observed across 
studies of differing patient populations and across the majority of efficacy endpoints 
assessed. 
1.3 
Rationale 
Metastatic prostate cancer growth, survival, and progression are intrinsically linked to the 
activity of the AR. Thus, first line therapies target AR either through suppression of androgen 
production or direct inhibition of the AR, resulting in the inability of the receptor to bind to 
chromatin and initiate AR-directed gene expression. Recurrent AR activity is the critical 
driver of CRPC; therefore, novel AR-targeted therapeutics were developed and show 
transient clinical benefit. Despite these advances, the vast majority of patients with CRPC 
succumb to disease within 2-3 years, indicating the need for metrics of precision medicine, 
and development of additional therapeutics.   
Our preclinical studies indicate, tumors that retain RB proved to be exquisitely responsive to 
CDK4/6 inhibitors, revealing cytostatic and cytotoxic effects specific to the tumor. These 
analyses strongly support the contention that CDK4/6 inhibitors can be used to activate the 
RB pathway, and impede the transition to CRPC. Our study showed that: i) CDK4 inhibitors 
can be used to engage RB activity; ii) CDK4 inhibitors can be used in concert with AR-directed 
therapeutics; iii) RB activation can selectively enhance the effects of castration + Casodex 
therapy by further reducing AR signaling (e.g., as observed by further suppressing PSA 
expression in LAPC4 cells); and iv) Most importantly, CDK4 inhibitors strongly suppressed 
prostate cancer cell growth in an RB-dependent manner.   
These preclinical findings suggest that selective CDK4/6 inhibition is a potential mode of 
intervention in prostate cancer and warrant future studies to evaluate its clinical efficacy 
[Comstock et al., 2013]. These findings together with the evidence from the scientific 
literature, demonstrating the important role of CDK4/6 in CRPC, provide the rationale for 
combination of ribociclib and enzalutamide in patients with mCRPC. 
Since the ribociclib and enzalutamide have not been combined together in patients, the first 
phase will be a dose escalating study to find a safe dose of the combination. The standard 
doses of enzalutamide will be used and there will be three dose levels of ribociclib. A 
traditional 3x3 dose escalation schema will be used to establish the safe dose of ribociclib to 
combine with enzalutamide. The safe dose of the combination will be used in the phase II 
portion of the study. This study will evaluate an early readout of the clinical activity, thus the 
primary endpoint of the phase II portion of the study will be a proportion of patients with ≥ 
50% PSA decline at 12 weeks. Secondary endpoints will be rPFS, PSA PFS, OS and safety. If 
there is clinical activity noted with the combination further testing will be required to 
establish ribociclib clinical benefit of the combination.   
At the time of protocol amendment version 5, the phase I portion of the study determined the 
RP2D of 600mg ribociclib with 160mg enzalutamide after enrollment of 12 subjects. The 
randomized phase II portion of the study commenced in November 2017.  We have shown 
that the combination of enzalutamide and ribociclib can be administered safely but also found 
that the over 90% of all patients enrolled into this study had had expression of RB by IHC, 
thus the study can be simplified and eliminate the need for re-biopsy and test for RB 
expression.   In addition, due to a change in treatment landscape, recruiting subjects to the 
initial randomized study design proved to be challenging. Subsequently, the study Sponsor 

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modified the protocol to a single arm Simon two-stage design using the RP2D of 600mg 
ribociclib with 160mg enzalutamide. There is now ample long-term historical data on single 
agent enzalutamide that we can use to gauge the overall efficacy of this combination to decide 
if further testing in men with mCRPC is warranted.  
Correlative Studies 
This trial offers an extraordinary opportunity to better understand the mechanisms of AR 
activity and identify subgroups of patients that would benefit further for AR directed therapy. 
The overarching supposition of the correlative endpoints is that ribociclib will hyperactivate 
RB and improve therapeutic response. Patients enrolled in the study will receive optional 
tumor biopsies at screening (or archival tissue sample within 6 months of enrollment) and at 
progression along with circulating tumor cells (CTCs) and plasma obtained for circulating 
DNA/exosome studies.    
The tissue obtained will allow researchers to assess the impact of RB- cyclin D1/CDK4/6 
alterations on therapeutic response and determine associated clinicopathological features 
associated with these alterations.  
CTCs will be analyzed using the Epic Sciences platform, with which we will be able to assess 
the correlation of RB expression in the CTC and tumor tissue. More recently, Antonarakis and 
colleagues detected androgen receptor splice variant 7 (AR-V7) in CTCs from patients with 
CRPC that showed a correlation of resistance to enzalutamide.43 These and other possible 
mechanisms of resistance will be further explored in CTCs and tissue. 
The correlative studies will investigate novel methods to determine RB functional status 
using CTCs and circulating DNA/exosomes but also correlate to more standard tests such as 
androgen levels. Combined clinical and correlative studies may help us develop and define 
the first biomarker for stratification of treatment for metastatic prostate cancer.  
2.  
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the phase IB component of this study is to determine the maximum 
tolerated dose of ribociclib in combination with 160 mg of enzalutamide.  
The primary objective for the phase II component of this study is to determine efficacy with 
respect to the proportion of subjects that achieve a ≥ 50% reduction in PSA at 12 weeks.   
2.2 
Secondary Objectives 
 PSA progression-free survival 
 Radiographic progression-free survival (rPFS) 
 Safety 
 Pharmacokinetics 
2.3 
Correlative/Exploratory/Tertiary Objectives 
 To evaluate the expression of RB in CTCs and tumor tissue. 
 To evaluate other mechanisms of castrate resistance (such as AR-V7) in tumor tissue and 
CTCs.  
 To explore resistance mechanisms of CDK4/6 inhibitors in tumor samples in patients that 
progress on enzalutamide and ribociclib.  

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 Explore the use/correlation of circulating DNA/exosomes in CRPC patients treated with 
enzalutamide with and without ribociclib.    
 Androgen profiles and correlation to clinical outcomes 
 Development of model explant systems to correlate with the clinical outcome.  
3. 
PATIENT SELECTION 
3.1 
Inclusion Criteria 
 Willing and able to provide written informed consent and HIPAA authorization for the 
release of personal health information. 
NOTE: HIPAA authorization may be either included in the informed consent or obtained 
separately.  Consent and HIPPA authorization must be obtained prior to any screening 
procedures. 
 Males 18 years of age and above 
 Histological or cytological proof of prostate cancer  
 Documented progressive mCRPC based on at least one of the following criteria:    
o PSA progression defined as 25% increase over baseline value with an increase in 
the absolute value of at least 2 ng/mL that is confirmed by another PSA level with 
a minimum of a 1 week interval and a minimum PSA of 2 ng/mL. 
o Soft-tissue progression defined as an increase ≥ 20% in the sum of the LD of all 
target lesions based on the smallest sum LD since treatment started or the 
appearance of one or more new lesions.  
o Progression of bone disease (evaluable disease) or (new bone lesion(s)) by bone 
scan.  
 Have testosterone < 50 ng/dL. Patients must continue primary androgen deprivation 
with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy 
 ECOG performance status of 0-1 
 Patients on long term (>6 months) anti-androgen therapy (e.g., flutamide, bicalutamide, 
nilutamide) will need to be off anti-androgen for 4 weeks (wash out period) and show 
evidence of disease progression off the anti-androgen. Patients that have been on an anti-
androgen 6 months or less will need to discontinue anti-androgen therapy prior to 
treatment start (no wash out period required).    
 Patient has adequate bone marrow and organ function as defined by the following 
laboratory values, obtained within 14 days prior to treatment start: 
o Absolute neutrophil count ≥ 1.5 × 109/L. 
o Platelets (UNVPLT) ≥ 100 × 109/L. 
o Hemoglobin (HGB) ≥ 9 g/dl. 
o Potassium (K), total calcium (CA)(corrected for serum albumin), magnesium, and 
phosphorus within normal limits for the institution or corrected to within normal 
limits with supplements before first dose of study medication. 

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o INR ≤ 1.5. 
o Serum creatinine (CREAT) ≤ 1.5 mg/dL or creatine clearance > 50 mL/min. 
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
ULN.  If the patient has liver metastases, ALT and AST must still be ≤ 2.5 x ULN. 
Patients with liver metastases and AST/ALT above this limit will not be enrolled. 
o Total serum bilirubin ≤ 1.5 x ULN; or total bilirubin (TBILI) ≤ 3.0 x ULN with 
direct bilirubin within normal range in patients with well documented Gilbert’s 
Syndrome. 
 The effects of ribociclib on the developing human fetus at the recommended therapeutic 
dose are unknown.  Men must agree to use adequate contraception prior to treatment 
start, for the duration of study participation and for at least 3 months thereafter. 
 Must be able to take oral medication without crushing, dissolving or chewing tablets. 
3.2 
Exclusion Criteria      
 Prior exposure to abiraterone acetate or other specific CYP-17 inhibitors. Abiraterone 
acetate given in the castration-sensitive setting is permissible if stopped at least 6 
months prior to initial protocol treatment. 
 Prior exposure to enzalutamide, apalutamide,  or other investigational AR directed 
therapy 
 Prior chemotherapy for castration resistant disease. Chemotherapy given in the 
castration-sensitive setting is permissible if stopped at least 4 weeks prior to treatment 
start.  
 Prior isotope therapy with strontium-89, samarium or radium-223 within 12 weeks of 
treatment start. 
 Administration of antifungal agents (itraconazole, fluconazole, etc) within 4 weeks of 
treatment start or unrecovered AEs due to agents administered more than 4 weeks of 
treatment start.   
 History of pituitary or adrenal dysfunction, active or symptomatic viral hepatitis or 
chronic liver disease. 
 Known symptomatic brain metastases.    
 Use of any prohibited concomitant medications: immunotherapy, 5 alpha reductase 
inhibitors, spironolactone, diethystilbestrol (DES), ketoconazole, newer medications 
targeting ARs. 
NOTE: Because of the potential for drug-drug interaction, the concurrent use of all other 
drugs, over-the-counter medications, or alternative therapies must be documented. The 
principal investigator should be alerted if the patient is taking any agent that interacts with 
CYP450 system. 
 Treatment-related toxicity from prior therapy > Grade 2. 
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 History of hypersensitivity to ribociclib or compounds of similar chemical or biologic 
composition to ribociclib including to peanut and soy or other drugs formulated with 
polysorbate 80; or enzalutamide.   
 Currently taking any herbal, alternative or food supplements (i.e., PC-Spes, Saw Palmetto, 
St John Wort, etc.). All herbal, alternative and food supplements must be discontinued 
prior to treatment start.  Patients may continue on a daily Multi-Vitamin, calcium and 
Vitamin D.   
 Planned surgery or radiation therapy during protocol treatment,     
 Hormonal-acting agents (including DES, aldosterone, and spironolactone but not 
including GnRH agonists or antagonists) are forbidden during the trial and must be 
stopped prior to treatment start. No washout period will be required for any of these 
agents. 
 Initiation of bisphosphonate/denosumab therapy during protocol treatment. Patients on 
stable doses of bisphosphonates or denosumab which have been started no less than 4 
weeks prior to treatment start may continue on this medication.  
NOTE: Initiation of bisphosphonate/denosumab therapy will be allowed for the 
treatment of osteoporosis or prevention of skeletal-related events (SRE) during protocol 
treatment.  
 Patient has a concurrent malignancy or malignancy within 3 years of treatment start, 
with the exception of adequately treated, basal or squamous cell carcinoma, non-
melanomatous skin cancer or curatively resected cervical cancer. 
 Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of the study drugs (e.g., ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel 
resection). 
 Patient has a known history of HIV infection (testing not mandatory). 
 Patient has any other concurrent severe and/or uncontrolled medical condition that 
would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate 
patient participation in the clinical study or compromise compliance with the protocol 
(e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled 
fungal, bacterial or viral infections, etc.). 
 Patient has clinically significant, uncontrolled heart disease and/or recent events 
including any of the following: 
o History of acute coronary syndromes (including myocardial infarction, unstable 
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or 
symptomatic pericarditis within 12 months prior to treatment start 
o History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
o Documented cardiomyopathy 
o Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by 
Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening 
o History of any cardiac arrhythmias, eg., ventricular, supraventricular, nodal 
arrhythmias, or conduction abnormality within 12 months prior to treatment 
start. 

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o Family history of QTc prolongation or of unexplainable sudden death at <50 
years of age. 
o On screening 12 lead ECG, any of the following cardiac parameters: bradycardia 
(heart rate < 50 at rest), tachycardia (heart rate > 90 at rest), PR interval > 220 
msec, QRS interval >109 msec, or QTcF >450 msec. Congenital long QT syndrome 
or family history of long QT syndrome. 
o Systolic blood pressure (SBP) >160 mmHg or <90 mmHg. 
o Bradycardia (heart rate < 50 at rest), by ECG or pulse, at screening 
 On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or not 
interpretable) or QTcF >450 msec (using Fridericia’s correction). All as determined by 
screening ECG (mean of triplicate ECGs) 
 Patient is currently receiving any of the following medications and cannot be 
discontinued 7 days prior to treatment start: 
o Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, 
grapefruit hybrids, pummelos, star-fruit, and Seville oranges. 
o That have a narrow therapeutic window and are predominantly metabolized 
through CYP3A4/5. 
o That have a known risk to prolong the QT interval or induce Torsades de Pointes.  
o Herbal preparations/medications, dietary supplements 
 Patient is currently receiving or has received systemic corticosteroids within <2 weeks 
prior to treatment start, or who have not fully recovered from side effects of such 
treatment. 
o The following uses of corticosteroids are permitted: a short duration (<5 days) of 
systemic corticosteroids; any duration of topical applications (e.g. for rash), 
inhaled sprays (e.g., for obstructive airways diseases), eye drops or local 
injections (e.g., intra-articular) 
 Patient is currently receiving warfarin or other coumarin-derived anticoagulant for 
treatment, prophylaxis or otherwise.  Therapy with heparin, low molecular weight 
heparin (LMWH) or fondaparinux is allowed. 
 Participation in other studies involving investigational drug(s) within 30 days prior to 
randomization or within 5 half-lives of the investigational product (whichever is longer) 
or participation in any other type of medical research judged not to be scientifically or 
medically compatible with this study. If the patient is enrolled or planned to be enrolled 
in another study that does not involve an investigational drug, the agreement of the 
Novartis study medical lead is required to establish eligibility.. 
 Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for palliation 
≤ 2 weeks prior to treatment start, and who has not recovered to Grade 1 or better from 
related side effects of such therapy (exceptions include alopecia) and/or in whom ≥ 30% 
of the bone marrow was irradiated. 
 Patients with central nervous system (CNS) involvement unless they meet ALL of the 
following criteria: 
o At least 4 weeks from prior therapy completion (including radiation and/or 
surgery) to treatment start 
o Clinically stable CNS tumor at the time of screening and not receiving steroids 
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 Patient has had major surgery within 14 days prior to treatment start or has not 
recovered from major side effects (tumor biopsy is not considered as major surgery). 
 Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-
CTCAE version 4.03 Grade <1 (Exception to this criterion: patients with grade 1 taxane-
induced neuropathy, any grade of alopecia, amenorrhea or other toxicities not 
considered a safety risk for the patient as per investigator’s discretion, are allowed to 
enter the study). 
 Patient with a Child-Pugh score B or C. 
 Patient has a history of non-compliance to medical regimen or inability to grant consent 
 Sexually active males, unless they use a condom during intercourse while taking the 
study drug and for at least 3 months after stopping study treatment. Sexually active 
males should not father a child during this period.  A condom is required to be used by 
vasectomized men in order to prevent delivery of the drug via seminal fluid. 
4. 
ENROLLMENT PLAN AND SUBJECT REGISTRATION 
4.1 
Enrollment Plan 
4.1.1 
Participating Study Centers 
This study is anticipated to be conducted in 4-6 site(s).  
 
4.1.2 
Recruitment 
Potential research subjects will be identified by a member of the patient’s treatment team, 
the protocol investigator, or research team at participating centers from Medical Oncology, 
Radiation Oncology and Urology offices. Investigators will screen the patient’s medical 
records for suitable research study participants and discuss the study and their potential for 
enrolling in the research study.  
4.1.3  Expected Enrollment 
This is a phase IB/II trial in which 9-18 patients will be enrolled onto the phase I portion and 
35 patients will be enrolled on the phase II portion receiving enzalutamide and ribociclib.  
Accrual is expected to be completed within 4 years after trial activation at participating sites. 
All patients will be followed for 24 months post-accrual or to death.  
4.2 
Registration Procedure 
After eligibility screening and confirmation that a subject is eligible, subjects who are selected 
to participate will be registered through Medidata Rave. A record of subjects who fail to meet 
eligibility criteria (i.e., screen failures) will be maintained. Patient registration must be 
complete before beginning any treatment or study activities.  
4.2.1 
PCCTC Registration 
Confirm eligibility as defined in Section 3 Patient Selection.  
Obtain informed consent, by following procedures in Section 11.3 Written Informed Consent.  
Obtain completed or partially completed protocol specific Eligibility Checklist. 
All participants will be registered through Medidata Rave. 

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To complete registration and enroll a participant, the study staff at that site must contact the 
designated research staff at PCCTC to notify him/her of the participant registration. The site 
staff then needs to email registration/eligibility checklist and source documents to the 
PCCTC at PCCTC@mskcc.org.    
These documents must be sent for each enrollment within 48 hours of the informed consent 
form being signed. 
Upon receipt, the research staff at PCCTC will conduct an interim review of all documents.   If 
the eligibility checklist is not complete, the patient will be registered pending enrollment and 
the site is responsible for sending a completed form and additional source documents if 
applicable within 30 days of the consent.  
Once eligibility has been established and the participant is registered and assigned to 
treatment, the participant will be allotted a PCCTC Subject ID. This number is unique to the 
participant and must be written on all data and correspondence for the participant. This 
Subject ID will be relayed back to study staff at the registering site via e-mail and will serve 
as the enrollment confirmation. 
Participating sites will register subjects locally per their Institutional guidelines. 
  
5. 
TREATMENT PLAN 
This is a phase IB/II study of subjects with mCRPC with RB positive tumors who have not 
received chemotherapy.   
The phase IB portion is a ‘3+3’ study. Enzalutamide will be administered at a dose of 160 mg 
(40 mg X 4 pills) once daily. Ribociclib will be given daily for 21 out of 28 days and the dose 
will be escalated from 200, 400 to 600 mg as shown in below in Table 1. 
Table 1. Phase IB dose escalation schema 
Dose 
Level 
Dose of ribociclib  
(days 1-21 of 28 day cycle) 
Dose of Enzalutamide 
Level 1 
200 mg daily 
160mg po daily 
Level 2 
400 mg daily 
160mg po daily 
Level 3 
600 mg daily 
160mg po daily 
The phase I portion of this study will follow a traditional 3+3 design, escalating to the next 
higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of 
therapy. A DLT is defined in section 5.7.1.1 dose limiting toxicity. If one DLT is recorded then 
three additional patients will be enrolled into the present cohort. If no further DLTs occur (1 
out of 6 DLTs) then the next patient will be enrolled in the next higher cohort. If 2 out 6 
patients have an observed DLT in any given cohort, 3 additional patients will be treated at 
one dose level lower, and if no additional DLTs are observed, this will be the maximum 
tolerated dose. If no DLTs are observed in all three cohorts then phase II dose will be cohort 
3 for the phase II study. The maximum possible sample size will be 18, corresponding to six 
at each cohort level. Toxicities will be graded according to the National Cancer Institute, 
Common Toxicity Criteria for Adverse Events version 4.03 (NCI CTCAE v 4.03). If multiple 
toxicities are seen, the presence of DLT will be based on the most severe toxicity experienced. 
At the completion of the phase I portion of the study, the investigators will review the toxicity 
profile and determine the RP2D. 

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Since protocol amendment version 5, the phase II portion of this study will be a single arm 
trial utilizing the recommended phase II dose from the phase IB component. Subjects will 
receive enzalutamide in combination with ribociclib.  
Figure 4. Phase II Schema (1 cycle = 28 days) 
 
 
Subjects will continue treatment until disease progression, unacceptable toxicity, or any 
criteria in Section 5.8 Removing Subjects from the Protocol. 
 
Metastatic castrate 
resistant 
 
Chemotherapy naïve  
 
Retains RB expression 
Enzalutamide 160mg po 
daily 
+ 
Ribociclib (Phase IB RP2D 
days 1-21 of 28) 
Progressive Disease or 
Unacceptable Toxicity 
Post Treatment 
Follow Up; EOT- 24 
Months 

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Table 2. Schedule of Study Procedures and Assessments – Phase I 
Please note: All visits have a window of ± 2 days 
 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
EOT 
Post 
Treatment 
Follow up1  
Study Day / 
Visit Day 
-28 
to 0 
-14 
to 0 
1 
8 
15 
22 
1 
15 
1 
15 
1 
1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
exam/Vital 
Signs/ECOG PS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Meds 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Procedures  
CBC w/ 
differential  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistries 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Magnesium, 
Phosphorus 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Coagulation2 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
Urinalysis/BUN 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
PSA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lipid Panel 
 
X 
 
 
 
 
 
 
 
 
X3 
 
 
Pharmacokinetics
4 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
ECG5 
 
X5 
 
 
X5 
 
X5 
X5 
X5 
 
X6 
X 
 
ECHO/MUGA 
X 
 
As clinically indicated  
 
Imaging Procedures 
CT/MRI or CXR 
(abd/pelvis)  
X7 
 
 
 
 
 
 
 
 
 
X 
X 
 
Bone scan 
X7 
 
 
 
 
 
 
 
 
 
X 
X 
 
Tumor 
measurement 
X7 
 
 
 
 
 
 
 
 
 
X 
X 
 
Treatment        
Ribociclib8 
 
 
X 
 
 
Enzalutamide9 
 
 
X 
 
 
Correlative Procedures 
Tumor biopsy  
X10 
 
 
 
 
 
 
 
 
 
 
X11 
 
CTCs 
X 
 
 
 
 
 
 
 
 
 
X13 
X 
 
Androgen Panel12 
X 
 
 
 
 
 
 
 
 
 
 
X 
 

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Please note: All visits have a window of ± 2 days 
 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
EOT 
Post 
Treatment 
Follow up1  
Study Day / 
Visit Day 
-28 
to 0 
-14 
to 0 
1 
8 
15 
22 
1 
15 
1 
15 
1 
1 
 
Circulating DNA/ 
Exosomes 
X 
 
 
 
 
 
 
 
 
 
X13 
X 
 
1. After treatment discontinuation, subjects will be followed for 24 months.  During this time, survival status will be confirmed every 12 
weeks.  
2. Coagulation profile includes a prothrombin time (PT) or International normalized ratio (INR) 
3. Every 4th cycle. 
4. PK assessment schedule: C1D1: Pre-dose, t + 1 hour, t + 2 hours, t + 4 hours; C2D1: Pre-dose 
5. Screening ECG will be performed in triplicate approximately 2 minutes apart. ECG will be performed at pre-dose and 2 to 4 hours 
post dose at Cycles 1 – 3. 
 
Note: For patients with QTcF ≥481 ms at any time, interrupt study treatment and follow the procedures described in Section 5.7.1. If 
treatment is resumed, repeat ECGs 7 days and 14 days after dose resumption (and then as clinically indicated). During subsequent 
cycles, perform pre-dose ECG for every cycle starting at cycle 6, and pre-dose and 2-4 post-dose starting at cycle 9 and every 3rd cycle 
thereafter. 
 
6. ECG will be performed pre-dose only at cycles 4-6 for all patients. 
7. Baseline imaging assessments can be done within 6 weeks of treatment start.  
8. Subjects will take ribociclib daily for the first 21 days of each cycle followed by 7 days of rest. 
9. Subjects will take Enzalutamide daily throughout each cycle. 
10. In the absence of archival metastatic tissue, an optional tumor biopsy should be performed to determine RB status retrospectively.  
Fresh or archival tissue should be obtained if feasible.  
11. A second optional tumor biopsy will be requested for subjects at progression of disease. 
12. Serum will be collected for analysis of an Androgen Panel (testosterone, androstenedione, DHEAS). 
13. CTCs and Circulating DNA will be collected at 12 weeks post treatment start. 
 
 
 

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Table 3. Schedule of Study Procedures and Assessments – Phase II 
Please note: All visits have a window of ± 2 days 
 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 
4+ 
EOT 
Post 
Treatment 
Follow up1 
Study Day/ 
Visit Day 
-28 to 
0 
-14 to 
0 
1 
15 
1 
15 
1 
15 
1 
1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history & 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam/Vital 
Signs/ECOG PS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Meds 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Procedures  
CBC w/ differential  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistries 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Magnesium, 
Phosphorus 
 
X 
 
 
 
 
 
 
 
 
 
Coagulation2 
 
X 
 
 
X 
 
X 
 
X 
X 
 
Urinalysis/BUN 
 
X 
 
 
X 
 
X 
 
X 
X 
 
PSA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lipid Panel  
 
X 
 
 
 
 
 
 
X3 
 
 
ECG4 
 
X4 
 
X4 
X4 
 
 
 
 
 
 
ECHO/MUGA 
X 
 
As clinically indicated 
 
Imaging Procedures  
CT/MRI or CXR 
(abd/pelvis)  
X5 
 
 
 
 
 
 
 
X 
X 
 
Bone scan 
X5 
 
 
 
 
 
 
 
X 
X 
 
Tumor measurement 
X5 
 
 
 
 
 
 
 
X 
X 
 
Treatment        
Ribociclib 
 
 
X 
 
 
Enzalutamide 
 
 
X 
 
 
Correlative Procedures 
Tumor biopsy  
X6 
 
 
 
 
 
 
 
 
X7 
 
CTCs 
X 
 
 
 
 
 
 
 
X9 
X 
 
Androgen Panel8 
X 
 
 
 
 
 
 
 
 
X 
 
Circulating DNA/ 
Exosomes 
X 
 
 
 
 
 
 
 
X9 
X 
 

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1. After treatment discontinuation, subjects will be followed for 24 months.  During this time, survival status will be confirmed every 12 
weeks.  
2. Coagulation profile includes a prothrombin time (PT) or International normalized ratio (INR) 
3. Every 4th cycle. 
4. ECG will be performed in triplicate approximately 2 minutes apart. Subsequent ECGs should be performed only if clinically indicated.  
Note: For patients with QTcF ≥481 ms at any time, interrupt study treatment and follow the procedures described in Section 5.7.1. If 
treatment is resumed, repeat ECGs 7 days and 14 days after dose resumption (and then as clinically indicated).  
5. Baseline imaging assessments can be done within 6 weeks of treatment start.  
6. In the absence of archival metastatic tissue, an optional tumor biopsy should be performed to determine RB status retrospectively. 
Fresh or archival tissue should be obtained, if feasible. 
7. A second optional tumor biopsy will be requested for subjects at progression of disease. 
8. Serum will be collected for analysis of an Androgen Panel (testosterone, androstenedione, DHEAS) 
9. CTCs and Circulating DNA/exosomes will be collected at 12 weeks post treatment start. 
 
5.1 
Screening/Pretreatment Assessment (Day -28 to Day 0) 
Before initiating any screening activities, the scope of the study should be explained to each 
subject. Subjects should be advised of any known risks inherent in the planned procedures, 
any alternative treatment options, their right to withdraw from the study at any time for any 
reason, and their right to privacy. After this explanation, subjects should be asked to sign and 
date a Notice of Privacy Practice research authorization/HIPAA form and an IRB-approved 
statement of informed consent that meets the requirements of the Code of Federal 
Regulations (Federal Register Vol. 46, No. 17, January 27, 1981, part 50). 
The screening visit will determine subject eligibility according to the inclusion and exclusions 
criteria (Sections 3.1 Inclusion Criteria and 3.2 Exclusion Criteria). The following 
assessments will be performed at this visit:  
 
Obtain informed consent and research authorization 
 
Record demographics (including age) and medical history (including prior treatment for 
prostate carcinoma) 
 
Physical exam 
 
ECOG performance status 
 
Vital signs [body temperature, blood pressure, pulse, respiratory rate, weight, height] 
 
Obtain histologic and radiologic confirmation of disease 
 
Confirm eligibility according to the inclusion/exclusion criteria 
 
ECG 
 
ECHO/MUGA 
 
Baseline imaging assessments within 6 weeks of treatment start: Bone scan, CT scan or 
MRI of the abdomen and pelvis and CT scan of the chest or Chest X-ray 
 
Laboratory tests within 14 days of treatment start:  hematology, chemistry, magnesium, 
phosphorus, PSA, coagulation, lipid panel 
 
Urinalysis/BUN within 14 days of treatment start 
 
PSA and Gleason score at the time of diagnosis 
 
Correlative studies: androgen panel, CTCs by Epic Sciences, circulating DNA, and AR-V7 
and other mechanisms of resistance 
 
Concomitant medications (see Appendix B for a listing of medications with the potential 
for drug interactions)  

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 
Optional RB status determined by tumor biopsy or archival tissue sample. Fresh or 
archival tissue should be obtained if feasible (see section 5.6.1 for details regarding RB 
positivity) 
 
5.2 
Treatment Period (Day 1 to POD/EOT ± 2 days) 
Subjects in the phase I portion of this study will return to the clinic Day 1, 8, 15 and 22 for 
cycle 1, then Day 1 and 15 for cycles 2 and 3, and then Day 1 of each cycle starting with cycle 
4 until POD.   
Subjects in the phase II portion of this study will return to the clinic Day 1 and 15 for cycles 
1, 2, and 3 and then Day 1 of each cycle starting with cycle 4 until POD.  The following 
assessments will be performed at these visits:  
 
Physical exam/Vital Signs/ECOG Performance Status  
 
Laboratory tests: hematology, chemistry, PSA, coagulation, lipid panel  
 
Urinalysis/BUN 
 
Pharmacokinetics (Phase 1 portion only)ECG (C1D15, C2D1) Subsequent ECGs should 
be performed if only clinically indicated  
 
Adverse events 
 
Concomitant medications 
 
Imaging assessments will be performed every 12 weeks ± 1 week during treatment 
period  
 
Correlative studies: CTCs and circulating DNA will be collected at 12 weeks post 
treatment start  
5.3 
End of Treatment/Treatment Discontinuation Visit (28 days from last dose ± 7 days) 
Subjects that have discontinued the medication for toxicity or POD will return for an End of 
Treatment visit within 28 days of last treatment dose. The following assessments will be 
performed: 
 
Physical exam/Vital Signs/ECOG Performance Status 
 
Laboratory tests: hematology, chemistry, PSA, coagulationECG (only if clinically 
indicated) 
 
AEs 
 
Concomitant medications 
 
Imaging assessments 
 
Correlative studies: CTCs, androgen panel, circulating DNA, and AR-V7 and other 
mechanisms of resistance 
 
Optional tumor biopsy 
5.4 
Post Treatment Follow-up (EOT – 24 months from last dose ± 7 days)  
Subjects will be followed every 3 months for 24 months after removal from treatment or until 
death. During this time, survival status will be confirmed every 3 months.  
5.5 
Safety assessments 

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Medical History 
Medical history findings (i.e., previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected: 
 
Pertaining to the study indication 
 
Start before signing of the informed consent 
 
Considered relevant to the study 
ECOG Performance Status 
Performance status will be assessed using ECOG performance status criteria. See Appendix 
A: Performance Status Criteria for a KPS-ECOG conversion chart. 
Vital Signs 
Vital signs include body temperature, blood pressure, respiratory rate, pulse, weight and 
height. Height will be performed at screening only. 
Physical Exam 
The physical exam will include a full review of the body systems.  
Electrocardiogram (ECG) 
Twelve-lead ECGs should be obtained after the patient has been resting for 5-10 minutes 
prior to each time point indicated. All ECGs should be recorded with the patient in the same 
physical position. 
Adverse Event Monitoring 
Subjects will be closely monitored throughout the study for AEs. AEs and other symptoms 
will be graded according to NCI CTCAE v4.03.   
Laboratory Test Assessments 
 CBC with differential: white blood cells count (WBC), red blood cell count (RBC), HGB, 
hematocrit (HCT), UNVPLT, neutrophils (NEUTP), lymphocytes (LYMP). 
 Chemistry: CA, ALB, total protein (TP), NA, K, chloride (CL), blood urea nitrogen (BUN), 
CREAT, alkaline phosphatase (ALK), ALT, AST, TBILI, LDH, Serum PSA (PSA). 
 Coagulation: prothrombin time (PT) or International normalized ratio (INR) 
 Lipid panel: cholesterol (CHOL), high-density lipoprotein cholesterol (HDL), low-density 
lipoprotein cholesterol (LDL), triglycerides (TRIG) 
 Urinalysis/BUN 
 
Tumor Assessment and Bone Scan 
Radiographic disease assessment will be obtained every 12 weeks during active treatment.  
5.6 
Correlative/Special Studies 
Each subject will have the following specimens obtained at the study site as described 
below: 
a) A paraffin embedded tumor sample from a metastatic site of disease (via biopsy) 
within 6 months prior to treatment start, if feasible. 

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b) In a subject undergoing a soft tissue biopsy or bone biopsy to determine RB status, 
an additional tumor sample will be collected to be placed in media/serum for 
explant culture in sites participating in the explant protocol.  This will apply to 
Thomas Jefferson University subjects only. 
c) Blood for CTC analysis using the Epic Sciences platform (Screening, Week 12, and 
upon progression/end of treatment; 1 Streck tube) 
d) Blood for androgen panel by HPLC (Screening and upon progression/end of 
treatment; 1 red top tube). 
e) Plasma collected for circulating DNA/exosomes (Screening, Week 12, and upon 
progression/end of treatment; 1 Streck tube) 
The collection and handling procedures for the correlative studies can be found in 
the Laboratory & Correlative Studies Manual. 
5.6.1 RB IHC from Paraffin Blocks 
If tissue is available, and a biopsy is determined safe and feasible by the treating 
investigator, RB status will be determined. Tissue will undergo immunohistochemistry 
(IHC) staining with the RB monoclonal antibody from Cell Signaling Technology® [Rb (4H1) 
Mouse mAb #9309L] and will be analyzed for total and phosphorylated RB in a CLIA 
certified laboratory. An automated IHC staining protocol (ultra View DAB v1.02.0018) will 
be used on the Ventana automated stainer (Benchmark XT, Ventana Medical Systems, Inc., 
Tucson, AZ).  
The stained slides will be evaluated by two pathologists without access to the clinical data 
to obtain an unbiased consensus result.  The IHC stained TMA slides will then be scanned 
and analyzed digitally using the Aperio® computer-assisted image analysis system.  A 
standardized nuclear analysis protocol will be used for scoring a minimum of 1,000 cells. 
The digital scoring will be reported as a percentage and absolute number of nuclear staining 
with nuclear scores from 0 to 3+ intensity.  Endothelial nuclear staining will be used as an 
internal control. The Aperio® results will be compared to the pathologists' consensus 
results and the discrepant cases will be excluded. RB will be considered positive when 25% 
or more of the nuclei have a combination of 2+ and 3+ scores. Samples will be considered 
weak positives when 10% to 24% of the cells have a combination of 2+ and 3+ scores; and 
samples will be considered negative when less than 10% of the cells have a combination of 
2+ and 3+ scores. This analysis was done prospectively for 25 subjects enrolled onto this 
study, but upon review of the requirement, the Sponsor Principal Investigator and study 
team determined that analysis will be done retrospectively for all subjects moving forward. 
Depending on tissue availability, other key biomarkers of the RB pathway will be assessed 
via multiplexed IHC, including cyclin D1, cyclin D1b, p16 (a CDK4/6 inhibitor which is 
frequently elevated in RB-deficient tumors), key RB target genes (Cyclin A, E2F1, and 
MCM7), CDK4, CDK6, and the RB family members p107 and p130.  Association of each 
parameter with the proliferative index (as determined by Ki67) and apoptotic indices (as 
determined by IHC to detect cleaved Caspase 3) will be determined.  
RNA-Seq will be performed if there is available tissue to quantify gene expression and 
correlated with IHC.  For biopsy specimens with sufficient tumor tissue, whole exome 
sequencing will be performed with Sanger sequencing used to identify potential AR 
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5.7 
Dose Modifications 
5.7.1  Dose Modifications for ribociclib 
Investigators should follow the guidelines described below for the modification of ribociclib 
treatment. Any plan to deviate from these guidelines in view of the patient safety must be 
previously discussed with Novartis unless there is an urgent need for action. 
All dose modifications should be based on the worst preceding toxicity. If study treatment is 
being held due to toxicity, scheduled visits and all assessments should continue to occur 
except the dosing of the study drug. If the patient requires a dose interruption of > 21 days 
from the previous dose, then the patient must be discontinued from study treatment. Patients 
who discontinue the treatment due to an AE or an abnormal laboratory value must be 
followed until resolution or stabilization of the event. All dose changes or interruptions must 
be recorded appropriately. Provisional dose levels can be found in the table below. 
Table 4. Provisional dose levels 
Dose level 
Proposed dose (mg) 
Frequency 
1 (starting dose) 
600 mg 
Daily (21 days followed by 7 days of rest) 
2 (First dose reduction) 
400 mg 
Daily (21 days followed by 7 days of rest) 
3 (Second dose 
reduction) 
200 mg 
Daily (21 days followed by 7 days of rest) 
 
5.7.1.1 Dose-limiting toxicity 
DLT will be defined as an AE or clinically significant abnormal laboratory value assessed as unrelated 
to disease, disease progression, inter-current illness, or concomitant medications that occurs within 
the first 28 days of treatment with ribociclib in cycle 1 and meets any of the criteria included in the  
 
Table 5 below. NCI CTCAE version 4.03 should be used for all grading.  
Patients who experience a DLT will have their therapy with ribociclib interrupted and will be 
followed until the toxicity has resolved to CTCAE grade ≤ 1 or to the patient’s baseline value. 
After recovery from the toxicity in question, if the investigator believes that it is in the 
patient’s best interest to resume therapy with ribociclib, the patient may resume therapy 
with a new cycle of treatment at a lower dose level. 
The investigator must notify Novartis immediately of any unexpected Grade ≥ 3 AEs or 
laboratory abnormalities. Prior to enrolling patients into a higher dose level, Grade ≥ 2 AEs 
should be reviewed for all patients at the current dose level. Management of severe or 
intolerable adverse reactions requires temporary dose reduction and/or interruption of 
ribociclib therapy. 
 
 
Table 5. Criteria for defining DLTs 
Toxicity 
DLT Criteria 

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General Laboratory 
Abnormalities 
CTCAE grade 3-4 laboratory abnormalities that result in hospitalization 
Hematology 
CTCAE grade 4 neutropenia lasting more than 7 consecutive days 
 
CTCAE grade 4 thrombocytopenia 
 
CTCAE grade 3 thrombocytopenia with bleeding 
 
Febrile neutropenia (Grade ≥3 decrease in neutrophils associated a single 
temperature of >38.3°C or a sustained temperature of ≥38°C for more than 1 hour) 
ECG QT interval 
QTc interval ≥501 ms on at least 2 separate ECGs 
Cardiac 
Cardiac toxicity ≥ CTCAE grade 3 
Clinical signs of cardiac disease, such as unstable angina or myocardial infarction, 
or 
Troponin ≥ CTCAE grade 3 
Gastro-intestinal 
≥ CTCAE grade 3 vomiting ≥48 hours despite optimal anti-emetic therapy 
≥ CTCAE grade 3 diarrhea ≥48 hours despite optimal anti-diarrhea treatment 
Hepato-biliary 
≥ CTCAE grade 2 total bilirubin for more than 7 consecutive days (those patients 
who recover in less than a week won’t be considered as DLT , and those patients 
who need more than 7 days to recover will be considered as DLT) 
≥ CTCAE grade 3 total bilirubin 
≥ CTCAE grade 2 ALT with a ≥grade 2 bilirubin elevation of any duration in the 
absence of liver metastases 
≥ CTCAE grade 3 ALT for >4 consecutive days  
CTCAE grade 4 ALT or AST 
Grade 4 serum alkaline phosphatase >7 consecutive days 
Renal  
≥ CTCAE grade ≥3 serum creatinine 
ILD/pneumonitis 
≥ CTCAE grade 3 
Non-hematologic events 
≥ CTCAE grade 3, except for the exclusions noted below: 
Exceptions to DLT criteria 
Grade 3 alopecia 
 
<5 days of CTCAE grade 3 fatigue 
 
Grade 3 fever or infection without neutropenia <5 days duration 
 
Grade 3 laboratory abnormalities that are responsive to oral supplementation or 
deemed by the investigator to be clinically insignificant 
CTCAE version 4.03 should be used for grading. 
Optimal therapy for vomiting and diarrhea should be based on institutional guidelines with consideration of 
the prohibited medications listed in these protocol guidelines. 
 
Table 6. Ribociclib dose adjustment and management recommendation for hematological 
adverse reactions 
Toxicity/Grade 
Dose Adjustment and Management Recommendations 
Thrombocytopenia 
Grade 1(≥75 x 109/L) 
No dose adjustment required. 
Grade 2 (≥50 x 109/L – <75 x 109/L) 
Dose interruption until recovery to grade 1. 
Re-initiate ribociclib at the same dose. 
Grade 3 (≥25 x 109/L - <50 x 109/L) 
Dose interruption until recovery to grade 1. 
Re-initiate ribociclib at the same dose level. 
If toxicity recurs at grade 3: temporary dose interruption 
until recovery to grade 1 and reduce ribociclib to the next 
lower dose level. 
Grade 4(<25 x 109/L) 
Dose interruption until recovery to grade 1. 
Re-initiate ribociclib at the next lower dose level. 
If toxicity recurs at grade 4: discontinue ribociclib 
Absolute neutrophil count (ANC) 

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Toxicity/Grade 
Dose Adjustment and Management Recommendations 
Grade 1 (≥1.5 x 109/L) 
No dose adjustment required. 
Grade 2 (≥1.0 - <1.5 x 109/L) 
No dose adjustment required. 
Grade 3 (≥0.5 - <1.0 x 109/L) 
Dose interruption until recovery to ≥1.0 x 109/L. 
Re-initiate ribociclib at the same dose level. 
If toxicity recurs at grade 3: temporary dose interruption 
until recovery to ≥1.0 x 109/L. 
If resolved in ≤7 days, then maintain dose level. 
If resolved in >7 days, then reduce ribociclib dose to the 
next lower dose level. 
Grade 4 (<0.5 x 109/L) 
Dose interruption until recovery to ≥1.0 x 109/L. 
Re-initiate ribociclib at the next lower dose level. 
If toxicity recurs at grade 4: temporary dose interruption 
until recovery to ≥1.0 x 109/L and reduce ribociclib at the 
next lower dose level. 
Febrile neutropenia 
Grade 3 
ANC <1.0 x 109/L with a single temperature of 
>38.3 ºC (101 ºF) or a sustained temperature of 
≥38 ºC (100.4 ºF) for more than one hour 
Dose interruption until improvement of ANC ≥1.0 x 109/L 
and no fever. Restart at the next lower dose level. 
If febrile neutropenia recurs, discontinue ribociclib. 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
Discontinue ribociclib. 
Anemia 
(Hemoglobin) 
Grade 1 (≥10.0 – LLN g/dL) 
No dose adjustment required. 
Grade 2 (≥8.0 – <10.0 g/dL) 
No dose adjustment required. 
Grade 3 (<8.0 g/dL) 
Dose interruption until recovery to grade 2. 
Re-initiate ribociclib at the same dose. 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
Discontinue ribociclib. 
 
Table 8: Recommendations for ribociclib dose modification in case of hepatic toxicities 
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST) 
TOTAL BILIRUBIN without ALT/AST increase above baseline value 
Grade 1 (> ULN – 1.5 x ULN) 
(confirmed 48 to 72hrs later) 
Maintain dose level with LFTs monitored every two weeks 
Grade 2 (>1.5 – 3.0 x ULN) 
Dose interruption of ribociclib 
If resolved to ≤ grade 1 in ≤21 days, then maintain dose 
level 
If resolved to ≤ grade 1 in >21 days or toxicity recurs, 
then reduce 1 dose level 
If toxicity recurs after two dose reductions, discontinue 
ribociclib 
Grade 3 (>3.0 – 10.0 x ULN) 
Dose interruption of ribociclib 
If resolved to ≤ grade 1 in ≤21 days, lower 1 dose level 
of ribociclib 
If resolved to ≤ grade 1 in >21 days or toxicity recurs, 
discontinue ribociclib 
Grade 4 (>10.0 x ULN) 
Discontinue ribociclib 

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Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before dose interruption/reduction. 
They include but are not limited to: evidence of obstruction, such as elevated ALP and GGT typical of gall bladder or bile duct 
disease, hyperbilirubinemia due to the indirect component only (i.e. direct bilirubin component ≤1 x ULN) due to hemolysis or Gilbert 
Syndrome, pharmacologic treatment, viral hepatitis, alcoholic or autoimmune hepatitis, other hepatotoxic drugs. 
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin only. Bilirubin will be fractionated 
if elevated. 
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST) 
AST or ALT 
AST or ALT without bilirubin elevation >2 x ULN 
Same grade as baseline or increase from baseline 
grade 0 to grade 1 
(confirmed 48 to 72 hrs later) 
No dose adjustment required with LFTs monitored per 
protocol if same grade as baseline or every two weeks  
in case of increase from baseline grade 0 to 1 
Increase from baseline grade 0 or 1 to grade 2 (>3.0 
– 5.0 x ULN) 
or 
from baseline grade 2 to grade 3 (>5.0 – 20.0 x ULN) 
Hold ribociclib until resolved to ≤ baseline grade, then 
lower 1 dose level of ribociclib 
If recovery to ≤ baseline grade is > 28 days, discontinue 
ribociclib 
If toxicity recurs, discontinue ribociclib treatment. 
Increase from baseline grade 0 or 1 to grade 3 (>5.0 
– 20.0 x ULN) 
Hold ribociclib until resolved to ≤ baseline grade, then 
lower 1 dose level of ribociclib 
If recovery to ≤ baseline grade is > 28 days, discontinue 
ribociclib 
If toxicity recurs, discontinue ribociclib treatment. 
Grade 4 (>20.0 x ULN) 
Discontinue ribociclib 
AST or ALT and concurrent Bilirubin 
AST or ALT ≥ grade 2 (>3 x ULN) in patients with 
normal values at baseline and total bilirubin  >2 x 
ULN 
or 
AST or ALT ≥ grade 3 (>5 x ULN) in patients with 
grade 1 or 2 at baseline, and total bilirubin  >2 x ULN 
Discontinue ribociclib 
Confounding factors and/or alternative causes for increased transaminases should be excluded before dose interruption/reduction. 
They include but are not limited to: concomitant medications, herbal preparations or dietary supplements, infection, hepato-biliary 
disorder or obstruction, new or progressive liver metastasis, and alcohol intake. 
 
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin 
(fractionated if total bilirubin > 2 x ULN), alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher) and GGT. For patients with Gilbert Syndrome: total 
and direct  bilirubin  must  be  monitored,  intensified  monitoring  applies  to  changes  in  
direct bilirubin only. 
 
Close observation is recommended in case of AST, ALT, and/or bilirubin increase 
requiring dose interruption, which involves: 
• 
Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency 
of re-testing can decrease to once a week or less if abnormalities stabilize or return to 
normal values. 
• 
Obtaining a more detailed history of current symptoms. 
• 
Obtaining a more detailed history of prior and/or concurrent diseases. 

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• 
Obtaining a history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplements), alcohol use, recreational drug use, and special diets. 
• 
Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections (CMV, 
EBV or HSV); autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; 
and biliary tract disease. 
• 
Obtaining a history of exposure to environmental chemical agents. 
• 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
• 
Considering gastroenterology or hepatology consultations. 
• 
Assessing cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure as possible etiologies for liver dysfunction. 
 
Table 9. Dose modification guidance in case of QT prolongation 
Grade 
Dose Modification 
For all grades 
 
Check the quality of the ECG and repeat if needed. 
 
Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If 
below the lower limit of normal, interrupt ribociclib administration, 
correct with supplements or appropriate therapy as soon as 
possible, and repeat electrolytes until documented as normal. 
 
Review concomitant medication usage for the potential to inhibit 
CYP3A4 and/or to prolong the QT interval. 
 
Check compliance with correct dose and administration of ribociclib. 
1 
QTc 450-480 ms 
Perform above steps as directed in “For All Grades”. No dose adjustment 
required. 
2 
QTc 481-500 ms 
Interrupt ribociclib. Perform above steps as directed in “For All Grades”. 
• 
Perform a repeat ECG one hour after the first QTcF of ≥481ms 
• 
Repeat ECG as clinically indicated until theIf QTcF returns to < 481 ms, 
restart ribociclib at the same dose reduced by 1 dose level. Refer to 
Section 5.7.1 for dosing schedule. No dose adjustment required for 
first occurrence. 
• 
If QTcF remains ≥ 481 ms recurs, ribociclib should be reduced again 
by 1 dose level. Repeat ECG as clinically indicated until the QTcF 
returns to < 481 ms and restart ribociclib at the same dose. No dose 
adjustment required for first occurrence. 
• If QTcF ≥ 481 ms recurs, ribociclib should be reduced by 1 dose level. 
Refer to Section 5.7.1 for dosing schedule. Repeat ECGs 7 days and 14 
days after dose resumption (then as clinically indicated) for any patient 
who has therapy interrupted due to QTcF ≥481 ms 
3 
QTc ≥501 ms on at 
least two separate 
ECGs 
Interrupt ribociclib. Perform above steps as directed in “For All Grades”. 
• 
Perform a repeat ECG within one hour of the first QTcF of ≥ 501 ms. 
• 
If QTcF remains ≥ 501 ms, consult with a cardiologist (or qualified 
specialist) and repeat cardiac monitoring as indicated until the QTcF 
returns to < 481 ms. 

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• 
If QTcF returns to < 481 ms, ribociclib will be reduced by 1 dose level. 
Refer to Section 5.7.1 for dosing schedule. 
• 
If QTcF remains ≥ 481 ms after performing steps 1-4 as directed in 
“For All Grades,” discontinue ribociclib. 
• 
Repeat ECGs 7 days and 14 days after dose resumption (then as 
clinically indicated) for any patients who had therapy interrupted due 
to QTcF ≥ 501 ms 
• If QTcF of ≥ 501 ms recurs, discontinue ribociclib. 
4 
QT/QTc ≥501 or >60 
ms change from 
baseline 
and 
Torsades de pointes 
or polymorphic 
ventricular 
tachycardia, or 
signs/symptoms of 
serious arrhythmia 
Discontinue ribociclib. Perform above steps as directed in “For All Grades”. 
• 
Obtain local cardiologist (or qualified specialist) consultation and 
repeat cardiac monitoring as indicated until the QTcF returns to 
<481 ms. 
•  
Guidance for Management of All Other Adverse Reactions 
• Consider performing an analysis of serum potassium, calcium, phosphorus, and magnesium for 
all adverse reactions that are potentially associated with electrolyte imbalance (e.g. diarrhea, 
nausea/vomiting).  If electrolyte values are below the lower limit of normal, interrupt ribociclib 
administration, correct electrolytes with supplements as soon as possible, and repeat electrolyte 
testing until documented normalization of the electrolytes. 
• 
For all other adverse events, including Toxic Epidermal Necrolysis (TEN), which is a grade 4 
event by CTCAE, ribociclib should be discontinued, and TEN should be treated with 
appropriate medical therapy.  
 
 
Table 10. Ribociclib dose adjustment and management recommendation for 
ILD/pneumonitis (CTCAE v4.03) 
Grade 
Dose Adjustment and Management Recommendations 
1 
(asymptomatic) 
No dose adjustment required..Initiate appropriate medical therapy 
and monitor as clinically indicated. 
2 
(symptomatic) 
Interrupt ribociclib dose until recovery to Grade ≤1, then resume 
ribociclib at the next lower dose level*.  
 
3 and 4 
(severe) 
Discontinue ribociclib 
* An individualized benefit-risk assessment should be performed before resuming ribociclib  

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Table 11. Ribociclib dose adjustment and management recommendation for all other 
adverse reactions 
Grade 
Dose Adjustment and Management Recommendations 
1 
No dose adjustment recommended. Initiate appropriate medical therapy and 
monitor. 
2 
Dose interruption until recovery to grade ≤1. Initiate appropriate medical 
therapy and monitor. 
Re-initiate ribociclib at the same dose. 
If the same toxicity recurs at grade 2, interrupt ribociclib until recovery to 
grade ≤1. Re-initiate ribociclib at the next lower dose level. 
3 
Dose interruption until recovery to grade ≤1. Initiate appropriate medical 
therapy and monitor. 
Re-initiate ribociclib at the next lower dose level. 
If toxicity recurs at grade 2: temporary dose interruption until recovery to 
grade ≤1 and reduce ribociclib dose the next lower dose level. 
If toxicity recurs at grade 3, discontinue ribociclib. 
4 
Discontinue ribociclib and treat with appropriate medical therapy. 
 
Adjustment of Starting Dose in Special Populations 
Renal impairment 
Insufficient data are available to provide a dosage recommendation for ribociclib in patients 
with renal impairment.  
Subjects with baseline renal impairment are excluded from the study (serum creatinine > 1.5 
mg/dL or creatinine clearance < 50 mL/min). Subjects who experience renal impairment of 
grade 2 or higher during the treatment period should discontinue treatment and should be 
followed for safety assessments. 
Elderly 
Physicians should exercise caution in monitoring the effects of ribociclib in the elderly. 
Insufficient data are available to provide a dosage recommendation. 
Follow-up for toxicities 
Subjects who   complete  treatment  or   whose  treatment  is   interrupted  or  permanently 
discontinued due to an AE or abnormal laboratory value must be followed at least once  a  
week  for  4 weeks,  and  subsequently  at  4-week  intervals,  until  resolution  or stabilization 
of the event. All subjects will be followed up for safety up to 30 days following the last dose 
of study treatment. 
5.7.2  Dose Modifications for Enzalutamide 
Table 12. Dose modification for enzalutamide 
Dose Level 
Enzalutamide 
 0      
160 mg daily 
-1 
120 mg daily 
-2 
80 mg daily  

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All dose adjustments should be made as per the local approved prescribing information and 
investigator’s best judgment. An example from the prescribing information is provided 
below: 
If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction, dosing should 
be withheld for one week or until symptoms improve to ≤ Grade 2, then resumed at the same 
or a reduced dose (120 mg or 80 mg) if warranted. 
5.8 
Removing Subjects from the Protocol 
In the absence of treatment delays because of AEs, treatment will continue until one of the 
following criteria applies: 
 
subject decides to withdraw from the study 
 
disease progression 
 
symptomatic disease progression at any time 
 
objective clinical disease progression 
 
intercurrent illness that prevents further administration of treatment 
 
unacceptable AE(s) that may or may not be directly related to treatment but that, 
in the judgment of the treating physician, makes it dangerous for the subject to be 
retreated 
 
general or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment, in the judgment of the investigator 
Because an excessive rate of withdrawals can render the study uninterruptable, unnecessary 
withdrawal of subjects should be avoided. When a subject discontinues treatment early, the 
investigator should make every effort to contact the subject and to perform a final evaluation. 
The reason(s) for withdrawal should be recorded. 
6. 
THERAPEUTIC/DIAGNOSTIC AGENT(S) 
6.1 
Ribociclib 
Ribociclib is an orally bioavailable, small molecule inhibitor of CDK4/6.  Ribociclib exhibits 
highly specific inhibitory activity against CDK4/cyclinD1 and CDK6/cylinD3 complexes, with 
concentration resulting in 50% inhibition (IC50) values of 10 nM and 39 nM, respectively, in 
isolated enzyme assays. 
6.1.1  Packaging and labeling 
The ribociclib drug product is available in the following clinical forms: hard gelatin capsules 
(10 mg, 50 mg and 200 mg), film-coated tablets (50 mg and 200 mg) and an oral solution 
(30 mg/mL).  
 
Medication will be labeled for Clinical Trial use and will include storage conditions for the 
drug and the medication number but no information about the patient. 
Packaging and labeling 
Study drug: Ribociclib 
Packaging: Hard gelatin capsules in bottles (50 and 200 mg) 
OR Film-coated tablets in bottles (200 mg) 
Labeling: Labeled as ‘Ribociclib’ or ‘LEE011’ 

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6.1.2 
Supply, receipt and storage 
Ribociclib will be supplied by Novartis or its designee. Study drug must be received by a 
designated person at the study site, handled and stored safely and properly, and kept in a 
secured location to which only the investigator and designated assistants have access. Upon 
receipt, ribociclib should be stored according to the instructions specified on the medication 
label. Medication labels will comply with the legal requirements of each country and be 
printed in the local language.  
Patients will be provided with adequate supply of ribociclib for self-administration at home 
until at least their next scheduled study visit. 
6.1.3 
Drug Accountability 
Clinical drug supply must be accounted for and patients will be asked to return all unused 
study drug and packaging on a regular basis, at the end of the study or at the time of study 
drug discontinuation. 
Compliance should be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver. Records of study medication used, dosages 
administered, and intervals between visits and the completion of the study should be captured in 
the Drug Accountability Form. This information must be captured in the source document at each 
patient visit.  
At the conclusion of the study, and, as appropriate during the course of the study, the 
Investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to Novartis. 
6.1.4 
Drug product administration 
Ribociclib will be taken orally, once a day for 21 consecutive days followed by a 7 day planned 
break. 
Patients will be provided with a diary in which to record their intake of study drug (Phase I 
Diary – Appendix E OR Phase II Diary – Appendix F). However, the actual number of tablets 
taken by the patient must be calculated from the number of tablets dispensed and returned. 
Ribociclib will be administered as a flat-fixed dose (200 mg, 400 mg or 600 mg daily), and not 
by body weight or body surface area. 
Patients must be instructed to return unused study drugs to the site at discontinuation or 
completion of treatment. The site personnel must ensure that the appropriate dose of each 
study drug is administered and that the drug accountability is performed. 
Ribociclib must be taken as follows: 
 
Patients should be instructed to take the ribociclib capsules with a large glass of water (~250 
ml) at the same time each day. 
 
Ribociclib can be taken without regard to meals; however dietary habits around the 
time of dosing should be as consistent as possible throughout the study, and in 
particular during those periods when samples are being taken for PK analysis. 

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 
Patients should be instructed to swallow the ribociclib capsules whole and not to 
chew, crush or open them. 
 
If vomiting occurs during the course of treatment, no re-dosing of the patient is 
allowed before the next scheduled dose 
 
Any doses that are missed (not taken within 6 hours of the intended time) should be 
skipped and should not be replaced or made up on a subsequent day. 
 
Patients must avoid consumption of grapefruit, Seville oranges or products 
containing the juice of each during the entire study and preferably 7 days before the 
first dose of study medications, due to potential CYP3A4 interaction with the study 
medications. Orange juice is allowed. 
On days with PK, ECG sampling, chemistry panel and/or lipid panel sampling, the following 
additional guidelines should be followed: 
 
On a day when PK blood collection is scheduled at the clinic, patients must take study 
treatment in the clinic under the supervision of the Investigator or designee. On all other 
days, patients may take the study treatment at home. 
 
On a day of chemistry panel and/or lipid panel sampling, patients must be fasting from all 
food and drink for at least 8 hours overnight. Water is allowed during all fasting periods; 
however, coffee, tea and juice are not permitted during the fasting period. Patients must 
also take study treatment in the clinic under the supervision of the Investigator or designee. 
On all other days, patients may take the study treatment at home. 
 
Pre-dose samples should be drawn prior to dosing. The sampling time of the PK samples 
and the dosing time must be precisely recorded in the CRF. Furthermore, the dosing date 
and time the study medication was taken on the day before the PK assessment must be 
precisely recorded in the CRF. 
 
Post-dose PK samples should be collected after dosing of the study treatment 
6.1.5 
Disposal and Destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations. 
6.2 
Enzalutamide 
Enzalutamide (MDV3100) is an AR signaling inhibitor that targets several steps in the AR 
signaling pathway. Enzalutamide competitively inhibits binding of androgens to ARs, inhibits 
nuclear translocation of receptors and inhibits the association of the AR with DNA, even in 
the setting of AR overexpression and in prostate cancer cells resistant to antiandrogens. 
6.2.1  Description of treatment 
Enzalutamide 40-mg capsules are oval, white to off-white and contain enzalutamide, 
caprylocaproyl macrogolglycerides, butylhydroxyanisole and butylhydroxytoluene. 
6.2.2  Handling and dispensing 
Enzalutamide will be prescribed by the treating physician and dispensed by a local pharmacy. 

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6.2.3  Drug product administration 
Patients will be instructed to take 4 tablets (160 mg total) of enzalutamide orally (PO) once 
daily. Enzalutamide can be taken with or without food. Capsules must be swallowed whole, 
and should not be chewed, dissolved, or opened. 
6.3 
Concomitant Medications 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, over-
the-counter medications, and alternative therapies must be documented. The principal 
investigator should be alerted if the patient is taking any prohibited agents.  
Concurrent enrollment in another therapeutic clinical investigation is prohibited. 
Permitted concomitant therapy 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheals are 
allowed. Please consult the list of prohibited medications and the list of use with caution 
medications for further guidance. 
The patient must be told to notify the investigational site about any new medications he takes 
after the start of the study treatment.  All medications (other than study drugs) and significant 
non-drug therapies (including vitamins, herbal medications, physical therapy and blood 
transfusions) administered within 30 days of study entry and during the study must be listed 
on the Concomitant medications/Significant non-drug therapies eCRF. 
Bisphosphonates and denosumab 
Bisphosphonates and denosumab are permitted for the treatment of osteoporosis and 
prevention of skeletal related events for patients with bone metastases. Chronic 
concomitant bisphosphonate/denosumab therapy for the prevention of bone metastasis is 
not permitted.  
Hematopoietic growth factors 
Hematopoietic growth factors may be used according to ASCO guidelines. 
Palliative radiotherapy 
Palliative radiation is permitted if done solely for bone pain relief. It should not be delivered 
to a target lesion and it should not encompass more than 25% of irradiated bone marrow. 
If palliative radiotherapy is initiated after the start of study treatment, the reason for its use 
must be clearly documented and progression as per RECIST 1.1 must be ruled out. 
No dose modification of study treatment is needed during palliative radiotherapy. 
Permitted concomitant therapy requiring caution 
Medications to be used with caution during ribociclib and in this study are listed below.  This 
list is not comprehensive and is only meant to be used as a guide. These medications should be 
excluded from patient use if possible. If they must be given, then use with caution and consider a 
ribociclib interruption if the concomitant medication is only needed for a short time. 
 
• 
Moderate inhibitors or inducers of CYP3A4/5 
• 
Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index 
• 
Strong inhibitors of BSEP 

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• 
Sensitive substrates of the renal transporters, MATE1 and OCT2 
• 
Sensitive substrates of BCRP 
• 
Medications that carry a possible risk for QT prolongation 
Prohibited concomitant therapy 
The following medications are prohibited during study treatment in the study.  This list is 
not comprehensive and is only meant to be used as a guide (Please see Appendix B): 
• 
Strong inhibitors or inducers of CYP3A4/5 
• 
Substrates of CYP3A4/5 with a narrow therapeutic index 
• 
Medications that carry a known risk for QT prolongation 
• 
Herbal medications/preparations, dietary supplements 
• 
Other investigational and antineoplastic therapies not part of this study 
Herbal medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh 
and ginseng. Patients should stop using all herbal medications and dietary supplements at least 7 
days prior to enrollment. 
Refer to the ribociclib Investigators Brochure and other drug package insert and Appendix X 
for information on possible interactions with other drugs. 
 
7.0 
ADVERSE EVENTS 
7.1 
Definitions 
7.1.1 
Adverse Event (AE)  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with this 
treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not related to the medicinal product. 
An AE will be recorded and followed from treatment administration to 30 days post treatment or 
resolution. 
7.1.2  Expected Adverse Events 
Expected AEs are those that have been previously identified as resulting from administration 
of the agent. An AE can be considered expected when it appears in the current AE list, the 
Investigator’s Brochure, the package insert or is included in the informed consent document 
as a potential risk. 
7.1.3 
Unexpected Adverse Events 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator's Brochure for an unapproved investigational 
medicinal product). 

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Contact the Principal Investigator or sponsor to confirm unexpected AEs when necessary.   
7.1.4 
Adverse Drug Reaction (ADR) 
A noxious and unintended response to a medicinal product related to any dose should be 
considered ADRs. The phrase "response to a medicinal product" means that a causal 
relationship between a medicinal product and an AE is at least a reasonable possibility, i.e., 
the relationship cannot be ruled out. ‘‘Reasonable possibility’’ means there is evidence to 
suggest a causal relationship between the drug and the AE.  
 
7.1.5 
Serious Adverse Event (SAE) 
An SAE/ADR as defined in the Code of Federal Regulations (21CFR312.32) is any event that: 
 results in death 
 is life-threatening 
 results in inpatient hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability or incapacity 
 results in congenital anomaly or birth defect 
 is medically significant in the opinion of the investigator 
 
Events that are not considered SAEs include: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
 elective or pre-planned treatment for a pre-existing condition that did not worsen 
 emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
 respite care 
7.1.6 
Progression of malignancy 
Progression of a patient’s malignancy should not be considered an AE, unless in the 
investigator’s opinion, study treatment resulted in an exacerbation of the patient’s condition. 
If disease progression results in death or hospitalization while on study or within 30 days of 
the last dose progressive disease will be considered an SAE. 
7.1.7 
Life-threatening events 
A life-threatening event is any AE that places the patient at immediate risk of death from the 
reaction as it occurs. It is not a reaction that, had it occurred in a more severe form, might 
have caused death. 
7.1.8 
Hospitalization or prolongation of hospitalization 
Hospitalization encompasses any inpatient admission (even for less than 24 hours) resulting 
from a precipitating, treatment-emergent AE. For chronic or long-term patients, inpatient 
admission also includes transfer within the hospital to an acute or intensive care inpatient 
unit. Hospitalizations for administrative reasons or a non-worsening preexisting condition 
should not be considered AEs (e.g., admission for workup of a persistent pretreatment 
laboratory abnormality, yearly physical exam, protocol-specified admission, elective 
surgery). Preplanned treatments or surgical procedures should be noted in the baseline 
documentation. Hospitalization because of an unplanned event will be deemed an SAE. 

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Prolongation of hospitalization is any extension of an inpatient hospitalization beyond the 
stay anticipated or required for the original reason for admission. 
7.1.9 
Significant disability 
Disability is a substantial disruption of the patient’s ability to conduct normal life functions. 
7.1.10 Congenital anomaly 
If the female partner of a male patient becomes pregnant during the course of the study, the 
treating physician must be notified immediately. All confirmed pregnancies must be 
immediately reported to the medical monitor. All pregnancies will be followed until 
resolution (i.e., voluntary or spontaneous termination or birth) and assessed for congenital 
anomalies and birth defects. 
7.2 
Recording and Grading of Adverse Events 
7.2.1 
Recording 
All observed or volunteered AEs, regardless of treatment group, severity, suspected causal 
relationship, expectedness, or seriousness will be recorded. 
A clinically significant change in a physical examination finding or an abnormal test result 
should be recorded as an AE, if it: 
 
is associated with accompanying symptoms 
 
requires additional diagnostic testing or medical or surgical intervention 
 
leads to a change in study dosing or discontinuation from the study 
 
requires additional concomitant drug treatment or other therapy, or 
 
is considered clinically significant by the investigator  
An abnormal test result that is subsequently determined to be in error does not require 
recording as an AE, even if it originally met one or more of the above criteria. 
7.2.2 
Grading severity 
All AEs will be graded based on the NCI CTCAE version 4.03. 
7.2.3 
Attributing causality 
After assigning a grade to an AE, the investigator must evaluate all clinical AEs and abnormal 
laboratory values for possible causal relationship to enzalutamide or ribociclib. Causality 
attribution will be decided using the criteria outlined in Table 12.  
Table13. Relationship of AE to Study Drug 
Relationship 
Description 
Unrelated 
AE is clearly not related  
Unlikely 
AE is doubtfully related  
Possible 
AE may be related  
Probable 
AE is likely related  
Definite 
AE is clearly related  
 
Abnormal laboratory values of clinical significance that were present at baseline and did not 
change in grade or frequency during experimental therapy or intervention and those that can 
obviously be attributed to underlying disease will be recorded as unrelated. 

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7.3 
Reporting Adverse Events 
7.3.1 
Reporting serious adverse events 
All SAEs, events determined to be medically significant by the treating Investigator, and 
unknown reactions or unexpected events should be reported to PCCTC, within 24 hours of 
knowledge of the event using the contact information below. The initial report should include 
the following information at a minimum:   
 protocol # and title 
 study identification number, sex, age at event 
 date the event occurred 
 description of the SAE 
The PCCTC SAE Report Form (Appendix H) will be used for reporting each SAE and should be 
submitted to PCCTC within 5 business days. 
Severity, causality, action taken, concomitant medications, outcome, etc should be reported 
to the PCCTC and the lead site as soon as possible.    
Follow-up of AEs should continue until the event and any sequela resolve or stabilize at a 
level acceptable to the investigator and the study site/sponsor or medical monitor. 
SAE Contact Information for PCCTC: 
Prostate Cancer Clinical Trials Consortium 
646-888-0434/646-422-4383 
Email: pcctc@mskcc.org  
SAE Contact Information for Sponsor Investigator: 
Wm. Kevin Kelly, DO 
1025 Walnut Street 
Thomas Jefferson University 
College Building, Suite 700 
Philadelphia, PA 19107 
Phone: 215-503-5455 
e-mail: William.Kelly@jefferson.edu 
SAE Contact Information for Novartis: 
Drug Safety & Epidemiology (DS&E) Department 
fax 1.888.299.4565 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 

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Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval and otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need 
to issue an Investigator Notification (IN), to inform all investigators involved in any study 
with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
The PCCTC will fax the PCCTC SAE Form (Appendix H) and the Novartis SAE Coversheet 
(Appendix G) to Novartis DS&E Department within 24 hours for deaths or life-threatening 
events and for all other SAEs. The original PCCTC SAE form, Novartis SAE coversheet, and the 
fax confirmation sheet must be kept with the case report forms at the study site.  
 
Safety Reporting Requirements for IND Holders 
 
In accordance with Code of Federal Regulations Title 21, Part 312 (21 CFR § 312.32), sponsor-
investigators of studies conducted under an IND must comply with following safety reporting 
requirements:  
 
Expedited IND Safety Reports: 
 
7 Calendar-Day Telephone or Fax Report 
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening 
AE that is unexpected and assessed by the investigator to be possibly related to the 
use of ribociclib with enzalutamide.  An unexpected AE is one that is not already 
described in the Investigator Brochure.   
Such reports are to be telephoned or faxed to the FDA within 7 calendar days and 
PCCTC and Novartis within 24 hours of first learning of the event. Each telephone call 
or fax transmission (see fax number below) should be directed to the FDA new drug 
review division in the Center for Drug Evaluation and Research or in the product 
review division for the Center for Biologics Evaluation and Research, whichever is 
responsible for the review of the IND. 
15 Calendar-Day Written Report  
The Sponsor-Investigator is also required to notify the FDA and all participating 
investigators, in a written IND Safety Report, of any serious, unexpected AE that is 
considered possibly related to the use of ribociclib with enzalutamide. The PCCTC will 
facilitate this notification to the FDA and all participating investigators. An 
unexpected AE is one that is not already described in the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed with 

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the IND concerning similar events should be analyzed. The new report should contain 
comments on the significance of the new event in light of the previous, similar 
reports.  
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, PCCTC, Novartis, and all participating investigators within 15 calendar days of 
first learning of the event. The FDA prefers these reports on a MedWatch 3500A Form 
but alternative formats are acceptable (e.g., summary letter). 
FDA fax number for IND Safety Reports: 
1 (800) FDA – 0178 
All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator 
must also be submitted to:  
Prostate Cancer Clinical Trials Consortium 
Phone: 646-888-0434/646-422-4383 
Email: pcctc@mskcc.org  
 
AND 
 
Thomas Jefferson University IRB 
 
IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the Sponsor-Investigator shall 
within 60 days of the anniversary date that the IND went into effect submit a brief 
report of the progress of the investigation. Please refer to 21 CFR § 312.32 for a list of 
the elements required for the annual report. All IND annual reports submitted to the 
FDA by the Sponsor-Investigator should be copied to PCCTC.   
7.4  
Safety Reports  
 
PCCTC will distribute outside safety reports to the participating sites immediately upon 
receipt.  
 
Participating sites must submit safety reports to their institution’s IRB/PBs within 30 
days of receipt from PCCTC or per participating site guidelines.  
8. 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE 
8.1 
Outcome Assessment 
All baseline evaluations will be performed as closely as possible to the beginning of 
treatment. For subsequent evaluations, the method of assessment and techniques will be the 
same as those used at baseline. 
8.1.1 
Primary endpoint 
The primary endpoint for the phase IB component of this study is dose limiting toxicity (DLT) 
of ribociclib that can be combined with enzalutamide in patients with mCRPC 
The primary endpoint for the phase II component of this study is the proportion of patients 
with a ≥ 50% reduction in PSA at 12 weeks in patients treated with enzalutamide with and 
without ribociclib with chemotherapy naïve mCRPC.   

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8.1.2 
Secondary endpoints 
To determine PSA PFS in patients treated with enzalutamide with and without ribociclib in 
patients with chemotherapy naïve mCRPC. 
To determine the rPFS in patients treated with enzalutamide with and without ribociclib in 
patients with chemotherapy naïve mCRPC. 
To determine the overall safety and survival for patients treated with enzalutamide with and 
without ribociclib in patients with chemotherapy naïve mCRPC.  
To determine the pharmacokinetics in patients treated with enzalutamide with and without 
ribociclib in patients with chemotherapy naïve mCRPC. 
8.2 
Therapeutic Response 
Response and progression will be evaluated in this study using a combination of the 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee4 and the guidelines for prostate cancer endpoints developed by the Prostate 
Cancer Clinical Trials Working Group (PCWG2).5 
Patients will need to be reevaluated for response every cycle (or more frequently if 
indicated), according to the guidelines below. 
8.2.1 
PSA 
Perform PSA testing at a minimum of 1-week intervals with the threshold PSA level at 2.0 
ng/mL. To report PSA-based outcomes, PCWG2 recommends that the percent of change in 
PSA from baseline to 12 weeks (or earlier for those who discontinue therapy) and the 
maximum decline in PSA that occurs at any point after treatment be reported for each patient 
using a waterfall plot. Because the rate of rise has shown prognostic significance, estimate a 
pretreatment PSA doubling time (PSA-DT) if at least 3 values are available, but do not delay 
either treatment or enrollment onto a trial simply to estimate PSA-DT. Because declines in 
serum PSA, if they occur, may not do so for several weeks, PSA measurements obtained 
during the first 12 weeks should not be used as the sole criterion for clinical decision making.5 
8.2.2 
Measurable disease 
According to RECIST, measurable disease is defined as at least 1 lesion > 20 mm in its longest 
diameter as measured with conventional techniques (i.e., CT [nonspiral or nonhelical], MRI, 
physical exam) or > 10 mm as measured with spiral CT scan. All tumor measurements will be 
taken using a ruler or calipers and recorded in millimeters (or decimal fractions of 
centimeters). 
8.2.3 
Nonmeasurable disease 
Following RECIST, all other lesions (or sites of disease) will be considered nonmeasurable 
disease. This includes small lesions (longest diameter < 20 mm with conventional techniques 
or < 10 mm using spiral CT scan) and any of the following: 
 bone lesions 
 ascites 
 pleural or pericardial effusion 
 lymphangitis cutis or pulmonis 

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 abdominal masses that are not confirmed and followed by imaging techniques 
 cystic lesions 
 lesions occurring within a previously irradiated area unless they are documented as 
new lesions since the completion of radiation therapy 
Note: If only a single, asymptomatic bone lesion is present at baseline, and will be 
irradiated, the metastatic nature of this lesion must be confirmed by x-ray, CT, or MRI. 
8.2.4 
Target (nodal and visceral) lesions 
Following RECIST, progression in a nodal or visceral site (i.e., liver and lung) is sufficient to 
document disease progression. The presence or absence of nodal and visceral disease before 
and after treatment should be recorded separately. 
All measurable lesions (up to a maximum of 5 lesions per organ and 10 lesions in total) will 
be identified as target lesions to be measured and recorded at baseline. The target lesions 
should be representative of all involved organs. Target lesions will be selected on the basis of 
size (i.e., the largest area) and suitability for accurate, repeated measurements (either by 
imaging techniques or clinically). The sum of the LD of all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as a reference by which 
to characterize the objective tumor response. 
Because small lymph nodes are difficult to measure accurately and may not be malignant, the 
greatest diameter of a lymph node must measure at least 2 cm by spiral CT to be considered 
a target lesion.5 
8.2.5 
Bone lesions 
When the bone scan is the sole indicator of progression, disease progression in bone is 
defined as 2 or more new lesions seen on bone scan compared with a prior scan used for trial 
entry.5 In situations where scan findings suggest a flare reaction or where new lesion(s) may 
represent trauma, confirm these results with other imaging modalities (e.g., MRI or fine-cut 
CT). If many new areas of uptake are observed, confirmation is generally not necessary. 
8.2.6 
Nontarget lesions 
All other lesions (or sites of disease) will be identified as nontarget lesions and recorded at 
baseline. Nontarget lesions will include measurable lesions that exceed the maximum 
number per organ (5) or total of all involved organs (10), as well as nonmeasurable lesions. 
The presence or absence of these lesions will be recorded on the CRF and should be evaluated 
at the same assessment time points as all target lesions. 
8.2.7 
New lesions 
The appearance of up to 10 new measurable lesions should be recorded. Each new lesion 
should be reassessed using the same imaging modality at each time point. If measurable, the 
LD of each new lesion should be recorded in the CRF and the sum LD of new and old lesions 
should be calculated. See Table 16for a description of the determination of progression based 
on the presence of new lesions. 
Note: The appearance of a new lesion does not by itself satisfy the criteria for confirmed 
progressive disease. Rather, the tumor burden imposed by the new lesions must be evaluated 
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progression in target lesions, nontarget (i.e., other than bone) lesions, and bone lesions 
requires two assessment time points. The first must occur at Week 12 (or later) and the 
second occurring at least 6 weeks after the first. Progression declared at the first time point 
remains unconfirmed unless assessments at the second time point demonstrate continuing 
or worsening progression, as described in Section 8.4. 
8.3 
Response Criteria for Control/Relieve/Eliminate Endpoints 
8.3.1 
Measurable soft-tissue lesions 
When evaluating soft-tissue lesions, the definitions in Table 13 apply. 
Table 14. RECIST response criteria for target (soft-tissue) lesions 
Response 
Evaluation of Soft-Tissue Lesions 
Complete response (CR) 
the disappearance of clinical and radiological evidence of all target 
lesions and normalization of tumor marker levels 
Partial response (PR) 
a decrease from baseline ≥ 30% in the sum of the LD of all target 
lesions 
Progressive disease 
(PD)  
an increase ≥ 20% in the sum of the LD of all target lesions based on 
the smallest sum LD since treatment started or the appearance of one 
or more new lesions or the appearance of new lesions 
Stable disease (SD) 
neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD based on the smallest sum LD recorded since treatment 
started  
Abbreviations: LD, longest diameter. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (e.g., fine needle aspirate or biopsy) before confirming 
the complete response status. 
Changes in nodal and visceral sites should be recorded and reported separately, and lymph 
nodes in the pelvis must measure at least 2 cm in greatest diameter to be considered target 
lesions. Complete elimination of disease at a particular site should be recorded separately. 
Any favorable change should be confirmed using a second follow-up scan. 
8.3.2 
PSA 
As long as patient safety is the primary concern, in the absence of other indicators of disease 
progression, therapy should not be discontinued solely on the basis of a rise in PSA. 
8.3.3 
Bone 
Record post-treatment changes as either “no new lesions” or “new lesions.” 
In the absence of clearly worsening soft-tissue (nodal and visceral) disease or disease-related 
symptoms, progression at the first scheduled assessment should be confirmed on a second 
scan performed 6 or more weeks later. In the rare case where visible lesions disappear, this 
too should be confirmed. 
 
 

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8.3.4 
Nontarget lesions 
When assessing nontarget lesions, the definitions in Table  will apply. 
Table 15. RECIST response criteria for nontarget lesions 
Response 
Evaluation of Nontarget Lesions 
Complete response 
(CR) 
the disappearance of all nontarget lesions and normalization of tumor 
marker levels 
Incomplete response/ 
stable disease (SD) 
the persistence of one or more nontarget lesions and/or maintenance of 
tumor marker levels above the normal limits 
Progressive disease 
(PD) 
the appearance of one or more new lesions and/or unequivocal 
progression of existing nontarget lesions 
 
A clear progression of nontarget lesions only is exceptional. In such circumstances, the 
progression status, as assigned by the investigator, may be reviewed by the Sponsor 
Investigator.  
8.3.6 
Evaluating best overall response 
The best overall response is the best response recorded from the start of treatment until 
either disease progression or recurrence. The investigator’s determination of best overall 
response will be based both on response criteria and on confirmation criteria. To be assigned 
a status of partial response or complete response, changes in tumor measurements must be 
confirmed by repeat assessment performed 4-6 weeks after the criteria for response are first 
met. To confirm stable disease, follow-up measurements must meet stable disease (SD) 
criteria at a minimum interval of 4 weeks after SD was first documented. Table  can be used 
as an assessment tool. 
Table 16. Assessing Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. 
 
Patients with global deterioration of health status who require treatment to be discontinued 
without objective evidence of disease progression should be classified as having symptomatic 
deterioration. Every effort should be made to document their objective progression, even 
after discontinuing treatment. 
Patients who do not have tumor response assessment due to rapid progression or toxicity 
will be considered nonresponders, will be included in the denominator for the response rate, 
and will be classified into one of the categories listed below: 
 
death attributed to disease progression 
 
early discontinuation attributed to disease progression 

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 
death attributed to drug toxicity 
 
early discontinuation attributed to drug toxicity 
Note: If a patient receives subsequent therapy before tumor progression is 
documented, the reason for changing therapy must be reported. Reasons 
include clinical progression, drug toxicity, or secondary therapy for 
maintaining tumor response.
8.4 
Confirmatory Measures/Duration of Response 
8.4.1 
Confirming time-to-event outcomes 
Any post treatment change in disease status, be it favorable or unfavorable, should be 
confirmed using a second assessment at 4 weeks later. 
8.4.2 
Duration of overall response 
Duration of overall response is measured from the time when partial response or complete 
response is first noted until the date when recurrent or progressive disease is objectively 
documented. Duration of overall complete response is measured from the time the criteria 
for complete response are first met until the first date that recurrent disease is objectively 
documented. Duration of stable disease is measured from the start of treatment until the 
criteria for progression are met. 
8.4.3 
Radiographic Progression-free survival 
Radiographic progression-free survival is a composite endpoint defined as the time from 
treatment start to disease progression in bone or soft-tissue, or death, whichever occurs 
first. All assessments of disease should be collected at the same time interval (e.g., bone scan, 
CT scan, and PSA at 12-week intervals). In addition to PSA, confirm posttreatment changes in 
measurable target lesions, radionuclide bone scans, and symptoms. 

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Table 17 Prostate Cancer Clinical Trials Working Group (PCWG2) Outcome Measures5 
Variable 
Control/Relieve/Eliminate Endpoints 
Prevent/Delay Endpoints 
PSA 
Record the percent change from baseline 
(rise or fall) at 12 weeks and, separately, 
the maximal change (rise or fall) at any 
time using a waterfall plot 
Decline from baseline: record time from 
start of therapy to first PSA increase that is 
~25% and ~2 ng/mL above the nadir, and 
which is confirmed by a second value 3 or 
more weeks later (i.e., a confirmed rising 
trend)† 
Recording the duration of PSA decline of 
little value 
No decline from baseline: PSA progression 
~25% and ~2 ng/mL after 12 weeks 
Soft-tissue lesions 
Use RECIST with caveats: 
Only report changes in lymph nodes that 
were ~2 cm in diameter at baseline 
Record changes in nodal and visceral soft 
tissue sites separately 
Record complete elimination of disease at 
any site separately 
Confirm favorable change with second 
scan 
Record changes using waterfall plot 
Use RECIST criteria for progression, with 
additional requirement that progression at 
first assessment be confirmed by a second 
scan 6 or more weeks later 
Note that for some treatments, a lesion may 
increase in size before it decreases 
Bone 
Record outcome as either new lesions or  
no new lesions 
First scheduled reassessment: 
No new lesions: continue therapy 
New lesions: perform a confirmatory scan 
6 or more weeks later 
Confirmatory scan: 
No new lesions: continue therapy 
Additional new lesions: progression 
Subsequent scheduled reassessments: 
No new lesions: continue 
New lesions: progression 
The appearance of ~2 new lesions, and, for 
the first reassessment only, a confirmatory 
scan performed 6 or more weeks later that 
shows at least 2 or more additional new 
lesions 
The date of progression is the date of the 
first scan that shows the change 
Symptoms 
Consider independently of other outcome measures 
Document pain and analgesia at entry with a lead-in period and measure repeatedly at 3- 
to 4-week intervals 
Perform serial assessments of global changes in HRQOL, urinary or bowel compromise, 
pain management, additional anticancer therapy 
Ignore early changes (~12 weeks) in pain or HRQOL in absence of compelling evidence of 
disease progression 
Confirm response or progression of pain or HRQOL endpoints ~3 weeks later 
Abbreviations: PSA, prostate-specific antigen; HRQOL, health-related quality of life. †Particularly important when anticipated effect on PSA 
is delayed or for biologic therapies. 

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8.5 
Progressive Disease (PD) 
 
Progressive disease will be defined by any one of the following: 
 
 
1. Appearance of new metastatic lesions outside the bone  
2. New metastatic lesions on bone scan confirmed as described above  
3. Unequivocal progression of non-target lesions  
4. Global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression as described above
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS 
9.1 
Data Collection and Management 
Data collected during this study will be entered into a secure database. 
9.1.1 
Electronic case report forms (eCRFs) 
Standardized eCRFs and completion guidelines will be created by the PCCTC for the collection 
of all study data. Access and training for Medidata Rave will be made available to participating 
sites upon local regulatory approval.  The participating site PI is responsible for ensuring 
eCRFs are completed accurately and in a timely manner. 
9.1.2 
Source documents 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation will be made 
available to support the subject’s research record.  
9.1.3 
Record retention 
The investigator will maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. After study 
closure, the investigator will maintain all source documents and study-related documents. 
Records are to be retained and securely stored until the later of:  (a) two (2) years following 
the date a New Drug Application (NDA) is approved for the Study Drug that is the subject of 
the Clinical Trial; or (b) two (2) years after the Investigational NDA for such Study Drug is 
terminated or withdrawn, or such longer period of time as may be required by Participant 
policies, applicable laws, rules or regulations. 
9.1.4 
Source Documentation Submission for Registration at Participating Sites 
Participating sites should email any source documentation that corresponds to data entered at 
registration into the eCRFs to PCCTC at PCCTC@mskcc.org.  
9.1.5 
 Data Submission Timelines  
All data should be transmitted to PCCTC within 14 days of visit except for SAE submission (see 
section 7.3.1).  
 
9.1.6 
Data Review and Queries 
PCCTC will review data and source documentation as it is submitted. Data will be monitored 
against source documentation as necessary and discrepancies will be sent as queries to the 
participating sites. In addition, PCCTC will review data for logic, consistency, and obvious 
anomalies. Queries will be sent by PCCTC to participating sites as needed. 
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9.2 
Data and Safety Monitoring 
Data and Safety Monitoring Committee (DSMC) is the Data and Safety Monitoring Board 
(DSMB) for the Thomas Jefferson University Sidney Kimmel Cancer Center (SKCC). The DSMC 
is a multidisciplinary committee charged with overseeing the monitoring of safety of 
participants in clinical trials, and the conduct, progress, validity, and integrity of the data for 
all clinical trials at the Thomas Jefferson University SKCC.  
 The DSMC meets quarterly. Additional DSMC meetings are scheduled based on the nature 
and number of trials being monitored over a specified time period. The DSMC meets (by 
conference call) within 24 hours following the notification of an unexpected AE felt to be 
related to the study drug.  
 Prior to each DSMC meeting Principal Investigator is provided a printout by PCCTC of all 
reported AEs and SAEs occurring during the reporting period for this clinical trial for 
submission to the DSMC. The Principal Investigator provides a detailed and comprehensive 
narrative assessment of current AEs to date, indicating their possible significance and 
whether these toxicities have affected the conduct of the trial. A review of outcome results 
(response, toxicity and AEs) and factors external to the study (such as scientific or 
therapeutic developments) is discussed, and the Committee votes on the status of the 
study.  
 A summary of the committee’s action is sent to each investigator, the Thomas Jefferson 
University Protocol Review Committee (PRC) and Thomas Jefferson University IRB. The 
DSMC actions may include recommendations/requirements that will lead to improved 
patient safety and/or efficacy, significant benefits or risks that have developed, or other 
changes determined to be necessary. The DSMC may also take note of slow accrual or lack 
of scientific progress, and refer such issues to the PRC. The DSMC provides the Principal 
Investigator with the rationale for any decision made, who in turn will submit it to the 
PCCTC.  
The Thomas Jefferson University Data and Safety Monitoring Committee reviews all 
AE/SAEs on open protocols.  Therefore, once AE/SAE reports from participating site 
are received by the Principle Investigator, a copy will be submitted to the Thomas 
Jefferson University IRB/Medical Monitor/DSMB. Medical Monitor and DSMB review 
and monitoring of participating site AEs/SAEs will follow the Thomas Jefferson 
University DSMP.  
9.2.1 
Study Monitoring and Quality Assurance 
In addition to review by the DSMC, PCCTC will conduct regularly scheduled monitoring visits. 
Registration reports will be generated by the PCCTC to monitor subject accruals and the 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and the extent and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period, and potential 
problems will be brought to the attention of the Principal Investigator for discussion and 
action. 
Each site participating in the accrual of participants to this protocol will be monitored by the 
PCCTC once shortly after initiation of subject recruitment at a site, annually during the study 
(or more frequently if indicated), and at the end or closeout of the trial, for protocol and 
regulatory compliance, data verification and source documentation. At initial visits, the first 
two subjects will be 100% source data verified (or one subject if site does not accrue 2 in a 

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year). At a minimum of 10% of all subjects, but at least 2 from each site, will be 100% source 
data verified by the PCCTC during interim visits (selected subjects). Monitoring visits may be 
accomplished in one of two ways: (1) sending source documents and research records for 
selected patients from participating sites to the PCCTC for audit, or (2) on-site auditing of 
selected patient records at participating sites. 
The monitoring visit will include a review of source documentation to evaluate compliance 
for: 
 Regulatory/IRB compliance (review of current protocol and amendments, 
Informed consent documents and procedures, annual continuing review 
reports, AEs/SAEs) 
 Protocol defined treatment compliance 
 Subject records  
 Informed consent for each subject 
 Adherence to eligibility criteria for each subject 
 Medical history/baseline for selected subjects 
 On study and follow-up protocol tests for selected subjects 
 eCRF completion for each subject 
Monitoring findings will be review and disseminated to the site PIs and staff. Following 
monitoring visits, data quality reports will be generated to asses error rate. 
All clinical work conducted under this protocol is subject to Good Clinical Practice (GCP) 
guidelines. This includes inspection of study-related records by the lead site, sponsor, its 
designee, or health authority representatives at any time. 
In addition, lead site/sponsor may conduct audits. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
10.1.1 Analysis of the primary endpoint 
The primary endpoint for the phase IB component is identification of a safe dose of the 
combination of ribociclib and enzalutamide. This phase follows a ‘3+3’ design and all analysis 
will be descriptive. 
The primary endpoint of the phase II component is the proportion of subjects with a ≥ 50% 
reduction in PSA at 12 weeks. A Simon two-stage design for a 12 week PSA50 endpoint with 
a null hypothesis of 78%, an alternative hypothesis of 93%, alpha of 0.10, power of 90%, 
and 11 subjects treated at the first stage will be used.  If at least 8 out of the first 11 subjects 
have a response (PSA50), the study will continue to enroll a total of 35 subjects.  If at least 
31 subjects respond, the null hypothesis will be rejected.   Subjects who were enrolled to the 
combination arm during the original randomized design will be incorporated into the 
analysis in the Simon two-stage design. 
 

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10.1.2 Analysis of secondary endpoints 
PSA progression-free survival will be measured from the time of first dose until progression 
(25% increase in PSA from nadir) or death and summarized by treatment arm using Kaplan-
Meier plots. Median PFS will be estimated from the Kaplan-Meier analysis. 
Radiographic progression-free survival will be measured from the time of first dose until 
progression and summarized using Kaplan-Meier plots.  Median rPFS will be estimated from 
the Kaplan-Meier analysis.   
10.1.3 Analysis of exploratory endpoints and correlative studies 
The proportion of patients with RB positive tumors among the screened patients by IHC and 
gene signature will be estimated along with appropriate 95% confidence intervals.  Similarly, 
the proportion of samples where RB status can successfully be obtained will be estimated as 
a measure of feasibility.   
Correlation of IHC and gene expression levels will be measured using Pearson or Spearman 
correlation coefficients.  Analysis of tumor explant data will use linear or generalized linear 
mixed effects models for repeated measurements depending on the outcome of interest.   
Association of androgen profiles with clinical outcomes will use logistic regression or Cox 
proportional hazards regression, as appropriate.   
10.2 
Analysis Populations 
10.2.1 Efficacy Analysis Set 
All subjects who meet eligibility criteria, and receive at least one dose of study medication, 
and have PSA data at baseline and 12 weeks will be included in the main analysis of the PSA 
response rate.    
Conclusions are to be based on the population of all eligible patients. Subanalyses will be 
performed on various subsets of subjects, such as those with no major deviations to 
treatment or those who continued in the study for the entire treatment period (i.e., did not 
withdraw prematurely). Subanalyses will not serve as the basis for drawing conclusions 
concerning treatment efficacy. 
10.2.2 Safety population 
All subjects enrolled and treated with ribociclib plus enzalutamide in the study will be 
included in the safety analysis population and considered evaluable for toxicity and safety 
from the time of their first dose.  
10.3 
Safety Analysis 
10.3.1 Evaluation of AEs 
Treatment-emergent AEs will be translated from investigator terms to MedDRA v6.0 
terminology and summarized (number and percentage of patients) by treatment arm for all 
subjects who receive at least one dose. AE summaries will be organized by body system, 
frequency of occurrence, intensity (i.e., severity grade), and causality or attribution. Subjects 
who experience an AE more than once will be counted only once. The occurrence with the 
maximum severity will be used to calculate intensity. 

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10.3.2 Evaluation of SAEs and premature withdrawals 
AEs deemed serious and those resulting in treatment withdrawal or death will be 
summarized separately. Please see section 7.3 for details on reporting SAEs.  
10.3.3 Evaluation of laboratory parameters and assays 
Selected clinical laboratory parameters will be summarized by treatment arm and clinically 
significant changes from baseline will be discussed.  
10.3.4 Extent of exposure 
Treatment exposure will be summarized for all subjects.  
10.4 
Statistical Procedures 
Summary statistics include the number of observations, mean, standard deviation, median, 
minimum, and maximum values. The PSA50 response rate will be estimated along with an 
exact 95% confidence interval.   
10.4.1 Sample size calculation 
 
The null hypothesis is that the PSA50 response rate is less than or equal to 78% and the 
alternative is that it is greater than or equal to 93%.  The study was designed with a target 
Type I error rate of 10% and power of 90%.  A Simon two-stage design with 11 patients at 
the first stage (requiring 8 or more responses to continue) and a total sample size of 35 
(requiring 31 or more for rejecting the null hypothesis) has an 8.9% probability of concluding 
the drug is effective, even if it is actually not effective (Type I error), and a 9.6% probability 
of concluding that it is not effective if it actually is effective (Type II error).   
10.4.2 Derived variables 
 Change from baseline will be calculated as the rating after baseline minus the rating at 
baseline 
 Time windows will be calculated as the visit day minus the first day of study treatment 
 Duration of treatment will be defined as the number of days from the first day of study 
treatment to the last day of study treatment. If the last day of study treatment is missing, 
the date of the last visit will be substituted for the missing value (i.e., LOCF).
11. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS 
11.1 
Role and Responsibilities 
11.1.1 Sponsor Investigator 
The Sponsor Investigator is responsible for performing the following tasks: 
 Responsibility for the overall conduct of the study at all participating sites and for 
monitoring the progress of the study 
 Reviewing and ensuring reporting of SAEs 
 Reviewing data from all participating sites 
 
11.1.2  PCCTC 

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The PCCTC is responsible for performing the following tasks: 
 Ensuring that IRB approval has been obtained at each participating site prior to the first 
patient registration at that site, and maintaining copies of IRB approvals and required 
regulatory documents from each site. 
 Managing subject registration 
 Developing and maintaining Clinical Data Management documents and procedures 
 CRF development, setup of study database, and subsequent design changes 
 Participating in review of content of the CRF against the protocol requirements 
 EDC system administration (user/site accounts setup, maintenance and revocation) 
 Data review, cleaning, query management and resolution 
 Establishing procedures for documentation, reporting and submitting of AEs and SAEs to 
the PCCTC 
 Reviewing SAEs 
 Training participating sites on EDC 
 Collecting and compiling data from each participating site 
 Data reviewing from all participating sites 
 Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
11.1.3  Participating Sites 
Participating sites are responsible for performing the following tasks: 
 Following the protocol as written, the guidelines of GCP, and applicable Standard 
Operating Procedures (SOPs). Registering all patients with the PCCTC by submitting the 
eligibility checklist, supporting source documentation, and signed informed consent 
promptly 
 Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol 
 Maintaining regulatory binders on site and providing copies of all required documents to 
the PCCTC 
 Collecting and submitting data according to the schedule specified by the protocol 
 Responding to queries in a timely manner 
11.2 
Ethical Considerations 
This study will be conducted in compliance with the protocol, GCP guidelines established by 
the International Conference on Harmonisation, and the ethical standards set forth in the 
Declaration of Helsinki 2004 (available at: www.laakariliitto.fi/e/ethics/helsinki.html). 
11.3 
Protocol Amendments 
Before starting the study, the protocol must be approved by each institution’s IRB or 
Independent Ethics Committee (IEC). Amendments to the protocol may be made only with 
consent of the sponsor investigator and Novartis and are subject to IRB approval before 
instituting. 

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11.4 
Written Informed Consent 
Before obtaining consent, members of the study team will review the rationale for the 
treatment program with the patient. The discussion will review the alternatives available 
(including hormonal therapy, chemotherapy, or supportive care as appropriate), the 
potential benefits of this program, the risks and the probability of their occurrence, and the 
procedures to minimize these risks. Should an AE occur, the provisions available to ensure 
medical intervention will also be reviewed. Why the risks are reasonable in relation to the 
anticipated benefits, incentives, or costs that will or may be incurred as a result of 
participating in the study, as well as the efforts to maintain confidentiality, will also be 
discussed with the patient. 
Patients will be required to sign and date a statement of informed consent that meets the 
requirements of the Code of Federal Regulations (Federal Register Vol. 46, No. 17, January 
27, 1981, part 50) and the IRB. The medical record will include a statement that written 
informed consent was obtained (and document the date that it was obtained) before the 
patient is enrolled in the study. The original signed document will become part of the patient’s 
medical record and a copy will be forwarded to PCCTC for subject registration.   
The consent form will include the following: 
 the nature and objectives, potential toxicities, and benefits of the intended study 
 the length of therapy and likely follow-up required 
 alternatives to the proposed therapy (including available standard and investigational 
therapies) 
 the name of the investigator(s) responsible for the protocol 
 the right of the patient to accept or refuse treatment and to withdraw from participation 
in this study 
 informed consent documents and sections in the research authorization/HIPAA forms 
should include who will have access to the subjects data and medical records including 
PCCTC  
11.5 
Protection of Privacy 
Subjects will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. After this discussion, they will 
be asked to sign a Notice of Privacy Practice research authorization/HIPAA form. The original 
signed documents will become part of the patient’s medical records, and each patient will 
receive a copy of the signed documents. The use and disclosure of protected health 
information will be limited to the individuals described in the research authorization form. 
The research authorization form must be completed by the principal investigator and 
approved by the IRB. 
11.6 
Terminating or Modifying the Study 
AE and laboratory data from this trial will be assessed by the lead site on an ongoing basis. At 
least quarterly, data from the clinical database will be reviewed. The results of this review 
will be shared with all investigators either in writing or as part of a teleconference. SAEs will 
be reviewed as they are reported to the lead site/sponsor, and the medical monitor will make 
an assessment regarding the safety of continuing or modifying the study. This assessment 

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will be shared with the investigators either in writing or as part of a teleconference. Should 
the assessment of either the lead site/sponsor or the principal investigator be that the study 
should be terminated, the study will be closed to further accrual. Patients who are receiving 
ribociclib with enzalutamide will be assessed individually by the investigator to see if it is in 
the patients’ best interest to continue, which might be the case for a patient that is responding 
to the intervention. Follow-up safety assessments will be performed for all patients who are 
terminated from the study prematurely. 

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12. 
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Appendix A: Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
% 
Description 
0 
Normal activity. Fully active, able to 
continue all predisease performance 
without restriction. 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity, 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or sedentary 
nature (eg, light housework, office 
work). 
80 
Normal activity with effort, some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time. Ambulatory 
and capable of all self-care but unable 
to carry out any work activities. Up 
and about more than 50% of waking 
hours. 
60 
Requires occasional assistance but is 
able to care for most needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time. Capable of 
only limited self-care, confined to bed 
or chair  
> 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled, cannot carry on any self-
care, totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 

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Appendix B: Medications with the Potential for Drug-Drug Interactions 
 
Enzalutamide 
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans 
[Xtandi® Prescribing Information] and may decrease the exposure of comedications that are 
substrates for these metabolizing enzymes.  
 
Ribociclib 
Based on in vitro data, ribociclib is primarily metabolized by CYP3A4. Based on clinical data, 
ritonavir (a strong CYP3A4 inhibitor) and rifampicin (a strong CYP3A4 inducer) markedly 
increased and decreased ribociclib exposure, respectively. Therefore, drugs that are strong 
inhibitors or inducers of CYP3A4 should not be co-administered with ribociclib. Patients who 
receive medications that are moderate inhibitors or inducers of CYP3A4/5 should be observed for 
signs of overexposure or potential reduced efficacy of ribociclib, respectively. 
 
Ribociclib inhibits transporter proteins in vitro, including human BSEP, MATE1, OCT2, and BCRP. 
The clinical relevance of these in vitro findings is not known. Co-administration of ribociclib with 
other drugs that inhibit BSEP may result in intrahepatic cholestasis and hepatic toxicity. Therefore 
known BSEP inhibitors should be used with caution during treatment with ribociclib. Additionally, 
caution is recommended with co-administration of sensitive substrates of the renal transporters, 
MATE1 and OCT2, and with sensitive substrates of BCRP. 
 
Prolongation of the QT interval has been observed with ribociclib. Caution should be exercised with all 
medications that are known to produce this effect. Those known to have a strong signal will be 
prohibited and others are to be used with caution.  
 
Concomitant Medications 
In general, the use of any concomitant medication deemed necessary for the care of the patient is 
permitted in this study, except as specifically prohibited below. Combination administration of study 
drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced activity or 
enhanced toxicity of the concomitant medication and/or ribociclib. 
 
The following lists are not comprehensive and are only meant to be used as a guide. The lists are based on 
the Oncology Clinical Pharmacology Drug-Drug Interaction Database (release date: 29 Oct 2012), which 
was compiled from the Indiana University School of Medicine’s P450 Drug Interaction Table 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft Guidance 
for Industry, Drug Interaction Studies – Study Design, Data Analysis, and Implications for Dosing and 
Labeling (February 2012) 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.
pdf), and the University of Washington’s Drug Interaction Database 
(http://www.druginteractioninfo.org/). For current lists of medications that may cause QT prolongation 
and/or torsades de pointes (TdP), refer to the CredibleMeds® website (https://crediblemeds.org/). Please 
contact the medical monitor with any questions 
Table 18. List of prohibited medications during study treatment 
Category 
Drug Name 

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Strong CYP3A4/5 
inhibitors 
Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, 
conivaptan, danoprevir/ritonavir, darunavir/ritonavir, 
elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir, 
indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, 
ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA PAK), 
posaconazole, ritonavir,  saquinavir/ritonavir, telaprevir, 
telithromycin, tipranavir/ritonavir, troleandomycin, voriconazole 
Strong CYP3A4/5 
inducers 
Apalutamide, carbamazepine3, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin3, rifabutin, rifampin (rifampicin)3, St. 
John's wort (hypericum perforatum)2,3 
CYP3A4/5 substrates 
with NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl,  pimozide, quinidine,  
sirolimus, tacrolimus 
Medications with a 
known risk for QT 
prolongation4 
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, 
chloroquine,  chlorpromazine, cilostazol, ciprofloxacin, cisapride, 
citalopram, clarithromycin, disopyramide, dofetilide, domperidone, 
donepezil, dronedarone, droperidol, erythromycin, escitalopram, 
flecainide, fluconazole, gatifloxacine, grepafloxacin, halofantrine, 
haloperidol, ibutilide, levofloxacin, levomepromazine, 
levosulpiride, methadone, moxifloxacin, ondansetron, oxaliplatin, 
papaverine HCl (intra-coronary), pentamidine, pimozide,  
procainamide, propofol, quinidine, roxithromycin, sevoflurane, 
sotalol,  sulpiride, sultopride, terlipressin, terodiline,  thioridazine, 
vandetanib 
Herbal preparations/ 
medications or dietary 
supplements 
Herbal preparations/medications or dietary supplements are 
prohibited throughout the study. These herbal medications include, 
but are not limited to: St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng. Patients should stop using these herbal 
medications or dietary supplements 7 days prior to first dose of 
study drug. 
Other investigational 
and antineoplastic 
therapies 
Other investigational therapies must not be used while the patient 
is on the study. Anticancer therapy (chemotherapy, all SERMS 
(including raloxifene) biologic or radiation therapy, and surgery) 
other than the study treatments must not be given to patients while 
the patient is on the study medication. If such agents are required 
for a patient then the patient must be discontinued study drug. 

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1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their exposure levels 
by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes) or 
drugs which have <2-fold difference in the minimum toxic concentrations and minimum effective concentrations in 
the blood. 
2 Herbal product 
3 P-gp inducer 
4 The list provided is as of December 2019.SoCheck https www crediblemeds.org/healthcare-providers/drug-list 
for the most updated list.www.crediblemeds.org 
 
Drug has warning for risk of hepatotoxicity.As far as possible, avoid co-administration of QT prolonging drugs or 
any other drugs with the potential to increase the risk of drug-related QT prolongation (e.g., via a potential DDI 
that increases the exposure of ribociclib or the exposure of the QT prolonging drug). A definitive list of drugs with 
a known risk, possible risk, or conditional risk of QT prolongation and/or Torsades de Pointes (TdP) is available 
online at qtdrugs.org. 
 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations for 
Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” Flockhart 
Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug Interactions: 
Table of Substrates, Inhibitors and Inducers. 
 
 
 
Table 19. List of medications to be used with caution during study treatment 
Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Aprepitant, amprenavir, asafoetida resin (Ferula 
asafoetida) cimetidine, crizotinib, diltiazem, faldaprevir,  
imatinib,  isavuconazole, netupitant, nilotinib, tofisopam, 
Schisandra sphenanthera (nan wu wei zi), verapamil 
Moderate CYP3A4/5 
inducers 
Bosentan, dabrafenib, efavirenz, etravirine, 
genistein,lopinavir5, modafinil, nafcillin,telotristat 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine,  aprepitant,  atorvastatin, 
avanafil, bosutinib,brotizolam, budesonide, buspirone,  
cannabinoids6, cannabidiol6 cobimetinib,   darifenacin, 
dasatininb, ebastine, eletriptan, eplerenone, everolimus, 
felodipine, fluticasone, grazoprevir, ibrutnib, 
isavuconazole, ivabradine, ivacaftor, , levomethadyl 
(LAAM), lomitapide, lovastatin, lumefantrine, lurasidone, 
maraviroc, midazolam, midostaurin, naloxegol, neratinib, 
nisoldipine, perospirone, quetiapine, ridaforolimus, 
sildenafil, simeprevir, simvastatin, ticagrelor, tilidine,  
tolvaptan, triazolam, ulipristal, vardenafil, venetoclax, 
vicriviroc, voclosporin 
BSEP inhibitors 
Alectinib, atorvastatin,  bromocriptine, candesartan, 
clobetasol, clofaziminie, dabigatran, dipyridamole, 
glyburide, grazoprevir, ledipasvir, 
mifepristone,pioglitazone, reserpine,rifamycin, simeprevir, 
telmisartan,timcodar, troglitazone, valinomycin, 
velpatasvir 

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Medications that carry a 
possible risk for QT 
prolongation2 
Alfuzosin, apomorphine, aripiprazole, 
artenimol+piperaquine , asenapine, atomoxetine,  
bedaquiline, bendamustine, bortezomib, bosutinib, 
buprenorphine, cabozantinib, capecitabine, ceritinib, 
clomipramine, crizotinib,clozapine, cyamemazine 
(cyamepromazine), dabrafenib, dasatinib, degarilix, 
delamanid, desipramine, dexmedetomidine, dolasetron, 
efavirenz, eliglustat, epirubicin, eribulin mesylate, 
ezogabine(retigabine), famotidine, felbamate, fingolimod, 
flupentixol,  gemifloxacin, granisetron, hydrocodone-ER, 
iloperidone, imipramine (melipramine), isradipine, 
ketanserin, lapatinib, lenvatinib, leuprolide, lithium, 
melperone, midostaurin, mifepristone, mirabegron, 
mirtazapine, moexipril/HCTZ, necitumumab, nicardipine, 
nilotinib, norfloxacin, nortriptyline, nusinersen, ofloxacin, 
osimertinib,  oxytocin, paliperidone, palonosetron,  
panabinostat, pasireotide, pazopanib, perflutren lipid 
microspheres, perphenazine, pilsicainide, pimavanserin, 
pipamperone, promethazine, prothipendyl,  rilpivirine, 
risperidone, romidepsin, sertindole, sorafenib, sunitinib, 
tamoxifen, tipiracil/trifluridine, tizanidine, tolterodine, 
toremifene,trimipramine, tropisetron, vardenafil, 
vemurafenib, venlafaxine, vorinostat, ziprasidone 
MATE1/2 substrates3 
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, 
glycopyrronium, metformin, pindolol, plisicainide, 
ranitidine, topotecan, varenicline 
OCT1/2 substrates4 
 Amantadine, 6-beta-hydroxycortisol, carboplatin, cisplatin, 
cephalexin, cephradine, ipratropium,  lamivudine, 
linagliptin, metformin, , oxaliplatin, oxybutynin, 
phenformin, picoplatin, pilsicainide, pindolol, , ranitidine, 
sorafenib,  tropisetron, trospium, umeclidinium, and 
zidovudine 
BCRP substrates 
Daunorubicin, dolutegravir, doxorubicin, 
hematoporphyrin, imatinib, methotrexate, mitoxantrone, 
pitavastatin, rosuvastatin, irinotecan, ethinyl estradiol, 
simvastatin, sulfasalazine, sofosbuvir, tenofovir, topotecan, 
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1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when 
co-administered with a potent inhibitor. 
2 The list provided is as of January 2018. Check https www crediblemeds.org/healthcare-providers/drug-list for 
the most updated list. 
3 MATE1 and MATE2 share considerable substrate specificity.  
4 OCT1 and OCT2 share considerable substrate specificity. 
5 Lopinavir and atazanavir is prohibited when combined with ritonavir (see Table 14-1) 
6 Based data that, exposure of cannabidiol (CBD), tetrahydrocannabinol (THC), 11-hydroxy THC, increased by 
~2-3 folds when co-administered with ketoconazole (CYP3A4 inhibitor); Stott et al, Springerplus. 2013; 2: 236 
 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations 
for Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” 
Flockhart Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug 
Interactions: Table of Substrates, Inhibitors and Inducers. 

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Appendix C: Laboratory Manual 
 
Please see the Laboratory & Correlatives Manual.  

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Appendix D: Glossary of Abbreviations and Acronyms 
ADME 
absorption, distribution, metabolism and exretion 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AR 
androgen receptor 
AR-V7 
androgen receptor, splice variant 7 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCtau 
area under the concentration-time curve in one dosing interval 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CDK 
cyclin-dependent kinase 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRPC 
castration resistant prostate cancer 
CS&E 
Novartis Clinical Safety & Epidemiology 
CT 
computerized tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
DES 
Diethylstilbestrol 
dL 
Deciliter 
DLT 
dose-limiting toxicity 
DS&E 
Novartis Drug Safety and Epidemiology 
DSMC 
Data and Safety Monitoring Committee 
DSMB 
Data and Safety Monitoring Board 
ECHO 
Echocardiogram 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
FIH 
first in human 
FM03 
flavin-containing monooxygenase 3 
GCP 
good clinical practice 

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GnRH 
gonadotropin-releasing hormone  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRQOL 
health-related quality of life 
HSV 
herpes simplex virus 
IC50 
50% inhibition 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IN 
Novartis Investigator Notification 
IND 
investigational new drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
KPS 
Karnofsky Performance Scale 
 
 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
MCL 
mantle cell lymphoma 
mCRPC 
metastatic castration-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
NIH 
National Institutes of Health 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
OS 
overall survival 
PCCTC 
Prostate Cancer Clinical Trials Consortium 
PCWG2 
Prostate Cancer Working Group 2 
PD 
progressive disease 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PI 
principal investigator 
PK 
Pharmacokinetics 
PO 
per os (by mouth) 

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PR 
partial response 
pRb 
retinoblastoma protein 
PSA 
prostate-specific antigen 
PSA PFS 
PSA progression-free survival 
PT 
prothrombin time 
QTc 
corrected QT interval 
Racc 
arithmetic mean of accumulation ratio 
RB 
Retinoblastoma 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
radiographic progression-free survival 
SAE 
serious adverse event 
SD 
SKCC 
stable disease 
Thomas Jefferson University Sidney Kimmel Cancer Center 
SOP 
Standard Operating Procedures 
SUSAR 
suspected unexpected serious adverse reaction 
SUV 
standardized uptake value 
T1/2 
terminal half-life  
TJU 
Thomas Jefferson University 
ULN 
upper limit of normal 
WBC 
white blood cell 

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Appendix E. Pill Diary (PHASE I) 
 
Phase IB/II study of enzalutamide with and without ribociclib in patients with 
metastatic castrate resistant, chemotherapy naïve prostate cancer that retains 
RB expression 
 
PCCTC LOI# c15-153 
 
Study ID #: _____________________________ 
Cycle #: _________________________________ 
Patient Name: __________________________                                 Dates: ____/____/________ to _____/_____/________ 
To be completed by MD/RN: 
Total Daily Dose of Enzalutamide: _160_ mg 
            Take: __4__ 40 mg capsule(s) once daily 
Total Daily Dose of Ribociclib: ______ mg 
 
            Take: ______ 200 mg tablet(s) once daily 
 
INSTRUCTIONS TO THE PATIENT: 
1. Please complete one form for each cycle (=28 days) while you are taking the study 
medication.  
2. Please record the date, the number of capsules/tablets you took, and what time you took 
them. If you did not take your medication, or if you only took part of the required dose, 
please provide a reason. 
3. Enzalutamide should be taken orally once daily. Enzalutamide can be taken with or 
without food. 
4. Ribociclib should be taken orally once daily for 21 consecutive days, followed by a 7-day 
break.  
5. All medications must be swallowed whole and should not be crushed, chewed, dissolved, or 
opened. 
6. If you forget to take your medication, do not “double-up” on the next dose to make-up for 
the skipped dose. If you vomit after you take your medication, do not take another dose 
until the next scheduled dosing.   
7. Please return this diary and all unused study medication to your research nurse. 
All herbal, alternative and food supplements should be avoided while taking study 
medication. 
Day 
Date 
 
Indicate number of capsules/tablets 
taken and time taken 
If dose not taken or if full 
dose not taken, please 
provide reason. 
Enzalutamide 
(40 mg capsules) 
Ribociclib 
(200 mg tablets) 
Example 
1/1/2016 
4 capsules –  
8:00 AM 
1 tablet –  
8:00 AM 
N/A 

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Day 
Date 
Indicate number of capsules/tablets 
taken and time taken 
If dose not taken or if full 
dose not taken, 
please provide 
reason. 
Enzalutamide 
(40 mg capsules) 
Ribociclib 
(200 mg tablets) 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
Patient’s Signature: _____________________________________ _____              
Date of Signature: _____/_____/_________ 
 
Physician’s/Research Nurse’s Signature: _____________________________________ _____              
Date of Signature: _____/_____/_________ 
 
 

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Appendix F. Pill Diary (PHASE II) 
 
Phase IB/II study of enzalutamide with ribociclib in patients with metastatic 
castrate resistant, chemotherapy naïve prostate cancer that retains RB 
expression 
 
PCCTC LOI# c15-153 
 
Study ID #: _____________________________ 
Cycle #: _________________________________                                  Assigned Treatment Arm: _______ 
Patient Name: __________________________                                 Dates: ____/____/________ to _____/_____/________ 
To be completed by MD/RN: 
Total Daily Dose of Enzalutamide: _160_ mg 
            Take: __4__ 40 mg capsule(s) once daily 
Total Daily Dose of Ribociclib: ______ mg  
 
            Take: ______ 200 mg tablet(s) once daily 
 
INSTRUCTIONS TO THE PATIENT: 
1. Please complete one form for each cycle (=28 days) while you are taking the study 
medication.  
2. Please record the date, the number of capsules/tablets you took, and what time you took 
them. If you did not take your medication, or if you only took part of the required dose, 
please provide a reason. 
3. Enzalutamide should be taken orally once daily. Enzalutamide can be taken with or 
without food. 
4. Ribociclib should be taken orally once daily for 21 consecutive days, followed by a 7-day 
break.  
5. All medications must be swallowed whole and should not be crushed, chewed, dissolved, or 
opened. 
6. If you forget to take your medication, do not “double-up” on the next dose to make-up for 
the skipped dose. If you vomit after you take your medication, do not take another dose 
until the next scheduled dosing.   
7. Please return this diary and all unused study medication to your research nurse. 
 
All herbal, alternative and food supplements should be avoided while taking study 
medication. 
 
 
 
 
 
 
 

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Day 
Date 
 
Indicate number of capsules/tablets 
taken and time taken 
If dose not taken or if full 
dose not taken, please 
provide reason. 
Enzalutamide 
(40 mg capsules) 
Ribociclib 
(200 mg tablets) 
Example 
1/1/2016 
4 capsules –  
8:00 AM 
1 tablet –  
8:00 AM 
N/A 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
Patient’s Signature: _____________________________________ _____              
Date of Signature: _____/_____/_________ 

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Physician’s/Research Nurse’s Signature: _____________________________________ _____              
Date of Signature: _____/_____/_________ 
 
 

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Appendix G. Novartis SAE Coversheet 
 

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Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk 1-877-778-9739 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
Relationship between study treatment and event(s) is: 
 
Suspected/Unknown 
 
  
Investigator Signature 
 
 
This document contains important safety information. 
If fax is received in error, please forward to 1-877-778-9739 

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Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk 1-877-778-9739 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
Relationship between study treatment and event(s) is: 
 
Not Suspected 
 
  
Investigator Signature 
 
 
This document contains important safety information. 
If fax is received in error, please forward to 1-877-778-9739 

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Appendix H. PCCTC SAE Report Form  
 
Please see the PCCTC SAE Report form.