The purpose of this amendment is to implement health authority mandated changes. In addition, editorial changes have been made to sections where previous language was deemed inaccurate or ambiguous by site staff and study investigators, to ensure better protocol compliance. - The statement, “there was no evidence of cardio vascular toxicity in the 4 week toxicology studies, and” “rare and isolated” have been removed from Section 1.2.1.3 to be consistent with language that will be included in an updated [LEE011 Investigator’s Brochure]. - Section 1.2.2.4.1 has been updated to include information on cardiac toxicity that has been observed in patients who have received MEK162 post the release of the version 8 [Investigator’s Brochure]. - Section 6.2.3.2 has been updated to include “if two or more patients experience CTCAE grade 2 or greater treatment-related toxicities at a dose level in any cohort, all future dose escalations of LEE011 will be 50%. Only toxicities that occur during the first cycle will necessarily be considered for decisions”. - Hepato-biliary related DLT criterion (Table 6-2) has been updated to “CTCAE grade 2 total bilirubin concurrent with grade 2 ALT is a DLT except for patients with known liver metastatic disease. The corresponding changes to the dose modification table have been made. Table 6-3 has been updated to “in the event of this DLT hold LEE011 and MEK162 until the toxicity resolves to Grade 1 and restart at one dose level below for both agents. If toxicity recurs at the lower dose, then discontinue from study”. - Blood chemistry panel (Table 7-2) has been updated to include brain natriuretic peptide (BNP) and troponin measurements at each cycle of treatment for additional cardiac monitoring in patients.

Emerging safety data from this and other studies with LEE011 and MEK162 warrant the following changes to the protocol: - Preliminary evaluation of LEE011 and MEK162 indicates it is an active combination but associated with frequent adverse events necessitating dosing interruptions and reductions. In order to determine the most tolerable and efficacious dosing schedule for the combination, evaluation of alternate dosing schedules are incorporated. - Evaluation of the 28 day continuous dosing schedule was performed in the phase 1 single agent LEE011 study [CLEE011X2101]. Due to hematological toxicity, this schedule will not be pursued any longer. Therefore all references to continuous dosing schedule will be removed from this protocol. In addition, the eligibility criterion is modified to include only patients with ECOG performance score of 0 and 1. - The phase II section has been updated to include information regarding the RSTANCE2101 companion protocol. The statement has been added to inform the Investigator that patients may elect to participate in a companion protocol to study the mechanisms of resistance to the study drugs. - Results from the MEK162 food effect study and preliminary results from the LEE011 food effect study indicate that MEK162 and LEE011 can be administered with or without food. As of this amendment, MEK162 and LEE011 may be administered irrespective of food. - The objectives and endpoints and PK sections were updated to include exploratory analysis of the possible relationship between exposures of LEE011 and/or LEQ803 and QT prolongation. Finally, changes to correct typographical errors and harmonize protocol text where applicable have been made.

The main purpose of this amendment is to address recently observed safety findings from patients treated with LEE0l 1 (Ribociclib) in other clinical trials. 1. Recent data suggests a potential risk of hepatic toxicity (drug induced liver injury [DILi] indicated by an increase of transaminases, in isolation or with bilirubin increase, in patients treated with LEE01. 2. Updates to monitoring and dose adjustment guidelines for QTcF prolongation in order to improve patient safety based on program standard language recommendations have been implemented. 3. Changes to specific sections of the protocol are shown in the track changes version of the protocol using strike through red font for deletions and red underlined for insertions. • The Protocol Summary is updated to reflect the changes to the inclusion and exclusion criteria • Section 5.2 Inclusion criteria has been updated with the following: • Clarification of inclusion criteria for serum total bilirubin for patients with Gilbert syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN • Update of AST and ALT <2.5 x ULN, except in patients with tumor involvement of the liver who must have AST and ALT< 5 x ULN. • Section 5.3 Exclusion criteria has been updated with the following: • Clarification of QTcF interval criteria on the ECG (ie: unreadable or not interpretable) or QTcF >450 ms (using Frederica's correction). All as determined by screening ECG (mean of triplicate ECGs). • Addition of symptomatic pericarditis within 12 months prior to starting study drug • Increase in exclusion window from 3 months to 12 months prior to starting study drug for angina pectoris • Increase in exclusion window from 3 months to 12 months prior to starting study drug for acute myocardial infarction