Ph1b/2 Open-Label,Multicenter Dose-Esc & Dose-Exp Study of Combo RMC4630 & Cobimetinib in Participants w/Relapsed/Refractory Solid Tumors & Ph1b Study of RMC4630 w/Osimertinib in Participants w/EGFR Mutation+,Locally Adv or Meta NSCLC
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: Revolution Medicines, Inc.

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Protocol Title:  
A Phase 1b/2, Open-Label, Multicenter Dose-Escalation and 
Dose-Expansion Study of the Combination of RMC-4630 with 
Cobimetinib in Adult Participants with Relapsed/Refractory 
Solid Tumors and a Phase 1b Study of RMC-4630 with 
Osimertinib in Participants with Epidermal Growth Factor 
Receptor Mutation Positive, Locally Advanced or Metastatic 
on-Small Cell Lung Cancer  
Protocol umber: 
RMC-4630-02 
Compound umber: 
RMC-4630 
Study Phase: 
Phase 1b/2
Short Title: 
Dose-Escalation and Dose-Expansion of RMC-4630 and Cobimetinib 
in Relapsed/Refractory Solid Tumors and Study of RMC-4630 with 
Osimertinib in EGFR Positive NSCLC after Osimertinib Progression 
Sponsor ame: 
Revolution Medicines, Inc.
Legal Registered
Address:
700 Saginaw Drive
Redwood City, CA 94063
Regulatory Agency
Identifying umber(s): IND 138359
Version/Date: 
V6.0 / 20 Nov 2020  

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CONFIDENTIAL 
Protocol RMC-4630-02 
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Revolution Medicines, Inc. 
Confidential 
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PROTOCOL SIGATORY, PRICIPAL IVESTIGATOR  
 
Title: 
A Phase 1b/2, Open-Label, Multicenter Dose-Escalation and 
Dose-Expansion Study of the Combination of RMC-4630 with 
Cobimetinib in Adult Participants with Relapsed/Refractory 
Solid Tumors and a Phase 1b Study of RMC-4630 with 
Osimertinib in Participants with Epidermal Growth Factor 
Receptor Mutation Positive, Locally Advanced or Metastatic 
on-Small Cell Lung Cancer 
Protocol o.: 
RMC-4630-02 
Version o. / Date: 
V6.0 / 20 Nov 2020 
Compound ID: 
RMC-4630 
Phase: 
1b/2 
Sponsor: 
Revolution Medicines 
Regulatory Agency 
Identifying o.: 
IND 138359 

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I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s ame (Print) 
 
Principal Investigator’s Signature 
 
 
 
Site umber 
 
Date (DD/MMM/YYYY) 

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Section 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF COTETS 
1. 
PROTOCOL SUMMARY ..............................................................................................27 
1.1. 
Synopsis .............................................................................................................................27 
1.1.1. 
RMC-4630 and Cobimetinib (Study in US and ex-US Countries) ...........................27 
1.1.2. 
RMC-4630 and Osimertinib (Study in US Only) .....................................................32 
1.2. 
Schemas .............................................................................................................................37 
1.3. 
Schedule of Activities (SoA) .............................................................................................40 
1.3.1. 
RMC-4630 and Cobimetinib SoA ............................................................................40 
1.3.2. 
RMC-4630 and Osimertinib SoA (Study in US Only) .............................................46 
2. 
ITRODUCTIO............................................................................................................55 
2.1. 
Study Rationale ..................................................................................................................55 
2.1.1. 
RMC-4630 and Cobimetinib Combination...............................................................55 
2.1.2. 
RMC-4630 and Osimertinib Combination (Study in US Only) ...............................56 
2.2. 
Background ........................................................................................................................57 
2.2.1. 
RMC-4630 and Cobimetinib Combination...............................................................57 
2.2.2. 
RMC-4630 and Osimertinib Combination (Study in US only) ................................60 
2.3. 
Benefit/Risk Assessment ...................................................................................................61 
2.3.1. 
Potential Risks ..........................................................................................................62 
2.3.2. 
Steps to Minimize Risk .............................................................................................71 
3. 
OBJECTIVES AD EDPOITS ................................................................................72 
3.1. 
RMC-4630 and Cobimetinib Combination ........................................................................72 
3.2. 
RMC-4630 and Osimertinib Combination (Study in US Only) ........................................73 
4. 
STUDY DESIG ..............................................................................................................74 
4.1. 
Overall Design for RMC-4630 and Cobimetinib...............................................................74 
4.1.1. 
Dose-Escalation Component.....................................................................................76 
4.1.2. 
Dose-Expansion Component ....................................................................................79 
4.1.3. 
Intra-participant Dose-Escalation .............................................................................80 
4.1.4. 
Duration of Therapy..................................................................................................81 
4.1.5. 
Scientific Rationale for Study Design ......................................................................81 
4.1.6. 
Justification for Starting Dose ..................................................................................82 

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4.2. 
RMC-4630 and Osimertinib Design (Study in US Only) ..................................................84 
4.2.1. 
Dose-Escalation Component.....................................................................................87 
4.2.2. 
Dose-Expansion Component ....................................................................................89 
4.2.3. 
Intra-participant Dose-Escalation .............................................................................89 
4.2.4. 
Duration of Therapy..................................................................................................89 
4.2.5. 
Scientific Rationale for Study Design ......................................................................90 
4.2.6. 
Justification for Starting Dose ..................................................................................90 
4.3. 
End of Study Definition .....................................................................................................90 
5. 
STUDY POPULATIO ..................................................................................................91 
5.1. 
Inclusion Criteria ...............................................................................................................91 
5.2. 
Exclusion Criteria ..............................................................................................................93 
5.3. 
Lifestyle Considerations ....................................................................................................96 
5.3.1. 
Meals and Dietary Restrictions .................................................................................96 
5.4. 
Screen Failures ...................................................................................................................96 
6. 
STUDY ITERVETIO ..............................................................................................96 
6.1. 
Study Intervention(s) Administered ...................................................................................96 
6.1.1. 
RMC-4630 and Cobimetinib ....................................................................................96 
6.1.2. 
RMC-4630 and Osimertinib (Study in US Only) .....................................................97 
6.2. 
Preparation/Handling/Storage/Accountability ...................................................................99 
6.3. 
Measures to Minimize Bias: Randomization and Blinding .............................................100 
6.4. 
Study Intervention Compliance .......................................................................................101 
6.4.1. 
Compliance Instructions .........................................................................................101 
6.4.2. 
Missed Dose ............................................................................................................101 
6.5. 
Permitted Concomitant Therapy ......................................................................................102 
6.5.1. 
Prohibited Concomitant Therapy ............................................................................103 
6.6. 
Dose Modification ...........................................................................................................103 
6.6.1. 
Dose Modification Rules ........................................................................................103 
6.6.2. 
Dose Modification Criteria for RMC-4630 and Cobimetinib ................................104 
6.6.3. 
Dose Modification Criteria for RMC-4630 and Osimertinib (Study in 
US Only) .................................................................................................................111 

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6.6.4. 
Supportive Care Guidelines for Selected Expected Toxicities ...............................117 
6.7. 
Intervention after the End of the Study ............................................................................121 
7. 
DISCOTIUATIO OF STUDY ITERVETIO AD 
PARTICIPAT DISCOTIUATIO/WITHDRAWAL .......................................122 
7.1. 
Discontinuation of Study Intervention .............................................................................122 
7.2. 
Participant Discontinuation/Withdrawal from the Study .................................................123 
7.3. 
Lost to Follow-Up ............................................................................................................124 
8. 
STUDY ASSESSMETS AD PROCEDURES ........................................................124 
8.1. 
Efficacy Assessments.......................................................................................................125 
8.2. 
Safety Assessments ..........................................................................................................125 
8.2.1. 
Physical Examinations ............................................................................................125 
8.2.2. 
Vital Signs...............................................................................................................126 
8.2.3. 
Weight and Height ..................................................................................................126 
8.2.4. 
Electrocardiograms .................................................................................................126 
8.2.5. 
Echocardiograms/Multigated Acquisition Scans ....................................................127 
8.2.6. 
Clinical Safety Laboratory Assessments ................................................................127 
8.2.7. 
ECOG Performance Status .....................................................................................128 
8.2.8. 
Retinal Examinations ..............................................................................................128 
8.3. 
Adverse Events and Serious Adverse Events ..................................................................128 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information ...................128 
8.3.2. 
Method of Detecting AEs and SAEs ......................................................................129 
8.3.3. 
Follow-up of AEs and SAEs ...................................................................................129 
8.3.4. 
Regulatory Reporting Requirements for SAEs .......................................................129 
8.3.5. 
Pregnancy................................................................................................................130 
8.3.6. 
Safety Committees ..................................................................................................130 
8.4. 
Treatment of Overdose ....................................................................................................131 
8.5. 
Pharmacokinetics .............................................................................................................131 
8.6. 
Pharmacodynamics ..........................................................................................................132 
8.8. 
Other Biomarkers .............................................................................................................133 
8.9. 
Health Economics and Medical Resource Utilization .....................................................134 

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9. 
STATISTICAL COSIDERATIOS .........................................................................134 
9.1. 
Statistical Hypotheses ......................................................................................................134 
9.2. 
Sample Size Determination..............................................................................................134 
9.3. 
Populations for Analyses .................................................................................................136 
9.4. 
Statistical Analyses ..........................................................................................................136 
9.4.1. 
Efficacy Analyses ...................................................................................................136 
9.4.2. 
Safety Analyses.......................................................................................................138 
9.4.3. 
Other Analyses ........................................................................................................138 
9.5. 
Interim Analyses ..............................................................................................................138 
10. 
REFERECES ...............................................................................................................139 
 
LIST OF APPEDICES 
Appendix 1  
Regulatory, Ethical, and Study Oversight Considerations...................................144 
Appendix 2  
Clinical Laboratory Tests .....................................................................................148 
Appendix 3  
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ....................................................................................150 
Appendix 4  
Contraceptive Guidance and Collection of Pregnancy Information ....................154 
Appendix 6  
Response Evaluation Criteria in Solid Tumours (RECIST v1.1) ........................158 
Appendix 7  
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale .........171 
Appendix 8  
Medication CLASSES that Potentially Prolong QTc and Strong CYP3A 
Inhibitors and/OR Inducers ..................................................................................172 
Appendix 10  Continual Reassessment Method .........................................................................177 
 
LIST OF FIGURES 
Figure 1  
Phase 1b/2 RMC-4630 and Cobimetinib Study Schema .......................................37 
Figure 2  
Dose Escalation Scenarios for RMC-4630 (D1, D4) and Cobimetinib 
(21/7) ......................................................................................................................37 
Figure 3  
RMC-4630 and Osimertinib Study Schema (Study in US only) ...........................39 
Figure 4  
Dose Escalation Scenario for RMC-4630 and Osimertinib ...................................39 

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Figure 6  
Staggered Enrollment Between Dose-Escalation and Dose-Expansion 
Cohorts for RMC-4630 and Cobimetinib Study ....................................................75 
 
LIST OF TABLES 
Table 1  
Sample Size Estimation .........................................................................................38 
Table 2  
Pharmacokinetic and Pharmacodynamic Sampling Timepoints: 
RMC-4630 + Cobimetinib: RMC-4630 – D1, D4 Q Week and 
Cobimetinib – Daily Dosing (21-on/7-off); RMC-4630 + Osimertinib (US 
Study Only): RMC-4630 – D1, D4 Q Week and Osimertinib – Daily 
Dosing (QD)...........................................................................................................52 
Table 3  
Pharmacokinetic and Pharmacodynamic Sampling Timepoints: 
RMC-4630 + Cobimetinib: D1, D2 Q Week  RMC-4630 + Cobimetinib: 
RMC-4630 D1, D2 Q Week and Cobimetinib Daily Dosing (21-on/7-off) 
RMC-4630 + Osimertinib (US Study Only): RMC-4630 – D1, D2 Q 
Week and Osimertinib – Daily (QD) Dosing ........................................................53 
Table 4   
Starting Dose of RMC-4630 ..................................................................................76 
Table 5 
Primary Dose Levels for RMC-4630 .....................................................................77 
Table 6  
Dose Escalation Rule of the Modified Toxicity Probability Interval-2 
Method ...................................................................................................................85 
Table 7  
Study Interventions Administered: RMC-4630 and Cobimetinib .........................98 
Table 8  
Study Interventions Administered: RMC-4630 and Osimertinib ..........................99 
Table 9   
Dose Modification Guidelines for RMC-4630 and Cobimetinib ........................106 
Table 10  
Dose Modification Guidelines with RMC-4630 and Cobimetinib During 
Final Dose Expansion ..........................................................................................109 
Table 11  
RMC-4630 and Cobimetinib Dose Levels (Final Expansion at RP2DS) ............111 
Table 12  
Osimertinib Dose Levels......................................................................................113 
Table 13  
RMC-4630 Dose Levels (Dose Escalation) .........................................................113 
Table 14  
Dose Modification Guidelines for RMC-4630 and Osimertinib .........................114 
Table 15  
Population Definitions .........................................................................................136 
Table 16  
Efficacy Analyses ................................................................................................137 
Table 17  
Safety Analyses ....................................................................................................138 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1b/2, Open-Label, Multicenter Dose-Escalation and Dose-Expansion 
Study of the Combination of RMC-4630 with Cobimetinib in Adult Participants with 
Relapsed/Refractory Solid Tumors and a Phase 1b Study of RMC-4630 with Osimertinib in 
Participants with Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or 
Metastatic Non-Small Cell Lung Cancer 
Short Title: Dose-Escalation and Dose-Expansion of RMC-4630 and Cobimetinib in 
Relapsed/Refractory Solid Tumors and Study of RMC-4630 with Osimertinib in EGFR positive 
NSCLC after Osimertinib Progression 
1.1.1. 
RMC-4630 and Cobimetinib (Study in US and ex-US Countries) 
 
 
 
 
 
 
 
 
 
 
 

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OBJECTIVES AD EDPOITS FOR RMC-4630 AD COBIMETIIB STUDY 
Objectives 
Endpoints 
Primary 
x 
To characterize the safety and tolerability of the 
combination of RMC-4630 and cobimetinib in 
participants with relapsed/refractory solid tumors 
x 
To define the MTD and RP2D and schedules for the 
combination of RMC-4630 and cobimetinib in 
participants with relapsed/refractory solid tumors 
x 
Incidence, nature, and severity of treatment 
emergent AEs and SAEs, graded according to the 
NCI CTCAE v5 for the combination of RMC-4630 
and cobimetinib 
x 
Incidence and nature of DLTs for the combination 
of RMC-4630 and cobimetinib 
Secondary 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Tertiary/Exploratory 
x 
 
  
 
 
 
x 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
x 
 
 
Abbreviations: AE, adverse events; AUC0-t, area under the curve from dosing time to time t; AUCinf, area under the curve from 
dosing time to infinity; 
; Cmax, peak concentration; ctDNA, circulating tumor 
DNA; DCR, disease control rate; DLT, dose limiting toxicity; DOR, duration of response; MTD, maximum tolerated dose; 
, mutations in neurofibromin 1 predicted to result in loss of function; ORR, objective response rate; PFS, progression 
free survival; PK, pharmacokinetic(s); NCI CTCAE v5, National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5; OS, overall survival; PFS, progression-free survival; PD, pharmacodynamic; RAS-MAPK, RAS-mitogen 
activated protein kinase; RECIST v1.1, Response Evaluation Criteria in Solid Tumours, Version 1.1; RP2D, recommended 
phase 2 dose; SAE, serious adverse events; t1/2, elimination half-life; Tmax, time to achieve peak plasma concentration. 

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Overall Design  
This study arm with RMC-4630 and cobimetinib will be conducted in US and ex-US countries. 
This arm includes two components: a Dose-Escalation Component and a Dose-Expansion 
Component. The overall schema is illustrated in Figure 1.  
Prior to enrollment, all participants will undergo screening based on prior genomic testing using 
a clinically validated or qualified assay on either tumor tissue or circulating tumor DNA 
(ctDNA) samples. Questions regarding eligible mutations may be addressed to the Sponsor. 
Participants with at least one the following genotypes and histotypes will be enrolled 
 
 
 
 
Archival tissue will be requested from all participants. For genomic reports based on clinically 
validated local tests and used for enrollment, retrospective analysis will be performed by a 
central lab on archival tissue for analysis and reporting purposes. A fresh biopsy will not be used 
to determine patient eligibility. 
Dose-Escalation Component:  This arm will begin with the Dose Escalation Component. The 
initial dose of RMC-4630 will be 80 mg administered orally (PO) twice weekly, D1 and D4, for 
28 days of a 28-day cycle. 
The starting dose of cobimetinib will be 20 mg PO administered daily (QD) on days 1-21 of a 
28-day cycle (21/7 schedule). This dose is two dose levels below the approved dose of 
cobimetinib of 60 mg PO QD on the 21/7 schedule.  
In addition to the planned dose levels, alternative dose schedules which allow D1, D2 dosing of 
either or both RMC-4630 and cobimetinib may be initiated and the starting dose will be based on 
the analysis of emerging safety and PK data. Therefore, RMC-4630 can be administered in either 
a D1, D4 or D1, D2 schedule. Whereas, cobimetinib can be administered in either once daily 
(21/7) or D1, D2 schedule. However, the single and monthly starting dose for cobimetinib will 
not exceed those already tested in clinical trials. The decision to trigger exploration of an 
alternative schedule will be made by the Dose-Escalation and Expansion Committee (also 
referred to as “Dose Committee”) after careful review of emerging toxicity profile of the 
combination. 

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Advancement to higher combination dose levels during the escalation phase will occur after an 
evaluation of safety and tolerability by the Dose Committee. The proposed continual 
reassessment method (CRM) will generate dose combination recommendations. The model 
estimates the probability of dose limiting toxicities (DLTs) in Cycle 1 (C1) at each candidate 
combination dose level to determine the dose combination to treat the next cohort. The MTD is 
selected as the combination associated with the highest posterior probability of DLT rating 
within the target interval of 25% - 35% and which have been used to treat at least 6 participants. 
During escalation, a minimum of 3 participants on a combination dose level are required to be 
DLT evaluable to render a decision to proceed to the next dose level. A 4th participant, if 
available, may enroll onto the escalation dose before the first 3 participants have completed the 
DLT evaluation. DLT events for all participants at a given combination dose level will be 
entered into the CRM model and assessed by the Study Dose Committee. The first cycle 
(28 days) constitutes the DLT assessment period. Parallel Dose-Escalation Cohorts may be 
allowed. 
Dose-Expansion Component:  After the Dose-Escalation Component has ended and the RP2D is 
determined, a Dose-Expansion cohort of up to 90 participants (including those already enrolled 
at this dose in the Dose-Escalation and Expansion cohorts) will be enrolled at the RP2D. In this 
Dose-Expansion cohort, up to 15 participants in each of the 6 genotypic/histotypic cohorts will 
be enrolled.  
Moreover, once the Dose-Escalation Component has reached a threshold of activity based on 
clinically meaningful reduction in tumor burden at a dose with acceptable toxicity, additional 
participants may possibly be enrolled at dose levels prior to the determination of RP2D. The 
Dose Committee will determine whether clinically meaningful reduction has been achieved 
(eg, UHGXFWLRQLQWKH sum of longest diameters of target lesions or a lesser diminution with 
a preponderance of clinical evidence of benefit). See ‘Dose-Escalation and Expansion 
Committee Charter’ for more information.   
Expansion prior to RP2D may occur at more than one dose level. The current Dose-Expansion 
cohort will stop enrollment after the next higher dose combination in the Dose-Escalation 
Component is completed. At this point, the Dose-Expansion Cohort at the new higher level will 
open for enrollment if the dose is considered to have acceptable tolerability during the 
Dose-Escalation Component. Parallel Dose-Expansion cohorts may occur. A maximum of 
12 participants (in both Dose-Escalation and Expansion cohorts) may enroll in each dose 
combination level. Once a dose level is expanded to include more slots, the sponsor may choose 
to reserve slots for genotypes/histotypes which are considered more likely to obtain clinical 
benefit based on the emerging clinical and/or biomarker data.   

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Duration of Therapy 
Participants will be permitted to remain on study therapy until disease progression per 
RECIST v1.1, unacceptable toxicity, other criteria for withdrawal are met, or end of study (refer 
to Section 4.3), whichever comes first. Participants will return to the clinical site for an End of 
Treatment (EOT) visit within 30 days after last dose of study treatment.  
1.1.2.
RMC-4630 and Osimertinib (Study in US Only) 
Duration of 
Participants will be permitted to remain on study therapy until disease progression per 
RECIST 1 1
t bl t
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th
it i f
ithd
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t
d f t
RECIST v1.1, unacceptable toxicity, other criteria for withdrawal are met, or end of study (refer
S
i
4 3)
hi h
fi
P
i i
ill
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li i
l i
f
E d f
to Section 4.3), whichever comes first. Participants will return to the clinical site for an End of
T
(EOT) i i
i hi 30 d
f
l
d
f
d
Treatment (EOT) visit within 30 days after last dose of study treatment. 
1.1.2.
RMC-4630 and Osimertinib (Study in US Only) 
32
f Th
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OBJECTIVES AD EDPOITS FOR RMC-4630 AD OSIMERTIIB STUDY  
Objectives 
Endpoints 
Primary 
x 
To characterize the safety and tolerability of the 
combination of RMC-4630 and osimertinib in 
participants with EGFR mutation-positive NSCLC 
who have progressed on or after osimertinib  
x 
To define the maximum tolerated dose (MTD), 
recommended Phase 2 dose (RP2D) and schedule 
for the combination of RMC-4630 and osimertinib 
in participants with EGFR mutation-positive 
NSCLC 
x 
Incidence, nature, and severity of treatment 
emergent AEs and SAEs, graded according to the 
NCI CTCAE v5 for the combination of 
RMC-4630 and osimertinib 
x 
Incidence and nature of DLTs for the combination 
of RMC-4630 and osimertinib 
Secondary 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

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Overall Design  
This arm with RMC-4630 and osimertinib will be conducted ONLY in the US. It will include 
two components: a Dose-Escalation Component and a Dose-Expansion Component. The overall 
schema is illustrated in Figure 3.  
Prior to enrollment into this arm, all participants will undergo screening to determine eligibility. 
Information regarding existing mutations at baseline will be collected using prior histological or 
ctDNA documentation for EGFR mutations. Sponsor will determine eligibility based on the 
presence of an EGFR mutation in the most recent genomic report (for the dose escalation 
component of the study). The following mutations/histologies will not be eligible to enroll: 
 
 
 
  
 
Dose-Escalation Component:  This arm will begin with the Dose Escalation Component. The 
starting dose of RMC-4630 will be 140 mg on D1 and D2. -The starting dose of osimertinib will 
be at the approved dose of 80 mg once daily. Alternative dose schedule for RMC-4630 including 
D1D4 dosing may be explored depending on emerging data from this study and other RMC-4630 
studies. The decision for initial dose/schedule of RMC-4630 was made by the Dose Committee 
after careful evaluation of the safety data. Dose-Escalation scenario for RMC-4630 and 
osimertinib is shown in Figure 3. 
The first cycle (eg, 28 days) constitutes the DLT assessment period. The first participant in the 
initial combination dose level will be observed for the first 7 days of dosing prior to dosing 
additional participants in this cohort. Following this 7-day observation period, additional 
participants may be enrolled in the cohort. In subsequent combination dose level cohorts, 
participants may be enrolled concurrently. 
Dose-Expansion Component:  After the Dose-Escalation Component has reached an MTD, the 
Dose committee will determine whether Dose-Expansion phase should be initiated and will 
determine RP2D which may or may not be the same as MTD but, would not exceed MTD. In 
Dose-Expansion, up to 6-18 participants may enroll depending on how many participants will 
enroll in the Dose-Escalation portion for a total of 24 participants in the RMC-4630 + 
osimertinib arm. 

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All participants in the Dose-Expansion phase will undergo screening to determine their 
eligibility. Participants will be eligible if the tumor harbors one or more of the genetic 
aberrations defined to be sensitive to SHP2 inhibition by the sponsor and does not harbor any 
co-occurring mutations which are not sensitive to SHP2 inhibition (Section 4.2, Appendix 9B).  
Duration of Therapy 
Participants will be permitted to remain on study therapy until disease progression per 
RECIST v1.1, unacceptable toxicity, other criteria for withdrawal are met, or end of study (refer 
to Section 4.3), whichever comes first. Participants will return to the clinical site for an End of 
Treatment (EOT) visit within 30 days after last dose of study treatment 
Safety Committees 
Two safety committees, the Dose-Escalation and Expansion Committee (“Dose Committee”) 
composed of Sponsor representatives and investigators, and the Internal Safety Monitoring 
Committee (ISMC), consisting of internal Sponsor representatives including Medical Monitors 
(Sponsor and contract research organization [CRO]), Drug Safety Monitor, and biostatistician, 
will monitor the safety data from RMC-4630 program. The Dose Committee is study-specific 
while the ISMC is RMC-4630 program-specific. Details regarding membership and roles and 
responsibilities will be provided in the respective committee charters.  
For both arms in this study, the Dose Committee will be responsible for evaluating the safety 
data during the DLT period and provide decisions regarding the actual dose escalation level 
based on safety data and any other relevant available information. The RP2D will be determined 
by the Sponsor based on the totality of the information available at all dose levels and should not 
exceed the MTD. Finally, the Dose Committee will determine whether the Dose Expansion 
Component may commence at the completion of a given Dose Escalation Cohort. 
The ISMC will conduct regular safety data reviews as well as ad hoc emergent safety data review 
for all participants during the course of the trial. 

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1.2.
Schemas 
Figure 1  
Phase 1b/2 RMC-4630 and Cobimetinib Study Schema 
Figure 2  
Dose Escalation Scenarios for RMC-4630 (D1, D4) and Cobimetinib (21/7)
Illustration of two possible dose escalation scenarios (Figure 2). Other scenarios are possible 
but not shown. Beginning at combination dose level 1, participants are enrolled in a series of 
cohorts with each cohort having a minimum of 3 participants. The dose level of the next cohort 

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will be recommended from the Bayesian model; however, the actual dose selected will be 
determined by the Dose Committee based on evaluation of DLTs, the CRM model 
recommendations, and other available relevant information. Scenario 1 is one possible scenario 
and is used to estimate the sample size in Table 1. The designations “a”, “b”, and “c” are used to 
demonstrate different cohorts. Enrollment into cohorts 2a and 2b, may occur simultaneously, as 
may cohorts 4b and 4c. Escalation to next dose level will only occur after DLT evaluation of one 
or both parallel cohorts (eg, escalation to level 3 will only occur after DLT evaluation for both 2a 
and 2b). An alternative dose escalation path is represented in Scenario 2. If dosing on D1, D2 is 
triggered for either or both RMC-4630 and cobimetinib, the dose escalation scenarios will 
remain the same.  
umber of Participants: Table 1 illustrates sample size estimation based on “Scenario 1” 
depicted in Figure 2. The study is expected to enroll approximately 144 participants in 
RMC-4630 and cobimetinib arm of the study.  
Table 1  
Sample Size Estimation 
 
 
  
  
  
 
 
 
 
 
a  
 
 
  
  
 
  
b  
 
  
c 
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Figure 3  
RMC-4630 and Osimertinib Study Schema (Study in US only)
Figure 4  
Dose Escalation Scenario for RMC-4630 and Osimertinib 
Illustration of possible dose escalation scenario (Figure 4). Beginning at combination dose 
level 1, participants are enrolled in a series of cohorts with each cohort having a minimum of 
3 participants. The dose level of the next cohort has been pre-specified in the protocol; however, 
the actual dose selected will be determined by the Dose-Escalation Committee based on 
evaluation of DLTs and other available relevant information. The designations “1”, “2”, and “3” 
are used to demonstrate different escalation cohorts at different dose levels. Enrollment into 
cohorts will be sequential. Escalation to next dose level will only occur after DLT evaluation. 

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1.3. 
Schedule of Activities (SoA)  
1.3.1. 

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X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

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. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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1.3.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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C3D1 
then QO 
cycle 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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See Footnotes on the following page. 

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Table 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
  
  
 
 
 
 
 
 
 
 
 
 
  
     
  
     
    
  
 
 
  

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See Footnotes on the following page. 

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2. 
ITRODUCTIO 
RMC-4630 is a potent, selective, and orally bioavailable SHP2 allosteric inhibitor that is being 
developed for patients with tumors harboring certain activating genotypic aberrations in the 
RAS/MAPK pathway. 
Cobimetinib is an orally bioavailable, small molecule inhibitor of MEK1/2 which is approved in 
combination with vemurafenib, a BRAF inhibitor, for the treatment of advanced BRAFV600E/K 
mutated melanoma.  
Osimertinib is an oral kinase inhibitor of the epidermal growth factor receptor (EGFR), which 
binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion), and 
is indicated for first-line treatment of patients with metastatic non-small cell lung cancer 
(NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected 
by a United States Food and Drug (US FDA)-approved test. It is also indicated for patients with 
metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, 
whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy. 
2.1. 
Study Rationale  
2.1.1. 
RMC-4630 and Cobimetinib Combination 
 
 
 
 
 
 
 
 
 
 

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2.1.2. 
RMC-4630 and Osimertinib Combination (Study in US Only) 
 
 
 
 
  
 
 

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2.2. 
Background 
2.2.1. 
RMC-4630 and Cobimetinib Combination 
SHP2 is a non-receptor protein tyrosine phosphatase and scaffold protein that functions 
downstream of multiple receptor tyrosine kinases (RTKs), integrating cell surface growth factor 
signals to promote RAS activation (Figure 5). RMC-4630 was designed as a potent and selective 
SHP2 allosteric inhibitor that suppresses RAS activation and the proliferation in cancers that, 
distinct from those dependent on oncogenic RTKs, are driven by nucleotide cycling oncogenic 
point mutations 
 
 

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Figure 5  
The RAS-MAPK Pathway Demonstrating the Convergence odal Position of 
SHP2 in the pathway 
Unfortunately, in most models, tumor cytostasis was followed by regrowth of tumors, 
reminiscent of patterns observed with BRAF and MEK inhibitors, where initial response to 
single agents is followed by tumor resurgence and resistance on treatment (Fedele 2018). In the 
NCI-H358 KRASG12C model of NSCLC, examination of the pharmacokinetic/ pharmacodynamic 
(PK/PD) relationship for SHP2 inhibition demonstrated that maximal concentrations of SHP2 
inhibitor achieved ~75% inhibition (relative to control) of phospho-ERK1/2 (pERK), a 
downstream indicator of oncogenic flux via RAS (RevMed data on file). In total, these results 
support the hypothesis that pharmacologic inhibition of a single node within the RAS-MAPK 
pathway results in incomplete pathway inhibition and tumor persistence. 
Consequently, the combination of MEK inhibitors and a SHP2 allosteric inhibitor was evaluated 
as a strategy to attenuate this feedback hyperactivation, restore efficacy, and forestall resistance 
in CDX and PDX models with oncogenic RAS-MAPK pathway mutations (RevMed data on 

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file). Concurrent targeting of SHP2 and the downstream MEK confers greater anti-tumor 
efficacy and was observed in models that were heretofore responsive to SHP2 inhibitor 
monotherapy. More consistent and greater tumor regressions with combination therapy were 
observed than can be attained with single agents that target these nodes within the RAS-MAPK 
pathway. Similarly, the combination of SHP2 and MEK inhibition enhance the sensitivity of 
KRAS-amplified cancer models both in vitro and in vivo (Wong 2018).  
 
 
 
 
The combination regimen achieved greater duration of tumor pERK inhibition, reflecting either 
SHP2 inhibitor-mediated attenuation of RTK-driven feedback mechanisms and/or stronger 
pathway suppression per se. As a consequence, the combinatorial effects on inhibition of tumor 
cell proliferation as well as induction of apoptosis were observed. Moreover, recent publications 
have highlighted the potential for the combination of SHP2 inhibition with MEK inhibition in 
RAS mutant cancer cell lines that are insensitive to SHP2 or MEK inhibitor monotherapy 
(RevMed data on file; Fedele 2018, Mainardi 2018, Ruess 2018). 
 
 
 
 
In summary, the findings reveal potential therapeutic approaches that use a potent SHP2 inhibitor 
in combination with another in-pathway inhibitor to counteract the evolution of resistance in 
tumors harboring alterations in the RAS-MAPK pathway. Additionally, the combination of 
SHP2 inhibition with MEK inhibition has the potential to provide therapeutic benefit in tumors 
driven by oncogenic mutations insensitive to either agent alone.   

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2.2.2.
RMC-4630 and Osimertinib Combination (Study in US only) 
The combination of RMC-4630 with osimertinib was examined under two different experimental 
paradigms using the osimertinib-sensitive NCI-H1975 xenograft model of human NSCLC driven 
by EGFRL858R,T790M. 
Resistance to osimertinib treatment is often driven by reactivation of RAS-MAPK signaling 
through myriad mechanisms including alternate RTK-mediated bypass (Oxnard 2018) such as 
amplification of MET.  SHP2 functions as a convergent node downstream of multiple RTKs to 
regulate RAS activation. SHP2 inhibition is predicted to be effective in a variety of situations 
wherein RTK bypass drives resistance to RAS-MAPK pathway inhibitors (Dardaei 2018, 
Lu 2019).  
In summary, these findings reveal potential therapeutic approaches that use a potent SHP2 
inhibitor in combination with a third-generation EGFR inhibitor, osimertinib, to either counteract 

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the evolution of resistance in tumors harboring EGFR alterations, or to re-sensitize osimertinib-
resistant tumors wherein RTK bypass mechanisms drive reactivation of RAS-MAPK signaling. 
2.3. 
Benefit/Risk Assessment 
RMC-4630 and Cobimetinib Combination 
Most patients with mutations/rearrangements that confer hyperactivation of the RAS-MAPK 
pathway have a poor prognosis. The combination of SHP2 inhibition together with MEK1/2 
inhibition provides a potentially novel targeted treatment for these patients with relapsed or 
refractory solid tumors harboring mutations resulting in hyperactivation of the RAS-MAPK 
pathway.  
RMC-4630 is currently being administered to humans in a phase 1 dose-escalation and dose-
expansion monotherapy study, Protocol RMC-4630-01, (https://clinicaltrials.gov; 
NCT03634982) evaluating its safety, tolerability, MTD, and RP2D, PK, and PD profiles. More 
detailed information about the expected benefits and risks and reasonably expected adverse 
events of RMC-4630 based on clinical and pre-clinical data and class of drugs may be found in 
the RMC-4630 IB.  
 
 
RMC-4630 and Osimertinib Combination (Study in US Only) 
Osimertinib has been administered in clinical trials and is approved as first line treatment of 
patients with metastatic NSCLC whose tumors have an EGFR exon 19 deletion or exon 21 
L858R mutation, as detected by an FDA approved test. Per National Comprehensive Cancer 
Network (NCCN) guidelines, osimertinib can be continued in patients post progression if benefit 
outweighs the risk. More detailed information regarding known benefits, risks, and expected 
adverse events of osimertinib may be found in the Tagrisso United States package insert. 
Most patients that are currently receiving treatment with osimertinib will progress due to a 
resistance mechanism which may or may not be detected by a tissue biopsy or ctDNA. Some of 
these patients will continue to receive treatment with osimertinib as a single agent 
(NCCN guidelines). In patients that have progressed on or after osimertinib or an osimertinib 
containing regimen, the combination of a SHP2 inhibitor with osimertinib may reverse 
osimertinib resistance mechanism(s) and prolong its benefit. Osimertinib may be the most recent 
prior therapy before starting combination treatment with SHP2 inhibitor. Alternatively, patients 
with intervening therapies (such as chemotherapy) after osimertinib progression may be allowed. 

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2.3.1.2. 
Potential Risks of Cobimetinib  
In a Phase 1a study, two dosing schedules of cobimetinib monotherapy were assessed: 21 days of 
a 28 cycle (21/7) and 14 days of a 28 day schedule (14/14) (MEK 4592g). All patients in this 
study experienced an adverse event (AE). The most frequent AEs were diarrhea (67.0%), fatigue 
(50.4%), rash (49.6%), nausea, vomiting (33.9% each), and edema peripheral (28.7%). Other 
events that occurred in t10% of patients included anemia, abdominal pain, constipation, 
hypokalemia, decreased appetite, headache, dizziness, back pain, increased aspartate 
aminotransferase (AST), dermatitis acneiform, pruritus, and dry skin. Four DLTs with a 21/7 
dosing schedule were observed in this monotherapy trial. At the 40 mg 21/7 dose level, a DLT of 
Grade 4 hepatic encephalopathy and Grade 3 elevated ammonia. At the 60 mg 21/7 dose level, a 
DLT of Grade 3 rash was reported. At the 80 mg 21/7 dose level, two DLTs were reported: 
1 patient with Grade 3 diarrhea and 1 patient with Grade 3 rash (cobimetinib IB). 
The best described combination studies of cobimetinib involve concurrent administration with 
vemurafenib in metastatic melanoma. In the Phase 1b dose-escalation study, the most common 
adverse events were diarrhea (64%), non-acneiform rash (60%), liver enzyme abnormalities 
(50%), fatigue (48%), nausea (45%), and photosensitivity (40%). Most adverse events were 
mild-to-moderate in severity. The most common Grade 3 or 4 adverse events were cutaneous 
squamous-cell carcinoma (9%; all Grade 3), raised alkaline phosphatase (ALP) (9%), and anemia 
(7%) (Ribas 2014). In the subsequent confirmatory phase 3 trial of cobimetinib and vemurafenib 
vs. vemurafenib in melanoma patients, the combination of vemurafenib and cobimetinib was 
associated with a higher frequency of certain events than the single-agent vemurafenib therapy, 
including central serous retinopathy, gastrointestinal events (eg, diarrhea, nausea, or vomiting), 
photosensitivity, elevated aminotransferase levels, and an increased creatine phosphokinase 
(CPK) level; the majority (>50%) of these individual events were Grade 1 or 2. Equivalent rates 
of Grade 3 events (49%) in the two study groups and substantially fewer Grade 4 events 
(9% control vs. 13% combination), with close to half of these in the experimental group being 

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due to laboratory abnormalities (elevated AST, alanine aminotransferase [ALT], and CPK levels) 
but without symptoms. An elevated CPK level, a known class effect of MEK blockade, was the 
single most common Grade 4 event (4%) with the combination therapy, although the majority of 
events related to CPK (66%) were Grade 1 or 2 (Larkin 2014). 
In total, the most common AEs of cobimetinib (t20%) are diarrhea, photosensitivity reaction, 
nausea, pyrexia, and vomiting. The most common (t5%) Grade 3-4 laboratory abnormalities are 
increased gamma-glutamyl transferase (GGT), increased CPK, hypophosphatemia, increased 
ALT, lymphopenia, increased AST, increased ALP, hyponatremia. Moreover, serious risks of 
cobimetinib and vemurafenib administration include (Cobimetinib US Package Insert):  
x ew primary cutaneous and non-cutaneous malignancies: Cutaneous neoplasms and 
premalignant lesions including keratoacanthoma, basal cell carcinoma, cutaneous 
squamous cell carcinoma, and secondary melanoma occurred in combination therapy of 
vemurafenib plus cobimetinib. Non-cutaneous malignancies were reported in 0.8% of the 
vemurafenib and cobimetinib arm and 1.2% of the vemurafenib arm. 
x Hemorrhage including major hemorrhagic events: The incidence of hemorrhage was 
higher in those receiving the combination of cobimetinib and vemurafenib therapy in 
comparison with those receiving vemurafenib (eg, Grade 3-4 hemorrhage 1.2% vs. 0.8%; 
all grades hemorrhage 13% vs. 7%). Cerebral, gastrointestinal, reproductive system 
hemorrhage, and hematuria were observed. 
x Cardiomyopathy: Grade 2 or 3 decrease in left ventricular ejection fraction (LVEF) 
occurred in 26% of patients receiving cobimetinib with vemurafenib and 19% of patients 
receiving vemurafenib plus placebo. The median time to first onset of LVEF decrease 
was 4 months (range 23 days to 13 months) and median time to resolution of 3 months 
(range: 4 days to 12 months, among 62% of affected participants). 
x Severe dermatologic reactions: Grade 3 to 4 rash, occurred in 16% of patients receiving 
cobimetinib with vemurafenib and in 17% of patients receiving vemurafenib plus 
placebo. The incidence of rash resulting in hospitalization was 3.2% in patients receiving 
cobimetinib with vemurafenib and 2.0% in patients receiving vemurafenib plus placebo. 
In patients receiving cobimetinib, the median time to onset of Grade 3 or 4 rash events 
was 11 days (range: 3 days to 2.8 months) and 95% experienced complete resolution with 
the median time to resolution of 21 days (range 4 days to 17 months). 
x Serous retinopathy and retinal vein occlusion: With prospective serial ocular 
examinations, 26% of patients receiving cobimetinib and vemurafenib demonstrated 
serious retinopathy. The majority of these events were reported as chorioretinopathy 
(13%) or retinal detachment (12%). The onset of serious retinopathy occurred between 
2 days to 9 months and the duration was 1 day to 15 days. Retinal vein occlusion 

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occurred in one patient in each arm (cobimetinib plus vemurafenib and vemurafenib 
arms). 
x Hepatotoxicity: The incidences of Grade 3 or 4 liver laboratory abnormalities among 
patients receiving cobimetinib with vemurafenib compared to patients receiving 
vemurafenib plus placebo were: 11% vs. 6% for ALT, 7% vs. 2.1% for AST, 1.6% vs. 
1.2% for total bilirubin, and 7% vs. 3.3% for ALP. Concurrent increase in 
ALT > 3 × upper limit of normal (ULN) and bilirubin > 2 × ULN in the absence of 
significant ALP > 2 × ULN occurred in 1 patient receiving cobimetinib and vemurafenib 
and no patients receiving vemurafenib. 
x Rhabdomyolysis and increased creatine phosphokinase: Grade 3 or 4 CPK elevations, 
including asymptomatic elevations over baseline, occurred in 12% of patients receiving 
cobimetinib with vemurafenib and 0.4% of patients receiving vemurafenib. The median 
time to first occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 12 days to 
11 months) in patients receiving cobimetinib with vemurafenib; the median time to 
complete resolution was 15 days (range: 9 days to 11 months). Elevation of blood CPK 
increase of more than 10 times the baseline value with a concurrent increase in blood 
creatinine of 1.5 times or greater compared to baseline occurred in 3.6% of patients 
receiving cobimetinib with vemurafenib and in 0.4% of patients receiving vemurafenib. 
Rhabdomyolysis has been observed in patients receiving cobimetinib. 
x Severe photosensitivity: Events of photosensitivity have been reported in 47% of 
participants receiving cobimetinib when administered with vemurafenib, although 
primarily reported as non-serious and low-grade events. 4% of patients experienced 
Grade t3 photosensitivity events. Median time to onset of photosensitivity of any grade 
was 2 months and the median duration was 3 months in patients receiving cobimetinib 
plus vemurafenib. The majority (63%) of patients experiencing photosensitivity had 
resolution of this symptom. 
x Embryo fetal toxicity: Based on its mechanism of action and findings from animal 
reproduction studies, cobimetinib can cause fetal harm when administered to a pregnant 
woman. In animal reproduction studies, oral administration of cobimetinib in pregnant 
rats during the period of organogenesis was teratogenic and embryotoxic at doses 
resulting in exposures (AUCs) that were 0.9 to 1.4X those observed in humans at the 
recommended dose of 60 mg. 
 
Refer to Cobimetinib US Package Insert for details and the most recent information.  
More recently, as a class, MEK inhibitors are reported to incur a posterior segment toxicity, 
known as MEK-associated retinopathy (Stjepanovic 2016). Affected patients may describe 
decreased acuity, altered color perception, shadows, light sensitivity, metamorphopsia and glare. 
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are not limited to neurosensory detachment, retinal pigment epithelial detachment, intraretinal 
edema, intraretinal cysts, vitelliform (exudative) findings, thickening or increased reflectivity of 
outer retina.  Fortunately, these events tend to resolve, often spontaneously, and long term 
sequalae are rarely reported. The mechanism of toxicity appears to be mediated by MEK-induced 
alterations in retinal pigment epithelial barrier functions that prevent the accumulation of 
subretinal fluid (Duncan 2015, Weber 2016, De La Cruz-Merino 2017, Tyagi 2018, 
Méndez-Martínez 2019). 
2.3.1.3. 
Potential Risks of RMC-4630 and Cobimetinib Combination  
The combination of RMC-4630 and cobimetinib has not been previously administered in 
humans. Overlapping toxicities are anticipated. The nonclinical toxicity findings identified with 
repeat daily dosing of RMC-4630 are largely similar to those described for cobimetinib. In 
general, toxicities are also predicted to be dose- and duration-dependent, monitorable and 
reversible. In combination, adverse events may also increase in frequency and severity with 
duration of therapy and/or manifest at lower individual dose of each drug. 
 
 
 
 
 
 
2.3.1.4. 
Potential Risks of Osimertinib (for US Study only) 
7KHPRVWFRPPRQDGYHUVHUHDFWLRQVLQSDWLHQWVWUHDWHGZLWKosimertinib as reported in 
the FLAURA study were diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), 
stomatitis (29%), and decreased appetite (20%). Serious adverse reactions were reported in 
4% of patients treated with oVLPHUWLQLEWKHPRVWFRPPRQVHULRXVDGYHUVHUHDFWLRQVZHUH
pneumonia (2.9%), interstitial lung disease (ILD)/pneumonitis (2.1%), and pulmonary embolism 
(1.8%). Dose reductions occurred in 2.9% of patients treated with osimertinib. The most frequent 
adverse reactions leading to dose reductions or interruptions were prolongation of the QT 

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interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse 
reactions leading to permanent discontinuation occurred in 13% of patients treated with 
osimertinib. The most frequent adverse reaction leading to discontinuation of osimertinib was 
ILD/pneumonitis (3.9%). The most common laboratory abnormality worsening from baseline 
were lymphopenia (63%), anemia (59%), thrombocytopenia (51%), and neutropenia (41%) any 
grade. High grade worsening (grade 3 or 4) in lymphopenia was observed in 5.6% of patients, 
anemia and thrombocytopenia in 0.7% of patients, and neutropenia in 3.0% of patients 
(Tagrisso USPI). 
Fatal adverse events occurred in 6 patients (2%) with osimertinib treatment which included 
pneumonia, respiratory tract infection, cerebral infarction, myocardial infarction, pulmonary 
embolism, and intestinal ischemia in 1 patient each. However, none of the fatal adverse events 
were assessed as related to the osimertinib. There were no fatal cases of torsades de pointes or 
prolongation of QT interval in patients treated with osimertinib (Soria 2018). 
Warnings and Precautions as reported in the osimertinib USPI are as follows:  
x Interstitial Lung Disease/Pneumonitis: Interstitial lung disease (ILD)/pneumonitis 
occurred in 3.9% of the 1142 osimertinib-treated patients; 0.4% of cases were fatal. 
Withhold osimertinib and promptly investigate for ILD in patients who present with 
worsening of respiratory symptoms which may be indicative of ILD (eg, dyspnea, cough 
and fever). Permanently discontinue osimertinib if ILD is confirmed. 
x QTc Interval Prolongation: Heart rate-corrected QT (QTc) interval prolongation occurs 
in patients treated with osimertinib. Of the 1142 patients treated with osimertinib in 
clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an 
increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported.  
Clinical trials of osimertinib did not enroll patients with baseline QTc of >470 msec. 
Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long 
QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are 
taking medications known to prolong the QTc interval. Permanently discontinue 
osimertinib in patients who develop QTc interval prolongation with signs/symptoms of 
life-threatening arrhythmia.  
x Cardiomyopathy: Across clinical trials, cardiomyopathy (defined as cardiac failure, 
chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection 
fraction) occurred in 2.6% of the 1142 osimertinib-treated patients; 0.1% of 
FDUGLRP\RSDWK\FDVHVZHUHIDWDO$GHFOLQHLQ/9()IURPEDVHOLQHDQGWROHVV
than 50% LVEF occurred in 3.9% of 908 patients who had baseline and at least one 
follow-up LVEF assessment. Conduct cardiac monitoring, including assessment of LVEF 
at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in 
patients who develop relevant cardiac signs or symptoms during treatment. For 
symptomatic congestive heart failure, permanently discontinue osimertinib.  

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x Keratitis: Keratitis was reported in 0.7% of 1142 patients treated with osimertinib in 
clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis 
(such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or 
red eye) to an ophthalmologist. 
x Erythema Multiforme and Stevens-Johnson syndrome: Postmarketing cases 
consistent with Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM) 
have been reported in patients receiving osimertinib. Withhold osimertinib if SJS or 
EMM is suspected and permanently discontinue if confirmed. 
x Embryo fetal toxicity: Based on data from animal studies and its mechanism of action, 
osimertinib can cause fetal harm when administered to a pregnant woman. In animal 
reproduction studies, osimertinib caused post-implantation fetal loss when administered 
during early development at a dose exposure 1.5 times the exposure at the recommended 
clinical dose. When males were treated prior to mating with untreated females, there was 
an increase in preimplantation embryonic loss at plasma exposures of approximately 
0.5 times those observed at the recommended dose of 80 mg once daily. Verify 
pregnancy status of females of reproductive potential prior to initiating osimertinib. 
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive 
potential to use effective contraception during treatment with osimertinib and for 6 weeks 
after the final dose. Advise males with female partners of reproductive potential to use 
effective contraception for 4 months after the final dose. 
 
Refer to Tagrisso (osimertinib) US Package Insert for more information 
2.3.1.5. 
Potential Risks of RMC-4630 and Osimertinib Combination 
(for US Study Only)  
The overlapping toxicities of a SHP2 inhibitor and an EGFR inhibitor have not been formally 
assessed in non-clinical models. As SHP2 is located downstream of EGFR receptor, both agents 
inhibit signaling in the RAS-MAPK signaling pathway and it is possible that overlapping 
toxicities may be observed. 
 
 
 
 
 
 
 

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2.3.2. 
Steps to Minimize Risk 
Safety measures to minimize risks to participants have been incorporated in the design of the 
study. Eligibility criteria specifically exclude patients who may be at increased risk of 
predictable toxicities.  
Safety monitoring (consisting of adverse events assessments, physical examinations, vital signs 
measurements, ECGs, clinical laboratory tests, Eastern Cooperative Oncology Group 
(ECOG) performance status, echocardiogram (ECHO)/multigated acquisition (MUGA) scans, 
and retinal examinations), will occur at regular intervals throughout the study. As a precaution, 
participants receiving strong CYP3A4 inhibitors (Appendix 8) and/or inducers are excluded until 
further data become available. 
In addition to dose DLT criteria, dose modifications after the DLT window have been included 
in order to reduce the risk of toxicity while continuing to provide participants a potential 
treatment opportunity.  
Invasive measures in this study are limited to venipuncture (all study participants) and tumor 
biopsies in participants when feasible. The primary purpose of the pre-treatment and on-study 
biopsies is to assess tumor biology and potential response to study intervention. The tumor tissue 
will also be used to explore predictive biomarkers (Section 8.7) (Hirsch 2003). 
Two safety committees, a Dose-Escalation and Expansion Committee (“Dose Committee”) and 
an ISMC, will be used to monitor the safety of RMC-4630 monotherapy, RMC-4630 with 
cobimetinib combination, and RMC-4630 with osimertinib combination therapy. The Dose 
Committee is study-specific while the ISMC is RMC-4630 program-specific. The Dose 
Committee, comprising of Sponsor representatives and investigators, will evaluate the safety 
data throughout the study and provide recommendations regarding dose levels during the 
escalation phase as well as decide whether the Dose-Expansion Component may commence at 
the completion of a given Dose-Escalation Cohort. The ISMC will review emergent safety data 
at regular intervals for all participants during the course of the trial in conjunction with data from 
other active RMC-4630 trials. Refer to Section 8.3.6 for details. 

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3. 
OBJECTIVES AD EDPOITS  
3.1. 
RMC-4630 and Cobimetinib Combination 
Objectives 
Endpoints 
Primary 
x 
To characterize the safety and tolerability of the 
combination of RMC-4630 and cobimetinib in 
participants with relapsed/refractory solid tumors 
x 
To define the MTD and RP2D and schedules for 
the combination of RMC-4630 and cobimetinib in 
participants with relapsed/refractory solid tumors 
x 
Incidence, nature, and severity of treatment 
emergent AEs and SAEs, graded according to the 
NCI CTCAE v5 for the combination of 
RMC-4630 and cobimetinib 
x 
Incidence and nature of DLTs for the combination 
of RMC-4630 and cobimetinib 
Secondary 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Tertiary/Exploratory 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 

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3.2.
RMC-4630 and Osimertinib Combination (Study in US Only) 
Objectives
Endpoints
Primary
x
To characterize the safety and tolerability of the 
combination of RMC-4630 and osimertinib in 
participants with EGFR mutation-positive NSCLC 
who have progressed on or after osimertinib
x
To define the maximum tolerated dose (MTD), 
recommended Phase 2 dose (RP2D) and schedule 
for the combination of RMC-4630 and osimertinib 
in participants with EGFR mutation-positive 
NSCLC
x
Incidence, nature, and severity of treatment 
emergent AEs and SAEs, graded according to the 
NCI CTCAE v5 for the combination of 
RMC-4630 and osimertinib
x
Incidence and nature of DLTs for the combination 
of RMC-4630 and osimertinib
  
.
  

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4. 
STUDY DESIG 
The designs of two combination studies, RMC-4630 with cobimetinib and RMC-4630 with 
osimertinib, are described below.  
4.1. 
Overall Design for RMC-4630 and Cobimetinib 
This is an open-label, multicenter, Phase 1b/2 of oral RMC-4630 in combination with 
cobimetinib in participants with advanced relapsed/refractory solid tumors with KRAS 
amplification or harboring certain specific classes of mutations 
 and 2) RMC-4630 in combination with osimertinib 
in participants with epidermal growth factor receptor (EGFR) mutation-positive NSCLC. 
This arm with RMC-4630 and cobimetinib will be conducted in US and ex-US countries. Prior to 
enrollment, all participants will undergo screening to determine study eligibility. Questions 
regarding eligible mutations may be addressed to the Sponsor. Information on tumor genotype 
will be collected on all participants. The following histotypes and genotypes will be enrolled in 
this study arm (Appendix 9A): 
 
 
 
The presence of one or more of these tumor genotypes is required for enrollment. Eligibility will 
be assessed based on prior genomic testing using a clinically validated or qualified assay of 
tumor samples. ctDNA mutational analysis using a clinically qualified or validated test may also 
be used for enrollment. All local tumor genotyping analyses will be confirmed by central testing 
when tumor tissue is provided. A fresh biopsy will not be used to determine eligibility. 
There will be two components to this arm: Dose-Escalation and Dose-Expansion. This arm will 
commence with the Dose-Escalation Component to determine the MTD and RP2D. A minimum 
of 3 participants will be enrolled at each dose combination level to evaluate for DLT events and 
identify the MTD. A Dose-Expansion cohort may follow each Dose-Escalation cohort below the 
RP2D. A final Dose-Expansion cohort will be evaluated at the RP2D. The purpose of the 
Dose-Expansion Component is to further evaluate the safety and tolerability of the combination 
of RMC-4630 and cobimetinib as well as assess preliminary signals of efficacy. 

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The Dose-Escalation and Dose-Expansion Components may enroll simultaneously but will have 
staggered start times such that the dose cohort within the Dose-Expansion Component will
always enroll at the dose level below that of the actively enrolling cohort in the Dose-Escalation 
Component. The current Dose-Expansion Cohort will close to enrollment once the DLT window 
has been completed for the next higher dose level in the Dose-Escalation Component. At that 
point, a new Dose-Expansion Cohort will open for enrollment at this next higher dose level. The 
staggered enrollment between the Dose-Escalation and Dose-Expansion Cohorts is illustrated in 
Figure 6. After determination of the RP2D, further expansion will occur at the RP2D.  
The diagram in Figure 6 below illustrates staggered enrollment for Scenario 1 in Figure 2. 
Figure 6 
Staggered Enrollment Between Dose-Escalation and Dose-Expansion 
Cohorts for RMC-4630 and Cobimetinib Study 
Abbreviations: DLT, dose-limiting toxicity; PK, pharmacokinetic(s); RP2D, recommended Phase 2 dose.
MTD will be identified based on safety data during the DLT assessment period (Cycle 1; 
Section 4.1.1.1). The RP2D will be based on all available safety, PK, PD, and efficacy data for 
all participants at the end of the Dose-Escalation Component and any available data from the 
Dose-Expansion Cohorts. 

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The Dose Committee will evaluate the safety data during the DLT period and render decisions 
whether dose escalation may proceed and whether the Dose-Expansion Component may 
commence. The ISMC will review emergent safety data from the RMC-4630 program at regular 
intervals for all participants during the course of the trial in conjunction with data from other 
active RMC-4630 trials (Section 8.3.6). 
4.1.1. 
Dose-Escalation Component  
4.1.1.1. 
Dose-Escalation Design 
The starting dose of RMC-4630 for twice weekly dosing schedule on D1, D4 is approximately 
50% of the dose intensity of the highest cleared dose from the Phase 1 monotherapy study 
RMC-4630-01, (https://clinicaltrials.gov; NCT03634982). 
 
 
Table 4   
Starting Dose of RMC-4630 
 
 
 
 
 
 
 
a 
 

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Table 5 
Primary Dose Levels for RMC-4630  
 
  
 
  
 
In addition to the planned dose levels, alternative schedules which allow D1, D2 dosing of either 
or both RMC-4630 and cobimetinib may be initiated and the starting dose will be based on the 
analysis of emerging safety and PK data. Therefore, RMC-4630 can be administered in either a 
D1, D4 or D1, D2 schedule. Whereas, cobimetinib can be administered in either once daily 
(21/7) or D1, D2 schedule. However, the single and monthly starting dose for cobimetinib will 
not exceed those already tested in clinical trials. The decision to trigger exploration of an 
alternative schedule will be made by the Dose Committee after careful review of emerging 
toxicity profile of the combination.  
The first cycle (eg, 28 days) constitutes the DLT assessment period. The first participant in the 
initial combination dose level will be observed for the first 7 days of dosing prior to dosing 
additional participants in this cohort. Following this 7-day observation period, additional 
participants may be enrolled in the cohort. In subsequent combination dose level cohorts, 
participants may be enrolled concurrently. 
4.1.1.2. 
Dose-Limiting Toxicity Criteria 
DLT is defined as any one of the following toxicities considered by the investigator to be related 
to study treatment: 
x Grade t4 adverse events (AEs) 
x Grade 3 febrile neutropenia or hemorrhage 
x Grade 3 thrombocytopenia with clinically significant bleeding 
x Grade 3 non-hematologic AEs, including rash, nausea/vomiting, hypertension, diarrhea, 
retinopathy, or blurred vision that remain uncontrolled GRHVQRWUHVROYHWR*UDGH for 

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>72 hours despite maximal supportive care. Electrolyte abnormalities or Grade 3 
asymptomatic CPK or GGT elevations that is corrected within 72 hours will not be 
considered DLTs. 
x Grade 3 AST, ALT, and/or total bilirubin elevations that persist >5 days  
x Concurrent elevation of AST or ALT >3 × ULN AD total bilirubin >2 × ULN or 
international normalized ratio (INR) >1.5 in the absence of cholestasis and other causes 
(eg, viral hepatitis, other pre-existing or acute liver disease, or another drug capable of 
the observed injury), which may indicate severe drug-induced liver injury (possible Hy’s 
law case) 
x Grade 3 QTcF (defined as QTc using Fridericia's formula [QTcF] >500 msec OR change 
from baseline of QTcF >60 msec) prolongation based on a triplicate ECG 
x Retinal vein occlusion (RVO) any grade 
x 50% or less dose intensity of RMC-4630 (eg, PLVV4 doses) and/or cobimetinib (eg, miss 
10 doses LIFRELPHWLQLELVGRVHGGDLO\GXULQJVFKHGXOHRUPLVVGRVHVLI
cobimetinib is dosed intermittently on D1, D2) due to study drug related toxicity 
x Ejection fraction <50% with an absolute decrease of >10% from baseline  
 
4.1.1.3. 
Dose-Escalation Rules 
Dose escalation will be guided using a CRM model (Appendix 10) to determine the MTD of the 
combination of RMC-4630 and cobimetinib. This CRM is an adaptive dose escalation approach 
based on a Bayesian statistical model to assess the MTD for drug combinations as a function of 
their doses. 
 
 
The MTD is selected as the combination associated with the 
highest posterior probability of DLT rating within the target interval of 25% - 35% with a target 
DLT rate of 30%, and which have been used to treat at least 6 participants. If alternative dosing 
schedule(s) are evaluated, a separate CRM model will be set up using the same modeling 
structure but potentially different parameters according to the updated prior knowledge of the 
safety of the alternative dosing schedule(s). 
During the escalation period, participants will be enrolled in a series of cohorts for each 
combination dose level. A minimum of 3 participants are required on a combination dose level to 
be DLT evaluable and to render a decision to proceed to the next dose level. A 4th participant, if 
available, may enroll onto the escalation dose before the first 3 participants have completed the 
DLT evaluation. However, in the case a 4th patient is enrolled in a cohort, dose escalation 
decision will take place after the first 3 patients have completed the DLT assessment period. 

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Once the DLT status of the 4th patient is available, and if this patient experiences a DLT after 
dose escalation decision and enrollment of the subsequent dose level, the Sponsor will rerun the 
Bayesian model and the Dose Committee will re-evaluate the dose escalation recommendation 
and continuation of treatment at the subsequent dose level. If a participant experiences a DLT, 
additional participants will be enrolled at that dose. The cohort at the MTD will include at least 
6 participants. 
A participant will be DLT non-evaluable in either of the following 2 scenarios where a 
replacement participant(s) will be enrolled:  
1. Receives less than 75% of planned dose of cobimetinib PLVVGRVHVRIFRELPHWLQLERQ
''LQWHUPLWWHQWVFKHGXOHDQGGRVHVRIFRELPHWLQLERQRQRIIVFKHGXOHZLWKLQWKH
DLT window) for reasons other than toxicity 
2. Misses 3 or more consecutive or non-consecutive doses of RMC-4630 within the DLT 
window for reasons other than toxicity 
 
Moving to a higher dose of both agents is not allowed. Moving to a higher dose of one agent and 
a lower dose of the other agent is allowed. Skipping a dose level as specified above is not 
allowed, but intermediate dose levels of RMC could be explored. Parallel dose cohorts may be 
allowed if the collective safety data are supportive (Appendix 10). The data in both Dose-
Escalation and Dose-Expansion Components (Section 4.1.1, Section 4.1.2) will be combined to 
fit the model and determine the recommended dose combination to treat the next cohort of 
patients.  
The Dose Committee will be responsible for evaluating the safety data during the DLT period 
and provide decisions regarding the actual dose escalation level based on safety data, updated 
model dose recommendations, and other relevant available information. The RP2D will be 
determined by the Sponsor based on the totality of the information available at all dose levels, 
combining the Dose-Escalation and Dose-Expansion Components, and should not exceed the 
MTD. The Dose Committee will determine regarding opening the Dose-Expansion Component.  
4.1.2. 
Dose-Expansion Component 
Once a combination dose level during the Dose-Escalation phase has reached a threshold level of 
activity based on clinically meaningful reduction in tumor burden at a dose with acceptable 
toxicity, additional participants may possibly be enrolled at dose levels prior to the determination 
of RP2D. The Dose Committee will determine whether clinically meaningful reduction has been 
DFKLHYHGHJUHGXFWLRQLQWKHVXPRIORQJHVWGLDPHWHUVRIWDUJHWOHVLRQVRUDOHVVHU
diminution with a preponderance of clinical evidence of benefit). The decision to open the 
Dose-Expansion Component will be made by the Dose Committee. See Dose-Escalation and 
Expansion Committee Charter for more information.  

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Multiple Dose-Expansion and Escalation Cohorts may occur in parallel. The current Dose 
Expansion Cohort will stop enrollment after the next higher dose combination in the Dose 
Escalation Component is completed. 
 
 
In the case of parallel Dose-Expansion cohorts below the RP2D, slot assignment to parallel 
cohorts will be in an alternating manner. Please refer to Figure 1. 
The MTD and RP2D will be determined after the Dose-Escalation and the Dose-Expansion 
(below the RP2D) Components are completed. 
 
 
 
4.1.3. 
Intra-participant Dose-Escalation 
Intra-participant dose escalation may be allowed to provide patients with an opportunity to 
receive a higher dose to potentially derive greater benefit from RMC-4630 and cobimetinib 
combination. Participants will be allowed to escalate to a higher dose once it has been cleared by 
the Dose Committee. For intraparticipant dose escalation to occur, the request must be approved 
by the sponsor Medical Monitor. Additionally, the following criteria must be met: 
x Participants should be able to tolerate the dose level at which they are enrolled, 
demonstrated by minimal dose holds and no dose reductions (Section 6.6.2). Participants 
who have previously had a tGrade 3 adverse event during the study will not be eligible 
for dose escalation unless the adverse event was clearly unrelated to study drugs. Low 
grade, ongoing adverse events will be evaluated on case-by-case basis and may restrict 
participant’s eligibility to escalate.   
x Participants should complete at least 2 cycles of treatment at the dose level cohort in 
which they were first enrolled into the study. In rare cases, a participant may be allowed 
to dose-escalate without completing 2 cycles of the treatment upon discussion with the 
Medical Monitor. A dose cannot be escalated before the DLT window ends. 
x If there are two higher combination dose levels which are cleared by the dose committee, 
then the participant will be allowed to escalate to the highest dose level which was 
cleared by the Dose Escalation and Expansion Committee. If two higher parallel cohorts 
are being evaluated, the investigator–after discussion with the Medical Monitor–will 
determine which combination dose level the participant may escalate to.  
 

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After intraparticipant dose escalation occurs, if a participant experiences an AE that meets the 
definition of a DLT at the dose level which has already been cleared, the participant should be 
managed according to the dose modification guidelines specified in Section 6.6.2. For any 
Grade 4 toxicities, treatment with RMC-4630 and cobimetinib should be discontinued.  
4.1.4. 
Duration of Therapy 
Participants will be permitted to remain on-study therapy until disease progression per 
RECIST v1.1, unacceptable toxicity, or other criteria for withdrawal are met (Section 7.1 and 
Section 7.2), or end of study (Section 4.3), whichever occurs first. Participants will return to the 
clinical site for an EOT visit within 30 days after last treatment dose. Alternatively, participants 
may withdraw from the study at any time with or without cause and will be encouraged for EOT 
evaluation. 
After termination of treatment, participants will continue on study for long-term survival 
follow-up every 3 months (±2 weeks), unless they withdraw consent for further follow-up or end 
of study. 
The anticipated duration of the study is approximately 3 years, including 2 years of enrollment 
and 1 year of follow-up visits. 
4.1.5. 
Scientific Rationale for Study Design 
The first phase constitutes a Dose-Escalation Component, which has been designed to minimize 
the number of participants exposed to potentially subtherapeutic doses.  
After the dose level achieves a threshold for activity (Section 4.1), Dose-Expansion Cohorts may 
be initiated. In the Dose-Escalation Component, assessment of safety and tolerability will be the 
primary endpoints and will be directly measured by the incidence of DLTs, AEs, and serious 
adverse events (SAEs). 
The Dose-Expansion Component below the RP2D provides a further assessment of safety and 
the tolerability, PK, and PD effects, as well as the preliminary activity of RMC-4630 and 
cobimetinib combination therapy at potentially active doses. The Dose-Expansion Component is 
designed such that multiple cohorts below the RP2D will be assessed and will provide additional 
information on the therapeutic index of RMC-4630 and cobimetinib, including any potential 
differential impact of dose based on genotype and histotype. 
For the RMC-4630 and cobimetinib arm, there is a concurrent but staggered enrollment strategy 
between the Dose-Escalation and Dose-Expansion Components. The Dose-Expansion 
Component begins only once a threshold for activity has been demonstrated during the 
Dose-Escalation Component (Section 4.1). Once a cohort in the Dose-Escalation Component has 
completed the DLT window, a Dose-Expansion Cohort at that dose may open at the same time as 
the next highest dose cohort in Dose-Escalation Component.  

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4.1.6. 
Justification for Starting Dose 
Justification for Starting Intermittent Dosing Schedule for RMC-4630 
Preclinical testing of intermittent dosing schedules was performed in the NCI-H358 xenograft 
model of KRASG12C mutant NSCLC.
 
 
 
 
 
Justification for Starting Intermittent Dosing Schedule for Cobimetinib 
 
 
 
 
Justification for Starting Dose 
 
 
 
 
 

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The starting dose for RMC-4630 for D1, D2 schedule will be decided based on the emerging 
toxicity profile of the combination and will be decided by the Dose Committee. 
 
  
The starting dose for cobimetinib for D1, D2 schedule will be decided based on the emerging 
toxicity profile of the combination and will be decided by the Dose Committee. 
 
 
 
 
 
 
 
 

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Justification for RMC-4630 dose reduction to 100 mg D1D2 (if needed) in the Final 
Expansion Phase: 
 
4.2. 
RMC-4630 and Osimertinib Design (Study in US Only) 
This arm with RMC-4630 and osimertinib will be conducted ONLY in the US. This is an 
open-label, Phase 1b exploratory study of RMC-4630 in combination with osimertinib in 
participants with epidermal growth factor receptor (EGFR) mutation-positive NSCLC.  
Prior to enrollment into this arm, all participants will undergo screening to determine eligibility. 
Information regarding existing mutations at baseline will be collected using prior histological or 
ctDNA documentation for EGFR mutations. Sponsor will determine eligibility based on the 
presence of an EGFR mutation in the most recent genomic report for the dose escalation 
component of the study. The following mutations/histologies will not be eligible to enroll:  
 
  
 
  
 
Eligibility into Dose Escalation: Eligibility will be assessed based on current genomic testing 
report either from tumor biopsy or ctDNA which confirms the presence of an EGFR mutation. 
The report should ideally be obtained at the time of progression on osimertinib or at the time of 
progression on most recent prior therapy if osimertinib is not the most recent prior therapy. 
Participants who received intervening chemotherapy or any other therapy after progression on 
Osimertinib will be eligible as long as the presence of EGFR mutation is noted on the most 
recent genomic report. The samples should have been tested using a clinically validated or 
qualified assay for tumor or blood samples which includes NGS, IHC, FISH or PCR. If the 
patient does not have an EGFR mutation either based on the tumor biopsy or ctDNA report, then 
the patient will be considered ineligible for participation.   

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There are two components in this arm: Dose-Escalation Phase and Dose-Expansion Phase. 
Enrollment in Dose-Expansion will be initiated after Dose-Escalation has ended and an MTD or 
RP2D has been established with the combination treatment. 
 
 
 
 
Table 6  
Dose Escalation Rule of the Modified Toxicity Probability Interval-2 Method 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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C) If the current dose is the lowest dose and the rule indicates dose de-escalation, treat the 
new patients at the lowest dose unless there is unacceptable high toxicity, at which point 
terminate the study for safety. If the decision based on the new cohort at the lowest dose 
still recommends dose de-escalation, new dose levels may be explored.  
D) If the current dose is the highest dose and the rule indicates dose escalation, treat the new 
patients at the highest dose. If the decision based on the new cohort at the highest dose 
still recommends dose escalation, new dose levels may be explored.  
E) At least 6 patients have to be treated at the recommended dose level, before declaring it 
the MTD.  
F) Skipping dose is not allowed. 
 
Once an MTD or RP2D is determined, Dose-Expansion Component will commence to further 
evaluate the safety and tolerability of the combination of RMC-4630 and osimertinib as well as 
assess preliminary signals of efficacy. The MTD or RP2D will be based on all available safety, 
PK, PD, and efficacy data for all participants at the end of the Dose-Escalation Component, and 
Dose-Expansion will only begin after Dose-Escalation is complete. 
Eligibility into Dose-Expansion – Will be determined using existing reports (either from tumor 
sample or ctDNA). On the most recent genomic report post Osimertinib progression, patient 
should have a mutation of interest as outlined in Appendix 9B for eligibility. If patient does not 
have a mutation of interest either using ctDNA or tumor biopsy, then they would be deemed 
ineligible to participate in Dose-Expansion (See Appendix 9B). On-study fresh-tumor biopsies 
for biomarker analyses will be mandatory for each Dose-Expansion participant unless the 
investigator determine that the tumor site is not amenable to biopsy and poses a significant risk 
to patient safety. The Sponsor will evaluate this requirement on a case-by-case basis. An EOT 
tumor biopsy will be requested but will not be mandatory for patients in Dose-Expansion 
component. 
Participants enrolled in the Dose-Escalation Phase or Dose-Expansion Phase will undergo 
regular safety assessments including physical examinations and laboratory testing. 
 
 
 
 
  

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4.2.1. 
Dose-Escalation Component 
4.2.1.1. 
Dose-Escalation Design 
RMC-4630 will be administered on an intermittent schedule throughout each 28-day cycle. Dose 
escalation will be conducted using a mTPI2 design to determine the MTD. 
 
The decision for the initial dose/schedule of RMC-4630 was made by the Dose 
Committee after careful evaluation of safety data. 
 
 
 
The first cycle (eg, 28 days) constitutes the DLT assessment period. The first participant in the 
initial combination dose level will be observed for the first 7 days of dosing prior to dosing 
additional participants in this cohort. Following this 7-day observation period, additional 
participants may be enrolled in the cohort. In subsequent combination dose level cohorts, 
participants may be enrolled concurrently. 
4.2.1.2. 
Dose-Limiting Toxicity Criteria 
DLT is defined as any one of the following toxicities considered by the investigator as related to 
study treatment: 
Hematologic 
x Grade 4 neutropenia or thrombocytopenia lasting >7 days 
x Grade >3 febrile neutropenia 
x Grade >3 hemorrhage 
x Grade >3 thrombocytopenia with clinically significant bleeding 
 

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on-hematologic 
x Grade >4 non-hematologic adverse events (AEs) 
x Retinal vein occlusion 
x Grade 3 heart failure 
x *UDGHSQHXPRQLWLV 
x Grade 3 fatigue lasting >7 days 
x Grade 3 hypertension or rash which does not improve or remains uncontrolled for >5 or 
more days despite maximal supportive care 
x Other Grade 3 nonhematologic AEs, including photosensitivity, nausea/vomiting, 
diarrhea, retinopathy, blurred vision, or corneal ulceration which does not improve or 
remains uncontrolled GRHVQRWUHVROYHWR*UDGH for >72 hours despite maximal 
supportive care. Electrolyte abnormalities that are corrected within 72 hours will not be 
considered DLTs 
x *UDGH$67$/7DQGRUWRWDOELOLUXELQHOHYDWLRQVwhich does not improve or remains 
uncontrolled >5 days  
x Concurrent elevation of AST or ALT >3 × ULN AD total bilirubin >2 × ULN or 
INR >1.5 in the absence of cholestasis and other causes (eg, viral hepatitis, other 
pre-existing or acute liver disease, or another drug capable of the observed injury), which 
may indicate severe drug-induced liver injury (possible Hy’s law) 
x Grade 3 QTcF (defined as QTc using Fridericia's formula [QTcF] >500 msec OR change 
from baseline of QTcF >60 msec) prolongation based on a triplicate ECG 
x 50% or less dose intensity of RMC-HJPLVVGRVHVIRUtwice-weekly (BIW) 
VFKHGXOHDQGRURVLPHUWLQLELHPLVVGRVHVIRU4'VFKHGXOHGXHWRVWXG\GUXJ
related toxicity 
 
4.2.1.3. 
Dose-Escalation Rules 
In the event a participant discontinues treatment prior to completion of the first cycle (DLT 
window), receives less than 75% of planned dose of osimertinib (defined as missing 8 or more 
consecutive or non-consecutive doses of osimertinib), receives less than 75% of planned dose of 
RMC-4630 (defined as missing 3 or more consecutive or non-consecutive doses of RMC-4630) 
for reasons other than toxicity, a replacement participant will be enrolled for a minimum of 
3 DLT evaluable participants.  
The Dose Committee will be responsible for reviewing and evaluating the safety, efficacy data 
and other relevant available information (PK or biomarker data) during the DLT period and 
provide a final decision regarding the next dose escalation level. The RP2D will be determined 

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by the Sponsor based on the totality of the information available at all dose levels and should not 
exceed the MTD. If 2 or more DLTs are observed beyond the DLT assessment period (ie, a 
delayed DLT) within a Dose-Escalation Cohort, further enrollment may be stopped pending 
safety analysis of the events. These events will not affect the determination of the MTD but will 
be used in determining the appropriate RP2D. Further details on the Dose Committee are 
provided in Section 8.3.6.  The Sponsor will determine regarding opening the Dose-Expansion 
Component. 
The ISMC will conduct regular safety data reviews of emergent data from the RMC-4630 
program as well as ad hoc emergent safety data reviews for all participants across RMC-4630 
trials. 
4.2.2. 
Dose-Expansion Component 
Once a combination dose level during the Dose-Escalation phase has reached an MTD, the Dose 
committee will determine whether Dose-Expansion phase should be initiated and will determine 
the RP2D which may or may not be the same as MTD but would not exceed the MTD. 
The Dose-Expansion phase may enroll 6-18 participants depending on how many participants 
will enroll in the Dose Escalation portion for a total of 24 participants in the RMC-4630 + 
osimertinib study arm. Please refer to Section 4.2 for eligibility.  
4.2.3. 
Intra-participant Dose-Escalation 
Participants may be allowed to escalate to a higher dose once it has been cleared by the Dose 
Committee and is deemed safe and tolerable. For intraparticipant dose escalation to occur, the 
request must be approved by the sponsor Medical Monitor.  
4.2.4. 
Duration of Therapy 
Participants will be permitted to remain on-study therapy until disease progression per 
RECIST v1.1, unacceptable toxicity, or other criteria for withdrawal are met (Section 7.1 and 
Section 7.2), or end of study (Section 4.3), whichever occurs first. Participants will return to the 
clinical site for an EOT visit within 30 days after last treatment dose. Alternatively, participants 
may withdraw from the study at any time with or without cause and will be encouraged for EOT 
evaluation. 
After termination of treatment, participants will continue on study for long-term survival 
follow-up every 3 months (±2 weeks), unless they withdraw consent for further follow-up or end 
of study. 
The anticipated duration of the study is approximately 3 years, including 2 years of enrollment 
and 1 year of follow-up visits. 

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4.2.5. 
Scientific Rationale for Study Design 
The first phase constitutes a Dose-Escalation Component, designed to understand the safety and 
tolerability of RMC-4630 in combination with osimertinib and determine the MTD and RP2D 
for this combination while also minimizing the number of participants exposed to potentially 
subtherapeutic doses. Given that osimertinib is an approved treatment for NSCLC with an EGFR 
mutation, only RMC-4630 
  
In the Dose-Escalation Component, assessment of safety and tolerability will be the primary 
endpoints and will be directly measured by the incidence of DLTs, AEs, and serious adverse 
events (SAEs). 
Since the primary objective of the study is to understand the safety and tolerability of this 
combination and the proposed sample size is limited to 24 participants, there will be no Dose-
Expansion Component below the RP2D for this combination. Once the combination dose level 
during Dose-Escalation has reached an MTD, initiation of final Dose-Expansion at RP2D would 
then be determined by the Dose Committee. 
4.2.6. 
Justification for Starting Dose 
 
 
 
 
 
 
4.3. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study 
(ie, last participant, last visit [LPLV]) or 12 months after the last participant receives the first 
dose of study treatment, whichever occurs first. 

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5. 
STUDY POPULATIO 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
For RMC-4630 + Cobimetinib only: 
1. Participants who have advanced solid tumors that have failed, are intolerant to or are 
considered ineligible for standard of care anti-cancer treatments including approved drugs 
for oncogenic drivers in their tumor type (eg, participants with NSCLC and KRAS 
mutations must have received or been offered treatment with platinum-based 
chemotherapy OR a PD-1 or PD-L1 inhibitor). 
2. Participants must have one of the following molecular aberrations and specific 
histotypes:  
 
 
 
For RMC-4630 + Osimertinib only: 
1. 
or in combination with other mutations which are considered 
sensitive to SHP2 inhibition (for dose expansion only)  at any time since the initial 
diagnosis of NSCLC (see Appendix 9B for a list of mutations eligible for dose 
expansion) 
2. Evidence of radiological documentation of progression with osimertinib monotherapy or 
an osimertinib containing regimen. Participants should not be considered a current 
candidate for 1st generation EGFR TKIs by the investigator. 
3. Previously able to tolerate osimertinib 80 mg QD and no current Grade 2 or greater AE 
attributable to osimertinib 
 

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All participants must meet ALL of the following inclusion criteria: 
1. Age \HDUV 
2. Evaluable or measurable disease per RECIST v1.1 criteria for Dose-Escalation; measurable 
disease (only) per RECIST v1.1 for Dose-Expansion 
3. Eastern Cooperative Oncology Group (ECOG) SHUIRUPDQFHVWDWXVRI1 with no 
deterioration over the previous 2 weeks 
4. Adequate hematological and organ function, confirmed by the following laboratory values at 
local investigative site: 
x Bone Marrow Function 
x $EVROXWHQHXWURSKLOFRXQW$1&× 109/L 
x 3ODWHOHWVî9/L without transfusion support 
x +HPRJORELQJPG/ 
x Hepatic Function 
o $VSDUWDWHDPLQRWUDQVIHUDVH$67DQGDODQLQHDPLQRWUDQVIHUDVH$/7îXSSHU
limit of normal (ULN)  
o %LOLUXELQî8/1 mg/dL if participant has Gilbert’s disease) 
x Renal Function  
o Blood cUHDWLQLQHî8/1RUFUHDWLQLQHFOHDUDQFHRI!P/PLQXVLQJ
Cockcroft-Gault formula or 24-hour urine collection)  
x Coagulation 
o Prothrombin time (PT)/international normalized ratio (INR) and activated partial 
thromboplastin time or partial thromboplastin time (aPTT/PTT) <1.3 × ULN (or 
partial thromboplastin time (PTT)) or within therapeutic range if receiving therapeutic 
anticoagulation that would affect the PT/INR. 
5. Capable of giving signed informed consent. Willing and able to compile with study 
requirements and restrictions. 
6. Life expectancy >12 weeks 
7. Females of childbearing potential must agree to always use 2 effective forms of 
contraception during the course of the study and for at least 3 months after completion of 
study therapy. 
8. Males with partners of childbearing potential must agree to always use 2 effective forms of 
contraception during the course of the study and for at least 3 months after completion of 
RMC-4630 and cobimetinib or 4 months after completion of RMC-4630 and osimertinib. 
9. Negative blood pregnancy test within 14 days of commencement of study medications in 
women of childbearing potential. 

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5.2. 
Exclusion Criteria  
AY of the following criteria will exclude participants from study participation: 
1. Excluded genotypes for both cobimetinib and osimertinib arms (including co-occurring 
mutations for both dose escalation and dose expansion): 
 
 
2. For RMC-4630 + cobimetinib arm, 
 
 
3. For RMC-4630 + osimertinib arm: 
  
4. 
  
5. 
 
o For RMC-4630 + osimertinib arm: 
 
6. History of cerebrovascular stroke or transient ischemic attack within previous 6 months. 
7. The following ocular abnormalities are excluded: 
o History or current retinal pigment epithelial detachment (RPED), central serous 
retinopathy, retinal vein occlusion (RVO), neovascular macular degeneration, or 
factors considered by the investigator to present an unacceptable risk of RPED or 
RVO.  
o Visible retinal pathology as assessed on ophthalmic examination that is considered a 
significant risk factor for RVO or RPED by an ophthalmologist 
o For RMC-4630 + osimertinib arm: any evidence of current keratitis  

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8. Any of the following cardiovascular abnormalities:  
i. 
0HGLFDOO\XQFRQWUROOHGK\SHUWHQVLRQHJPP+JV\VWROLFRUPP+J
diastolic) 
ii. 
Acute coronary syndrome (eg, unstable angina, coronary artery stenting, or 
angioplasty, bypass grafting) within prior 6 months 
iii. 
History or current uncontrolled clinically significant unstable arrhythmias 
iv. 
Participants who have pacemakers to control atrial arrhythmias are candidates for 
the study. Participants with medically controlled atrial fibrillation >1 month prior to 
C1D1 are eligible.   
v. 
History of congenital long QT syndrome or prolonged QTcF interval >480 ms using 
Fridericia’s formula (unless a pacemaker is in place) or uncorrectable abnormalities 
in blood electrolytes (sodium, potassium, calcium, magnesium, phosphorus). 
vi. 
Left ventricular ejection fraction (LVEF) < institutional LLN or <50%, whichever 
is lower. 
vii. 
Symptomatic congestive heart failure, New York Heart Association Class II or 
higher  
9. Active, clinically significant interstitial lung disease or pneumonitis 
o For RMC-4630 + osimertinib arm: participants with a past medical history of 
interstitial lung disease (ILD), drug induced ILD, radiation pneumonitis which 
required steroid treatment, or evidence of clinically active ILD will be excluded  
10. Grade t2 proteinuria 
11. Active autoimmune disease requiring systemic treatment within past 6 months (ie, with use 
of disease modifying agents, non-physiologic doses of corticosteroids or immunosuppressive 
drugs); includes current autoimmune sequelae or previous Grade > 2 autoimmune sequelae 
from checkpoint inhibitors or other immunomodulatory treatments which requires systemic 
therapy. Participants with autoimmune endocrinopathies on hormonal supplementation may 
enroll if approved by the Medical Monitor. 
12. Known HIV infection or active/chronic Hepatitis B or C 
13. Known history of bleeding diathesis 
14. Inability to swallow tablets/ capsules or impairment of gastrointestinal function that may alter 
the absorption of RMC-4630, cobimetinib or osimertinib (eg, uncontrolled nausea and 
vomiting, diarrhea, malabsorption syndrome, inflammatory bowel disease, gastrectomy, 
small bowel resection) 
15. History of severe allergic reaction to any of the study intervention components  
16. Patients receiving specific oncologic therapies are excluded: 
a. Treatment with chemotherapy or biologics/monoclonal antibodies <21 days of 
C1D1 

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b. Treatment with radiation therapy <14 days of C1D1 
c. Treatment with TKI, hormonal therapy (except megesterol acetate) <7 days of 
C1D1 
i. For RMC-4630 + osimertinib arm: Osimertinib can continue uninterrupted 
during screening.  
d. Treatment with immunotherapy (eg, checkpoint inhibitors) <14 to 28 days of 
C1D1 of immunotherapy depending on specific immunotherapy agent and 
duration of treatment 
e. Treatment with KRASG12C inhibitors, MEK inhibitors, and/or SHP2 inhibitors 
including RMC-4630 < 21 days of C1D1  
f. Treatment with all other anti-cancer treatments including investigational agents 
that do not fit in the above categories <21 days of C1D1  
17. 0DMRUVXUJHU\GD\VSULRUWR&',QDOOFDVHVWKH patient must be sufficiently recovered 
and stable before treatment administration. 
18. Medication and supplements that may interfere or potentiate with RMC-4630, cobimetinib or 
osimertinib metabolism or toxicity PRIOR or DURING study intervention are excluded: 
 
 
 
 
 
  
  
19. Females who are pregnant or breastfeeding 
20. Any other unstable or clinically significant concurrent medical condition (eg, substance 
abuse, uncontrolled intercurrent illness including active infection, arterial thrombosis, and 
symptomatic pulmonary embolism, etc.) that would, in the opinion of the investigator, 
jeopardize the safety of a participant, impact their expected survival through the end of the 
study participation, and/or impact their ability to comply with the protocol. 
 

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5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
Refrain from consumption of grapefruit or grapefruit-containing products, or Seville oranges 
from 7 days before the start of study intervention until after the final dose. 
Fasting (except water) 1 hour prior to and 1 hour after each RMC-4630 dose is required. Fasting 
is OT required for cobimetinib; however, on days when both medications are taken together, 
fasting is requisite due to the requirements of RMC-4630. Similarly, fasting is NOT required for 
osimertinib; however, on days when both medications are taken together, fasting is requisite due 
to the requirements of RMC-4630. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently able to receive treatment in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (ie, screen failure) may be 
rescreened within 5 days of the initial screening date of screen failure. Rescreened participants 
should be assigned the same participant number as for the initial screening. Only hematology, 
chemistry, and coagulation tests may need to be repeated if outside the screening window. Other 
clinical testing will not need to be repeated if outside screening window (ie, within 5 days).  
6. 
STUDY ITERVETIO 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
Study Intervention(s) Administered 
6.1.1. 
RMC-4630 and Cobimetinib  
 
  
In addition to the planned dose levels, alternative dose schedules which allow D1, D2 dosing of 
either or both RMC-4630 and cobimetinib may be initiated and the starting dose will be based on 

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the analysis of emerging safety and PK data. Therefore, RMC-4630 can be administered in either 
a D1, D4 or D1, D2 schedule. Whereas, cobimetinib can be administered in either once daily 
(21/7) or D1, D2 schedule. However, the single and monthly starting dose for cobimetinib will 
not exceed those already tested in clinical trials. The decision to trigger exploration of an 
alternative schedule will be made by the Dose Committee after careful review of emerging 
toxicity profile of the combination.   
RP2DS for final expansion is RMC-4630 140 mg on D1D2 and cobimetinib 40 mg on D1D2.  
The tablets and capsules should not be crushed or chewed. The participant should administer the 
study intervention approximately the same time every day except for clinic visit days as listed in 
the SoA (Section 1.3). On these clinic visits, the participant should await instruction from the 
study staff to coordinate with the timing of PK and/or PD sampling. 
6.1.2. 
RMC-4630 and Osimertinib (Study in US Only) 
During the Dose Escalation Component, RMC-4630 will be administered orally on an 
intermittent basis with twice weekly dosing on D1 and D2 with a starting dose of 140 mg. 
Alternative dose schedule for RMC-4630 including D1D4 dosing may be explored depending on 
emerging data from this study and other RMC-4630 studies. Osimertinib will be dosed orally on 
the approved monotherapy dose and schedule of 80 mg once daily. The tablets and capsules 
should not be crushed or chewed. The participant should administer the study intervention 
approximately the same time every day except for clinic visit days as listed in the SoA 
(Section 1.3). 
Dosing in the Dose-Expansion Component of RMC-4630 will be determined from the respective 
Dose-Escalation Component. 
The participant is expected to administer a dose twice weekly on D1 and D2 (or D1D4 if an 
alternative schedule is implemented) except clinic visit days as listed in SoA. On these clinic 
visits, the participant should await instruction from the study staff to coordinate with the timing 
of PK and/or biomarker sampling. 

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Table 7  
Study Interventions Administered: RMC-4630 and Cobimetinib 
Component ame 
Dose-Escalation and Dose-Expansion 
Intervention Name 
RMC-4630 and Cobimetinib  
Type 
Drugs  
Dose Formulation 
RMC-4630: 
Cobimetinib: Film-coated Tablet 
Unit Dose Strength(s) 
 
Dosage Level(s) 
 
 
 
Route of Administration 
Oral with water after 1 hour fast; no food or drink (other than water) allowed 
for 1 hour after administration for RMC-4630 alone or RMC-4630 in 
combination with cobimetinib. 
No restrictions for cobimetinib when taken alone  
Investigational Product 
RMC-4630 
Cobimetinib  
Sourcing 
RMC-4630
 
 
Cobimetinib: Supplied by Roche 
Packaging and Labeling 
 
Cobimetinib: Supplied as 63-count in HDPE bottles, overlabeled 
Current/Former Name(s) or Alias 
RMC-4630, 
COTELLIC, cobimetinib, cobimetinib fumarate 
Abbreviations: CMO, contract manufacturing organization; HDPE, high-density polyethylene;  
PIC, powder-in-capsule.  

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Table 8  
Study Interventions Administered: RMC-4630 and Osimertinib
Component ame
Dose-Escalation and Dose-Expansion
Intervention Name
RMC-4630 and Osimertinib 
Type
Drugs 
Dose Formulation
RMC-4630: 
Osimertinib: Film-coated Tablet
Unit Dose Strength(s)
Dosage Level(s)
  
Route of Administration
Oral with water after 1 hour fast; no food or drink (other than water) allowed 
for 1 hour after administration for RMC-4630 alone or RMC-4630 in 
combination with osimertinib.
No restrictions for osimertinib when taken alone 
Investigational Product
RMC-4630
Osimertinib 
RMC-4630: 
Osimertinib: Commercially available via pharmacy
Packaging and Labeling
RMC-4630: Study drugs (PIC drug products) are packaged in 
Osimertinib: Supplied as 30-count in HDPE bottles
Current/Former Name(s) or Alias
RMC-4630, RMC
TAGRISSO, osimertinib, osimertinib mesylate, mereletinib
Abbreviations: CMO, contract manufacturing organization; HDPE, high-density polyethylene; 
PIC, powder-in-capsule; QD, daily. 
6.2.
Preparation/Handling/Storage/Accountability 
RMC-4630 
are packaged in 
high-density polyethylene (HDPE) bottles with open labeling and are shipped and stored 
  
Cobimetinib (COTELLIC) is shipped and stored 
Osimertinib (TAGRISSO) is shipped and stored at 15°C to 30°C (59-86°F). 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
 Study drugs (PIC drug products) are packaged in
Osimertinib: Supplied as 30-count in HDPE bottles
RMC-4630, RMC
Current/Former Name(s) or Alias
TAGRISSO, osimertinib, osimertinib mesylate, mereletinib
Abbreviations: CMO, c

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Only participants enrolled in the study may receive RMC-4630 or cobimetinib and only 
authorized site staff may supply study intervention. Osimertinib will be supplied by the local 
pharmacy. All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the study Pharmacy and Investigational Product Administration Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study without randomization. In order to minimize bias, the participants 
will be assigned sequentially as they are enrolled into the study using the inclusion and exclusion 
criteria as outlined in Section 5.1 and Section 5.2. Enrollment will be confirmed by the sponsor 
Medical Monitor after review of all supporting documentation for eligibility criteria.  
The following guidelines will be considered for enrollment and cohort assignment for 
participants enrolled in the RMC-4630 and cobimetinib cohort: 
x Once the Dose-Expansion Component commences, enrollment into the Dose-Escalation 
cohort will have priority over the Dose-Expansion cohort   
x For parallel Dose-Escalation cohorts slot assignment will be completed in an alternating 
manner 
x For parallel Dose-Expansion cohorts below the RP2D, slot assignment will be completed 
in an alternating manner, taking into account that each cohort aims to have 50% of 
participants have 
x In the Dose-Expansion Cohort at the RP2D, participants will be stratified based on 
histotype/genotype. If more than one mutation is present, participants will be stratified 
into the genotype with the lowest enrollment. 
x Sites may enroll participants into the Dose-Expansion Component if there is no 
Dose-Escalation Cohort open for enrollment (Appendix 9A) 
 
Participants will be allocated a screening number at the time of signing the informed consent 
form (ICF). If a participant is a screen failure, the number will not be reassigned. 

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6.4. 
Study Intervention Compliance 
6.4.1. 
Compliance Instructions 
Dosing instructions will be provided to the participant, and participant compliance with study 
intervention will be reviewed at each visit. Compliance will be assessed by counting returned 
capsules (RMC-4630) and tablets (cobimetinib), in conjunction with participant diary 
information and participant questioning. Since Osimertinib is supplied as part of Standard of 
Care by local pharmacies, compliance will only be assessed by reviewing participants’ diaries 
and questions asked during clinic visits. Refer to Section 8.4 in the event a participant is 
suspected to have taken greater than the assigned dosage. 
6.4.2. 
Missed Dose 
RMC-4630: If a participant misses a dose, it may be taken at the time the omission was 
discovered provided that it is within 24 hours of the original administration time. Otherwise, the 
dose should not be administered and should be recorded as an omission. The participant should 
not administer more than the recommended dose. 
Cobimetinib: If a dose of COTELLIC is missed or if vomiting occurs when the dose is taken, 
resume dosing with the next scheduled dose. 
RMC-4630 and Cobimetinib: Twice weekly dosing schedule on D1, D2  
If a participant misses a D1 dose of either drug, it should be taken as soon as the missed dose is 
discovered. The D2 dose should then follow 24-hours after. If the participant misses D2 dose, it 
should be taken as soon as the missed dose is discovered provided there is at least a 24-hour gap 
between D1 dose and D2 dose. If the gap between D1 and D2 dose is more than 48 hours, D2 
dose should not be administered and should be recorded as an omission. The participant should 
not administer more than the recommended dose. 
RMC-4630 Twice weekly dosing schedule on D1, D4 and Osimertinib QD (alternative 
schedule) (Study in US only) 
If a participant misses a dose of RMC-4630, it may be taken at the time the omission was 
discovered provided that is within 24 hours of the original administration time. Otherwise, the 
RMC-4630 dose should not be administered and should be recorded as an omission. The 
participant should not administer more than recommended dose.  
If a participant misses a dose of osimertinib, do not make up the missed dose and take the next 
dose as scheduled 

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RMC-4630 Twice weekly dosing schedule on D1, D2 and osimertinib QD (Study in US only) 
If a participant misses a D1 dose of RMC-4630, it should be taken as soon as the missed dose is 
discovered. The D2 dose should then follow 24-hours after. If the participant misses D2 dose, it 
should be taken as soon as the missed dose is discovered provided there is at least a 24-hour gap 
between D1 dose and D2 dose. If the gap between D1 and D2 dose is more than 48 hours, D2 
dose should not be administered and should be recorded as an omission. The participant should 
not administer more than the recommended dose. If a participant misses a dose of osimertinib, do 
not make up the missed dose and take the next dose as scheduled. 
6.5. 
Permitted Concomitant Therapy 
Supportive care (eg, antiemetics, analgesics, blood transfusions, hematopoietic growth factor 
support) may be used at the investigator’s discretion and in accordance with institutional 
procedures. Localized radiotherapy used for palliative purposes may be considered after 
discussion with the Medical Monitor. Anticoagulation with low-dose aspirin, low-molecular 
weight heparin (LMWH), and direct Factor-Xa inhibitors are allowed. Contraceptives are also 
allowed throughout the study as described in Section 5.1. 
Antacids are permitted but should not be consumed within 3-4 hours before or after RMC-4630 
and cobimetinib or RMC-4630 and osimertinib administration. 
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with the following: 
x Reason for use 
x Dates of administration including start and end dates 
x Dosage information including dose and frequency 
x Route of administration 
 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 

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6.5.1. 
Prohibited Concomitant Therapy 
In addition to prohibited medications/foods listed in Exclusion Criteria (Section 5.2), a complete 
list of prohibited medications during study treatment are provided in this section (Appendix 8). 
The following medications are prohibited while on study treatment: 
x 
  
x 
x 
  
 
 
 
 
x 
x 
x 
 
6.6. 
Dose Modification  
6.6.1. 
Dose Modification Rules  
A 28-day cycle will be maintained, and dose interruption will be noted in the 28-day cycle 
schedule.  
In the Dose-Escalation cohorts, there will be no dose reductions or modifications during C1, 
28-day DLT assessment period unless a DLT has occurred. After C1 and in the Dose-Expansion 
cohorts, if a dose reduction is recommended, then the combination dose level should be the 
previous lower dose level considered to be tolerable in prior participants receiving that dose. If 
the previous lower dose level comprised of two parallel cohorts (ie, two combination dose 
levels), the investigator and sponsor Medical Monitor may choose one of two lower combination 
dose level based on the participant’s medical and study drugs history.  
 
  
 
 

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Two types of dose modifications are allowed, “dose interruption” and “dose level reduction.” 
The decision will be per investigator, according to the dose modification criteria and guidelines 
outlined in Section 6.6. Any allowed dose modification and any deviation from the intended dose 
(missed doses or overdoses due to participant error) should be documented on the dose electronic 
Case Report Form (eCRF). 
6.6.2. 
Dose Modification Criteria for RMC-4630 and Cobimetinib 
In general, dose adjustments should be based on attribution to a particular drug, if known. 
Certain adverse events are known to be associated with administration of cobimetinib 
(cobimetinib IB) whereas others have been observed with the administration of RMC-4630 in 
clinical or preclinical studies (RMC-4630 IB). 
 
The following principles apply to Dose Escalation component of the study and should be 
employed for Grade 3 and certain Grade 4 AEs. 
x If the AE is a known toxicity of cobimetinib only, cobimetinib should be interrupted and 
then dose reduced one level if recovery to <Grade 1 occurs within 28 days. RMC-4630 
should be continued at the same dose. However, at the investigator’s discretion, 
RMC-4630 may be held if the AE does not improve with holding cobimetinib. If the AE 
does not resolve within 28 days from onset, permanently discontinue cobimetinib.  
x If the AE is suspected to be due to RMC-4630, RMC-4630 should be interrupted and then 
dose reduced one level if recovery to <Grade 1 occurs within 28 days. Cobimetinib 
should be continued at the same dose. However, at the investigator’s discretion, 
cobimetinib may be held if the AE does not improve with holding RMC-4630. If the AE 
does not resolve within 28 days from onset, permanently discontinue RMC-4630.  
x If the AE is known for both drugs, hold both drugs until recovery to <Grade 1. Restart at 
a reduced dose of the drug that was last escalated by one dose level if the recovery to 
Grade <1 is within 28 days. The second drug may also be dose reduced by one level at 
the investigator’s discretion and after discussion with the sponsor Medical Monitor.  
x If the AE is unknown for either drug, hold both drugs until recovery to <Grade 1. Restart 
at a reduced the dose of the drug that was last escalated by one dose level if the recovery 
to grade <1 is within 28 days. The second drug may also be dose reduced by one level at 
the investigator’s discretion and after discussion with the sponsor Medical Monitor.  
 

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Dose escalation- If more than 2 dose reductions are required of cobimetinib, then permanently 
discontinue cobimetinib. RMC-4630 may be continued as monotherapy provided that the 
participant is benefitting from treatment with no evidence of disease progression. If RMC-4630 
is continued as a single agent, please refer to specific guidelines provided at the bottom of this 
section. If more than 2 dose reductions of RMC-4630 are required, permanently discontinue both 
drugs. 
Final expansion at RP2DS (Refer to Table 11) 
x 
  
x There are no dose reductions permitted for cobimetinib. If dose reduction for cobimetinib 
is required, then permanently discontinue cobimetinib.  
RMC-4630 may be continued as monotherapy provided that the participant is clinically 
benefitting from treatment with no evidence of disease progression. 
 
Guidelines in Table 9 mainly pertain to the dose 
escalation phase of the study. The investigator or treating physician should use his/her best 
medical judgement for management.  
General guidance for dose modification during final dose expansion is shown in Table 10.   

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Table 9   
Dose Modification Guidelines for RMC-4630 and Cobimetinib  
 
 
 
 
 
 
  
 

 
 
 
 
 
 
 

 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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Table 10  
Dose Modification Guidelines with RMC-4630 and Cobimetinib During Final 
Dose Expansion  
Severity Grade  
Action  
Grade 1  
Continue both drugs at the current dose 
Grade 2  
May continue both drugs without dose interruption and manage the toxicity using 
institutional guidelines. However, depending on the toxicity, dose interruption may be 
considered for one drug if the toxicity is a known toxicity of RMC-4630 versus 
cobimetinib. Upon recovery to baseline or Grade 1, re-start treatment at the same dose. If 
the toxicity re-occurs, consider a dose reduction.  
Grade 3-4 
 
  
 
 
 
  
 

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Dose modifications may also occur following the first cycle (DLT assessment period) during the 
Dose-Escalation Component or Dose-Expansion Component (where applicable) in the following 
specific instances: 
x Any participant who experiences a Grade 3 AE that constitutes a DLT may be considered 
for dose reduction to last dose cohort upon recovery of the AE to Grade 1 or baseline if 
deemed medically appropriate by the investigator and Medical Monitor. These 
participants will be considered to have experienced a DLT at the original dose and, 
therefore, will not be permitted to remain at the same dose.  
o For participants in the Final Expansion Cohort – if an AE/SAE occurs within the first 
cycle and meets the DLT definition, participant may dose reduce RMC-4630 to 100 
mg D1D2. 
x Any participant who experiences a < Grade 3 AE that does not constitute a DLT but that 
recurs more than once  Grade 2) after recovering from the initial onset of the AE may 
be considered for a dose reduction upon recovery of the AE to Grade 1 or baseline if 
deemed medically appropriate by the investigator and sponsor Medical Monitor. 
Discontinuation of the study medications after third occurrence of the AE that is Grade 2 
(intolerable) or Grade 3.  
x Re-challenge at the same or lower dose may be considered after resolution of 
treatment-related or treatment-unrelated AEs provided the AE did not meet DLT criteria. 
If the AE recurs, dose modification may be considered.  
x Continuation of a single agent RMC-4630 may be allowed if there is presence of, or 
potential for, clinical benefit as assessed by the investigator and sponsor Medical 
Monitor. The dose and schedule of RMC-4630 may be cross-referenced to the on-going 
monotherapy study RMC-4630-01. The options are: 
Dose Escalation:  
 
 
ࡳ
 
   
ࡳ
 
  
ࡳ
 
ࡳ
 
 

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Final Expansion at RP2DS: 
 
  
Table 11  
RMC-4630 and Cobimetinib Dose Levels (Final Expansion at RP2DS) 
 
 
 
    
  
  
  
  
  
 
6.6.3. 
Dose Modification Criteria for RMC-4630 and Osimertinib 
(Study in US Only) 
In general, dose adjustments should be based on attribution to a particular drug, if known. 
 
 
 
 
 
x 
 
 

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If more than 1 dose reduction is required of osimertinib, then permanently discontinue 
osimertinib (please see Table 12). RMC-4630 may be continued as monotherapy provided that 
the participant is benefiting from treatment with no evidence of disease progression (Table 13). 
If more than 2 dose reductions of RMC-4630 are required, permanently discontinue both drugs. 
Table 12  
Osimertinib Dose Levels  
 
 
Table 13  
RMC-4630 Dose Levels (Dose Escalation) 
 
 
 
  
  
 
Actual dose levels during dose escalation may be different as intermediate dose levels of RMC 
could be explored per Dose Committee decision. 
General guidance and dose modification guidelines for a subset of common AEs seen with 
osimertinib or other inhibitors of the RAS-MAPK pathway are shown in Table 14 below. The 
investigator or treating physician should use his/her best medical judgement for management. 

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Table 14  
Dose Modification Guidelines for RMC-4630 and Osimertinib  
AE 
Action 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 

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AE 
Action 
Dose Modification Guidelines for RMC-4630 and Osimertinib (cont.) 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose modifications may occur at any time during the study with following specific instances:  
x During DLT assessment period of the Dose-Escalation Component, dose level reduction 
is not allowed unless participant has already experienced a DLT. 
x Any participant who experiences a Grade 3 AE that constitutes a DLT may be considered 
for dose reduction to last dose cohort upon recovery of the AE to Grade 1 or baseline if 
deemed medically appropriate by the investigator and Medical Monitor. These 
participants will be considered to have experienced a DLT at the original dose and, 
therefore, will not be permitted to remain at the same dose. The starting dose level for 
RMC-4630 for osimertinib combination arm is 140 mg D1D2.  
 
 
x Any participant who experiences a < Grade 3 AE that does not constitute a DLT but that 
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be considered for a dose reduction upon recovery of the AE to Grade 1 or baseline if 
deemed medically appropriate by the investigator and sponsor Medical Monitor.  
x Any participant who requires a dose interruption of >4 doses for RMC-4630 or >14 doses 
for osimertinib due to a treatment-related AE Grade < 3 may be considered for a dose 
reduction. Participants in the DLT window will be considered to have experienced a DLT 

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at the original dose and schedule and, therefore, will not be permitted to remain at the 
same dose and schedule. 
x Re-challenge at the same or lower dose may be considered after resolution of 
treatment-related or treatment-unrelated AEs provided the AE did not meet DLT criteria. 
If the AE recurs, dose modification may be considered.  
x If both drugs have been on hold for a treatment related AE, a staggered re-challenge 
strategy may be considered by re-starting either RMC-4630 or osimertinib first followed 
by the second agent a week later. This strategy might minimize the risk of recurrence of 
the AE which led to dose interruption and may help understand which drug may be 
driving the toxicity.   
x Continuation of RMC-4630 alone may be allowed if there is presence of clinical benefit 
as assessed by the investigator and sponsor Medical Monitor. 
 
6.6.4. 
Supportive Care Guidelines for Selected Expected Toxicities 
Please refer to Table 9 for dose modification guidelines for RMC-4630 and cobimetinib or 
Table 14 for RMC-4630 and osimertinib. 
 
The 
investigator or treating physician should use his/her best medical judgement for management. 
Published guidelines are available for MEK, BRAF and RTK inhibitors (Califano 2015, 
Welch 2015, Daud 2017) and guidelines for selected toxicities are summarized below. 
6.6.4.1. 
 
 
 
 
 
 
 

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6.6.4.2. 
 
 
 
 
 
 
 
 
6.6.4.3. 
 
 
 
  
 
 
 
 
 
 

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. 
6.6.4.4.
6.6.4.5.
6.6.4.6.
  

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6.6.4.7.
6.6.4.8.
6.6.4.9.
  

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6.6.4.10.
6.6.4.11.
6.6.4.12.
6.6.4.13.
6.7.
Intervention after the End of the Study 
Participants who continue to receive study intervention at the end of the study and are considered 
to be deriving clinical benefit from RMC-4630 and cobimetinib or RMC-4630 and osimertinib 
will be considered for enrollment in a separate extended use or roll-over study.

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7. 
DISCOTIUATIO OF STUDY ITERVETIO AD PARTICIPAT 
DISCOTIUATIO/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In some instances, it may be necessary for a participant to permanently discontinue study 
intervention. Refer to the SoA (Section 1.3) for data to be collected at the time of discontinuation 
of study intervention. 
Participants may stop study therapy yet continue to be monitored in the study under the 
following circumstances: 
x A participant who experiences a Grade 4 AE, including those that meet the criteria of a 
DLT (ie, during C1), but is deemed by the investigator not to meet the criteria for 
withdrawal from the study (Section 7.2). 
x Prolonged QTcF (defined as QTc using Fridericia's formula [QTcF] >500 msec OR 
change from baseline of QTcF >60 msec) and that does not resolve after excluding other 
causes 
A participant must be discontinued from protocol-prescribed therapy and removed from the 
study if any of the following apply: 
x Documented disease progression based on RECIST v1.1 
o In certain circumstances (eg, an isolated site of progression with responses at other 
sites that may be amenable to localized radiotherapy), participants may be allowed to 
continue therapy during and after radiation with approval from sponsor Medical 
Monitor. 
x Significant adverse events leading to discontinuation of study medications (report on 
adverse event eCRF) (Section 6.6) 
x Death 
x Participant’s request to withdraw from study treatment or withdraw consent 
x Ineligibility 
x Unwillingness or inability to comply with study requirements 
x Initiation of alternative anticancer therapy 
x Investigator’s decision 
o Clinical need for concomitant or other ancillary therapy that is not permitted in the 
study 
o Unrelated intercurrent illness that, in the judgment of the investigator, will affect 
assessments of clinical status to a significant degree 

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o Investigator believes that it is in the best interest of the participant to withdraw from 
the study 
x Pregnancy 
x Lost to follow-up 
x Sponsor’s decision to terminate the study 
 
Participants who have stable disease as best response will be allowed to continue on treatment 
provided the investigator believes it is in the participant’s best interest and none of the above 
criteria have been met. 
Participants who discontinue study treatment should complete the safety follow-up or EOT visit, 
within 30 days after the last treatment dose. Participants who do not withdraw consent will also 
undergo long-term follow-up until death or end of study or lost to follow-up. See Section 7.2 for 
details on study discontinuation. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
A participant may be withdrawn from the study for any of the following reasons: 
x Participant’s withdrawal of consent for participation in the study  
x Sponsor’s decision to terminate the study 
x Participant is lost to follow-up  
x Death  
 
If study discontinuation occurs at the same time as treatment discontinuation, every effort should 
be made to complete the safety follow-up or EOT visit, within 30 days after the last treatment 
dose. Participants who do not withdraw consent will also undergo a long-term follow-up for 
survival (SoA in Section 1.3).  
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request in writing destruction of any 
samples taken and not tested, and the investigator must document this in the site study records. 

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7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
x The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
x Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
x Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
8. 
STUDY ASSESSMETS AD PROCEDURES 
x Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
x Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
x Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
x All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
x Procedures conducted as part of the participant’s routine clinical management (e.g. blood 
count) and obtained before signing of the ICF may be used for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 

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x The maximum amount of blood collected from each participant over a 12-cycle duration 
of the study, including any extra assessments that may be required, will not exceed 0.9 L. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
 
8.1. 
Efficacy Assessments 
Participants will be assessed for response using RECIST v1.1 (Appendix 6) as assessed by the 
investigator. All measurable disease must be documented at screening and reassessed at each 
subsequent tumor evaluation. Measurable disease is not required in the Dose-Escalation 
Component; however, disease must be evaluable by other measures and documented 
accordingly. Response assessments will be assessed by the investigator based on physical 
examination (including measurement of cutaneous lesions) and CT scans or MRI. Imaging 
should include chest and abdomen (neck and pelvis are to be included depending on primary 
tumor type and investigator assessment). At the investigator’s discretion, the imaging studies 
may be repeated at any time if disease progression is suspected. Additional studies, such as 
positron emission tomography (PET) scans, should be performed if clinically indicated. Care 
should be taken to repeat the same modality used at screening throughout the study and to ensure 
all anatomy imaged at screening is again imaged at follow-up scans for any given participant. As 
part of the tumor assessment, physical examinations should include all areas of tumor 
involvement that are amenable to examination, including biopsy sites, lymph nodes, and bone 
tenderness, if applicable. 
All imaging studies should be evaluated by a local radiologist with expertise in the imaging 
modality. The investigator is responsible for determining the overall response at each timepoint. 
The first response assessment will occur after completion of C2 (C3D1 ± 7 days). Subsequent 
response assessments will occur every 2 cycles through the end of C6 (C7D1 ± 7 days) and then 
every 3 cycles. 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
x A complete physical examination will include, at a minimum, assessments of the head, 
eyes, ears, nose, and throat (HEENT), dermatologic, cardiovascular, respiratory, GI, 
lymphatic, musculoskeletal, and neurological systems. Height and weight will also be 
measured and recorded. A symptom/AE-directed physical examination should be 
performed as indicated by participant presentation or participant reported symptoms. 

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x A limited examination should include an evaluation of the HEENT, dermatologic, 
cardiovascular, respiratory, and GI systems. A symptom/AE-directed physical 
examination should be performed as indicated by participant presentation or participant 
reported symptoms. 
x Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 
8.2.2. 
Vital Signs 
Vital signs will be measured, preferably in a seated position, after approximately 5-minutes rest 
and will include temperature, systolic and diastolic blood pressure, pulse, respiratory rate, and 
pulse oximetry. Results should be recorded on the appropriate eCRF. 
8.2.3. 
Weight and Height 
Weight should be measured throughout the study as indicated in the SoA. Coats and shoes 
should be removed prior to measurement. Height should be measured at baseline, preferably 
without shoes. 
8.2.4. 
Electrocardiograms 
  
 
 
 
 
 
 

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8.2.5.
Echocardiograms/Multigated Acquisition Scans 
8.2.6.
Clinical Safety Laboratory Assessments 
x
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3) for the timing and frequency. 
x
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE Section of the eCRF. 
The laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition. 
x
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or Medical Monitor. 
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified where possible, and 
the Sponsor notified. 
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA. 
o
If laboratory values from non–protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 

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considered clinically significant by the investigator (eg, SAE, AE, or dose 
modification), then the results must be recorded in the eCRF. 
 
8.2.7. 
 
 
8.2.8. 
 
 
 
 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention(s) (Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
Monitoring and recording of AEs and SAEs will be conducted throughout the study. After the 
signing of the ICF, but prior to initiation of study intervention, only SAEs caused by a 
protocol-mandated intervention will be collected (eg, SAEs related to invasive procedures, such 
as biopsies or medication washout). Any medical occurrence that begins before the start of study 
intervention but after obtaining informed consent, and which is not considered an SAE caused by 
a protocol-mandated intervention, will be recorded on the Medical History/Current Medical 
Conditions Section of the eCRF not the AE section. 
All AEs and SAEs will be collected from the start of intervention until the safety visit or EOT 
visit, whichever is later. Any SAE that is determined to be study-drug related (possibly, 
probably, or definitely related) will be followed to resolution or stabilization, is determined to be 
irreversible by the investigator, the participant is lost to follow-up, or it has been determined that 
the study treatment is not the cause of the AE/SAE, whichever occurs first. After this period, 

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investigators should report only SAEs that are thought to be related to RMC-4630, RMC-4630 
and cobimetinib combination, or RMC-4630 and osimertinib combination. AE/SAE reporting 
will end after the participant initiates alternative cancer treatment. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours of 
investigator awareness, as indicated in Appendix 3. The investigator will submit any updated 
SAE data to the Sponsor within 24 hours of it being available. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts through the last study visit. All AEs (regardless of relationship to 
study intervention) and SAEs determined not to be study intervention related (ie, not related and 
unlikely related) will be followed through the last study visit and be noted as “continuing” if not 
resolved at this visit. 
All SAEs considered study-drug related will be followed until resolution, stabilization, is 
determined to be irreversible by the investigator, the participant is lost to follow-up (as defined in 
Section 7.3), or it has been determined that the study treatment is not the cause of the AE/SAE, 
whichever occurs first. AE/SAE reporting will end after the participant initiates alternative 
cancer treatment. 
Further information on follow-up procedures is given in Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
x Prompt notification (eg, 24 hours of becoming aware of the event) by the investigator to 
the Sponsor of a SAE is essential so that legal obligations and ethical responsibilities 
toward the safety of participants and the safety of a study intervention under clinical 
investigation are met. 
x The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs), and investigators. 

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x Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
x An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB, if appropriate according 
to local requirements. 
 
8.3.5. 
Pregnancy 
x Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until EOT visit. 
x If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
x Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
8.3.6. 
Safety Committees 
Two safety committees will be employed during this study: the Dose Committee and the ISMC. 
The Dose Committee, composed of Sponsor representatives and investigators, will evaluate the 
C1 safety data after the 28-day DLT window once the third participant in each dose cohort has 
completed. This committee will make the final decision on dosing for the next cohort, taking in 
to account all available safety data including any available data on any fourth participant enrolled 
in a dose cohort, if applicable (Section 4.1.1.1). In addition, all available efficacy, safety, and 
PK/PD data will be used to determine whether Dose-Expansion may commence at the end of 
each Dose-Escalation Cohort. 
In addition to the safety data reviews for dose escalation and cohort expansion, the ISMC will 
review emergent safety data from the RMC-4630 program after approximately every 3 months or 
after the first 6 participants have completed 2 cycles, whichever is earlier. Subsequently the 
committee will review data approximately every 3 months. The committee may adjust the timing 
of the review from the defined schedule, depending on the rate of enrollment. The committee 
will consist of the Medical Monitor, Drug Safety Monitor, and a Biostatistician. Relevant 
findings from the safety data reviews will be discussed with the study investigators. Based on the 
ongoing safety assessments, the committee may recommend changes in dosing regimen or other 
alterations to study procedures. The Medical Monitor or Drug Safety Monitor may convene a 
meeting sooner should any concerns arise from review of data or from the investigators. 

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8.4. 
Treatment of Overdose 
For this study, any dose of RMC-4630, cobimetinib, or osimertinib, 1.5× greater than the 
intended dose per administration or 2 administrations at the intended dose or more within 
<12 hours for QD dosing or < 24 hours for intermittent dosing will be considered an overdose. 
Similarly, for twice weekly D1, D2 dosing schedule, 2 administrations of the same agent 
<12 hours apart will be considered an overdose. There is no clinical experience with an overdose 
of RMC-4630, cobimetinib, or osimertinib in human clinical trials. No experiments have been 
performed to determine whether the effects of an overdose can be reversed, and there are no 
known antidotes.  
Revolution Medicines does not recommend specific treatment for an overdose. The individual 
should be monitored clinically, and supportive care should be undertaken as clinically indicated. 
In the event of an overdose, the investigator should:  
1. Halt the dispension and administration of the involved medication. The investigator may also 
hold the second medication based on his/her clinical judgement. 
2. Contact the Medical Monitor immediately. 
3. Closely monitor the participant for any AE/SAE, ECG, and laboratory abnormalities (blood 
glucose, liver function tests, creatinine, blood urea nitrogen (BUN), CPK, and complete 
blood count) until RMC-4630 and/or cobimetinib can no longer be detected systemically. 
4. Obtain a plasma sample for PK analysis within 1 to 2 days from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case basis). 
5. Document the quantity as well as the duration of the overdose in the eCRF. 
6. Decisions regarding resumption of study intervention will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
 
8.5. 
Pharmacokinetics 
 
 
 

  
8.6.
Pharmacodynamics 
. .

  
 
 
 
 
 
 
 
 
 
 
8.8. 
Other Biomarkers 
 
  
 
  
 
 
 

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8.9. 
Health Economics and Medical Resource Utilization 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
9. 
STATISTICAL COSIDERATIOS 
This is a 2-arm, Phase 1b/2 dose-escalation study designed to assess safety, to define an MTD 
and a recommended dose and regimen for a phase 2 study, and to obtain a preliminary 
assessment of efficacy of RMC-4630 in combination with cobimetinib in 1 arm and RMC-4630 
in combination with osimertinib in the 2nd arm in adult participants with relapsed/refractory 
solid tumors. The emphasis will be on safety evaluation and any efficacy analyses will be an 
estimation of the treatment effect. Descriptive statistics will be used to summarize baseline 
demographic and disease characteristics, treatment administration, efficacy and safety outcomes, 
as well as PK and PD outcomes. 
Descriptive summaries of discrete data will present the number of study participants and the 
incidence as a frequency and as a percentage. Descriptive summaries of continuous data will 
present the group mean, standard deviation, median, minimum, maximum, and sample size. 
9.1. 
Statistical Hypotheses 
There are no formal hypotheses to be tested in this study. 
9.2. 
Sample Size Determination 
Both arms of the study will include two components: a Dose-Escalation Component and a 
Dose-Expansion Component consisting of 6 genotypic/histotypic cohorts.  
Doses for both RMC-4630 and cobimetinib will vary in dose escalation component of arm 1. 
Dose escalation recommendations will be conducted using a CRM model for RMC-4630 and 
cobimetinib arm (Appendix 10). Table 1 illustrates sample size estimation based on “Scenario 1” 
depicted in Figure 2. The study is expected to enroll approximately 144 participants as follows: 
x Up to 42 participants during the Dose-Escalation Component, assumes 7 total 
combination dose cohorts (RMC-4630 dosed twice weekly on D1, D4 or D1, D2 with 
cobimetinib dosed once daily on 21/7 schedule; RMC-4630 and cobimetinib dosed twice 
weekly on D1, D2) with 3 to 6 participants per dose. The MTD cohort will enroll at least 
6 participants.  
x After reaching threshold of activity and achieving DLT clearance at a dose level, at least 
24 additional participants may be enrolled during expansion prior to RP2D for a 
maximum 12 participants per dose level (assumes 4 combination dose expansion 
cohorts). 

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x Up to 90 participants (15 per class of mutation x 6 strata) will be enrolled at RP2D 
(combination dose level 4a). Assuming 12 participants are already enrolled during dose 
escalation and expansion into cohort that will be declared RP2D, additional 78 
participants will be enrolled into RP2D cohort. 
 
The primary objective of this study is safety evaluation. The objective the efficacy evaluation is 
to generate data which will enable a preliminary estimation of the treatment effect. The treatment 
effect will be interpreted in the clinical context of specific genotypes and histotypes.  The target 
disease stabilization rate is 30%. If 5 out of 15 participants have achieved disease stabilization, 
the observed disease stabilization rate would be 33% where the lower limit of the 95% CI is 
12%, which excludes a null rate of 10%. A sample size of 15 will provide preliminary evidence 
of efficacy of RMC-4630 and cobimetinib. Replacement of efficacy unevaluable participants at 
RP2D may be considered. 
With a sample size of 144 study participants, the probability of observing 1 or more instances of 
a specific AE with a true incidence rate of 1%, 2%, or 5% is 76%, 95%, or > 99%, respectively. 
Only dose for RMC-4630 may vary in dose escalation component of arm 2, while dose of 
osimertinib will remain constant at 80 mg once daily. Dose escalation/de-escalation 
recommendations will be following mTPI-2 design for RMC-4630 and osimertinib arm.  
x Up to 18 participants during the Dose-Escalation Component, assumes up to 3 total 
combination dose cohorts with maximum of 6 participants per dose cohort. The MTD 
cohort will enroll at least 6 participants.  
x After reaching threshold of activity and achieving DLT clearance at a dose level, 6-18 
participants may be enrolled in the dose expansion cohort for a total of 24 participant in 
RMC-4630 and osimertinib arm 2 of the study. 
 

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9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined in Table 15. 
Table 15  
Population Definitions 
Population 
Description 
Enrolled  
All participants who sign an ICF and meet eligibility criteria 
Treated 
All participants who take at least 1 dose of study intervention 
Evaluable 
Evaluable for DLT: All participants in the treated population who have completed the DLT 
period or who have discontinued due to AEs or death (unless relationship to RMC-4630 and 
cobimetinib can be ruled out) prior to the end of the DLT period. In addition, participants 
must receive at least 75% of planned dose (not miss > 3 doses of RMC-4630 and 
cobimetinib on D1D2 intermittent schedule and > 6 doses of cobimetinib on 21 on/7 off 
schedule, and > 8 doses of osimertinib within the DLT window for reasons other than 
toxicity). This population will be the primary population for fitting the dose-toxicity model. 
Evaluable for efficacy: All participants with measurable disease at baseline, who take at 
least 1 dose of study intervention and underwent one post-baseline response assessment or 
who die or had clinical progression prior to first post-baseline response assessment 
Safety 
All participants who take at least 1 dose of study intervention 
Abbreviations: AE, adverse event; DLT, dose-limiting toxicity; ICF, informed consent form. 
 
9.4. 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock. This section is 
a summary of the planned statistical analyses of the primary and secondary endpoints. The full 
details of the escalation and expansion rules, including prior distributions for the dose-toxicity 
model, simulations, and operating characteristics, will be documented in separate statistical 
simulation report. 
9.4.1. 
Efficacy Analyses 
The statistical analysis methods to be used during the efficacy analyses by endpoint is presented 
in Table 16. 

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Table 16  
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
ORR is defined as the proportion of participants who achieve a CR or PR per RECIST v1.1. 
ORR and the corresponding 95% two-sided confidence interval will be derived. 
DOR is defined as the interval from the first documentation of CR or PR to the earlier of 
first documentation of definitive disease progression or death due to any cause, whichever 
occurs first. Participants who are still alive and free from progression at the time of data 
cutoff date, are lost to follow-up, have discontinued from the study, or have initiated 
subsequent anticancer therapy will be censored at the last adequate tumor assessment. The 
Kaplan-Meier method will be used to estimate PFS and DOR curves and corresponding 
quartiles. Kaplan-Meier median will be calculated with a 2-sided 95% confidence interval. 
Pharmacokinetics assessed by noncompartmental methods and summarized by descriptive 
statistics (mean or geometric mean, standard deviation, coefficient of variation, minimum, 
and maximum). 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock. 
Absolute and percentage changes of pharmacodynamic assessments at baseline and during 
treatment. 
Abbreviations: CR, complete response; DOR, duration of response; ORR, objective response rate; PR, partial 
response; RAS-MAPK, RAS-mitogen-activated protein kinase; RECIST v1.1, Response Evaluation Criteria in 
Solid Tumors, Version 1.1. 
 
The secondary efficacy endpoints of ORR and DOR will be summarized for participants enrolled 
at the RP2D. If available, genotyping results from the central laboratory will supersede those 
from local tests for primary and secondary endpoints. Local results may be included in 
exploratory analyses. 
PK parameter estimates, including but not limiting to the ones listed below, will be determined 
when possible for RMC-4630 and cobimetinib: 
x Cmax (observed) 
x Tmax (observed) 
x AUC0-t and AUCinf 
x t1/2 
x Accumulation ratio 
 
Unless otherwise specified, the PK parameters will be estimated based on noncompartmental 
analysis methods. These estimates will be summarized descriptively by dose cohort. All PK 
parameters will be computed using actual elapsed time calculated relative to dose administration. 
Dose proportionality across dose levels will be characterized by plotting Cmax and AUC versus 
dose. Exploratory analyses may be performed to evaluate the relationship between the estimated 
PK parameters and PDs, selected safety, biomarker, or clinical effect endpoints. 

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The PK and PD analyses will be presented in a separate report that may be integrated into the 
main clinical study report. 
9.4.2. 
Safety Analyses 
All DLT modeling will be performed on the DLT-evaluable population. All other safety analyses 
will be performed on the Safety Population. The statistical analysis methods to be used during 
the safety analyses by endpoint is presented in Table 17. 
Table 17  
Safety Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
Summaries of AEs, SAEs, and AEs leading to treatment discontinuation and dose 
modification, changes in laboratory test results and changes in vital signs, and DLT rate 
Secondary 
Not applicable 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock 
Abbreviations: AE, adverse event; DLT, dose-limiting toxicity; SAE, serious adverse event. 
 
AEs and SAEs will be displayed by combination dose level. 
9.4.3. 
Other Analyses 
Additional efficacy and biomarker exploratory analyses will be described in the statistical 
analysis plan finalized before database lock. 
9.5. 
Interim Analyses 
No formal interim analysis will be conducted. However, as this is an open-label study with 
regular determinations of dosing levels, several analyses may be conducted at specific points 
during the study as well as at the end of the study. The Sponsor reserves the right to report 
interim data after discussion with the principal investigators. 

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10. 
REFERECES 
Bollag G, Tsai J, Zhang J, et al. Vemurafenib: the first drug approved for BRAF-mutant cancer. 
Nat Rev Drug Discov. 2012;11(11):873-86. doi:10.1038/nrd3847. 
Brown AP. Development of serum calcium and phosphorus as clinical biomarkers for 
drug-induced systemic mineralization: case study with a MEK inhibitor. In: Bleavins 
MR, Carini C, Jurima-Romet M, and Rahbari R, editors. Biomarkers in Drug 
Development: A Handbook of Practice, Application, and Strategy. Hoboken, NJ. John 
Wiley & Sons; 2010. p. 301–22. 
Califano R, Tariq N, Compton S, Fitzgerald DA, et al. Expert Consensus on the Management of 
Adverse Events. Drugs. 2015;75(12):1335-1348. doi:10.1007/s40265-015-0434-6 
Caunt CJ, Sale MJ, Smith PF, et al. MEK1 and MEK2 inhibitors and cancer therapy: the long 
and winding road. Nat Rev Cancer. 2015; 15:577-592. doi:10.1038/nrc4000. 
Chen YN, LaMarche MJ, Chan HM, et al. Allosteric inhibition of SHP2 phosphatase inhibits 
cancers driven by receptor tyrosine kinases. Nature. 2016;535(7610):148-52. 
doi:10.1038/nature18621. 
Cheng Y, Tian H. Current Development Status of MEK Inhibitors. Molecules. 
2017;22(1551):1-20. 
Dardaei L, Wang HQ, Singh M, et al. SHP2 inhibition restores sensitivity in ALK-rearranged 
non-small-cell lung cancer resistant to ALK inhibitors. 2018. Nature Medicine. 
doi:10.1038/nm.4497. 
Daud A and Tsai K. Management of Adverse Events with Agents Targeting the MAPK Pathway 
in Patients with Metastatic Melanoma. The Oncologist. 2017;22(7):823-833. 
doi:10.1634/theoncologist.2016-0456. 
DeGeorge JJ, Ahn CH, Andrews PA, et al. Regulatory considerations for nonclinical 
development of anticancer drugs. Cancer Chemother Pharmacol. 1997;41(3):173-85. 
doi:10.1007/s002800050726. 
De La Cruz-Merino, Luis, et al. "Clinical features of serous retinopathy observed with 
cobimetinib in patients with BRAF-mutated melanoma treated in the randomized 
coBRIM study." Journal of translational medicine 15.1 (2017):146. 
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signaling pathways in cancer. Oncogene. 
2007;26(22):3279-90. doi:10.1038/sj.onc.121042. 
Duncan KE, Chang LY, Patronas M. "MEK inhibitors: a new class of chemotherapeutic agents 
with ocular toxicity." Eye 29.8 (2015):1003-1012. 

CONFIDENTIAL 
Protocol RMC-4630-02 
  V6.0 / 20 Nov 2020 
 
Revolution Medicines, Inc. 
Confidential 
140 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-247. 
Doi:10.1016/j.ejca.2008.10.026. 
Fedele C, Ran H, Diskin B, et al. SHP2 inhibition prevents adaptive resistance to MEK inhibitors 
in multiple cancer models. Cancer Discov. 2018;8 (10) 1237-1249. doi:10.1158/2159-
8290. 
Han K, Jin JY, Marchand M, et al. Population pharmacokinetics and dosing implications for 
cobimetinib in patients with solid tumors. Cancer Chemother Pharmacol. 2015:76:917-
924. doi:10.1007/s00280-015-2862-0. 
Heuchel R, Berg A, Tallquist M, et al. Platelet derived growth factor ß receptor regulates 
interstitial fluid homeostasis through phosphatidylinositol-3’ kinase signaling. Proc Natl 
Acad Sci USA. 1999;96 : 11410-11415. doi:10.1073/pnas.96.20.11410 
Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Epidermal growth factor receptor in 
non-small-cell lung carcinomas: Correlation between gene copy number and protein 
expression and impact on prognosis. J Clin Oncol. 2003;21:3798-807. 
doi:10.1200/JCO.2003.11.069. 
Hui E, Cheung J, Zhu J, et al. T cell costimulatory receptor CD28 is a primary target for 
PD-1ímediated inhibition. Science. 2017;355(6332):1428-33. doi:10.1126/science. 
aaf1292 
Krauthammer M, Kong Y, Bacchiocchi A, et al. Exome sequencing identifies recurrent 
mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet. 
2015;47(9):996-1002. doi:10.1038/ng.3361 
Larkin J, Ascierto P, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated 
melanoma. N Engl J Med. 2014;371(20):1867-1876. doi:10.1056/NEJMoa1408868 
Lee L, Niu H, Rueger R, et al. The safety, tolerability, pharmacokinetics, and pharmacodynamics 
of single oral doses of CH4987655 in healthy volunteers: target suppression using a 
biomarker. Clin Cancer Res. 2009;15(23):7368-74. doi:10.1158/1078-0432.CCR-09-
1696 
Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant 
KRAS G12C by a trapping mechanism. Science. 2016;351(6273):604-8. 
doi:10.1126/science.aad6204 
Liu F, Yang X, Geng M, et al. Targeting ERK, an Achilles' Heel of the MAPK pathway, in 
cancer therapy. Acta Pharm Sinica B 2018;8(4):552-562. doi:10.1016/j/apsb.2018.01.008 

CONFIDENTIAL 
Protocol RMC-4630-02 
  V6.0 / 20 Nov 2020 
 
Revolution Medicines, Inc. 
Confidential 
141 
Loboda A, Nebozhyn M, Klinghoffer R, et al. A gene expression signature of RAS pathway 
dependence predicts response to PI3K and RAS pathway inhibitors and expands the 
population of RAS pathway activated tumors. BMC Med Genomics. 2010; 3: 26. 
doi:10.1186/1755-8794-3-26 
Lu H, Chen L, Velazquez R, et al. SHP2 inhibition overcomes RTK-mediated pathway re-
activation in KRAS mutant tumors treated with MEK inhibitors. Mol Cancer Ther. 
2019;19(7):1323-1334. doi:10.1158/1535-7163.MCT-18-0852 
Mainardi S, Mulero-Sanchez A, Prahallad A, et al. SHP2 is required for growth of KRAS-mutant 
non-small-cell lung cancer in vivo. Nat Med. 2018;24(7):961-967. 
Mazharian A, Mori J, Wang Y, et al. Megakaryocyte-specific deletion of the protein-tyrosine 
phosphatases Shpl and Shp2 causes abnormal megakaryocyte development, platelet 
production, and function. Blood. 2013 :121(20):4205-4219. doi:10.1182/blood-2012-08-
449272 
Méndez-Martínez S, et al. "Ocular adverse events associated with MEK inhibitors." Retina 39.8 
(2019):1435-1450. 
Nichols RJ, Haderk F, Stahlhut C, et al. Efficacy of SHP2 phosphate inhibition in cancers with 
nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF and NF1 
loss. bioRxiv. 2017. doi:10.1101/188730 
Nichols RJ, Haderk F, Stahlhut C, et al. RAS nucleotide cycling underlies the SHP2 phosphatase 
dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nature Cell Biology. 
2018;20(9):1064-1073. doi:10.1038/s41556-018-0169-1 
Niihori T, Aoki Y, Ohashi H, et al. Functional analysis of PTPN11/SHP-2 mutants identified in 
Noonan syndrome and childhood leukemia. J Hum Genet. 2005;50(4):192-202. 
doi:10.1007/s10038-005-0239-7 
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell 
receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. P Natl Acad Sci USA. 2001;98(24):13866-13871. 
doi:10.1073/pnas.231486598 
Ostrem JM, Peters U, Sos M, Wells J, Shokat K. K-Ras(G12C) inhibitors allosterically control 
GTP affinity and effector interactions. Nature. 2013;503(7477):548-551. 
doi:10.1038/nature12796 
Patricelli MP, Janes MR, Li LS, et al. Selective inhibition of oncogenic KRAS output with small 
molecules targeting the inactive state. Cancer Discov. 2016;6(3):316-329. 
doi:10.1158/2159-8290.CD-15-1105 

CONFIDENTIAL 
Protocol RMC-4630-02 
  V6.0 / 20 Nov 2020 
 
Revolution Medicines, Inc. 
Confidential 
142 
Peled M, Tocheva AS, Sandigursky S, et al. Affinity purification mass spectrometry analysis of 
PD-1 uncovers SAP as a new checkpoint inhibitor. P Natl Acad Sci USA. 
2018;115(3):E468-E477. doi:10.1073/pnas.1710437115 
Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive 
non-small-cell lung cancer. N Engl J Med. 2017;377(9):829-38. 
doi:10.1056/NEJMoa1704795 
Pietras K, Ostman A, Sjoquist M et al. Inhibition of platelet-derived growth factor receptors 
reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer 
Research. 2001;61:2929-2934. 
Planchard D, Loriot Y, Andre F, et al. EGFR-independent mechanisms of acquired resistance to 
AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015;26(10):2073-8. 
doi:10.1093/annonc/mdv319. 
Prahallad A, Heynen GJ, Germano G, et al. PTPN11 is a central node in intrinsic and acquired 
resistance to targeted cancer drugs. Cell Rep. 2015;12(12):1978-85. 
doi:10.1016/j.celrep.2015.08.037 
Redig AJ, Capelletti M, Dahlberg SE, et al. Clinical and molecular characteristics of NF1-mutant 
lung cancer. Clin Cancer Res. 2016;22(13):3148-56. 
doi:10.1158/1078-0432.CCR-15-2377 
Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients 
with advanced BRAFV600-mutated melanoma: a phase 1b study. Lancet Oncol 
2014;15(9):954-965. doi:10.1016/S1470-2045(14)70301-8. 
Riviere MK, Yuan Y, Dubois F, Zohar S. A Bayesian dose-finding design for drug combination 
clinical trials based on the logistic model. Pharmaceutical statistics. 2014;13(4):247-57. 
doi:10.1002/pst.1621. 
Ruess DA, Heynen GJ, Ciecielski KJ, et al. Mutant KRAS-driven cancers depend on 
PTPN11/SHP2 phosphatase. Nat Med. 2018;24(7):954-960. 
Shapiro GI, LoRusso P, Kwak E, et al. Phase Ib study of the MEK inhibitor Cobimetinib (GDC-
0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with 
advanced solid tumors. Invest New Drugs. 24 Apr 2019. doi.org/10.1007/s10637-019-
00776-6 
Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T cell receptor induced phosphorylation of 
WKH=$3&'ȗVLJQDORVRPHDQGGRZQVWUHDPVLJQDOLQJWR3.&ș)(%6/HWW
2004;574(1-3):37-41. doi:10.1016/j.febslet.2004.07.083 
Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–
small-cell lung cancer. N Engl J Med 2018;378(2):113-125. 
doi:10.1056/NEJMoa1713137 

CONFIDENTIAL 
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Stjepanovic N, Velazquez-Martin JP, Bedard PL. Ocular toxicities of MEK inhibitors and other 
targeted therapies. Ann Oncol. 2016;27(6):998-1005. doi:1093/annonc/mdw100 
Tartaglia M, Gelb BD. Germ-line and somatic PTPN11 mutations in human disease. Eur J Med 
Genet. 2005;48(2):81-96. doi:10.1016/j.ejmg.2005.03.001 
TGCA – The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of 
lung adenocarcinoma. Nature. 2014;511(7511):543-50. doi:10.1038/nature13385 
Tricker EM, Xu C, Uddin S, Capelletti M, et al. Combined EGFR/MEK Inhibition Prevents the 
Emergence of Resistance in EGFR-Mutant Lung Cancer. Cancer Discov. 2015;5(9):960-
971. doi:10.1158/2159-8290.CD-15-0063 
Tyagi, Pallavi, and Cynthia Santiago. "New features in MEK retinopathy." BMC ophthalmology 
18.1 (2018):1-6. 
United States Food and Drug Administration. Guidance for Industry: S9 Nonclinical Evaluation 
for Anticancer Pharmaceuticals. FDA, Rockville, MD. 2010. 
https://www.fda.gov/downloads/Drugs/Guidances/ucm085389.pdf 
Wagle M, Kirouac D, Klijn C, Liu B, Mahajan S, et al. A transcriptional MAPK Pathway 
Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types. 
Precision Onco. 2018;2(1):7 doi:10.1038/s41698-018-0051-4 
Wang Y et al. Erlotinib in the treatment of advanced non-small cell lung cancer: an update for 
clinicians. Ther Adv Med Oncol. 2012 Jan; 4(1): 19-29 
Weber ML et al. "Subretinal fluid associated with MEK inhibitor use in the treatment of 
systemic cancer." JAMA ophthalmology 134.8 (2016):855-862. 
Welch SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with 
metastatic melanoma. Ther Adv Med Oncol. 2015;7(2):122-36. 
doi:10.1177/1758834014566428 
Wong GS, Zhou J, Liu JB, et al. Targeting wild-type KRAS-amplified gastroesophageal cancer 
through combined MEK and SHP2 inhibition. Nat Med. 2018;24(7):968-977. 
doi:10.1038/s41591-018-0022-x 
Yang JC-H, Wu Y-L, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR 
mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of 
overall survival data from two randomised, Phase 3 trials. Lancet Oncol 
2015;16:141-151. doi:10.1016/S1470-2045(14)71173-8 
Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al. Programmed cell death 1 forms 
negative costimulatory microclusters that directly inhibit T cell receptor signaling by 
recruiting phosphatase SHP2. J Exp Med. 2012;209(6):1201-17. 
doi:10.1084/jem.20112741 

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APPEDIX 1  
REGULATORY, ETHICAL, AD STUDY OVERSIGHT 
COSIDERATIOS 
REGULATORY AD ETHICAL COSIDERATIOS 
x This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines 
o Applicable laws and regulations 
x The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure (IB), and other relevant documents (eg, patient information, advertisements) 
must be submitted to an Institutional Review Board (IRB) by the investigator and 
reviewed and approved by the IRB before the study is initiated. 
x Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
x The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
o Notifying the IRB of serious adverse events or other significant safety findings as 
required by IRB procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, and all other applicable local 
regulations 
 
 
FIACIAL DISCLOSURE 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study. 

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IFORMED COSET PROCESS 
x The investigator or his/her designated representative will explain the nature of the study 
to the participant or his/her legally authorized representative and answer all questions 
regarding the study. 
x Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB or study center. 
x The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
x Per IRB requirements, participants must be reconsented to the most current version of the 
ICF(s) during their participation in the study. 
x A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
 
Participants who are re-screened are not required to be re-consented; all re-screening should 
occur within 5 days of the initial date of the screen failure (Section 5.4) 
The investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Any remaining mandatory samples may be used for optional exploratory 
research. Participants will be told that they are free to refuse to participate and may withdraw 
their consent at any time and for any reason during the storage period.  
DATA PROTECTIO 
x Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
x The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
x The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB members, and by inspectors from regulatory authorities. 

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DISSEMIATIO OF CLIICAL STUDY DATA 
x The posting of company-Sponsored clinical trial information and tabular study results on 
the US National Institute of Health (NIH) website (www.clinicaltrials.gov) and on other 
regional clinical trial registries in countries or regions where the clinical trial is 
conducted, will comply with local regulations. 
x Periodic safety reports will be submitted as required by regulation in the countries where 
the study is conducted. 
 
DATA QUALITY ASSURACE 
x All participant data relating to the study will be recorded on electronic Case Report Form 
(eCRF) unless transmitted to the Sponsor or designee electronically (eg, laboratory data). 
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
x The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
x The investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents. 
x Monitoring details describing methods, responsibilities, and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
x The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
x The Sponsor assumes accountability for actions delegated to other individuals (eg, 
contract research organizations [CROs]). 
x Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
x Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator 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 fur such indication, 
until 2 years after the investigation is discontinued and US Food and Drug 
Administration (FDA) is notified (ie, in accordance with 21 CFR 312.62(c), unless local 
regulations or institutional policies require a longer retention period). No records may be 

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destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 
 
SOURCE DOCUMETS 
x Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
x Data entered on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
 
STUDY AD SITE CLOSURE 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to: 
x Failure of the investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
x Inadequate recruitment of participants by the investigator 
x Discontinuation of further study intervention development 
 
PUBLICATIO POLICY 
x The Sponsor will comply with the requirements for publication of study results, and the 
results of this study may be published or presented at scientific meetings. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. The 
coordinating investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
x Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

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APPEDIX 2  
CLIICAL LABORATORY TESTS 
x The tests detailed in Table A2-1 will be performed by the local laboratory. 
x Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol. 
x Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
x Pregnancy Testing: Refer to Section 5.1 for screening criteria, Appendix 4 for women of 
childbearing potential (WOCBP) criteria, and SoA (Section 1.3) for timepoints. 
x The results of each test must be entered into the electronic Case Report Form (eCRF). 
x Investigators must document their review of each laboratory safety report. 
 

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Table A2-1  Protocol-Required Safety Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
Abbreviations: ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate 
aminotransferase; CPK, creatine phosphokinase; hCG, human chorionic gonadotropin; HBcAb, hepatitis B 
core antibody; HBsAg, hepatitis B surface antigen; IRB, institutional review board; INR, international normalized ratio; 
MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; PTT, partial thromboplastin time; RBC, red 
blood cell; SAE, serious adverse event; ULN, upper limit of normal; WBC, white blood cell. 
a 
Concurrent elevation of AST or ALT >3 × ULN AD total bilirubin >2 × ULN or INR >1.5 in the absence of 
cholestasis and other causes (eg, viral hepatitis, other pre-existing or acute liver disease, or another drug capable of 
the observed injury), which may indicate severe drug-induced liver injury (possible Hy’s law case). All events with 
the defined biochemical abnormalities must be reported as an SAE; and study medications should be permanently 
discontinued. 
b See Appendix 4. 
c 
Local urine testing will be standard for the protocol unless blood testing is required by local regulation or IRB. 
For screening, a blood test is required. 
 

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APPEDIX 3  
ADVERSE EVETS: DEFIITIOS AD PROCEDURES FOR 
RECORDIG, EVALUATIG, FOLLOW-UP, AD REPORTIG 
DEFIITIO OF ADVERSE EVET (AE) 
Adverse Event (AE) Definition 
x 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related to the study 
intervention. 
x 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. 
 
Events Meeting the AE Definition 
x 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, electrocardiogram [ECG], radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease). 
x 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
x 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
x 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
x 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/serious adverse event (SAE) unless it 
is an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
 
Events OT Meeting the AE Definition 
x 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition. 
x 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being 
studied, unless more severe than expected for the participant’s condition. 
x 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is 
the AE. 
x 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
x 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start 
of the study that do not worsen. 
 

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DEFIITIO OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it 
were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are adverse events 
(AEs). If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
d. 
Results in persistent disability/incapacity 
x 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
x 
This definition is not intended to include experiences of relatively minor medical significance, such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle), 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations 
x 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations such as important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually be considered serious. 
Examples of such events include other invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
x 
Concurrent elevation of AST or ALT >3 × ULN AD total bilirubin >2 × ULN or INR >1.5 may indicate 
severe drug-induced liver injury (possible Hy’s law case). All qualifying events must be reported as an SAE. 
 

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RECORDIG AD FOLLOW-UP OF AE AD/OR SAE 
AE and SAE Recording 
x 
When an adverse event (AE)/serious adverse event (SAE) occurs, it is the responsibility of the investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related to 
the event. 
x 
The investigator will then record all relevant AE/SAE information in the electronic Case Report Form 
(eCRF). Additionally, investigative sites should report SAEs within 24 hours of becoming aware of the event 
to the Chiltern/Covance Pharmacovigilance Department using the paper SAE report form.  See section below 
on the Reporting of SAEs. 
x 
It is not acceptable for the investigator to send photocopies of the participant’s medical records to the 
Sponsor or designee in lieu of completion of the AE/SAE CRF.  
x 
There may be instances when copies of medical records for certain cases are requested by the Sponsor or 
designee. In this case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission to the Sponsor or designee. 
x 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of Intensity 
The investigator will assess intensity (severity) for each AE and SAE reported during the study using the 
definitions found in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5 
(NCI CTCAE v5) or later. The NCI CTCAE v5 displays Grades 1 through 5 with unique clinical descriptions of 
severity for each referenced AE. Should a participant experience any AE not listed in the NCI CTCAE v5, the 
following grading system should be used to assess severity: 
 
x 
Grade 1 (Mild) – experiences which are usually transient, requiring no special treatment, and not interfering 
with the participant’s daily activities 
x 
Grade 2 (Moderate) – experiences which introduce some level of inconvenience or concern to the 
participant, and which may interfere with daily activities, but are usually ameliorated by simple therapeutic 
measures 
x 
Grade 3 (Severe) – experiences which are unacceptable or intolerable, significantly interrupt the participant’s 
usual daily activity, and require systemic drug therapy or other treatment 
x 
Grade 4 (Life-threatening) – experiences which cause the participant to be in danger of life-threatening 
consequences and urgent intervention is required 
x 
Grade 5 (Death) – experiences which result in participant death 
 
An AE that is assessed as severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. An event is defined as ‘serious’ when it 
meets at least 1 of the predefined outcomes as described in the definition of an SAE, not when it is rated as 
severe. 
 

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Assessment of Causality 
x 
The investigator is obligated to assess the relationship between both study interventions/study drugs and each 
occurrence of each AE/SAE. 
x 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out. 
x 
The investigator will use clinical judgment to determine the relationship. 
x 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration will be considered and investigated. 
x 
The investigator will also consult the Investigator’s Brochure in his/her assessment. 
x 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
x 
There may be situations in which an SAE has occurred, and the investigator has minimal information to 
include in the initial report to the Sponsor or designee. However, it is very important that the investigator 
always make an assessment of causality for every event before the initial transmission of the SAE data 
to the Sponsor or designee. 
x 
The investigator may change his/her opinion of causality in light of follow-up information and send a SAE 
follow-up report with the updated causality assessment. 
x 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
 
Follow-up of AEs and SAEs 
x 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by the Sponsor or designee to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
x 
If a participant dies during participation in the study or during a recognized follow-up period, the investigator 
will provide the Sponsor or designee with a copy of any post-mortem findings including histopathology. 
x 
New or updated information will be recorded in the originally completed eCRF. 
x 
The investigator will submit any updated SAE data to Covance Pharmacovigilance Department within 
24 hours of receipt of the information on an updated SAE report form to either the email or fax listed below. 
 
REPORTIG OF SAES 
SAE Reporting to the Sponsor or Designee via Paper CRF 
x 
Investigative sites should report SAEs within 24 hours of becoming aware of the event to the 
Chiltern/Covance Pharmacovigilance department using the paper SAE report form and any supporting 
documentation either by email or fax.   
Email:  SAEIntake@covance.com 
Fax: 1 888 887 8097 
x 
In rare circumstances and in the absence of email or facsimile equipment, notification by telephone to the 
Medical Monitor is acceptable with a copy of the SAE report form sent by overnight mail or courier service 
to Chiltern/Covance CRO Pharmacovigilance Department. 
x 
Contacts for SAE reporting can be found in the Regulatory binder. 
 

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APPEDIX 4  
COTRACEPTIVE GUIDACE AD COLLECTIO OF 
PREGACY IFORMATIO 
DEFIITIOS 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
ࡳ 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g. mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry. 
ࡳ 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
ࡳ 
A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
o Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 

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COTRACEPTIO GUIDACE 
COTRACEPTIVES a ALLOWED DURIG THE STUDY ICLUDE: 
Highly Effective Methods b That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
x 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation c 
x 
Intrauterine device (IUD) 
x 
Intrauterine hormone-releasing system (IUS)c 
x 
Bilateral tubal occlusion 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential (WOCBP) and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days.) 
Highly Effective Methods b That Are User Dependent Failure rate of <1% per year when used consistently and 
correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation c 
x 
oral 
x 
intravaginal 
x 
transdermal 
x 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulation c 
x 
oral 
x 
injectable 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.) 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are NOT acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction). 
a 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c 
Hormonal contraception efficacy may potentially be decreased due to interaction with RMC-4630 thus male 
condoms must be used in addition to hormonal contraception. 

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COLLECTIO OF PREGACY IFORMATIO 
Male Participants With Partners Who Become Pregnant 
x The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive RMC-4630 and cobimetinib under this 
protocol. 
x After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
 
Female Participants Who Become Pregnant 
x The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. 
x The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure. 
x While pregnancy itself is not considered to be an adverse event (AE) or serious adverse 
event (SAE), any pregnancy complication or elective termination of a pregnancy will be 
reported as an AE or SAE. A spontaneous abortion is always considered to be an SAE 
and will be reported as such. Any post-study pregnancy-related SAE considered 
reasonably related to the study intervention by the investigator will be reported to the 
Sponsor as described in Section 8.3.5. While the investigator is not obligated to actively 
seek this information in former study participants, he/she may learn of an SAE through 
spontaneous reporting. 
x Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study. 

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APPEDIX 6  
RESPOSE EVALUATIO CRITERIA I SOLID TUMOURS 
(RECIST V1.1) 
For this study, response and progression will be evaluated using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumours guideline version 1.1 
(RECIST v1.1; Eisenhauer 2009). 
MEASURABILITY OF TUMOR AT BASELIE 
DEFIITIOS 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or nonmeasurable as 
follows. 
a. 
Measurable Tumor Lesions 
Tumor Lesions. Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
x 10 mm by computed tomography (CT) or magnetic resonance imagining (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm) 
x 10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as nonmeasurable) 
x 20 mm by chest X-ray 
 
Malignant Lymph odes. To be considered pathologically enlarged and measurable, a lymph 
QRGHPXVWEH15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
b. 
onmeasurable Tumor Lesions 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with 10 to <15 mm short axis), as well as truly nonmeasurable lesions. Lesions considered truly 
nonmeasurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
c. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 

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Bone Lesions: 
x Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions. 
x Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
x Blastic bone lesions are nonmeasurable. 
 
Cystic Lesions: 
x Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts. 
x Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
 
Lesions with Prior Local Treatment: 
x Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
 

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SPECIFICATIOS BY METHODS OF MEASUREMETS 
MEASUREMET OF LESIOS 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
METHODS OF ASSESSMET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TUMOR RESPOSE EVALUATIO 
ASSESSMET OF OVERALL TUMOR BURDE AD MEASURABLE DISEASE 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and to use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion, as detailed above. 
BASELIE DOCUMETATIO OF “TARGET” AD “OTARGET” LESIOS 
 
 
 
 
Lymph odes 
 
 
 
 
 
Sum of Diameters 
 

  
 
 
 
 
 
 
RESPOSE CRITERIA 
a. 
Evaluation of Target Lesions 
Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
nontarget) must have reduction in short axis to <10 mm). 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum of diameters. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. NOTE: the appearance of one or more new lesions 
is also considered progression. 
 
b. 
Special otes on Assessment of Target Lesions 
Lymph odes: 
 
 
 
Target Lesions that Become “Too Small to Measure”: 
 

  
Lesions that Split or Coalesce on Treatment: 
c. 
Evaluation of ontarget Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. Although some non-target lesions may actually be measurable, they 
need not be measured and, instead, should be assessed only qualitatively at the timepoints 
specified in the protocol. 
Response
Evaluation of ontarget Lesions
Complete Response (CR)
Disappearance of all nontarget lesions and normalization of tumor marker level. 
All lymph nodes must be nonpathological in size (<10 mm short axis)
Non-CR/ Non-PD
Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker 
level above the normal limits
Progressive Disease (PD)
Appearance of one or more new lesions and/or unequivocal existing non-target
l
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d. 
Special otes on Assessment of Progression of on-target Disease 
When the Patient also has Measurable Disease 
 
 
 
When the Patient Has Only onmeasurable Disease 
 
 
 
 
 
 
e. 
ew Lesions 
 
 
 
 
 
 
 

  
 
 
 
 
f. 
FDG-PET 
 
 
 
 
 
 
 
 
 
 
 
 
 

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EVALUATIO OF BEST OVERALL RESPOSE 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. 
a. 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. Table A6-1 
provides a summary of the overall response status calculation at each timepoint for patients who 
have measurable disease at baseline. 
When patients have nonmeasurable (therefore non-target) disease only, Table A6-2 is to be used. 
Table A6-1  Timepoint Response: Patients with Target Lesions (with or without 
on-target Lesions) 
Target Lesions 
ontarget Lesions 
ew Lesion? 
Overall Response 
CR 
CR 
No 
CR 
CR 
NonCR/NonPD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; 
SD, stable disease. 
 
 

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Table A6-2  Timepoint Response: Patients with on-target Lesions Only 
ontarget Lesions 
ew Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease. 
a  “Non-CR/non-PD” is preferred over “stable disease” for nontarget disease since stable disease is increasingly 
used as an endpoint for assessment of efficacy in some trials; thus, assigning “stable disease” when no lesions 
can be measured is not advised. 
 
b. 
Missing Assessments and Unevaluable Designation 
 
 
 
 
c. 
Best Overall Response: All Timepoints 
 
 
 

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Table A6-3  Best Overall Response when Confirmation Is Required 
Overall Response 
at First Timepoint 
Overall Response at 
Subsequent 
Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum duration for SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration for SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration for SD was met; otherwise, NE 
NE 
NE 
NE 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease. 
a  If a CR is truly met at the first timepoint, any disease n at a subsequent timepoint, even disease meeting PR 
criteria relative to baseline, qualifies as PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether the minimum duration for SD was met. However, sometimes CR may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR, at the first timepoint. Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
  
d. 
Special otes on Response Assessment 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
 
 
 
 
 

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APPEDIX 7  
EASTER COOPERATIVE OCOLOGY GROUP (ECOG) 
PERFORMACE STATUS SCALE 
ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature (e.g. light house work or office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more 
than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Abbreviations: ECOG, Eastern Cooperative Oncology Group. 

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APPEDIX 8  
MEDICATIO CLASSES THAT POTETIALLY PROLOG QTC 
AD STROG CYP3A IHIBITORS AD/OR IDUCERS  
A partial list of drug classes that potentially prolong QTc and drugs that are strong CYP3A 
inhibitors and/or inducers is provided below.  
Medications known to prolong QTc 
Amiodarone 
Anagrelide 
Arsenic Trioxide  
Azithromycin 
Chloroquine 
Chlorpromazine 
Cilostazol 
Ciprofloxacin 
Citalopram 
Disopyramide 
Dofetilide 
Donepezil 
Dronedarone 
Droperidol 
Erythromycin 
Escitalopram 
Flecainide  
Fluconazole 
Haloperidol 
Ibutilide 
Levofloxacin 
Methadone 
Moxifloxacin 
Ondansetron 
Oxaliplatin 
Pentamidine  
Pimozide 
Procainamide 
Propofol 
Quinidine 
Sevoflurane 
Sotalol 
Thioridazine 
Vandetanib 
 
 
Strong CYP3A Inhibitors 
Boceprevir 
Itraconazole 
Ritonavir 
Clarithromycin 
Ketoconazole 
Saquinavir and ritonavir 
Cobicistat 
Lopinavir and ritonavir 
Telaprevir 
Danoprevir and ritonavir 
Nefazodone 
Tipranavir and ritonavir 
Elvitegravir and ritonavir 
Nelfinavir 
Telithromycin 
Grapefruit juice 
Paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir) 
Troleandomycin 
Idelalisib  
Posaconazole 
Voriconazole 
Indinavir and ritonavir 
 
 
Moderate CYP3A Inhibitors 
Aprepitant 
Diltiazam 
Imatinib 
Ciprofloxacin 
Dronedarone 
Tofisopam 
Conivaptan 
Erythromycin 
Verapamil 
Crizotinib 
Fluconazole 
 
Cyclosporine 
Fluvoxamine 
 

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Strong CYP3A Inducers 
Apalutamide 
Mitotane 
St. John’s wort 
Carbamazepine 
Phenytoin 
 
Enzalutamide 
Rifampin 
 
Moderate CYP3A Inducers 
Bosentan 
Phenobarbital 
 
Efavirenz 
Primidone 
 
Etravirine 
 
 
Proton Pump Inhibitors (PPIs) – Excluded only during the dose escalation portion of the study 
Omeprazole  
Lansoprazole  
Dexlansoprazole 
Rabeprazole 
Pantoprazole  
Esomeprazole 
H-2 Receptor Antagonists – Excluded only during the dose escalation portion of the study  
Ranitidine  
Famotidine  
Cimetidine  
Nizatidine  
 
 
Strong P-gp Inhibitors  
Amiodarone  
Carvedilol  
Clarithromycin  
Dronedarone  
Itraconazole  
Lapatinib 
Lopinavir and Ritonavir  
Propafenone  
Quinidine  
Ranolazine  
Ritonavir  
Saquinavir and Ritonavir  
Telaprevir  
Tipranavir and Ritonavir  
Verapamil 
 
Please note that this list is not comprehensive.  
The list and updates of medications that are known to prolong QTc may be obtained from 
www.crediblemeds.org.  
For additional information and updates concerning strong CYP3A inhibitors and inducers and 
strong P-gp inhibitors, refer to the following link: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm 
In addition, consult the prescribing information when determining whether a concomitant 
medication can be safety administered with study treatment. Contact the Medical Monitor if 
questions arise regarding medications not listed. 

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APPEDIX 9  
GEOTYPIC MUTATIOS REQUIRED FOR EROLLMET 
9A  
GEOTYPIC MUTATIOS REQUIRED FOR EROLLMET OF RMC-4630 
AD COBIMETIIB STUDY 
 
 
 
 
 
 
 
 
 
 
 
 

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9B  
GEOTYPIC MUTATIOS REQUIRED FOR EROLLMET OF RMC-4630 
AD OSIMERTIIB STUDY DURIG DOSE EXPASIO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPEDIX 10  
 
 
 
 
 
 
 
 
 
 
 
 

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Table A10-2  
 
 

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Conclusions 
 

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Table A10-3  Case Studies for RMC-4630 and Cobimetinib 
 
 

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APPEDIX 11  
ABBREVIATIOS 
Abbreviation 
Definition 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-t 
area under the curve from dosing time to time t 
AUCinf 
area under the curve from dosing time to infinity 
BCVA 
best corrected visual acuity 
BIW 
twice weekly 
 
BRAT 
banana, rice, apples, toast 
BUN 
blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
Cmax 
peak concentration 
CNS 
central nervous system 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
complete response 
CRM 
continual reassessment method 
CRO 
contract research organization 
CSR 
central serous retinopathy 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 

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Abbreviation 
Definition 
EGFR 
epidermal growth factor receptor 
EMM 
erythema multiforme major 
EOT 
End of Treatment 
FFPE 
formalin fixed, paraffin embedded 
FDA 
Food and Drug Administration 
GAP 
GTPase activating protein 
GCP 
Good Clinical practice 
GDP 
guanosine diphosphate 
GGT  
gamma-glutamyl transferase 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
GTP 
guanosine triphosphate 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HEENT 
head, eyes, ears, nose, and throat 
hERG 
human Ether-à go-go 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISMC 
Internal Safety Monitoring Committee 
LLN 
lower limit of normal 
LMWH 
low molecular weight heparin 
LPLV 
last participant, last visit 
LVEF 
left ventricular ejection fraction 
MAD 
multiple ascending dose 
MAPK 
mitogen-activated protein kinase 
MCMC 
Markov Chain Monte Carlo 
MRI 
magnetic resonance imaging 

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Abbreviation 
Definition 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NE 
not evaluable 
 
 
NIH 
National Institute of Health 
NSCLC 
non–small-cell lung cancer 
OCT 
optical coherence tomography 
ORR 
objective response rate 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamic(s) 
PD-1 
programmed cell death protein 1 
pERK 
phosphorylated extracellular signal regulated kinase 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
oral(ly) 
PR 
partial response 
PT 
prothrombin time 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using Fridericia's formula 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RP2D 
recommended Phase 2 dose 
RPED 
retinal pigment epithelial detachment 
RTK 
receptor tyrosine kinase 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SD 
stable disease 
SHP2 
Src Homology 2 domain-containing protein tyrosine phosphatase 2 
SJS 
Stevens-Johnson syndrome 
SoA 
Schedule of Activities 
t1/2  
elimination half-life 

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Abbreviation 
Definition 
Tmax 
time to achieve peak concentration 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
WBC 
white blood cell 
WOCBP 
women of childbearing potential