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10.1 definitions

An **Adverse Event (AE)** is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment.  
A **Serious Adverse Event (SAE)** is an adverse event occurring at any dose that results in any of the following outcomes:
a. Death b. Life-threatening1 c. Persistent or significant disability/incapacity2 d. In patient hospitalization or prolongation of existing hospitalization e. Congenital anomaly/birth defect 1 The term "life-threatening" in the definition of "serious" refers to an event in which in the view of the initial reporter the patient was at immediate risk of death from the adverse experience as it occurred; it does not refer to an event which had it occurred in a more severe form, might have caused death.  
2 A substantial disruption of a person's ability to conduct normal life functions.  
An event may not meet any of the above seriousness criteria but still be judged as medically serious. That is, important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes (a-e) listed above. Some examples of this type of event are:
blood dyscrasia without inpatient hospitalization convulsions without inpatient hospitalization intensive treatment in an emergency room or at home for allergic bronchospasm without inpatient hospitalization development of drug dependency drug abuse overdose with an associated serious event, or required intervention to prevent impairment/damage An **Unexpected Adverse Event** is not listed in the current US Package Insert (USPI) or an event that may be mentioned in the USPI, but differs from the event because of greater severity or specificity.  
Causality is a determination of whether there is a reasonable possibility that the drug may have caused or contributed to an adverse event. It includes assessing temporal relationships dechallenge/rechallenge information, association (or lack of association) with underlying diseases, and the presence (or absence) or a lack of one or more likely causes. The Investigator must determine if an adverse event is in some way related to the use of the study drug. This relationship should be described as follows:
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unlikely

The event is clearly due to causes distinct from the use of the study drug, such as a documented preexisting condition, the effect of a concomitant medication, a new condition which, based on the pathophysiology of the condition, and the pharmacology of the study drug, would be unlikely related to the use of the study drug.
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possible

The event follows a reasonable temporal sequence from administration of the study drug or the event follows a known response pattern to the study drug *BUT* the event could have been produced by an intercurrent medical condition which, based on the pathophysiology of the condition, and the pharmacology of the study drug, would be unlikely related to the use of the study drug or the event could be the effect of a concomitant medication
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probable

The event follows a reasonable temporal sequence from administration of the study drug and the event follows a known response pattern to the study drug AND the event cannot have been reasonably explained by an intercurrent medical condition or the event cannot be the effect of a concomitant medication
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definite

The event follows a reasonable temporal sequence from administration of the study drug, the event follows a known response pattern to the study drug and based on the known pharmacology of the study drug, the event is clearly related to the effect of the study drug Unknown: Based on the evidence available, causality cannot be ascribed
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11 data safety monitoring plan

The UCSF Helen Diller Family Comprehensive Cancer Center (UCSF-HDFCCC) Data Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for all UCSF-HDFCCC institutional clinical studies. PCCTC will facilitate this responsibility. A summary of DSMC and PCCTC activities for this study includes:
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dsmc

Review of subject data in each cohort Approval of dose escalation by DSMC Chair (or qualified alternate) Monthly monitoring (depending on study accrual) Review of suspected adverse reactions considered "serious" Minimum of a yearly audit
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pcctc

- Weekly UCSF Site Committee Meetings: PCCTC will generate the necessary report and participate in the meeting and document minutes as necessary.  
- UCSF DSMC Reports every 6 weeks: PCCTC will generate the report (in a format agreed upon at the onset of the protocol) and provide to Study Chair to submit to DSMC.  
- Bi-Weekly Conference Calls with Participating Sites: PCCTC will coordinate, schedule, provide reports for this meeting in a format agreed upon at the onset of the protocol as well as participate and take minutes.  
- PCCTC will perform monitoring per the Monitoring Plan (MP) and Data Management Plan
(DMP) and these reports will be submitted to the Study Chair to submit to the DSMC.  
- PCCTC will monitor grade 3 or 4 adverse events and report to the Study Chair if the incidence of adverse events are above the range stated in the IB so that the Study Chair may report this information to the DSMC.  
- PCCTC will maintain an electronic regulatory binder for each of the participating sites and supply documentation to UCSF as needed.
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11.1 monitoring and reporting guidelines

All institutional Phase 1 therapeutic studies are designated with a high risk assessment. The data is monitored monthly as subjects are enrolled and includes all visits monitored up through the Dose Limiting Toxicity (DLT) period. At the time of dose escalation, a written report generated by PCCTC will be submitted to the DSMC Chair outlining the cohort dose, all adverse events and suspected adverse reactions considered "serious," and any Dose Limiting Toxicity as described in the protocol. The report will be reviewed by the DSMC Chair or qualified alternate and written authorization to proceed or a request for more information will be issued within 2 business days of the request. The report is then reviewed at the subsequent DSMC meeting. In the event that the committee does not concur with the DSMC Chair's decision, further study accrual is held while further investigation takes place. The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The Study Chair is responsible for the overall conduct of the study and for monitoring its safety and progress at all participating sites. The Study Chair will conduct continuous review of data and subject safety and discuss each subject's treatment at weekly UCSF Site Committee meetings. PCCTC will generate any necessary reports and participate in the meeting as necessary. The discussions are documented in the UCSF Site Committee meeting minutes. For each dose level, the discussion will include the number of patients, significant toxicities in accordance with the protocol, doses adjustments, and observed responses.
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dose level considerations

The PI/Study Chair, participating sites, investigators, and research coordinators will review enrollment for each dose level cohort during the weekly site committee meetings. The dose level for ongoing enrollment will be confirmed for each subject scheduled to be enrolled. Dose level assignments for any subject scheduled to begin treatment must be confirmed with Principal Investigator.  
The DSMC will be responsible for monitoring all data entered in Medidata Rave®. Approval for dose escalation must be obtained from DSMC chair.
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11.2 review and oversight requirements

All clinically significant adverse events (AEs), whether or not unexpected, and whether or not considered to be associated with the use of study drug, will be entered into Medidata Rave®.  
All clinically significant adverse events entered into Medidata Rave® will be reviewed on a weekly basis at the UCSF Genitourinary Oncology Site Committee. The Site Committee will review and discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the administration of the study drug(s). The weekly reports for this meeting will be prepared by PCCTC. In addition, all suspected adverse reactions considered "serious" are entered into Medidata Rave® and will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC meetings, which take place every six (6) weeks. The report for this meeting will be prepared by PCCTC and submitted to the DSMC by the Study Chair. If a death occurs during the treatment phase of the study or within 30 days after the last administration of the study drug(s) and is determined to be related either to the investigational drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or the assigned designee and PCCTC must be notified within 24 hours of knowledge of the event from the participating site(s) and the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of this notification. The contact may be by phone or e-mail.
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11.2.2 serious adverse event reporting

Serious Adverse Event reporting will be facilitated by PCCTC in accordance with the UCSF
Institutional Review Board(IRB) Regulations and Food and Drug Administration (FDA) guidelines. UCSF IRB website for guidance in reporting serious adverse events:
http://irb.ucsf.edu/adverse-event FDA website for guidance in reporting serious adverse events: http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm For clinical trials conducted under an IND, SAE reporting will in accordance with Code of Federal Regulations Title 21 volume 5 Part 312 subpart B (21CFR312.32): http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32 SAEs will be reported on a MedWatch form. A copy of the MedWatch report must be sent to the DSMC . The date the SAE was sent to all required reporting agencies will be documented in the EDC. Hard copies of the report will be maintained in the regulatory files. If the SAE is death and determined to be possibly, probably or definitely related to the investigational drug or any research related procedure, the event must be reported to PCCTC and the DSMC Chair or his designee within 24 hours of becoming aware of the event. This will be done by personal communication via phone or in person. The reporting investigator will confirm the verbal communication via e-mail and will copy the e-mail to the DSMC Administrator.  
If the above action occurs in a multiple-institutional clinical trial coordinated by UCSF, PCCTC will insure that all participating sites are notified. 11.2.3 SAE Reporting: Novartis Adverse Event Reporting Requirements The principal investigator has the obligation to report all serious adverse events to the FDA (if applicable), IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E). All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A (MedWatch Form), if applicable. 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. Information about all SAEs is collected and recorded on a Serious Adverse Event Report Form. The investigator must assess and record the relationship of each SAE to each specific study treatment (if there is more than one study treatment), complete the SAE Report Form in English, and send the completed, signed form along with the Novartis provided fax cover sheet to the Novartis Oncology Drug Safety and Epidemiology (DS&E) department within 24 hours.  
Any additional information for the SAE including complications, progression of the initial SAE, and recurrent episodes 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 or otherwise considered completely unrelated to a previously reported one should be reported separately as a new event. Any SAEs experienced after the 30 day safety evaluation follow-up period should only be reported to Novartis if the investigator suspects a causal relationship to the study treatment.  
Follow-up information is submitted in the same way as the original SAE Report. Each reoccurrence, complication, or progression of the original event should be reported as a follow-up to that event regardless of when it occurs. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, whether the blind was broken or not, and whether the patient continued or withdrew from study participation. 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.
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pregnancies

To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy should be reported by the investigator to the Novartis Oncology Drug Safety and Epidemiology Department (DS&E) Pregnancy follow-up should include an assessment of the possible relationship
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11.2.4 review of adverse event

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is responsible for notifying the DSMC at the time the increased rate is identified. The report will be generated by PCCTC and indicate if the incidence of adverse events observed in the study is above the range stated in the Investigator Brochure or package insert.  
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC
Chair and DSMC Manager must be notified within **1 business day** via e-mail. The DSMC must receive a formal letter within **10 business days** and the IRB must be notified.  
Data and Safety Monitoring Committee Contacts:  
DSMC Chair:
DSMC Monitors Phone: Email: Address:
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12 data management

This study is a multi-institution, investigator- sponsored trial (IST) coordinated by UCSF and the Prostate Cancer Clinical Trials Consortium (PCCTC). The Principal Investigator at UCSF holds the role of Study Chair. The Principal Investigator and/or PCCTC is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects, as well as written records of the disposition of the drug when the study ends. The Principal Investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Participating sites will prepare and maintain adequate and accurate case histories as per their standard institutional guidelines. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study.  
Study documentation includes all CRFs, data correction forms or queries, source documents, SponsorInvestigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms).  
Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study. In accordance with FDA regulations, the investigator shall retain records for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified. Study drugs will be shipped from the drug manufacturer directly to the site for direct distribution of the drugs to the study patients. Each site will be responsible for drug accountability at their site.
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approval of protocol and amendments

All protocol amendments must be approved by the participating site's IRB within 90 days of receipt.  
Failure to do so may result in the suspension of study activities at that site. Upon approval of the protocol or amendment by a participating site's IRB, a copy of the approval documentation must be submitted (electronic or hardcopy) to PCCTC. PCCTC will inform the Study Chair.
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data submission

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. All participating sites will be granted access to Medidata Rave and will be expected to enter data as described in the Medidata Rave Data Guidelines provided by PCCTC.
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13 ethical and regulatory considerations

This study will be reviewed by the UCSF Comprehensive Cancer Center Protocol Review Committee (PRC) for scientific merit. After initial review and approval, the study will be reviewed at least once a year for scientific progress. Any changes to the protocol are to be reviewed and approved by the PRC. Participating sites will review this study as per their standard scientific review and approval process.
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13.2 institutional review board (irb)

The study will be reviewed by the IRB. After initial review and approval, the study will be reviewed at least once a year as per FDA regulations (21 CFR 56.109). Any changes to the protocol and consent form are to be reviewed and approved by the IRB. Participating sites will review this study as per their standard IRB/IEC review and approval process. It is the responsibility of the Principal Investigator to keep the IRB informed of the progress of the study, including changes to the protocol or consent form, exceptions or deviations from the protocol, and any new developments which may affect subject safety or willingness to participate.
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13.3 investigational new drug application

IND application will be filed and approved with FDA prior to study initiation.  
A copy of all FDA correspondence will be maintained by the centralized regulatory staff of the UCSFHDFCCC and PCCTC. It is the responsibility of the Study Chair to forward any correspondence concerning the IND and FDA to the centralized regulatory staff and PCCTC.
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13.4 conduct of the trial

The investigators will obtain informed consent and will conduct the trial in accordance with Federal regulations, institutional requirements, and the Declaration of Helsinki.
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role and responsibilities 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
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pcctc (prostate cancer clinical trials

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 Electronic Data Capture (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 and UCSF as outlined in Sections 10 and 11 Reviewing SAEs and facilitating regulatory reporting in coordination with SponsorInvestigator.  
Training participating sites on EDC
Collecting and compiling data from each participating site Data reviewing from all participating sites Facilitating monitoring by securing selected source documents and research records from participating sites for audit, or by auditing at participating sites.  
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
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references

1. Siegel R, Ma J, Zou Z, and Jemal A. Cancer statistics, 2014. CA: A Cancer Journal for Clinicians 2014; 64(1):9-29.  
2. Aggarwal R, Zhang T, Small E, and Armstrong A. Neuroendocrine prostate cancer: subtypes, biology, and clinical outcomes. J Natil Compr Canc Netw 2014; 12:719-726 3. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. New Engl J Med 2004; 351:1502-1512.  
4. Kelly WK, Halabi S, Carducci M, et al. (2012) Randomized, double-blind, placebo-controlled phase 3 trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol; 30:1534-1540.  
5. Quinn DI, Tangen CM, Hussain M, et al. (2013) Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncology; 14:893-900.  
6. Scher HI, Jia X, Chi K, et al. (2011) Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol; 29(16):2191-2198.  
7. Fizazi KS, Higano C, Nelson JB, et al. (2013) Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J Clin Oncol; 31:1740-1747.  
8. Tannock IF, Fizazi K, Ivanov S, et al. (2013) Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol; 14:760-768.  
9. Araujo JC, Trudel GC, Saad F, et al. (2013) Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol; 14:1307-1316.  
10. Higano C, Saad F, Somer B, et al. (2009) A phase III trial of GVAX immunotherapy for prostate cancer versus docetaxel plus prednisone in asymptomatic, castration-resistant prostate cancer (CRPC). J Clin Oncol; 27:14 11. Petrylak DP, Fizazi K, Sternberg CN, et al. (2012) A phase III study to evaluate the efficacy and safety of docetaxel and prednisone with or without lenalidomide in patients with castrate-resistant prostate cancer: The MAINSAIL trial. Meeting of the European Society of Medical Oncology, Vienna, Austria, September 28-October 2, 2012 (abstr LBA24).  
12. Cho H, Herzka T, Zheng W, et al. (2014) RapidCaP, a novel GEM model for metastatic prostate cancer analysis and therapy, reveals MYC as a driver of Pten-mutant metastasis. Cancer Discovery; 4:318-333.  
13. Korpal M, Korn JM, Gao X, et al. (2013) An F876L mutation in androgen receptor confers phenotypic resistance to MDV3100 (enzalutamide). Cancer Discovery; 3:1030-1043.  
14. Horiuchi D, Kusdra L, Huskey NE, et al. (2012) NYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. J of Experimental Medicine;679-696.  
15. Taylor BS, Schultz N, Hieronymous H, et al. (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell; 18:11-22.  
16. Beltran H, Rickman DS, Park K, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discovery 2011;1:487-495.  
17. Rigas AC, Robson CN, and Curtin NJ. Therapeutic potential of CDK inhibitor NU2058 in androgen-independent prostate cancer. Oncogene 2007;26:7611-7619.  
18. Liu G, Gandara DR, Lara PN, et al. (2004) A phase II trial of flavopiridol in patients with previously untreated metastatic androgen-independent prostate cancer. Clin Cancer Res; 10:924928.  
19. Nanni, C. (2010). 68Ga-citrate PET/CT for evaluating patients with infections of the bone:
preliminary results. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 51, 1932-1936
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appendix 1 ecog performance status

| DESCRIPTION                                                       | SCALE   |
|-------------------------------------------------------------------|---------|
| Normal Activity                                                   | 0       |
| Symptoms of disease, able to carry out activities of daily living | 1       |
| Out of bed >50% of time; occasionally needs help                  | 2       |
| In bed >50% of time; needs nursing care                           | 3       |
| Bedridden; may need hospitalization                               | 4       |
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appendix 2 list of prohibited

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/ucm2923 62. 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.  
| Category                                                                   | Drug Name Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
|----------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Strong CYP3A4/5 inhibitors                                                 | 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,  troleandomycinvoriconazole carbamazepine3 , enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin3 , rifabutin,                                                                                                                   |
| Strong CYP3A4/5 inducers                                                   | rifampin (rifampicin)3 , St. John's wort (hypericum perforatum)2,3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Medications with a known                                                   | Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, chloroquine,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| risk for QT prolongation4                                                  | 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 |
| CYP3A4/5 substrates with NTI1                                              | Alfentanil, astemizole, cisapride, cyclosporine, diergotamine (dihydroergotamine),  ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Other investigational and  antineoplastic therapies  not part of the study | 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 from the study.                                                                                                                                                                                     |
| Herbal  preparations/  medications                                         | Herbal preparations/medications that are strong inhibitors or inducers of CYP3A4/5 or  those with a known risk of QT prolongation are prohibited throughout the study. These  herbal medications include, but are not limited to: black cohosh, St. John's wort, Kava,  ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw  palmetto, and ginseng. Patients should stop using these herbal medications 7 days prior to  first dose of study drug.                                                                                                                          |  
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 January 2018.Check https www crediblemeds.org/healthcare-providers/drug-list for the most updated list. 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.  
| 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, 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                                                                                                                                                                                                                                                                                                                                                          |
| 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, oxyplatin, 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,  venetoclax                                                                                                                                                                                                                                                                                                                                                                                            |
untitled h1
appendix 3 list of medications

| Medications that carry a possible risk   | Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine , asenapine,   |
|------------------------------------------|----------------------------------------------------------------------------|
| for QT prolongation2                     | 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, hydrocodoneER, 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                                                                            |  
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when coadministered 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 is prohibited when combined with ritonavir (see Table 14-1)
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.
appendix 4 pharmacokinetics (pks) collection
appendix 3 list of medications

Please see separately attached Appendix 4. APPENDIX 5: Plasma/Serum/Peripheral Blood Mononuclear Cell (PBMC) Banking (Optional) Please see separately attached Appendix 5. APPENDIX 6: Circulating Tumor Cells (CTCs) and Cell-Free Circulating Tumor DNA (ctDNA) Collection and Processing Instructions Please see separately attached Appendix 6. APPENDIX 7: Tumor Biopsy Procedure (Optional) Please see separately attached Appendix 7.
appendix 4 pharmacokinetics (pks) collection
appendix 8 ecog/kps conversion scale

| ECOG PERFORMANCE STATUS                         | KARNOFSKY PERFORMANCE STATUS               |
|-------------------------------------------------|--------------------------------------------|
| 100—Normal, no complaints; no evidence of       |                                            |
| disease                                         |                                            |
| 0—Fully active, able to carry on all pre-       |                                            |
| disease performance without restriction         | 90—Able to carry on normal activity; minor |
| signs or symptoms of disease                    |                                            |
| 80—Normal activity with effort, some signs or   |                                            |
| 1—Restricted in physically strenuous activity   | symptoms of disease                        |
| but ambulatory and able to carry out work of a  |                                            |
| light or sedentary nature, e.g., light house    | 70—Cares for self but unable to carry on   |
| wrk, office work                                | normal activity or to do active work       |
| 60—Requires occasional assistance but is        |                                            |
| able to care for most of personal needs         |                                            |
| 2—Ambulatory and capable of all selfcare but    |                                            |
| unable to carry out any work activities; up and | 50—Requires considerable assistance and    |
| about more than 50% of waking hours             | frequent medical care                      |
| 40—Disabled; requires special care and          |                                            |
| assistance                                      |                                            |
| 3—Capable of only limited selfcare; confined    |                                            |
| to bed or chair more than 50% of waking         | 30—Severely disabled; hospitalization is   |
| hours                                           | indicated although death not imminent      |
| 20—Very ill; hospitalization and active         |                                            |
| 4—Completely disabled; cannot carry on any      | supportive care necessary                  |
| selfcare; totally confined to bed or chair      | 10—Moribund                                |
| 5—Dead                                          | | 0—Dead                                   |