Clinical trial NCT02967692
Conditions: Melanoma
Keywords: Spartalizumab (PDR001) dabrafenib trametinib melanoma immunotherapy PD 1 inhibitor anti PD1 PD-1 anti-PD-1 combination treatment malignant skin cancer skin cancer BRAF V600 unresectable BRAF V600 mutated melanoma metastatic BRAF V600 mutated melanoma
Sponsor: Novartis Pharmaceuticals
Start date: 2017-02-17; Completion date: 2024-08-21
Enrollment: 568 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate safety and efficacy of the combination of an anti-PD-1 antibody (PDR001), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in patients with BRAF V600 mutant, unresectable and metastatic melanoma.

Detailed description:
This study was designed as a phase III, multi-center study consisting of 3 parts:

* Part 1: Safety run-in part The safety run-in part aimed to determine the recommended regimen of PDR001 in combination with dabrafenib and trametinib for previously untreated patients with BRAF V600 mutant unresectable or metastatic melanoma (stage IIIC/IV). Spartalizumab was administered at a starting dose level (DL1) of 400 mg every 4 weeks (Q4W), along with fixed doses of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily). The RP3R for Part 3 was determined using the Bayesian Logistic Regression Model (BLRM) with escalation with overdose control (EWOC) criteria.
* Part 2: Biomarker cohort Part 2 was run to explore changes in the immune microenvironment and biomarker modulations upon treatment with the combination of dabrafenib, trametinib and PDR001. Part 2 started when the fourth subject in dose level 1 (DL1) of Part 1 completed approximately 4 weeks of study treatment, and fewer than 3 dose-limiting toxicities (DLTs) were observed. Participants in Part 2 received PDR001 (spartalizumab) at a dosage of 400 mg Q4W, in combination with dabrafenib (150 mg BID) and trametinib (2 mg QD).
* Part 3: Double-blind, randomized, placebo-controlled part Part 3 was comparing the efficacy and safety of spartalizumab in combination with dabrafenib and trametinib to placebo in combination with dabrafenib and trametinib. Part 3 was initiated after determining the RP3R for the combination of spartalizumab with dabrafenib and trametinib in Part 1. Subjects were randomized in a 1:1 ratio to receive either the RP3R dose of spartalizumab identified in Part 1 or placebo, along with dabrafenib (150 mg BID) and trametinib (2 mg QD).

For all parts of the study, the treatment continued until the subject experiences any of the following events: disease progression according to RECIST 1.1 as determined by the Investigator, unacceptable toxicity, initiation of a new anti-neoplastic therapy, pregnancy, withdrawal of consent, physician's decision, loss to follow-up, death, or termination of the study by the Sponsor. Safety evaluations are conducted for all subjects for up to 150 days after the last dose of spartalizumab/placebo (safety follow-up period).

Subjects who discontinued study treatment without disease progression as per RECIST 1.1 continued with tumor assessments according to the protocol until documented disease progression, withdrawal of consent, loss to follow-up, or death, regardless of the initiation of new anti-neoplastic therapy (efficacy follow-up period).

Subjects entered the survival follow-up period after completing the safety follow-up period or experiencing disease progression as per RECIST 1.1 or response criteria for immunotherapy, whichever period is longer (survival follow-up period).

Arms: arm 1: In Part 1, participants are treated at different dose levels to determine the recommended Phase 3 regimen of spartalizumab in combination with dabrafenib and trametinib. The starting dose of spartalizumab is 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD). arm 2: In Part 2, participants are treated with spartalizumab 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD). arm 3: In Part 3, participants are randomized to receive spartalizumab at the RP3R identified in Part 1 (400 mg Q4W) in combination with approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD) arm 4: In Part 3, participants are randomized to receive matching placebo in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD)
Interventions: intervention 1: Spartalizumab intervention 2: Placebo intervention 3: Dabrafenib intervention 4: Trametinib
Intervention descriptions: intervention 1: Spartalizumab powder for solution is used in Part 1 and Part 2, and as concentrate for solution for infusion for Part 3. Spartalizumab is administered via intravenous infusion over 30 minutes once every 4 weeks intervention 2: Placebo is administered via intravenous infusion over 30 minutes once every 4 weeks intervention 3: Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions. intervention 4: Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions

Protocol documents:
SAP_002.pdf: 
Clinical Development 
PDR001, dabrafenib, trametinib 
CPDR001F2301 /  NCT02967692
A randomized, double-blind, placebo-controlled phase III study 
comparing the combination of PDR001, dabrafenib and trametinib versus 
placebo, dabrafenib and trametinib in previously untreated patients with 
unresectable or metastatic BRAF V600 mutant melanoma 
Statistical Analysis Plan (SAP) – Final and 5 year OS 
analysis 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
21-Aug-24
Number of pages: 
16 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason 
for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
21 
August 
2024 
Prior to 
DB 
lock 
Creation 
of 
final 
version 
To incorporate required analysis for OS 
and Safety. First Version. 
Only 
the 
relevant 
required 
analysis 
for 
final 
analysis 
has 
been 
incorporated. 
 


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Table of contents 
Statistical Analysis Plan (SAP) – Final and 5 year OS analysis ................................................ 1 
Table of contents ................................................................................................................. 3 
1 
Introduction ......................................................................................................................... 4 
2 
Cut-off date .......................................................................................................................... 4 
3 
Statistical Analysis .............................................................................................................. 4 
3.1 
Efficacy .................................................................................................................... 4 
3.2 
Exposure and Safety ................................................................................................ 4 
4 
General Guidance for programming .................................................................................... 5 
5 
List of outputs to be developed for this reporting activity .................................................. 5 
6 
References ......................................................................................................................... 16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the five year follow-up 
overall survival (OS) and safety of Part 1 (safety run-in) , Part 2 (Biomarker cohort) and  
part 3 (randomized part)  of the clinical study report (CSR) of study CPDR001F2301, a 
randomized, double-blind, placebo-controlled, phase III study comparing the combination of 
PDR001, dabrafenib and trametinib versus placebo, dabrafenib and trametinib in previously 
untreated patients with unresectable or metastatic BRAF V600 mutant melanoma. This will be 
also the final analysis for this study.  
The content of this SAP is based on protocol CPDR001F2301 version 07 (Amendment 7, 
release date 27 Jan 2023). All decisions regarding  follow-up analysis, as defined in the SAP 
document, have been made prior to database lock of the study data. 
2 
Cut-off date 
All analyses specified in this document will be conducted using the data from CPDR001F2301 
study (cut-off date: 24Aug2024)  
3 
Statistical Analysis  
Unless otherwise stated, all definitions and analysis methods are the same as given in the SAP 
used for the primary analysis of the study. Please refer to the final PFS analysis SAP for Part 
3 (CPDR001F2301 Statistical Analysis Plan (SAP) for Part 3_Amendment3_Final) stored in 
CREDI dated 30-July-2020. And Part 1 and 2 ((CPDR001F2301 Statistical Analysis Plan 
(SAP) for Part 1 and 2_Amendment3_Final) stored in CREDI dated 30-July-2020. 
The subject disposition will be summarized along with the overall survival and key safety 
endpoints for both Part 1 and 2 and Part 3 of the study separately.  
Note: Any data entered after subject discontinued study due to any reason will be 
documented. However it will not be considered for analysis. 
3.1 
Efficacy  
The following efficacy endpoints will be analyzed –  
• Overall survival (OS)  
All analyses will use the FAS, with no supportive analyses performed. 
3.2 
Exposure and Safety 
The following aspects will be summarized –  
• Duration of exposure, dosing information and dose modifications will be summarized 
• Overview of adverse events (number and % of subjects who died, with any AE, any 
SAE, any dose reductions/interruptions etc.), AEs by SOC and PT, summarized by 
relationship to study treatment (all AEs and AEs related to study treatment), seriousness 


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(SAEs and non-SAEs), AEs leading to treatment discontinuation and adverse events of 
special interest (AESI) 
• Notable Vital Signs and ECG 
• Deaths 
• Hematology and Biochemistry laboratory data  
4 
General Guidance for programming  
The same specification as in the TFL shells for Final PFS Analysis should be followed, unless 
otherwise specified as programming notes. 
Note – The output numbers will be the same as to the primary CSR reporting activity.  
5 
List of outputs to be developed for this reporting activity 
 
Table number in 
final PFS CSR 
deliverables  
Output title 
Table 14.1-1.3 
Subject disposition (Full Analysis Set - Part 3) 
Table 14.1-1.3b 
Subject disposition (Full Analysis Set - Part 1 and 2) 
Table 14.1-1.4 
Protocol deviations (Full Analysis Set - Part 3) 
Table 14.1-1.4b 
Protocol deviations (Full Analysis Set - Part 1 and 2) 
Table 14.1-1.4a 
Protocol deviations (Full Analysis Set - Part 3) – COVID-19 
related PD’s 
Table 14.1-1.4a1 
Protocol deviations   with relationship to COVID-19 (Full 
Analysis Set – Part 3) – COVID -19 related PD’s 
Table 14.1-3.8 
Post-treatment antineoplastic therapies by ATC class and 
preferred term (Full Analysis Set - Part 3) 
Table 14.1-3.8b 
Post-treatment antineoplastic therapies by ATC class and 
preferred term (Full Analysis Set - Part 1 and 2) 
Table 14.1-3.9 
Post-treatment antineoplastic therapies by category (Full 
Analysis Set - Part 3) 
Table 14.1-3.9b 
Post-treatment antineoplastic therapies by category (Full 
Analysis Set - Part 1 and 2) 
Table 14.1-3.10 
Summary of Best Overall Response on Subsequent Anti-
cancer therapy (Full Analysis Set – Part 3)  
Figure 14.2-2.1 
Kaplan-Meier plot of Overall survival (OS) (months) (Full 
Analysis Set - Part 3) 
Figure 14.2-2.1b 
Kaplan-Meier plot of Overall survival (OS) (months) (Full 
Analysis Set - Part 1 and 2) 
Figure 14.2-2.2 
Kaplan-Meier plot of Overall Survival (OS) (months) by 
stratification factors (Full Analysis Set - Part 3) 


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Figure 14.2-2.3 
Kaplan-Meier plot of Overall Survival (OS) (months) based on 
local investigator review and using RECIST 1.1 criteria –  
biomarker subgroups (Full Analysis Set - Part 3) 
Figure 14.2-2.4 
Kaplan-Meier plot of Overall Survival (OS)(months) –Key 
subgroups of interest variables(Full Analysis Set - Part 3) 
Figure 14.2-2.7 
Forest plot of Overall Survival (OS) (months)  - Key 
subgroups of interest (Full Analysis Set - Part 3) 
Figure 14.2-2.8 
Forest plot of Overall Survival (OS) (months)  - Biomarker 
subgroups (Full Analysis Set - Part 3) 
Figure 14.2-2.9 
Forest plot of Overall Survival (OS) (months)  - Exploratory 
subgroups (Full Analysis Set - Part 3) 
Table 14.2-2.6 
Stratified Piecewise Cox Regression analysis of Overall 
Survival (OS) (months) (Full Analysis Set - Part 3) 
Table 14.2-3.1 
Kaplan-Meier estimates of Overall Survival (OS) (months) 
(Full Analysis Set - Part 3) 
Table 14.2-3.1a 
Estimates of Overall Survival (OS) (months) (Full Analysis 
Set - Part 3) – Sensitivity analysis based on COVID-19 
Table 14.2-3.1.1 
Kaplan-Meier estimates of Overall Survival (OS) (months) 
(Pre-Protocol Set - Part 3) 
Table 14.2-3.1b 
Kaplan-Meier estimates of Overall Survival (OS) (months) 
(Full Analysis Set - Part 1 and 2) 
Table 14.2-3.2 
Kaplan-Meier estimates of Overall Survival (OS) (months) by 
stratification factors (Full Analysis Set - Part 3) 
Table 14.2-3.10 
Censoring reasons for Overall Survival (OS) (months) (Full 
Analysis Set - Part 3) 
Table 14.2-3.10b 
Censoring reasons for Overall Survival (OS) (months) (Full 
Analysis Set - Part 1 and 2) 
Table 14.2-3.11 
Duration of follow-up (Full Analysis Set - Part 3) 
Table 14.2-3.11b 
Duration of follow-up (Full Analysis Set - Part 1 and 2) 
Table 14.2-3.12 
Time on study (Full Analysis Set - Part 3) 
Table 14.2-3.12b 
Time on study (Full Analysis Set - Part 1 and 2) 
Table 14.2-4.4 
Overall Survival (OS) (months) - Key subgroups (Full 
Analysis Set - Part 3) 
Table 14.2-4.5 
Overall Survival (OS) (months) - Exploratory subgroups (Full 
Analysis Set - Part 3) 
Table 14.2-4.6 
Overall Survival (OS) (months) - Biomarker subgroups (Full 
Analysis Set - Part 3) 
Table 14.2-4.7 
Kaplan-Meier estimates of Overall Survival (OS) (months) by 
PD-L1 expression status (Full Analysis Set - Part 3) 
Table 14.2-4.8 
Kaplan-Meier estimates of Overall Survival (OS)(months) by 
Cold tumors with lack of immunogenicity as defined by low 
TMB (< 10 mut/Mb) and low T-cell inflamed signature levels 
vs. all others (Full Analysis Set - Part 3) 


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Table 14.2-4.9 
Kaplan-Meier estimates of Overall Survival (OS)(months) by 
Cold tumors with lack of immunogenicity as defined by low 
TMB (<10 mut/Mb) and low PDL1 (<1% expression in tumor 
cells) vs. all others (Full Analysis Set - Part 3) 
Table 14.2-4.13 
Kaplan-Meier estimates of Overall Survival (OS) (months) by 
TMB (Full Analysis Set - Part 3) 
Table 14.2-4.14 
Kaplan-Meier estimates of Overall Survival (OS) (months) by 
T-cell inflamed subgroups (Full Analysis Set - Part 3) 
Listing 14.2-2.6 
Overall Survival (OS) (months) (Full Analysis Set - Part 3) 
Figure 14.3-1.6 
eDISH plot: Peak total bilirubin vs Peak ALT and Peak AST  
(Safety set – Part 3) 
Table 14.3-1.1 
Duration of exposure to PDR001/Placebo and summary of 
infusions (Safety Analysis Set - Part 3) 
Table 14.3-1.1b 
Duration of exposure to PDR001 and summary of infusions 
(Safety Analysis Set - Part 1 and 2) 
Table 14.3-1.2 
Duration of exposure to trametinib (Safety Analysis Set - Part 
3) 
Table 14.3-1.2b 
Duration of exposure to trametinib (Safety Analysis Set - Part 
1 and 2) 
Table 14.3-1.3 
Duration of exposure to dabrafenib (Safety Analysis Set - Part 
3) 
Table 14.3-1.3b 
Duration of exposure to dabrafenib (Safety Analysis Set - Part 
1 and 2) 
Table 14.3-1.4 
Duration of exposure to study treatment (Safety Analysis Set - 
Part 3) 
Table 14.3-1.4b 
Duration of exposure to study treatment (Safety Analysis Set - 
Part 1 and 2) 
Table 14.3-2.1 
Dose of PDR001/Placebo received (Safety Analysis Set - Part 
3) 
Table 14.3-2.1b 
Dose of PDR001 received (Safety Analysis Set - Part 1 and 2) 
Table 14.3-2.2 
Dose of trametinib received (Safety Analysis Set - Part 3) 
Table 14.3-2.2b 
Dose of trametinib received (Safety Analysis Set - Part 1 and 
2) 
Table 14.3-2.3 
Dose of dabrafenib received (Safety Analysis Set - Part 3) 
Table 14.3-2.3b 
Dose of dabrafenib received (Safety Analysis Set - Part 1 and 
2) 
Table 14.3-2.5 
Dose adjustments and discontinuation of PDR001/Placebo 
(Safety Analysis Set - Part 3) 
Table 14.3-2.5b 
Dose adjustments and discontinuation of PDR001 (Safety 
Analysis Set - Part 1 and 2) 
Table 14.3-2.6 
Dose adjustments and discontinuation of dabrafenib (Safety 
Analysis Set - Part 3) 
Table 14.3-2.6b 
Dose adjustments and discontinuation of dabrafenib (Safety 
Analysis Set - Part 1 and 2) 


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Table 14.3-2.7 
Dose adjustments and discontinuation of trametinib (Safety 
Analysis Set - Part 3) 
Table 14.3-2.7b 
Dose adjustments and discontinuation of trametinib (Safety 
Analysis Set - Part 1 and 2) 
Table 14.3-3.4 
Concomitant medications by ATC class and preferred term 
(Safety Analysis Set - Part 3) 
Table 14.3-3.4b 
Concomitant medications by ATC class and preferred term 
(Safety Analysis Set - Part 1 and 2) 
Table 14.3-3.4.1 
Concomitant medications by ATC class and preferred term  - 
Extended follow-up (Safety Analysis Set - Part 3) 
Table 14.3-3.4.1b 
Concomitant medications by ATC class and preferred term - 
Extended follow-up (Safety Analysis Set - Part 1 and 2) 
Table 14.3-3.7 
Concomitant medications with immunosuppressive intent by 
preferred term (Safety Analysis Set - Part 3) 
Table 14.3-3.7b 
Concomitant medications with immunosuppressive intent by 
preferred term (Safety Analysis Set - Part 1 and 2) 
Table 14.3-3.8 
Concomitant medications with immunosuppressive intent by 
preferred term - Extended follow-up (Safety Analysis Set - 
Part 3) 
Table 14.3-3.8b 
Concomitant medications with immunosuppressive intent by 
preferred term - Extended follow-up (Safety Analysis Set - 
Part 1 and 2) 
Table 14.3-5.1 
Worst post-baseline biochemistry abnormalities based on CTC 
grades (Safety Analysis Set - Part 3) 
Table 14.3-5.1b 
Worst post-baseline biochemistry abnormalities based on CTC 
grades (Safety Analysis Set - Part 1 and 2) 
Table 14.3-5.2 
Worst post-baseline hematology abnormalities based on CTC 
grades (Safety Analysis Set - Part 3) 
Table 14.3-5.2b 
Worst post-baseline hematology abnormalities based on CTC 
grades (Safety Analysis Set - Part 1 and 2) 
Table 14.3-5.4 
Hematology shift table based on CTC grades (Safety Analysis 
Set - Part 3) 
Table 14.3-5.4b 
Hematology shift table based on CTC grades (Safety Analysis 
Set - Part 1 and 2) 
Table 14.3-5.5 
Biochemistry shift table based on CTC grades (Safety Analysis 
Set - Part 3) 
Table 14.3-5.5b 
Biochemistry shift table based on CTC grades (Safety Analysis 
Set - Part 1 and 2) 
Table 14.3-5.6 
Hematology shift table based on normal ranges (Safety 
Analysis Set - Part 3) 
Table 14.3-5.6b 
Hematology shift table based on normal ranges (Safety 
Analysis Set - Part 1 and 2) 
Table 14.3-5.7 
Biochemistry shift table based on normal ranges (Safety 
Analysis Set - Part 3) 


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Table 14.3-5.7b 
Biochemistry shift table based on normal ranges (Safety 
Analysis Set - Part 1 and 2) 
Table 14.3-5.8 
Summary of hepatic laboratory values (Safety Analysis Set - 
Part 3) 
Table 14.3-5.8b 
Summary of hepatic laboratory values (Safety Analysis Set - 
Part 1 and 2) 
Table 14.3-5.10 
Notable ECG values (Safety Analysis Set - Part 3) 
Table 14.3-5.10b 
Notable ECG values (Safety Analysis Set - Part 1 and 2) 
Table 14.3-5.11 
Shift tables of ECOG performance status from baseline  to 
worst post-baseline ECOG status by score (Safety Analysis Set 
- Part 3) 
Table 14.3-5.11b 
Shift tables of ECOG performance status from baseline to 
worst post-baseline ECOG status by score (Safety Analysis Set 
- Part 1 and 2) 
Table 14.3-5.12 
Shift tables of ECOG performance status from baseline to best 
post-baseline ECOG status by score (Safety Analysis Set - Part 
3) 
Table 14.3-5.12b 
Shift tables of ECOG performance status from baseline to best 
post-baseline ECOG status by score (Safety Analysis Set - Part 
1 and 2) 
Table 14.3-5.15 
Notable vital sign values (Safety Analysis Set - Part 3) 
Table 14.3-5.15b 
Notable vital sign values (Safety Analysis Set – Part 1and 2) 
Table 14.3-5.16 
Change from baseline vital signs by timepoint (Safety Analysis 
Set - Part 3) 
Table 14.3-5.16b 
Change from baseline vital signs by timepoint (Safety Analysis 
Set - Part 1 and 2) 
Table 14.3.1-1.1.2 
Overview of adverse events (Safety Analysis Set - Part 3) 
Table 14.3.1-1.1.2b 
Overview of adverse events (Safety Analysis Set - Part 1 and 
2) 
Table 14.3.1-1.1.3 
Overview of adverse events  - Extended follow-up (Safety 
Analysis Set - Part 3) 
Table 14.3.1-1.1.3b 
Overview of adverse events - Extended follow-up (Safety 
Analysis Set - Part 1 and 2 
Table 14.3.1-1.2.2 
Adverse events by preferred term (Safety Analysis Set - Part 3) 
Table 14.3.1-1.2.2b 
Adverse events by preferred term (Safety Analysis Set - Part 1 
and 2) 
Table 14.3.1-1.2.2a 
Adverse events by preferred term (Safety Analysis Set - Part 3) 
– Non-specific COVID -19 related terms(pre-COVID period) 
Table 14.3.1-
1.2.2a1 
Adverse events by preferred term (Safety Analysis Set - Part 3) 
– Non-specific COVID -19 related terms(Complete study 
period) 
Table 14.3.1-
1.2.2a2 
Adverse events by preferred term (Safety Analysis Set - Part 3) 
– specific COVID -19 related terms 


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Table 14.3.1-1.2.3 
Adverse events by system organ class and preferred term 
(Safety Analysis Set - Part 3) 
Table 14.3.1-1.2.3b 
Adverse events by system organ class and preferred term 
(Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.2.4 
Adverse events by system organ class and preferred term - 
extended follow-up (Safety Analysis Set - Part 3) 
Table 14.3.1-1.2.4b 
Adverse events by system organ class and preferred term - 
extended follow-up (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.2.7 
Adverse events suspected to be study treatment related by 
system organ class and preferred term (Safety Analysis Set - 
Part 3) 
Table 14.3.1-1.2.7b 
Adverse events suspected to be study treatment related by 
system organ class and preferred term (Safety Analysis Set - 
Part 1 and 2) 
Table 14.3.1-1.2.8 
Adverse events suspected to be study treatment related by 
system organ class and preferred term - Extended follow-up 
(Safety Analysis Set - Part 3) 
Table 14.3.1-1.2.8b 
Adverse events suspected to be study treatment related by 
system organ class and preferred term - Extended follow-up 
(Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.2.9 
Treatment-related adverse events by preferred term (Safety 
Analysis Set - Part 3) 
Table 14.3.1-1.2.9b 
Treatment-related adverse events by preferred term (Safety 
Analysis Set - Part 1 and 2) 
Table 14.3.1-1.3.1 
Serious adverse events by preferred term (Safety Analysis Set 
- Part 3) 
Table 14.3.1-1.3.1b 
Serious adverse events by preferred term (Safety Analysis Set 
- Part 1 and 2) 
Table 14.3.1-1.3.2 
Serious adverse events by system organ class and preferred 
term (Safety Analysis Set - Part 3) 
Table 14.3.1-1.3.2b 
Serious adverse events by system organ class and preferred 
term (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.3.3 
Serious adverse events by system organ class and preferred 
term - Extended follow-up (Safety Analysis Set - Part 3) 
Table 14.3.1-1.3.3b 
Serious adverse events by system organ class and preferred 
term - Extended follow-up (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.3.4 
Serious adverse events with fatal outcome (Safety Analysis Set 
- Part 3) 
Table 14.3.1-1.3.4b 
Serious adverse events with fatal outcome (Safety Analysis Set 
- Part 1 and 2) 
Table 14.3.1-1.3.5 
Serious adverse events with fatal outcome - Extended Follow-
up (Safety Analysis Set - Part 3) 
Table 14.3.1-1.3.5b 
Serious adverse events with fatal outcome - Extended Follow-
up (Safety Analysis Set - Part 1 and 2) 


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Table 14.3.1-1.3.6 
Serious adverse events with fatal outcome - Key subgroups 
(Safety Analysis Set - Part 3) 
Table 14.3.1-1.3.7 
Serious adverse events with fatal outcome - Extended Follow-
up - Key subgroups (Safety Analysis Set - Part 3) 
Table 14.3.1-1.3.8 
Serious adverse events suspected to be study treatment related 
by system organ class and preferred term (Safety Analysis Set 
- Part 3) 
Table 14.3.1-1.3.9 
Serious adverse events suspected to be study treatment related 
by system organ class and preferred term - Extended follow-up 
(Safety Analysis Set - Part 3) 
Table 14.3.1-1.3.9b 
Serious adverse events suspected to be study treatment related 
by system organ class and preferred term - Extended follow-up 
(Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.4.1 
Adverse events leading to treatment discontinuation by 
preferred term (Safety Analysis Set - Part 3) 
Table 14.3.1-1.4.1b 
Adverse events leading to treatment discontinuation by 
preferred term (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.4.2 
Adverse events leading to study treatment discontinuation, 
regardless of study treatment relationship by system organ 
class and preferred term (Safety Analysis Set - Part 3) 
Table 14.3.1-1.4.2b 
Adverse events leading to study treatment discontinuation, 
regardless of study treatment relationship by system organ 
class and preferred term (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.4.3 
Adverse events leading to study treatment discontinuation, 
suspected to be study treatment related by system organ class 
and preferred term (Safety Analysis Set - Part 3) 
Table 14.3.1-1.4.3b 
Adverse events leading to study treatment discontinuation, 
suspected to be study treatment related by system organ class 
and preferred term (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.12.1 
All Deaths (Safety Analysis Set - Part 3) 
Table 14.3.1-
1.12.1b 
All Deaths (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.13.1 
Non-serious adverse events (threshold = 5%) by system organ 
class and preferred term (Safety Analysis Set - Part 3) 
Table 14.3.1-
1.13.1b 
Non-serious adverse events (threshold = 5%) by system organ 
class and preferred term (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-1.13.2 
Non-serious adverse events (threshold = 5%) by system organ 
class and preferred term including extended safety follow-up 
(Safety Analysis Set - Part 3) 
Table 14.3.1-
1.13.2b 
Non-serious adverse events (threshold = 5%) by system organ 
class and preferred term including extended safety follow-up 
(Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-2.1.1 
Overview of adverse events of special interest for PDR001 
(Safety Analysis Set - Part 3) 


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Table 14.3.1-2.1.1b 
Overview of adverse events of special interest for PDR001 
(Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-2.1.2 
Overview of adverse events of special interest for PDR001  - 
Extended follow-up (Safety Analysis Set - Part 3) 
Table 14.3.1-2.1.2b 
Overview of adverse events of special interest for PDR001  - 
Extended follow-up (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-2.3.1 
Overview of serious adverse events of special interest for 
PDR001 (Safety Analysis Set - Part 3) 
Table 14.3.1-2.3.1b 
Overview of serious adverse events of special interest for 
PDR001 (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-2.3.3 
Overview of serious adverse events of special interest for 
dabrafenib and trametinib (Safety Analysis Set - Part 3) 
Table 14.3.1-2.3.3b 
Overview of serious adverse events of special interest for 
dabrafenib and trametinib (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-2.5.1 
Overview of adverse events of special interest for combination 
of dabrafenib and trametinib (Safety Analysis Set - Part 3) 
Table 14.3.1-2.5.1b 
Overview of adverse events of special interest for combination 
of dabrafenib and trametinib (Safety Analysis Set - Part 1 and 
2) 
Table 14.3.1-2.6.1 
Overview of adverse events of special interest for PDR001 
leading to treatment discontinuation (Safety Analysis Set - Part 
3) 
Table 14.3.1-2.6.1b 
Overview of adverse events of special interest for PDR001 
leading to treatment discontinuation (Safety Analysis Set - Part 
1 and 2) 
Table 14.3.1-2.7.1 
Overview of adverse events of special interest for PDR001 
requiring immunosuppressive medication (Safety Analysis Set 
- Part 3) 
Table 14.3.1-2.8.1b 
Overview of adverse events of special interest for PDR001 
requiring immunosuppressive medication (Safety Analysis Set 
- Part 1 and 2) 
Table 14.3.1-2.9.1 
Overview of adverse events of special interest for PDR001 
leading to dose adjustment/interruption (Safety Analysis Set - 
Part 3) 
Table 14.3.1-2.9.1b 
Overview of adverse events of special interest for PDR001 
leading to dose adjustment/interruption (Safety Analysis Set - 
Part 1 and 2) 
Table 14.3.1-2.10.1 
Overview of adverse events of special interest for dabrafenib 
and trametinib leading to dose adjustment/interruption of 
dabrafenib or trametinib (Safety Analysis Set - Part 3) 
Table 14.3.1-
2.10.1b 
Overview of adverse events of special interest for dabrafenib 
and trametinib leading to dose adjustment/interruption of 
dabrafenib or trametinib (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-2.11.1 
Overview of adverse events of special interest for PDR001 
leading to death (Safety Analysis Set - Part 3) 


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Table 14.3.1-
2.11.1b 
Overview of adverse events of special interest for PDR001 
leading to death (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-2.12.1 
Overview of adverse events of special interest for dabrafenib 
and trametinib leading to death (Safety Analysis Set - Part 3) 
Table 14.3.1-
2.12.1b 
Overview of adverse events of special interest for dabrafenib 
and trametinib leading to death (Safety Analysis Set - Part 1 
and 2) 
Table 14.3.1-2.13.1 
Overview of adverse events of special interest for PDR001 
requiring systemic corticosteroid with >= 10 mg of prednisone 
or equivalent (Safety Analysis Set - Part 3) 
Table 14.3.1-
2.13.1b 
Overview of adverse events of special interest for PDR001 
requiring systemic corticosteroid with >= 10 mg of prednisone 
or equivalent (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-2.13.2 
Overview of adverse events of special interest for PDR001 
requiring systemic corticosteroid with >= 40 mg of prednisone 
or equivalent (Safety Analysis Set - Part 3) 
Table 14.3.1-
2.13.2b 
Overview of adverse events of special interest for PDR001 
requiring systemic corticosteroid with >= 40 mg of prednisone 
or equivalent (Safety Analysis Set - Part 1 and 2) 
Table 14.3.1-2.14.1 
Overview of adverse events of special interest for combination 
of dabrafenib and trametinib requiring systemic corticosteroid 
with >= 10 mg of prednisone or equivalent (Safety Analysis 
Set - Part 3) 
Table 14.3.1-
2.14.1b 
Overview of adverse events of special interest for combination 
of dabrafenib and trametinib requiring systemic corticosteroid 
with >= 10 mg of prednisone or equivalent (Safety Analysis 
Set - Part 1 and 2) 
Table 14.3.1-2.14.2 
Overview of adverse events of special interest for combination 
of dabrafenib and trametinib requiring systemic corticosteroid 
with >= 40 mg of prednisone or equivalent (Safety Analysis 
Set - Part 3) 
Table 14.3.1-
2.14.2b 
Overview of adverse events of special interest for combination 
of dabrafenib and trametinib requiring systemic corticosteroid 
with >= 40 mg of prednisone or equivalent (Safety Analysis 
Set - Part 1 and 2) 
Table 14.3.1-2.15.1 
Summary of incidence of AESI (Safety Analysis Set - Part 3) 
Table 14.3.1-
2.15.1b 
Summary of incidence of AESI (Safety Analysis Set - Part 1 
and 2) 
Table 14.3.1-2.15.2 
Incidence of AESI including preferred term level (Safety 
Analysis Set - Part 3) 
Table 14.3.1-
2.15.2b 
Incidence of AESI including preferred term level (Safety 
Analysis Set - Part 1 and 2) 
Table 14.3.1-2.15.4 
Time to first occurrence and duration of AESI (Safety 
Analysis Set - Part 3) 


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Table 14.3.1-2.15.6 
Grade 3 or higher AESIs by month of occurrence (Safety 
Analysis Set - Part 3 
Table 14.3.1-3.1.1 
Summary of event of pyrexia (Preferred Term) (Safety 
Analysis Set - Part 3) 
Table 14.3.1-3.1.1b 
Summary of event of pyrexia (Preferred Term) (Safety 
Analysis Set - Part 1 and 2) 
Listing 14.3.2-1.1 
Deaths (Safety Analysis Set - Part 3) 
Listing 14.3.2-1.1a 
Deaths – COVID-19 related (Safety Analysis Set - Part 3) 
Listing 14.3.2-1.1b 
Deaths (Safety Analysis Set - Part 1 and 2) 
Listing 14.3.2-
1.1b1 
Deaths – COVID-19 related (Safety Analysis Set - Part 1 and 
2) 
Listing 14.3.2-1.4 
Adverse events leading to discontinuation (Safety Analysis Set 
- Part 3) 
Listing 14.3.2-1.4b 
Adverse events leading to discontinuation (Safety Analysis Set 
- Part 1 and 2) 
Listing 14.3.2-1.5 
Adverse events leading to dose adjustment and/or interruption 
(Safety Analysis Set - Part 3) 
Listing 14.3.2-1.5b 
Adverse events leading to dose adjustment and/or interruption 
(Safety Analysis Set - Part 1 and 2) 
Listing 14.3.2-1.6 
Serious adverse events (Safety Analysis Set - Part 3) 
Listing 14.3.2-1.6b 
Serious adverse events (Safety Analysis Set - Part 1 and 2) 
Listing 14.3.2-1.7 
Serious adverse events with fatal outcome (Safety Analysis Set 
- Part 3) 
Listing 14.3.2-1.7b 
Serious adverse events with fatal outcome (Safety Analysis Set 
- Part 1 and 2) 
Listing 14.3.2-2.1 
Adverse events of special interest of PDR001 (Safety Analysis 
Set - Part 3) 
Listing 14.3.2-2.1b 
Adverse events of special interest of PDR001 (Safety Analysis 
Set - Part 1 and 2) 
Listing 14.3.2-2.2 
Adverse events of special interest for combination of 
dabrafenib and trametinib (Safety Analysis Set - Part 3) 
Listing 14.3.2-2.2b 
Adverse events of special interest for combination of 
dabrafenib and trametinib (Safety Analysis Set - Part 1 and 2) 
Listing 14.3.4-1.1 
Subjects with notable ECG values (Safety Analysis Set - Part 
3) 
Listing 14.3.4-1.1b 
Subject with notable ECG values (Safety Analysis Set - Part 1 
and 2) 
Listing 16.2.1-1.1 
Subject disposition (Full Analysis Set - Part 3) 
Listing 16.2.1-1.1b 
Subject disposition (Full Analysis Set - Part 1 and 2) 
Listing 16.2.2-1.1 
Protocol deviations (Full Analysis Set - Part 3) 
Listing 16.2.2-1.1b 
Protocol deviations (Full Analysis Set - Part 1 and 2) 
Listing 16.2.2-1.1a 
Protocol deviations (Full Analysis Set - Part 3) – COVID-19 
related PD’s 


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Listing 16.2.2-
1.1b1 
Protocol deviations (Full Analysis Set - Part 1 and 2) – 
COVID-19 related PD’s 
Listing 16.2.4-5.5 
Post treatment antineoplastic therapy – Surgery (Full Analysis 
Set - Part 3) 
Listing 16.2.4-5.5b 
Post treatment antineoplastic therapy – Surgery (Full Analysis 
Set - Part 1 and 2) 
Listing 16.2.4-5.6 
Post treatment antineoplastic therapy – Radiotherapy (Full 
Analysis Set - Part 3) 
Listing 16.2.4-5.6b 
Post treatment antineoplastic therapy – Radiotherapy (Full 
Analysis Set - Part 1 and 2) 
Listing 16.2.4-5.7 
Post treatment antineoplastic therapy – Medications (Full 
Analysis Set - Part 3) 
Listing 16.2.4-5.7b 
Post treatment antineoplastic therapy – Medications (Full 
Analysis Set - Part 1 and 2) 
Listing 16.2.5-1.1 
Dose administration record for PDR001/Placebo (Safety 
Analysis Set - Part 3) 
Listing 16.2.5-1.1b 
Dose administration record for PDR001 (Safety Analysis Set - 
Part 1 and 2) 
Listing 16.2.5-1.2 
Dose administration record for Dabrafenib (Safety Analysis 
Set - Part 3) 
Listing 16.2.5-1.2b 
Dose administration record for dabrafenib (Safety Analysis Set 
- Part 1 and 2) 
Listing 16.2.5-1.3 
Dose administration record for Trametinib (Safety Analysis 
Set - Part 3) 
Listing 16.2.5-1.3b 
Dose administration record for trametinib (Safety Analysis Set 
- Part 1 and 2) 
Listing 16.2.7-1.2 
Adverse events (Safety Analysis Set - Part 3) 
Listing 16.2.7-1.2b 
Adverse events (Safety Analysis Set - Part 1 and 2) 
Listing 16.2.7-
1.2b1 
Adverse events (Safety Analysis Set - Part 1 and 2) – COVID-
19 related 
Listing 16.2.7-1.2a 
Adverse events (Safety Analysis Set - Part 3) – Specific 
COVID-19 related 
Listing 16.2.7-
1.2a1 
Adverse events (Safety Analysis Set - Part 3) – Non-Specific 
COVID-19 related (Complete study period) 
Listing 16.2.7-2.2 
Infusion Reaction Related Adverse Events of AESI after Dose 
(Safety Analysis Set - Part 3) 
Listing 16.2.7-2.2b 
Infusion Reaction Related Adverse Events of AESI after Dose 
(Safety Analysis Set - Part 1 and 2) 
Listing 16.2.8-1.1 
Subject with CTC grade 3 or 4 laboratory values (Safety 
Analysis Set - Part 3) 
Listing 16.2.8-1.1b 
Subject with CTC grade 3 or 4 laboratory values (Safety 
Analysis Set - Part 1 and 2) 
Listing 16.2.8-1.2 
Subject laboratory profile: Hematology (Safety Analysis Set - 
Part 3) 


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Listing 16.2.8-1.2b 
Subject laboratory profile: Hematology (Safety Analysis Set - 
Part 1 and 2) 
Listing 16.2.8-1.3 
Subject laboratory profile: Biochemistry (Safety Analysis Set - 
Part 3) 
Listing 16.2.8-1.3b 
Subject laboratory profile: Biochemistry (Safety Analysis Set - 
Part 1 and 2) 
Listing 16.2.8-1.4 
Subject laboratory profile of hepatic laboratory values (Safety 
Analysis Set - Part 3) 
Listing 16.2.8-1.4b 
Subject laboratory profile of hepatic laboratory values (Safety 
Analysis Set - Part 1 and 2) 
Listing 16.2.9-1.1 
Subjects with notable Vital signs (Safety Analysis Set - Part 3) 
Listing 16.2.9-1.1b 
Subjects with notable Vital signs (Safety Analysis Set - Part 1 
and 2) 
Listing 16.2.9-2.1 
ECOG performance status (Safety Analysis Set - Part 3) 
Listing 16.2.9-2.1b 
ECOG performance status (Safety Analysis Set - Part 1 and 2) 
Listing 16.2.9-4.1 
Cardiac imaging (Safety Analysis Set - Part 3) 
Listing 16.2.9-4.1b 
Cardiac imaging (Safety Analysis Set - Part 1 and 2) 
6 
References 
1. Protocol amendment 7, release date 27 Jan 2023 
2. SAP used for the primary analysis of the study. 
 
CPDR001F2301 TFL 
for final PFS analysis
CPDR001F2301 
Statistical Analysis P
CPDR001F2301 
Statistical Analysis P 

Prot_000.pdf: 


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Protocol No. CPDR001F2301
Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................8
List of figures.....................................................................................................................11
List of abbreviations ..........................................................................................................12
Glossary of terms...............................................................................................................16
Amendment 7 (27-Jan-2023).............................................................................................18
Amendment 6 (13-Oct-2020).............................................................................................21
Amendment 5 (08-Mar-2019)............................................................................................26
Amendment 4 (14-Aug-2018) ...........................................................................................29
Amendment 3 (14-Jul-2017)..............................................................................................33
Amendment 2 (07-Mar-2017)............................................................................................36
Amendment 1 (27-Jan-2017).............................................................................................44
Protocol summary..............................................................................................................45
1
Background........................................................................................................................49
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............49
1.2
Introduction to investigational treatment(s) and other study treatment(s).............51
1.2.1
Overview of PDR001 ............................................................................51
1.2.2
Overview of dabrafenib and trametinib.................................................53
2
Rationale ............................................................................................................................58
2.1
Study rationale and purpose...................................................................................58
2.2
Rationale for the study design................................................................................61
2.3
Rationale for dose and regimen selection ..............................................................63
2.4
Rationale for choice of combination drugs............................................................64
2.5
Rationale for choice of comparator drugs..............................................................64
2.6
Risks and benefits ..................................................................................................65
2.7
Rationale for public health emergency mitigation procedures ..............................67
3
Objectives and endpoints...................................................................................................67
4
Study design.......................................................................................................................71
4.1
Description of study design....................................................................................71
4.1.1
Screening phase.....................................................................................74
4.1.2
Treatment phase.....................................................................................74
4.1.3
End of treatment ....................................................................................75
4.1.4
Safety follow-up....................................................................................75
4.1.5
Efficacy follow-up.................................................................................75
4.2
Timing of interim analyses and design adaptations...............................................76


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4.3
Definition of end of study......................................................................................76
4.4
Early study termination..........................................................................................76
5
Population ..........................................................................................................................77
5.1
Subject population..................................................................................................77
5.2
Inclusion criteria ....................................................................................................77
5.2.1
Specific inclusion criteria for safety run-in (part 1) ..............................77
5.2.2
Specific inclusion criteria for biomarker cohort (part 2).......................77
5.2.3
Specific inclusion criteria for double-blind, randomized, placebo-
controlled part (part 3)...........................................................................77
5.2.4
Inclusion criteria for all subjects ...........................................................77
5.3
Exclusion criteria ...................................................................................................78
5.3.1
Specific exclusion criteria for safety run-in (part 1) .............................78
5.3.2
Specific exclusion criteria for the biomarker cohort (part 2) and the 
double-blind, randomized, placebo-controlled part (part 3)..................78
5.3.3
Exclusion criteria for all subjects ..........................................................78
6
Treatment...........................................................................................................................81
6.1
Study treatment ......................................................................................................81
6.1.1
Dosing regimen .....................................................................................82
6.1.2
Ancillary treatments ..............................................................................85
6.1.3
Rescue medication.................................................................................85
6.1.4
Guideline for continuation of treatment ................................................85
6.1.5
Treatment duration ................................................................................85
6.2
Determination of recommended regimen for the randomized part of the study....87
6.2.1
Starting dose rationale...........................................................................87
6.2.2
Provisional dose levels ..........................................................................87
6.2.3
Guidelines for determination of recommended regimen for part 3.......87
6.2.4
Definition of dose limiting toxicities in the safety-run in part (part 
1)............................................................................................................88
6.3
Dose modifications and reductions........................................................................90
6.3.1
General dose modification instructions for PDR001 or placebo...........93
6.3.2
General dose modification instructions for dabrafenib and 
trametinib:..............................................................................................93
6.3.3
Dose modification and management guideline for adverse events 
common to PDR001, dabrafenib and trametinib...................................94
6.3.4
Mandatory dose modifications and recommended clinical 
management guidelines for infusion reactions....................................114
6.3.5
Dose modification and management guideline for adverse events 
suspected to be related to dabrafenib and/or trametinib......................116


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6.3.6
Follow-up for toxicities.......................................................................125
6.4
Concomitant medications.....................................................................................126
6.4.1
Permitted concomitant therapy............................................................126
6.4.2
Permitted concomitant therapy requiring caution and/or action .........127
6.4.3
Prohibited concomitant therapy...........................................................128
6.4.4
Use of bisphosphonates (or other concomitant agents).......................129
6.5
Subject numbering, treatment assignment or randomization...............................129
6.5.1
Subject numbering...............................................................................129
6.5.2
Treatment assignment or randomization .............................................129
6.5.3
Treatment blinding ..............................................................................130
6.6
Study drug preparation and dispensation.............................................................131
6.6.1
Study treatment packaging and labeling..............................................132
6.6.2
Drug supply and storage......................................................................133
6.6.3
Study drug compliance and accountability..........................................133
6.6.4
Disposal and destruction......................................................................133
7
Visit schedule and assessments........................................................................................133
7.1
Study flow and visit schedule ..............................................................................133
7.1.1
Molecular pre-screening......................................................................166
7.1.2
Screening.............................................................................................166
7.1.3
Treatment period .................................................................................168
7.1.4
Discontinuation of study treatment .....................................................169
7.1.5
Withdrawal of study consent...............................................................170
7.1.6
Follow up for safety evaluations .........................................................171
7.1.7
Follow up for efficacy evaluations -....................................................172
7.1.8
Survival follow-up...............................................................................172
7.1.9
Lost to follow-up.................................................................................173
7.2
Assessment types .................................................................................................173
7.2.1
Efficacy assessments ...........................................................................173
7.2.2
Safety and tolerability assessments .....................................................177
7.2.3
Pharmacokinetics.................................................................................184
7.2.4
Biomarkers ..........................................................................................189
7.2.5
Patient reported outcomes ...................................................................198
8
Safety monitoring and reporting......................................................................................199
8.1
Adverse events.....................................................................................................199
8.1.1
Definitions and reporting.....................................................................199
8.1.2
Laboratory test abnormalities..............................................................201


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8.1.3
Adverse events of special interest .......................................................202
8.2
Serious adverse events .........................................................................................203
8.2.1
Definitions...........................................................................................203
8.2.2
Reporting.............................................................................................203
8.3
Emergency unblinding of treatment assignment..................................................204
8.4
Pregnancies ..........................................................................................................205
8.5
Warnings and precautions....................................................................................206
8.6
Data Monitoring Committee................................................................................206
8.7
Steering Committee..............................................................................................206
9
Data collection and management.....................................................................................207
9.1
Data confidentiality..............................................................................................207
9.2
Site monitoring.....................................................................................................207
9.3
Data collection .....................................................................................................208
9.4
Database management and quality control ..........................................................209
10 Statistical methods and data analysis...............................................................................209
10.1
Analysis sets.........................................................................................................210
10.1.1
Full Analysis Set..................................................................................210
10.1.2
Safety set .............................................................................................210
10.1.3
Per-Protocol set ...................................................................................211
10.1.4
Dose-determining analysis set.............................................................211
10.1.5
Pharmacokinetic analysis set...............................................................212
10.1.6
Other analysis sets...............................................................................212
10.2
Subject demographics/other baseline characteristics...........................................212
10.3
Treatments (study treatment, concomitant therapies, compliance)......................213
10.4
Primary objective.................................................................................................213
10.4.1
Variables..............................................................................................214
10.4.2
Statistical hypothesis, model, and method of analysis ........................214
10.4.3
Handling of missing values/censoring/discontinuations .....................217
10.4.4
Supportive and sensitivity analyses.....................................................217
10.5
Secondary objectives............................................................................................218
10.5.1
Key secondary objectives....................................................................219
10.5.2
Other secondary efficacy objectives....................................................220
10.5.3
Safety objective(s)...............................................................................221
10.5.4
Pharmacokinetics.................................................................................223
10.5.5
Immunogenicity...................................................................................224
10.5.6
Biomarkers ..........................................................................................224


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10.5.7
Resource utilization.............................................................................226
10.5.8
Patient-reported outcomes...................................................................226
227
10.7
Interim analysis....................................................................................................227
10.7.1
Progression-Free Survival ...................................................................228
10.7.2
Overall Survival (OS)..........................................................................229
10.8
Sample size calculation........................................................................................230
10.9
Power for analysis of key secondary variables....................................................231
11 Ethical considerations and administrative procedures.....................................................232
11.1
Regulatory and ethical compliance......................................................................232
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................232
11.3
Informed consent procedures...............................................................................232
11.4
Discontinuation of the study ................................................................................233
11.5
Publication of study protocol and results.............................................................233
11.6
Study documentation, record keeping and retention of documents.....................234
11.7
Confidentiality of study documents and subject records .....................................235
11.8
Audits and inspections .........................................................................................235
11.9
Financial disclosures............................................................................................235
12 Protocol adherence...........................................................................................................235
12.1
Amendments to the protocol................................................................................235
13 References (available upon request)................................................................................237
14 Appendices.......................................................................................................................243
14.1
Appendix 1: RECIST 1.1.....................................................................................243
14.1.1
Introduction .........................................................................................245
14.1.2
Efficacy assessments ...........................................................................245
14.1.3
Efficacy definitions .............................................................................254
14.1.4
Data handling and programming rules ................................................263
14.1.5
References (available upon request)....................................................267
14.2
Appendix 2: The Bayesian logistic regression model, prior, and dosing 
regimen recommendations in hypothetical scenarios ..........................................268
14.2.1
Introduction .........................................................................................269
14.2.2
Statistical model ..................................................................................269
14.2.3
Prior specifications..............................................................................270
14.2.4
Hypothetical scenarios.........................................................................281
14.2.5
References ...........................................................................................284
14.3
Appendix 3: Safety follow up flow chart.............................................................285


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14.4
AJCC Melanoma Staging System (Edition 8) .....................................................286


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List of tables
Table 3-1
Objectives and related endpoints...........................................................68
Table 6-1
Dose and treatment schedule.................................................................82
Table 6-2
Part 1 (safety run-in part): Provisional dose levels ...............................82
Table 6-3
Part 2 (biomarker cohort): Dose and treatment schedule ......................83
Table 6-4
Part 3 (randomized part): Dose and treatment schedule........................83
Table 6-5
Provisional dose levels ..........................................................................87
Table 6-6
Criteria for defining dose-limiting toxicities.........................................89
Table 6-7
Dose modification steps for PDR001/placebo, dabrafenib and 
trametinib...............................................................................................92
Table 6-8
Reference of AEs and toxicity management guidelines........................92
Table 6-9
Mandatory dose modifications and recommended clinical 
management guidelines for diarrhea/colitis...........................................94
Table 6-10
Mandatory dose modifications and recommended clinical 
management guidelines for abnormal liver enzyme test .......................96
Table 6-11
Mandatory dose modifications and recommended clinical 
management guidelines for rash............................................................97
Table 6-12
Mandatory dose modifications and recommended clinical 
management guidelines for renal function alterations...........................99
Table 6-13
Mandatory dose modifications and recommended clinical 
management guidelines for pneumonitis.............................................101
Table 6-14
Mandatory dose modifications and recommended clinical 
management guidelines for encephalitis .............................................103
Table 6-15
Mandatory dose modifications and recommended clinical 
management guidelines for endocrine events......................................105
Table 6-16
Mandatory dose modifications and recommended clinical 
management guidelines for hand foot skin reaction (palmar-plantar 
erythrodysesthesia)..............................................................................106
Table 6-17
Mandatory dose modifications and recommended clinical 
management guidelines for neutropenia and thrombocytopenia.........108
Table 6-18
Mandatory dose modifications and recommended clinical 
management guidelines for adverse events including abnormal 
laboratory related AEs.........................................................................110
Table 6-19
Mandatory dose modifications and recommended clinical 
management guidelines for other AEs of special interest ...................113
Table 6-20
Mandatory dose modifications and recommended clinical 
management guidelines for infusion reaction and cytokine release 
syndromes............................................................................................115
Table 6-21
General guidelines for dose modification for adverse events 
suspected to be related to dabrafenib and/or trametinib treatment......117


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Table 6-22
Mandatory dose modification and recommended clinical 
management for changes in LVEF suspected to be related to 
dabrafenib and/or trametinib treatment ...............................................118
Table 6-23
Mandatory dose modification and recommended clinical 
management for hypertension suspected to be related to dabrafenib 
and/or trametinib treatment .................................................................119
Table 6-24
Mandatory dose modification and recommended clinical 
management for pyrexia syndrome suspected to be related to 
dabrafenib and/or trametinib treatment ...............................................121
Table 6-25
Mandatory dose modification and recommended clinical 
management for visual changes and/or ophthalmic examination 
findings suspected to be related to dabrafenib and/or trametinib 
treatment..............................................................................................123
Table 6-26
Mandatory dose modification and recommended clinical 
management for retinal pigment epithelial detachments (RPED) 
suspected to be related to trametinib treatment ...................................123
Table 6-27
Packaging and labeling........................................................................132
Table 7-1
Visit evaluation schedule: Safety run-In part (Part 1) – visit 
schedule updated and applicable following final PFS analysis...........135
Table 7-2
Visit evaluation schedule: Biomarker cohort (Part 2) – visit 
schedule updated and applicable following final PFS analysis...........145
Table 7-3
Visit evaluation schedule: Double-blind, randomized, placebo-
controlled part (Part 3) – visit schedule updated and is applicable 
following final PFS analysis................................................................155
Table 7-4
Imaging assessment collection plan for Parts 1, 2, 3...........................174
Table 7-5
ECOG performance status scale..........................................................179
Table 7-6
Clinical laboratory parameters collection plan for all 3 parts .............180
Table 7-7
ECG collection plan for safety run-in (part 1), biomarker cohort 
(part 2), and randomized part (part 3) .................................................183
Table 7-8
Parts 1 & 2 Safety run-in and biomarker cohorts: Blood (serum) 
collection schedule for PDR001 PK and IG........................................185
Table 7-9
Part 3 Double-blind, randomized, placebo-controlled part: Blood 
(serum) collection schedule for PDR001/placebo PK and IG.............186
Table 7-10
Part 1 & 2 Safety run-in and biomarker cohorts: Pharmacokinetic 
blood (plasma) collection schedule for trametinib and dabrafenib .....187
Table 7-11
Part 3 Double-blind, randomized, placebo-controlled part: 
Pharmacokinetic blood (plasma) collection schedule for trametinib 
and dabrafenib .....................................................................................188
Table 7-12
Biomarker sample collection plan for Safety run-in (part 1) and 
double-blind, randomized, placebo-controlled parts (part 3) ..............189
Table 7-13
Biomarker sample collection plan for Biomarker cohort (part 2) .......192


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Table 10-1
Estimated timelines for interim and final PFS analyses......................229
Table 14-1
Response criteria for target lesions......................................................250
Table 14-2
Response criteria for non-target lesions ..............................................252
Table 14-3
Overall lesion response at each assessment.........................................253
Table 14-4
Options for event dates used in PFS, TTP, duration of response........261
Table 14-5
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single agent dabrafenib model parameters.....271
Table 14-6
Historical data from dabrafenib single agent clinical study ................272
Table 14-7
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single agent trametinib model parameters......272
Table 14-8
Historical data from trametinib single agent clinical study.................273
Table 14-9
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single agent PDR001 model parameters for 
model 1 (dosing regimen 1).................................................................273
Table 14-10
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single agent PDR001 model parameters for 
model 2 (dosing regimen -1a)..............................................................274
Table 14-11
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single agent PDR001 model parameters for 
model 3 (dosing regimen -1b) .............................................................274
Table 14-12
Historical data from PDR001 Q4W single agent clinical study..........275
Table 14-13
Historical data for combination of dabrafenib and trametinib ............277
Table 14-14
Prior distribution for model parameters: model 1 (dosing regimen 
1)..........................................................................................................278
Table 14-15
Summary of prior distribution of DLT rates (with dabrafenib fixed 
at 150 mg BID and trametinib fixed at 2 mg QD) for model 1 
(dosing regimen 1)...............................................................................278
Table 14-16
Prior distribution for model parameters: model 2 (dosing regimen -
1a)........................................................................................................279
Table 14-17
Summary of prior distribution of DLT rates (with dabrafenib fixed 
at 150 mg BID and trametinib fixed at 2 mg QD) for model 2 
(dosing regimen -1a)............................................................................279
Table 14-18
Prior distribution for model parameters: model 3 (dosing regimen -
1b)........................................................................................................280
Table 14-19
Summary of prior distribution of DLT rates (with dabrafenib fixed 
at 150 mg BID and trametinib fixed at 2 mg QD) for model 3 
(dosing regimen -1b) ...........................................................................280
Table 14-20
Hypothetical scenarios (with dabrafenib fixed at 150 mg BID and 
trametinib fixed at 2 mg QD) for all 3 dosing regimens, given 0-6 


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DLT’s are observed in the first 6 patients receiving dosing regimen 
16-6......................................................................................................281
Table 14-21
Hypothetical scenarios (with dabrafenib fixed at 150 mg BID and 
trametinib fixed at 2 mg QD) for cohorts -1a and -1b, given 3 
DLT’s are observed in first 6 patients receiving dosing regimen 1 ....282
Table 14-22
Definition of primary tumor (T)..........................................................286
Table 14-23
Definition of Regional Lymph Node (N)............................................287
Table 14-24
Definition of Distant Metastasis (M)...................................................288
Table 14-25
Pathological (pTNM)...........................................................................289
List of figures
Figure 4-1
Part 1: Safety run-in overview of study design .....................................72
Figure 4-2
Part 2: Biomarker cohort overview of study design..............................73
Figure 4-3
Part 3: Double blind, randomized, placebo-controlled part 
overview of study design.......................................................................73


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List of abbreviations
ADA
Anti-Drug Antibodies
ADL
Activities of Daily Living
AE
Adverse Event
AESI
Adverse Events of Special Interest
AJCC
American Joint Committee on Cancer
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Concentration-time Curve
AV
Atrioventricular
BID
bis in diem/twice a day
BLQ
Below Limit of Quantification
BLRM
Bayesian Logistic Regression Model
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CD4
Cluster of Differentiation 4
CD8
Cluster of Differentiation 8
CI
Confidence interval
Cmax
Maximum Concentration
CMO&PS
Chief Medical Office and Patient Safety 
CNS
Central Nervous System
COVID-19
Coronavirus disease-19
CT
Computed Tomography
CRF
Case Report/Record Form
CRO
Contract Research Organization
CRP
C-Reactive Protein
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T Lymphocyte Antigen 4
CV
Coefficient of Variation
CYP
Cytochromes P450
D + T
Dabrafenib and trametinib
D5W
Dextrose 5% in Water
DAR
Dosage Administration Record
DBP
Diastolic Blood Pressure
DCO
Data cut-off
DCR
Disease Control Rate
DDI
Drug-Drug Interaction
DDS
Dose-Determining Set
DILI
Drug Induced Liver Injury
DL
Dose Level
DLRT
Dose Level Review Team


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DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DOR
Duration of Response
DTIC
Dacarbazine
DVT
Deep Vein Thrombosis
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG-PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic Case Report Form
EEA
European Economic Area
EMA
European Medicines Agency
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of Treatment
EQ-5D
Quality of life questionnaire consisting of five dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) offered by EuroQoL group
EWOC
Escalation With Overdose Control
FACT-M
Functional Assessment of Cancer Therapy–Melanoma
FAS
Full Analysis Set
FDG-PET
FluoroDeoxyGlucose Positron Emission Tomography
FFPE
Formalin Fixed Paraffin Embedded
GDPR
General Data Protection Regulation
GI
Gastrointestinal
GLP
Good Laboratory Practice
HLA-A2
HLH
Human Leukocyte Antigen class 2
Hemophagocytic LymphoHistiocytosis
HNSCC
Head and Neck Squamous Cell Carcinoma
HNSTD
Highest Non-Severely Toxic Dose
HR
Hazard Ratio
HRQoL
Health Related Quality of Life
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
IG
Immunogenicity
IL-2
Interleukin-2
IL-6
Interleukin-6
IN
Investigator Notification
INR
International Normalized Ratio
IO
Immuno-oncology
irAE
Immune related Adverse Events
IRB
Institutional Review Board
irRECIST
Immune related RECIST
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine System
i.v.
intravenous(ly)


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IWRS
Interactive Web Response System
LAG525
Lymphocyte Activation Gene525
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LLN
Lower Limit of Normal
LVEF
Left Ventricular Ejection Fraction
MAP
Master Analysis Plan
MAPK
Mitogen-Activated Protein Kinase
MedDRA
Medical Dictionary for Regulatory Activities 
MEK
Mitogen activated Extracellular Signal-regulated Kinase
mmHg
Millimeter Mercury
MRI
Magnetic resonance imaging
MUGA
Multigated Acquisition
N/A
Not Applicable
NCI
National Cancer Institute
NONMEM
Nonlinear Mixed Effects Modeling
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PD
Progressive Disease
PD-1
Programmed Cell Death-1
PD-L1
Programmed Cell Death-Ligand 1
PE
Pulmonary Embolism
PET
Positron Emission Tomography
PFS
Progression-Free Survival
P-gp
P-glycoprotein
PHI
Protected Health Information
PK
Pharmacokinetic
PPES
Palmar Plantar Erythrodysesthesia Syndrome
PPS
Per Protocol Set
PR
Partial Response
PRO
PSDS
PTA
Patient Reported Outcome
Post Study Drug Supply
Post-Trial Access
QD
quaque die/once a day
QLQ-C
Quality of Life Questionnaire Core
QoL
Quality of Life
RAF
v-raf murine leukemia viral oncogene homolog serine/threonine protein kinase
RBC
Red Blood Cell
RCC
Renal Cell Carcinoma
REB
Research Ethics Board
RECIST
Response Evaluation Criteria in Solid Tumors
RMST
Restricted Mean Survival Time
RoW
Rest of World
RP2D
Recommended Phase 2 Dose
RP3R
Recommended Phase 3 Regimen


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RPED
Retinal Pigment Epithelial Detachment
R Value
ALT/ALP in multiples of ULN
RVO
Retinal Vein Occlusion
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SC
Steering Committee
SD
Stable Disease
SLN
Sentinel Lymph Node
SOP
Standard Operating Procedure
SRS
Stereotactic RadioSurgery
SSD
Study Specific Document
SUSARs
Suspected Unexpected Serious Adverse Reactions
TBIL
Total Bilirubin
TIL
Tumor Infiltrating Lymphocyte
tmax
Time to reach Cmax
Tregs
Regulatory T Cells
ULN
Upper Limit of Normal
WBC
White Blood Cell
WT
Wild Type


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
COVID-19
An infectious disease discovered in 2019, caused by a coronavirus
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug.”
Investigational 
treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes approved 
drugs used outside of their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study
Subject Number
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Personal data
Subject information collected by the Investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes patient identifier information, study 
information and biological samples.
Randomization 
number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body
Stop study 
participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
interruption
Includes any delay or withholding of study treatment for any reason as well as an 
interruption during an infusion of study treatment for any reason
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
Treatment group
A treatment group defines the dose and regimen or the combination, and may consist 
of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled.


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Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points
Withdrawal of study 
consent
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer, and does not allow any further collection of 
personal data


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Amendment 7 (27-Jan-2023) 
Amendment rationale 
As of the release of this amendment 7, there are 2 patients ongoing on treatment in part 1 (safety 
run-in), one patient ongoing on treatment in part 2 (biomarker) and 88 patients ongoing on 
treatment (out of 531 enrolled) in part 3 of the study (randomized, placebo-controlled).
The main purpose of this amendment is to: 1) revise the definition of end of study (section 4.3) 
to include Post-Trial Access (PTA) program i.e rollover protocol or a post study drug supply 
(PSDS) option for patients still on study treatment and in the opinion of the investigator still 
deriving clinical benefit at the time of end of the study, 2) update safety information on 
hemophagocytic lymphohistiocytosis (HLH), and update of “dose modification and 
recommended clinical management guidelines” in the safety section including treatment 
resumption for recurrent grade 4 asymptomatic amylase or lipase elevation per UK Health 
Authority (MHRA) request.
In addition, the following changes are implemented: 
•
A sub-section 2.7 related to public health emergency mitigation procedures was added.
•
Section 8.3 related to “Emergency unblinding of treatment assignment” was updated for 
clarification per Swissmedic feedback.
•
Language was updated to align with the latest Novartis protocol template (OneCTP version 
5.0).
In addition, editorial revisions, clarifications, and corrections are made throughout the protocol 
to improve consistency.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
The following sections have been changed in the amended protocol:
•
List of abbreviations and some protocol sections have been revised to comply with the latest 
Novartis protocol template (OneCTP version 5.0).
•
New sub-section 2.7 Rationale for public health emergency mitigation procedures has been 
added.
•
Section 4.3: The definition of end of study has been updated: addition of language to account 
for patients who continue to derive benefit from the study treatment to have the option to 
transfer into another study for drug access or an alternative treatment option to continue 
provision of study treatment.
•
Section 6.1.5: Paragraphs added to include PTA information and procedures.
•
Section 6.3: Table 6-8 “Reference of AEs and toxicity management guidelines” has been 
updated to add HLH reference. 
•
Section 6.3.3.6: Table 6-13 has been updated to clarify the mandatory dose modifications 
and recommended clinical management guidelines for pneumonitis. 


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•
Section 6.3.3.10: Table 6-17 has been updated with removal of “permanetly discontinue 
PDR001/placebo” in the 3rd occurrence of the mandatory dose modifications and 
recommended clinical management guidelines for neutropenia and thrombocytopenia for 
clarity.
•
Section 6.3.3.11: Table 6-18 dose modification has been 1) clarified for dabrafenib and 
trametinib dose interruption for 3rd occurrence of grade 2 or 3 AEs and 2) per UK Health 
Authority (MHRA) request, updated for consideration of PDR001 resumption at 2nd 
occurrence of grade 4 asymptomatic amylase and/or lipase only in patients who are deriving 
benefit and have recovered from the events after approval of both investigator and medical 
monitor. 
•
Section 6.3.5.9: This section has been added to include the guidance for hemophagocytic 
lymphohistiocytosis (HLH).
•
Section 6.5.3: This section has been updated to re-include the following revised sentence 
“Placebo administrations to those patients randomized to the placebo arm will discontinue 
while dabrafenib and trametinib may continue for the same patients” due to editorial error 
merge with the title of the section 6.6. This section has also been updated for clarification.
•
Section 6.6: Title has been updated to “Study drug preparation and dispensation“ due to 
editorial error merge with previous section and last list level text.
•
Section 6.6: This section has been updated to add “public health emergency” disruption 
proofing language.
•
Section 7.1: Study flow and visit schedule has been updated to add “public health 
emergency” disruption proofing language.
•
Sections 7.1.4, 7.1.6 and 7.1.8: Additional language has been added to clarify that safety 
and survival follow ups will not be needed for patients who transfer to Post-Trial Access 
(PTA) as an alternative treatment option to continue provision of study treatment. These 
patients will still complete end of treatment procedures.
•
Section 7.1.7: Sub-title “Prior to the final PFS analysis” has been updated based on protocol 
amendment 06 by adding in parenthesis “not applicable after primary end point interim 
analysis”.
•
Section 7.2.1: Table 7-4 “Imaging assessment collection plan” table has been updated to 
add “public health emergency” disruption proofing language.
•
Section 7.2.2: Safety and tolerability assessment section has been updated to add “public 
health emergency” disruption proofing language.
•
Section 7.2.2.6: Laboratory evaluations section has been updated to add “public health 
emergency” disruption proofing languages.
•
Section 7.2.2.6.6: Pregnancy and assessments of fertility section has been updated to add 
“public health emergency” disruption proofing languages.
•
Section 7.2.5: Patient reported outcomes section has been updated to add “public health 
emergency” disruption proofing languages. 
•
Section 8.3: This section related to “Emergency unblinding of treatment assignment” has 
been updated with removal of part of the wording for clarification per Swissmedic feedback.


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•
Section 10.7.2: This section related to overall survival (OS) has been updated for clarity 
(until definition for end of study is met).
•
Section 11.3: Informed consent procedures section has been udpated to add “public health 
emergency” disruption proofing language.
•
Section 13: Reference has been updated to include the reference related hemophagocytic 
lymphohistiocytosis (HLH).
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 6 (13-Oct-2020) 
Amendment rationale 
As of 01-Jul-2020 in Part 1 (safety run-in), all 9 patients completed the 8 weeks dose limiting 
toxicity period and in Part 2 (biomarker cohort), 27 patients were enrolled and have received at 
least one dose of PDR001, dabrafenib, and trametinib. Among 532 patients randomized in Part 
3 (randomized, placebo-controlled part), 531 patients have received at least 1 dose of 
PDR001/placebo, dabrafenib, and trametinib, and 1 patient died before receiving any study 
treatment. The last randomized patient’s first visit occured on 08-Jun-2018. The final 
Progression-Free Survival (PFS) analysis occurred using a data cut-off date of 01-Jul-2020. 
The primary objective of this amendment is to enable continuation of the study following the 
final PFS analysis, in order to characterise the overall survival benefit observed at the final PFS 
analysis.
The final PFS analysis showed that the study did not meet its primary endpoint of investigator-
assessed PFS. The combination of PDR001, dabrafenib and trametinib resulted in a limited 
benefit and did not significantly improve PFS vs placebo, dabrafenib and trametinib (median 
PFS, 16.2 months vs 12.0 months; HR=0.820 [95% CI, 0.655-1.027]; P = 0.042). The OS 
analysis provided HR=0.785 [95%CI (0.587, 1.047)] and median OS was not reached in either 
of the treatment arms. Since the primary endpoint was not met the key secondary endpoint OS 
was not formally statistically tested. Overall, no new safety concerns were identified and overall 
the AEs were manageable with dose interruptions and reductions. The safety data demonstrated 
that the treatment related AEs (TRAEs) all grades occurred in 98.5% vs. 87.5% of patients, and 
≥ grade 3 in 54.7% vs. 33.3% of patients in the PDR001 in combination with dabrafenib and 
trametinib arm and placebo in combination with dabrafenib and trametinib arm, respectively. 
Furthermore, AEs leading to discontinuation of all three drugs occurred in 15.7% vs. 9.1% of 
patients and AEs leading to discontinuation of any drug in 36.3% vs. 17.8 % of patients in the 
PDR001 in combination with dabrafenib and trametinib arm and placebo in combination with 
dabrafenib and trametinib arm, respectively. No treatment related deaths were reported in the 
PDR001 in combination with dabrafenib and trametinib arm. Two treatment related deaths were 
reported in the placebo in combination with dabrafenib and trametinib arm. 
Immuno-oncology agents such as checkpoint inhibitors are associated with a distinct response 
kinetics. Based on this, separation of estimated survival curves might therefore occur 
significantly late after the start of treatment. Long-term survival has been observed with the use 
of checkpoint inhibitors therapies in certain cancer types, including melanoma (Hersh et al 2011, 
Garon et al 2015, Weber et al 2015, Harris et al 2016). In a Phase III trial of tremelimumab in 
metastatic melanoma, an early interim analysis showed no survival benefit and the study was 
terminated; however, extended follow-up showed delayed separation of the survival curves 
(Ribas et al 2013, Eroglu et al 2015). 
Based on this, the study protocol is amended to allow the study to continue and maintain the 5-
year follow-up for overall survival despite the study not meeting the primary endpoint. Safety 
assessments and overall survival follow-up visits will continue, however efficacy assessments 
(other than overall survival) are no longer required, after implementation of this protocol 


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amendment. Mandatory blood and optional tissue sample collection at the time of progression 
will continue as originally planned to identify and characterize potential resistance mechanism
Unblinding of study treatment is mandatory and the decision to continue study treatment with 
PDR001 in combination with dabrafenib and trametinib should be made by the physician on a 
case by case basis following medical judgement and considering the risk/benefit assessment 
upon discussion with the patient. Placebo administrations to those patients randomized to the 
placebo arm will stop. 
Furthermore, this protocol amendment will also incorporate the following changes:
•
Removal of the crossover schedule as this is no longer applicable as protocol defined criteria 
for crossover was not met.
•
Inclusion of all general recommendations already provided to the investigators in a letter 
dated 7-Apr-2020 to provide guidance on coronavirus disease-19 (COVID-19) related 
challenges that may affect the study protocol execution.
•
While no new safety concerns have been observed in the program and/or trial, the 
contraception information has been updated:
•
To align the contraception requirements during and after dabrafenib and trametinib 
treatment based on dabrafenib and trametinib Investigator’s Brochure edition 12 
(following results from a trametinib drug interaction study, which showed that no 
clinically significant interaction is expected when combined hormonal contraceptives 
(norethindrone and ethinyl estradiol) are coadministered with trametinib
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Major Changes
•
Study rationale and purpose: (Section 2.1) to update on primary PFS analysis outcome and 
provide rationale for continued safety and overall survival follow-up of ongoing patients.
•
Risks and benefits: (Section 2.6) updated with adverse event and PFS results summary from 
final PFS analysis and COVID-19.
•
Objectives and Endpoints: (Section 3) updated to redefine study objective of overall survival 
following final PFS analysis results.
•
Study design Part 3: Treatment Phase (Section 4.1.2) updated following PFS analysis for 
mandatory unblinding while patients continue on study treatment. Also to redefine 
parameters upon which a decision of continuation of treatment with PDR001 in combination 
with Dabrafenib and Trametinib and clarify that placebo administrations are to stop.
•
Efficacy follow-up: (Section 4.1.5) to clarify that following final PFS analysis efficacy data, 
other than overall survival, will no longer be collected.
•
Definition of end of study (Section 4.3) updated to include further follow-up to collect 
additional survival and safety data. Crossover schedule was also removed.
•
Exclusion criteria (Section 5.3.3) update for women of child bearing potential


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•
PDR001 infusion (Section 6.1.1.4) updated for instances of delays due to the COVID-19 
pandemic and clarification that following final PFS analysis and subsequent unblinding, 
placebo administrations will stop.
•
Dabrafenib and Trametinib administration (Section 6.1.1.5) updated to allow delivery of 
Trametinib and Dabrafenib directly to a patients home where the COVID-19 pandemic 
limits or prevents on-site study visits.
•
Treatment duration (Section 6.1.5) updated following the final PFS analysis.
•
Dose modifications and reductions (Section 6.3) updated for where a patient is either 
confirmed to be infected by COVID-19 or an infection is suspected.
•
Treatment blinding (Section 6.5.3) updated to mandate unblinding for all subjects without 
treatment discontinuation or Novartis study physician approval and confirm that placebo 
administrations will stop.
•
Section 7: Crossover part was removed following final PFS analysis results.
•
Study flow and visit schedule (Section 7.1) updated to allow virtual contacts/phone 
calls/visits by site staff to replace on-site study visits where COVID-19 pandemic limits or 
prevents on-site study visits. Updates to physical assessment and safety laboratory testing 
also made where COVID-19 limits or prevents on-site study visits.
•
Table 7-1, Table 7-2 and Table 7-3 visit schedules updated following final PFS analysis to 
remove the requirement for evaluation of tumor response per a defined schedule and by 
RECIST 1.1. PRO requirements removed and confirmation that PK and IG sampling is 
discontinued following DCO on 01-Jul-2020. References to RECIST 1.1 removed for 
unscheduled biomarker testing.
•
Table 7-4 visit evaluation schedule: crossover removed.
•
Treatment period (Section 7.1.3) crossover schedule removed
•
Discontinuation of study treatment (Section 7.1.4) updated to define the decision to 
discontinue study treatment as based on investigators decision
•
Efficacy evaluations (Section 7.1.7 and Section 7.2.1) updated following final PFS analysis 
to confirm that efficacy data, other than overall survival, will no longer be collected. Also 
images no longer need to be sent to the central imaging vendor. Standard local medical 
practice is to be applied.
•
Survival follow-up (Section 7.1.8) updated to remove the reference to RECIST in defining 
the follow-up period.
•
Efficacy assessments (Section 7.2.1) updated to reflect requirements following final PFS 
analysis
•
Table 7-4 updated to remove references to crossover schedule
•
Post baseline imaging assessments (Section 7.2.1.2) updated to reflect requirements 
following final PFS analysis
•
Safety and tolerability assessments (Section 7.2.2) updated to allow virtual calls where on-
site visits are not possible due to the COVID-19 pandemic.
•
Pharmacokinetics (Section 7.2.3) updated to indicate no longer applicable after DCO for 
final PFS analysis.


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•
Table 7-9 ECG collection plan for crossover schedule, Table 7-12 Crossover subjects only: 
Blood (serum) collection schedule for PDR001 PK and IG and Table 7-15 Crossover 
subjects only: Pharmacokinetic blood (plasma) collection schedule for trametinib and 
dabrafenib removed.
•
Table 7-12 updated to remove references to crossover schedule and references to RECIST 
1.1 removed
•
Patient reported outcomes (Section 7.2.5) updated to indicate that PROs are not to be 
collected 
•
Emergency unblinding of treatment assignment (Section 8.3) updated to indicate that 
following final PFS analysis unblinding is mandatory for all subjects without the need for 
treatment discontinuation.
•
Pregnancies (Section 8.4) updated to further define follow-up period.
•
Statistical methods and data analysis (Section 10) updated to reflect descriptive analysis of 
overall survival following final PFS analysis.
•
Crossover section references removed from Section 10.4.4
•
Key secondary objectives (Section 10.5.1) updated to reflect descriptive analysis of overall 
survival following final PFS analysis.
•
Other secondary efficacy objectives (Section 10.5.2) updated as not applicable after final 
PFS analysis
•
Safety objectives (Section 10.5.3) updated to reflect analysis of safety following final PFS 
analysis.
•
Pharmacokinetics (Section 10.5.4 and Section 10.6) updated to reflect PK samples no longer 
collected following DCO for final PFS analysis.
•
Immunogenicity (Section 10.5.5) updated to reflect IG samples no longer collected 
following DCO for final PFS analysis.
•
Patient reported outcomes (Section 10.5.8) updated to reflect PRO data not collected.
•
Overall survival (Section 10.7.2) updated to reflect analysis to be done using safety and 
overall survival data.
Minor Changes
•
List of abbreviations updated
•
Table numbering updated to reflect deletion of tables pertaining to the crossover schedule
•
Clinical experience with PDR001 (Section 1.2.1.2) to reference latest version of the 
Investigator’s Brochure for current clinical experience.
•
Follow-up for safety evaluations (Section 7.1.6) confirmed to continue per existing protocol 
schedule.
•
Biomarkers (Section 7.2.4) updated to confirm that mandatory blood and optional tissue 
sample collection will continue under new amendment.
•
References (Section 13) updated


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Summary of previous amendments 
Amendment 5 (08-Mar-2019) 
In Part 1 (safety run-in), all 9 patients completed the 8 weeks dose limiting toxicity period and 
in Part 2 (biomarker cohort), 27 patients were enrolled and have received at least one dose of 
PDR001, dabrafenib, and trametinib. Among 532 patients randomized in Part 3 (randomized, 
placebo-controlled part), 531 patients have received at least 1 dose of PDR001/placebo, 
dabrafenib, and trametinib, and 1 patient died before receiving any study treatment. The last 
randomized patient’s first visit occured on 8 June 2018 and the last randomized patient’s first 
treatment on 11 July 2018. 
Amendment rationale 
The primary objective of this protocol amendment is to adjust the timing of the final PFS 
analysis and to include an interim anaysis for PFS based on revised assumptions on the delayed 
treatment effect. The original trial design of COMBI-i (CPDR001F2301) assumed a delayed 
treatment effect of 1.5 months for PFS and of 3 months for OS. However, a delayed treatment 
effect of 5 months for PFS was observed in the KEYNOTE-022 trial in a similar patient 
population and treatment combination as the COMBI-i (CPDR001F2301) trial, as recently 
presented at the European Society of Medical Oncology 2018 conference (Ascierto et al., 
2018a). KEYNOTE-022 is a Phase II randomized study with pembrolizumab or placebo in 
combination with dabrafenib and trametinib in patients with untreated BRAF V600 mutant 
melanoma. Results from KEYNOTE-022 Part 3 (Ascierto et al., 2018b) suggest a 5 months 
delayed treatment effect for PFS in the investigational arm compared to the control arm. This 
delayed treatment effect of pembrolizumab is suggestive of unique immune therapy response 
kinetics, which manifest as a slow change in tumor response over time (Wolchok et al., 2009). 
Such response kinetics have already been observed with other checkpoint inhibitors in 
unresectable or metastatic melanoma and other tumor types (Ascierto et al. (2018b); Hoos et al. 
(2010); Wolchok et al. (2017)). Available data suggest that the delayed treatment effect can be 
seen from 1.5-6 months for PFS and 3-9 months for OS, based on the tumor type and 
combination used (Ascierto et al. (2018b); Hoos et al. (2010); Wolchok et al. (2017).
Should a delayed treatment effect of this magnitude be found in the COMBI-i (CPDR001F2301) 
study it will result in a substantial loss of statistical power for the PFS analysis (refer to Section 
10.8 for statistical analysis and assumptions); therefore the study design is revised to address 
this eventuality. In order to achieve a statistical power of 80% based on a conservative 
assumption of a 5 months delayed treatment effect and followed by an effect of the same 
magnitude as assumed in the original protocol (i.e. HR=0.60), the number of PFS events for the 
final PFS analysis is increased from 246 to approximately 352 PFS events. Furthermore, an 
interim PFS analysis is being introduced at approximately 260 PFS events for the reasons 
described below. 
Since the KEYNOTE-022 study is a small Phase II study with a total of 120 patients, there is 
still some uncertainty over the exact duration of the delayed effect. The introduction of an 
interim PFS analysis provides an opportunity to detect a compelling clinical benefit at an earlier 
timepoint if the delayed effect is in fact less than 5 months and/or there is a very high treatment 
effect following the no-effect period. The timing and significance boundary of this interim PFS 


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analysis has been chosen so that the efficacy threshold is met only when the magnitude of the 
PFS treatment effect is sufficient and clinically relevant (i.e. using a stringent significance level 
at interim PFS analysis with a small penalty for the final PFS analysis). As mentioned above, 
the final PFS analysis, performed at approximately 352 PFS events, will provide an 80% 
cumulative power to detect a statistically significant treatment effect if the delayed treatment 
effect is indeed 5 months long as observed in KEYNOTE-022 and the subsequent effect is of 
the same magnitude as currently assumed (i.e. HR=0.60).
Since the total of 352 PFS events targeted for the final PFS analysis represent a large percentage 
of the patients randomized in the study (66.2%) the rate of events is likely to decrease with 
longer follow-up and formation of a plateau in the PFS Kaplan-Meier curve might occur in the 
combination arm with PDR001 based on response patterns seen in studies with other checkpoint 
inhibitors (Robert et al., 2015; Schachter et al., 2017), hence achieving the target number of 
events for the final PFS analysis might be challenging to obtain within a reasonable period of 
follow-up. Therefore, the actual data cutoff date for the final PFS analysis will occur when the 
target number of approximately 352 PFS events has been observed or approximately 24 months 
after the last patient has been randomized, whichever occurs first. Furthermore, the 24 months 
cut off date allows for sufficient mature 24 months follow up for the landmark PFS as well as 
OS Kaplan-Meier estimates. 
Additionally, the OS analysis is also revised based on an assumed 5 months delayed treatment 
effect (changed from 3 months delayed effect for the original study design). Although there is 
now provision to additionally test for OS at the interim PFS analysis with a proper control of 
the type I error rate it is acknowledged that the power of this first interim OS analysis will be 
limited. 
The Data Monitoring Committee (DMC) will be responsible for reviewing the efficacy results 
from the interim PFS analysis, which will be performed by an independent external statistician. 
If the efficacy threshold has been crossed at the time of the interim PFS analysis, the DMC may 
recommend to consider making the unblinded study results available to Novartis. However, the 
individual patient blind should still be maintained for investigators and patients at least until the 
final OS analysis (or a significant interim OS result).
This protocol amendment will also incorporate the following changes:
•
Clarification of the PRO administration and review requirements
•
Clarification on the timing of the required imaging assessments during efficacy follow-up
•
Clarification for patients to resume treatment in case of asymptomatic amylase and/or lipase 
elevation grade 4 once AE is resolved to baseline or grade ≤ 1 within 4 weeks. 
Asymptomatic elevation of amylase and lipase are observed in approximately 14 % of 
patients treated with checkpoint inhibitors. Discontinuing treatment based on the mere 
elevation of lipase and amylase in the absence of pancreatitis carries the risk of 
unnecessarily terminating treatment prematurely for patients (Brahmer et al., 2018; Puzanov 
et al., 2017).


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Changes to the protocol
•
Protocol summary and Sections 2.2, 4.1.2, 4.2, 4.3, 7.1.3, and 10: Revised number of PFS 
events for the final PFS analysis, included an interim PFS analysis, and modified OS 
analyses.
•
Section 6.3, Table 6-8: Added asymptomatic amylase and/or lipase elevation to the list of 
AEs
•
Section 6.3.3, table 6-18: Modified for cases with asymptomatic grade 4 elevation of 
amylase and/or lipase. 
•
Section 6.3.3.12, Table 6-19: Moved footnote text ‘for asymptomatic amylase and/or lipase 
elevations refer to Table 6-18’ into the table heading
•
Section 7.1, Tables 7-1 through 7-5: Clarified that imaging assessments during efficacy 
follow-up should be performed every 12 weeks starting from the last assessment.
•
Section 7.1, Tables 7-3: Corrected error in visit evaluation schedule for Part 3 only, where 
the urinalysis assessment (microscopy and macroscopic) was categorized incorrectly.
•
Section 7.1, Tables 7-3 and 7-4, and Section 7.2.5: Changed the requirement for the 
investigator to review the PRO for responses which may indicate potential AEs or Serious 
Adverse Events (SAEs) before the clinical examination to a recommendation. This change 
is made to allow sites more flexibility given the cumbersome and impractical nature of these 
requirements.
•
Section 7.2.1: Included central review of imaging data using RECIST 1.1 and tumor 
response criteria based on guidelines for immunotherapy at the time of the added interim 
PFS analysis and clarified that this is not needed at the time of the final OS analysis. 
•
Section 8.3: Clarified that emergency unblinding decisions must only be undertaken by the 
investigator. The actual unblinding procedure in the Interactive Web Response System 
(IWRS) can be performed either by the investigator or a designee.
•
Sections 8.6 and 10.7.1: Added the review of efficacy results by the DMC.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 4 (14-Aug-2018)
In Part 1 (safety run-in part) and Part 2 (biomarker cohort) of the study, 36 patients have been 
enrolled and received at least 1 dose of PDR001, dabrafenib, and trametinib. In Part 3 
(randomized part), 532 patients have received at least 1 dose of PDR001/placebo, dabrafenib, 
and trametinib. The last patient’s first visit (i.e., date Main Study Informed Consent Form (ICF) 
signed) was completed on 08 June 2018. 
Amendment rationale 
The primary objective of this protocol amendment is to align the contraception requirements 
during and after study treatment based on the dabrafenib Investigator’s Brochure (IB) Edition 
10 and trametinib IB Edition 9. Further, the safety follow-up periods have been aligned with 
the contraception requirements after study treatment has been discontinued.
Further, this protocol amendment will incorporate the following:
•
Revised individual subject unblinding requirements to limit the impact of unblinding on the 
scientific validity of the study results. Except for medical emergencies, for regulatory 
reporting purposes, or if it is critical to determine subsequent therapy after disease 
progression, documented approval by the Novartis study physician is required prior to 
unblinding a subject's treatment assignment.
•
Corrected language that if a subject is unblinded, he/she must be discontinued from the 
study treatment and must be followed for efficacy and survival, if applicable.
•
Updated definition of personal data and withdrawal of consent to reflect the European 
Economic Area (EEA) General Data Protection Regulation (GDPR) requirements.
•
Other minor corrections are also applied throughout the protocol.
Changes to the protocol (in order of appearance in the protocol)
Changes to specific sections of the protocol are shown in the track changes using strike through 
red font for deletions and red underline for insertions.
Major changes
•
Changed the 150 day contraception follow up period from “150-days after stopping 
treatment with PDR001” to “150-days after stopping treatment with PDR001/placebo, 30-
days after dabrafenib, or 120-days after trametinib, whichever is longer” in exclusion 
criterion 28 and 29 (Section 5.3). No new safety concerns have been observed in the 
program and/or trial. However, to align the contraception requirements during and after 
dabrafenib and trametinib based on dabrafenib Investigator’s Brochure edition 10 and 
trametinib Investigator’s Brochure edition 9 the protocol has been updated.


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•
Part 3 Other Secondary Endpoint #6 was clarified 
 
 by adding “in subgroups defined” after OS: “PFS by investigator’s 
assessment according to RECIST 1.1 and OS in subgroups defined by centrally assessed 
PD-L1 status” in Section 3.
•
Changed the start of the 150 day safety follow up period from “the last dose of PDR001” to 
“the last dose of PDR001/placebo” throughout the document in Sections 6.3.6, 7.1.6, 8.1.1, 
8.2.2 and 10.5.3 for the randomized, placebo-controlled part (Part 3) of the study. 
•
Added requirements for unblinding in Section 6.5.3 and 8.3 to limit the impact of unblinding 
on the scientific validity of the study results. “Individual patient unblinding will be 
prohibited, except for medical emergencies, for regulatory reporting purposes, or if it is 
critical to determine subsequent therapy after disease progression. Except in these cases, 
documented approval by the Novartis study physician is required prior to unblinding a 
subject's treatment assignment. In case of unblinding, all data is required to be captured in 
the eCRF prior to unblinding. Data after unblinding will continue to be collected as per 
protocol.”
•
Removed language “The study will be unblinded either at interim or final analysis if 
statistically significant overall survival results are demonstrated.” in Section 6.5.3 for clarity. 
•
Added “In case where individual drug components of the study treatment are discontinued 
at different times, subjects must be followed for safety evaluation up to 150 days following 
the last dose of PDR001/placebo or up to 30 days after the last dose of dabrafenib or 120 
days after the last dose of trametinib, whichever is longer.” in Section 7.1.6 to update and 
clarify safety follow up periods for each drug components of the study treatment to align 
with contraception requirements. Subsequently, revised the AE monitoring and Serious 
Adverse Event (SAE) reporting period in Sections 8.1.1 and 8.2.2, respectively, to align 
with Section 7.1.6.
•
Added language that requires subjects to be followed for skin related toxicity every month 
for 6 months from the last dose of dabrafenib in Section 7.1.6 to align with Section 6.3.5.3.
•
Added language in Section 8.3 to ensure continued efficacy and survival follow up for 
unblinded patients: “If a subject is unblinded, he/she must be discontinued from the study 
treatment and must be followed for efficacy and survival, as applicable per Section 7.1.7 
and 7.1.8.”
Minor changes
•
Removed “taking medicinal products known to prolong the QT interval” from exclusion 
criterion 23 (Section 5.3) as dedicated QT studies in humans or analysis of phase I study 
ECG data showed no clinically relevant effect of dabrafenib, metabolites of dabrafenib, 
trametinib or PDR001 to alter the QTc interval.
•
Removed “dietary” supplements from the list of products that are not permitted for use 
during dabrafenib and trametinib dosing in Section 6.1.1.5. Based on the available data, 




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•
New references cited under Amendment 04 have been added to Section 13.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 3 (14-Jul-2017)
The first patient’s first visit (i.e., date Main Study ICF signed) was completed on 17 February 
2017. Subsequently, the first treatment of a patient occurred on 07 March 2017. As of 17 July 
2017, 12 patients have received at least 1 dose of PDR001, dabrafenib, and trametinib in Part 1 
and Part 2 of the study. 
Amendment rationale 
The primary objective of this protocol amendment is to change pyrexia management guidelines 
based on the safety profile observed in the safety run-in (part 1) and feedback received from 
investigators upon review of safety data.
At the same time, changes to improve data collection for radiotherapy events, central review 
using tumor response criteria based on guidelines for immunotherapy, ophthalmologic 
examination assessment frequency, and patient reported outcomes are implemented. In 
addition, the BRAF V600 testing method was clarified and language was added to reflect the 
AJCC edition 8 melanoma staging system. Further, the frequency the data monitoring 
committee will review safety data was revised from 6 to 3-6 months to ensure appropriate safety 
monitoring. Other minor corrections are also applied throughout the protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
•
‘Absence of irPD’ in Section 6.1.5.1 was removed, given local assessment based on 
response criteria for immunotherapy is not required in this study. Subsequently, the text 
was adjusted in Sections 2.2, 4.1, 7.2.4.1; Figure 4-3; Tables 7-1, 7-2, 7-3, 7-4, 7-16, 7-17 
to reflect this change.
•
To allow further central analysis using tumor response criteria based on guidelines for 
immunotherapy by the blinded independent radiology committee, at least two additional 
tumor assessments that are at least 4 weeks apart should be performed no less than 4 weeks 
after the criteria for PD are first met. Additionally, clarification was added to require an 
additional tumor assessment to be performed to confirm response (CR or PR) to be 
consistent with Section 7.2.1.2. (Sections 4.1.5, 6.1.5.1, 7.1.7, 7.2.1.2 and Tables 7-1, 7-2, 
7-3, 7-4).
•
Clarified definition of end of study (Section 4.3) in the case that statistically significant 
interim (at the time of the primary PFS analysis) or final OS results are demonstrated.
•
Changed dose modification guidelines for pyrexia syndrome to reflect that dabrafenib and 
trametinib must be interrupted promptly at the very first symptom of pyrexia or its 
associated prodrome and should be restarted at the same dose if symptom free at least 24 
hours (Section 6.3.5.4). 
•
Clarified dose modification guidelines for abnormal liver enzyme test to reflect that 
PDR001/placebo must be permanently discontinued if abnormal liver enzyme functions are 
considered to be related to study treatment by the investigator (Table 6-10).
•
Changed the reporting of concurrent radiotherapies during study treatment from ‘Surgical 
and Medical Procedures’ to ‘Concomitant Antineoplastic Therapy – Radiotherapy’ 


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electronic Case Report Form (eCRF) in order to capture all required data fields for analysis 
(Sections 6.4.1, 6.4.4).
•
Removed statement alluding to “If the dose of prednisone or equivalent cannot be reduced 
to less than 10 mg/day before the administration of next dose of study treatment then 
PDR001/placebo must be discontinued” (Section 6.4.3.1) as this language is not applicable 
to this study.
•
Decreased the ophthalmologic examination assessment frequency (Tables 7-1, 7-2, 7-3, 7-
4) in order to align with clinical practice and label. In addition, to reflect clinical practice, 
clarified that dilation of pupils is only required if clinically indicated (e.g., changes in visual 
acuity), and optical coherence tomography is recommended at scheduled visits, and 
mandated if retinal abnormalities are suspected (Section 7.2.2.5).
•
Added more specific imaging-related instructions to visit evaluation schedules (Tables 7-1, 
7-2, 7-3, 7-4) in alignment with Section 7.1.4, Table 7-5, and Section 7.2.1.2 for clarity. 
Further, updated Section 4.1.2 to be consistent with Section 7.1.4.
•
Revised patient reported outcome schedule of assessments to align with imaging 
assessments (Tables 7-1, 7-2, 7-3, 7-4).
•
Added that needle aspiration, biopsy or any other form of collection (e.g., paracentesis, 
punctuation) performed for any reason must be collected to capture all data required data 
fields for analysis (Tables 7-1, 7-2, 7-3, 7-4).
•
Added clarification for the timing of when PRO assessments should be completed to align 
with Section 7.2.5 (Tables 7-3, 7-4).
•
Clarified that a validated tissue-based molecular test is required to determine the BRAF 
V600 mutation status. Immunohistochemistry is not an accepted method and liquid biopsy 
based BRAF V600 results cannot be used to enroll patients. Further, clarified that if the local 
lab uses a non-FDA approved BRAF V600 assay, this information must be provided to the 
Sponsor or representative for review. (Section 7.1.2).
•
Added language in Section 7.1.2.3 to allow data collection of newly published AJCC edition 
8 melanoma staging (published Q4/2016). In addition, the AJCC edition 8 staging 
parameters were added as an appendix (Section 14.4).
•
Added that tumor and PRO assessments performed as part of End of Treatment (EOT) in 
part 3 will not be required to be repeated if performed within 30 days prior to the first dose 
of study treatment in crossover part (Section 7.1.3; Tables 7-4, 7-5).
•
Revised central review of imaging data from irRECIST criteria to tumor response criteria 
based on guidelines for immunotherapy (e.g., Seymour 2017) (Sections 7.2.1, 10.4.1, 
10.4.4, 10.5.2).
•
Revised data transfer requirements for blinded independent radiology committee review 
(Section 7.2.1).
•
Removed language to be consistent with mandatory brain imaging requirement at screening 
(Section 7.2.1.1).
•
Clarified in footnote that PK and immunogenicity samples for PDR001 will not be collected 
at Cycle 1 Day 8 for Part 2 (Table 7-10).
•
Added language to allow request for additional archival tumor tissue in case the sample 
provided is insufficient for the proposed biomarker analyses (Section 7.2.4.1).




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Amendment 2 (07-Mar-2017)
As of 07-Mar-2017, 3 patients have signed Main ICF, and 1 patient has received study treatment 
in the study. The original protocol has been initiated at 2 study centers globally. 
Amendment rationale 
Amendment 2 (substantial amendment) is required to implement specific feedback received 
from the U.S. Food and Drug Administration (FDA) and the German Paul-Ehrlich Institute (PEI) 
and the French health authority ANSM (agence nationale de sécurité du medicament) upon 
review of the protocol. In addition, clarifications and corrections are made throughout the 
protocol next to editorial change to improve flow and consistency. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Major changes

Updated criteria for dose-limiting toxicities (DLTs) for part 1 (Table 6-6):

Added ‘Grade 4 anemia’, ‘Grade 4 hypertension of any duration’ and ‘≥ Grade 3 
infusion related reaction’. Changes mandated by FDA. 

Subsequently, ‘Severe infusion reactions’ were deleted from ‘Events which will 
NOT be considered as DLT’, and in addition, the following language was added 
in Section 6.1.1.5: ‘For part 1, on days of coadministration with PDR001, 
dabrafenib and trametinib should be taken approximately 90 minutes after 
completion of PDR001 administration.’ 

Added ‘≥ Grade 3 AEs that are known to occur with dabrafenib, trametinib and/or 
PDR001, but cannot be controlled using the recommended product-specific 
management guidelines or lead to 50% of planned exposure to study medications’. 
Change mandated by FDA.

Added window for correction of ≥ Grade 3 electrolyte abnormalities to specify the 
exception from the definition of DLT: ‘For laboratory values ≥ Grade 3, the 
maximum allowable time limit for correction of electrolyte abnormalities to ≤ Grade 
1 is 72 hr’. Change mandated by FDA.

Changed threshold for subjects with normal baseline AST and ALT values: ‘AST or 
ALT > 8.0 × ULN’. Change mandated by FDA.

Subsequently, ‘Grade 4 AST or ALT elevation’ was removed. 

Changed definition for thrombocytopenia to be independent of duration and 
transfusion requirement: ‘Grade 3 thrombocytopenia with clinically significant 
bleeding regardless of duration or requirement of platelet transfusion’. Change 
mandated by FDA.

Deleted ‘or test results (e.g., ECG, ECHO/MUGA)’ from ‘Events which will NOT be 
considered as DLT for the purpose of this protocol’ as these are covered under cardiac 
events.




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order to cap the enrollment window at 28 days, considering the broad therapeutic index of 
dabrafenib and expected positive risk benefit profile in patients with unresectable and 
metastatic melanoma.
•
Corrected ‘lyophilisate in vial for iv infusion’ to ‘powder for solution for infusion’ in 
Sections 6.1 (Tables 6-1, 6-3, 6-4) and 6.6.1 to harmonize with a standard pharmaceutical 
term. Change requested by Swedish Medical Products Agency.
•
Added instructions (Sections 6.1.1.4., 6.6) to counsel subjects to notify study personnel for 
suspected infusion reactions: ‘Subjects should be provided instructions to notify study 
personnel if symptoms of infusion reaction occur after any PDR001 infusion.’ Change 
mandated by German Paul-Ehrlich Institute.
•
Specified dose interruptions for PDR001/placebo include delaying or withholding the 
treatment for any reason as well as an interruption of treatment during an infusion 
(Section 6.3.1). Further, removed the criteria that ‘if a subject requires a dose interruption 
of > 12 weeks from the time the immune-related AE reaches a grade that leads to 
PDR001/placebo interruption, then the subject must be discontinued from the study’, in 
order to allow for dabrafenib and/or trametinib to be continued if tolerated. 
•
Revised general dose modification instructions (Section 6.3.2) and mandatory dose 
modification and management guideline for pyrexia (Section 6.3.5.4; Table 6-24) 
suspected to be related to dabrafenib and/or trametinib treatment to withhold trametinib in 
addition to dabrafenib when the fever is higher than 40°C or104°F or the fever is 
complicated by rigors, hypotension, dehydration, or renal failure. Change mandated by 
FDA. Added ‘Monitor renal function for complicated pyrexia’ in the recommended 
management guideline for the 1st, 2nd and subsequent occurrences of pyrexia. Removed 
‘trametinib may be continued’ in dose modification requirements for the subsequent 
occurrences of pyrexia. 
•
Added mandatory dose modification and management guideline for serious skin reactions 
(Section 6.3.3.4) to include Stevens-Johnson syndrome and toxic epidermal necrolysis. 
Change mandated by FDA.
•
Revised mandatory dose modification and management for visual changes 
(Section 6.3.5.5; Table 6-25) suspected to be related to dabrafenib and/or trametinib 
treatment to permanently discontinue dabrafenib for ≥ Grade 2 uveitis (including iritis and 
iridocyclitis) of > 6 weeks duration. Change mandated by FDA.
•
Added mandatory dose modification and management guideline for hemorrhage 
(Section 6.3.5.7) and thromboembolic events (Section 6.3.5.8) suspected to be related to 
dabrafenib and/or trametinib treatment. Change mandated by FDA.
•
Clarified and better aligned Section 6.4.3.2 with the SPC. Although not contraindicated, 
certain medications should be used with caution due to potential drug-drug interactions. In 
addition a cross-reference to Section 6.4.2.2 was added. Change requested by French 
health authority (AMNS).
•
After Cycle 1, changed the window for all assessments from ± 3 days to ± 7 days, to allow 
more time for adverse event management before skipping of PDR001 dose if required. 
Subsequently, removed the ± 7 day window of assessment for radiographic assessments 
and patient reported outcome and during holidays to avoid redundancy (Section 7.1).


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•
Revised schedule of assessments for ECHO and biomarker sample collection plans 
(Tables 7-1, 7-2, 7-3, 7-4).
•
Specified that the BRAF V600 mutation will be assessed using a validated test and added 
Biomerieux THxID™-BRAF as an example of FDA approved assay (Section 7.1.2). 
Change mandated by FDA.
•
Implemented mandatory brain imaging (MRI/CT) as part of the screening assessment, and 
removed ‘as clinically indicated’ (Sections 7.2.1, 7.2.1.1). Change mandated by German 
Paul-Ehrlich Institute.
•
Added an additional optional tumor biopsy collection at Cycle 1 Day 15 for part 3 to 
expand biomarker analyses with samples collected in part 3 (Tables 7-3; Table 7-16); 
(Section 7.2.4.1)
•
Updated adverse events of special interest (AESI) to align with current prescribing 
information and AEs of other immune checkpoint inhibitors. Removed ‘Deep vein 
thrombosis/pulmonary embolism’ as AESI for dabrafenib but added to AESI for 
trametinib. (Section 8.1.3). Change mandated by FDA. 
•
Clarified ‘Neutropenia (in combination with trametinib)’ is considered AESI for 
dabrafenib and trametinib. Updated AESI for PDR001 based on most recent safety data: 
endocrinopathies, colitis, and rash; added infusion reaction and other immune disorders as 
AESI. (Section 8.1.3)
•
Added clarification to allow Novartis drug safety to be unblinded to study treatment per 
Novartis SOP if a SAE is confirmed as SUSAR (Section 8.2.2). Change mandated by 
FDA.
•
Added language to convene DMC quickly if warranted: ‘The DMC will be informed and 
convened quickly for DMC evaluation and input in the event of unexpected results that 
raise concerns’ (Section 8.6). Change mandated by FDA. 
•
Specified that PD-L1 expression levels will be determined by immunohistochemistry 
(Section 10.5.2). Change mandated by FDA.
•
Added additional criteria to the dose-determining set (DDS) (Section 10.1.4) to clarify that 
subjects who do not meet the minimum exposure criterion due to an AE will be counted as 
having a DLT. Subjects who do not meet the minimum exposure criterion for reasons 
other than AE’s (e.g., rapid disease progression or non-compliance) will not be included in 
the DDS. 
•
Added that PD-L1 level cut-off value of 10% will also be part of an efficacy subgroup 
analysis (in addition to the analysis using a 1% cut-off) (Section 10.5.2).
Other protocol changes:
•
Protocol summary: Updated to reflect the major changes throughout the document
•
To be consistent with Section 4.1, revised language from ‘six to or 18’ to ‘at least 6 
subjects, and up to approximately 18’ subjects will be enrolled in part 1 (Section 2.2). 
•
Aligned rationale for the dose of dabrafenib and trametinib with the label (Section 2.3). 
•
Added ‘rash’ as an example of potential irAE of immune checkpoint inhibitors (Section 
2.6).


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•
Added language ‘it is possible for additional dosing regimens to be used based on 
emerging data from part 1, and recruitment may be suspended at any time’ in Section 4.1 
to align with Sections 2.2 and 4.1.2.
•
Added that every effort will be made ‘in alignment with local regulations’ to continue 
provision of investigational treatment outside the study to subjects who are deriving 
clinical benefit (Section 4.3).
•
Revised inclusion criterion 13 to remove ‘albumin infusion’ for consistency (Section 
5.2.4).
•
Moved exclusion criterion 30 to the notes of exclusion criteria 28 for flow and clarity 
(Section 5.3).
•
The start day of PDR001 for part 1 DL-1b was revised from ‘from Day 29’ to ‘starting at 
C2D1 (Day 29)’ in Table 6-2 to align with Table 6-5.
•
Clarified that the study treatment duration presented in Section 6.1.5 applies to all 3 parts 
of the study.
•
Added Q8W regimen for PDR001/placebo as the potential starting dose level to Table 6-7 
(Section 6.3).
•
Updated the ‘Reference of AEs and toxicity management guidelines’ and added serious 
skin reaction, hemorrhage, and thromboembolic events to the guideline to Table 6-8 
(Section 6.3) to be consistent with the changes mandated by the FDA.
•
Updated the list of AEs that require dose modification for only dabrafenib to specify 
‘uncomplicated’ pyrexia (Section 6.3.2). Change mandated by FDA.
•
Added ‘mandatory’ to the section titles of all dose modifications and recommended 
clinical management guidelines for AEs (Section 6.3).
•
Applied consistent titles to accommodate for casual relationship (‘suspected to be related 
to dabrafenib and trametinib’) for mandatory dose modifications for dabrafenib and 
trametinib (Section 6.3.5). 
•
Revised permitted concomitant therapies to include RANK-ligand inhibitors (e.g., 
denosumab) for bone targeted therapies. Clarified that any radiotherapy needs to be listed 
in the Surgical and Medical Procedures eCRF page. Further, the name of the eCRF page to 
record concomitant therapy was corrected to be consistent with CRF database. 
(Section 6.4.1).
•
Added cautionary language when co-administration of CYP2C or CYP3A4 substrates 
with narrow therapeutic index is required, while taking dabrafenib (Section 6.4.2.2).
•
As steroids may be used for treatment of pyrexia, added ‘pyrexia’ to one of the conditions 
that require tapering of systemic corticosteroids if used and dose should be at non-
immunosuppressive doses (< 10 mg/day of prednisone or equivalent) before the next 
administration of study treatment (Section 6.4.3.1).
•
To maintain the scientific integrity of the study, specific guidance was provided to 
maintain blinding for part 3 (Section 6.5.3): 
•
Added exceptions to who may be unblinded to randomization data until the time of 
unblinding: ‘unblinded CRAs, independent biostatistician and programmer who will 
perform DMC analysis’.


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•
Added that the sleeve used to cover the infusion bag will be ‘non-translucent’ in 
addition to opaque, to ensure any potential visible differences in treatments will be 
concealed. 
•
Added language to clarify that unblinding will be permitted if information is critical 
to determine the optimal subsequent treatment for the subject. Further, added 
language that in case of unblinding for post progression determination to subsequent 
treatment, all data up to the point of the unblinding is required to be captured in the 
eCRF. The study will be unblinded either at interim or final analysis if statistically 
significant overall survival results are demonstrated.
•
Added language to specify that the unblinded pharmacist must not administer the drug 
to the subject nor have any contact with the study participants.
•
Specified that the CRA (part 1 and part 2) and unblinded CRA (part 3) are responsible for 
drug accountability (Section 6.6.3.2).
•
Updated instructions for disposal and destruction of study drug to follow ‘local regulations 
and institutional guidelines’ (Section 6.6.4).
•
Removed ECHO assessment and ophthalmic examination on C1D1 from Tables 7-1, 7-2, 
7-3, 7-4 to avoid repeating assessments performed at Screening. 
•
Added ‘physical examination’, in addition to laboratory assessments, as one of the 
screening evaluation that will not require to be repeated prior to dosing if performed 
within 7 days prior to the first dose of treatment (Section 7.1.2).
•
Added ‘For the retrospective central confirmation all subjects will be required to provide a 
tumor tissue sample at screening prior to study treatment, as either a tumor block or a 
minimum of 25 FFPE slides (see Section 7.2.4)’ in Section 7.1.2 for clarification. 
•
Added ‘BRAF mutation status by local assessment’ eCRF to the eCRFs to be completed 
for screen failures (Section 7.1.2.2). 
•
Added ‘skin exam’ as part of the physical examination to be performed at screening 
(Section 7.1.2.3), to a short physical exam and to a periodic exam (every 8 weeks) 
(Section 7.2.2.1) to closely examine for new cutaneous malignancies and skin toxicities, 
which are AESIs of dabrafenib and trametinib. 
•
Added that physical examinations, laboratory, ECG, and ECHO assessments performed as 
part of the EOT in part 3 will not require to be repeated if performed within 7 days prior to 
the first dose of study treatment in crossover (Section 7.1.3).
•
Clarified that central review will be performed for both RECIST and irRECIST in 
Section 7.2.1 to be consistent with Section 10.4.
•
Added an instruction that new cutaneous lesions need to be color photographed including 
a metric ruler to measure the size of the lesion (Section 7.2.1.2).
•
Added an instruction for physical examination that ‘if indicated based on medical history 
and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be performed’ 
(Section 7.2.2.1).
•
Added chloride to chemistry assessment to Table 7-7 to obtain additional information for 
potential electrolyte changes (Section 7.2.2.6).


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•
Corrected an error in hepatitis monitoring period from ‘until 30-day safety follow up’ to 
‘until 150 day safety follow up’ (Section 7.2.2.6.7).
•
Updated a footnote in blood collection schedule for PDR001 PK and IG table (Table 7-10) 
to clarify that PK and IG samples will not be collected during Cycle 1 for the DL-1b 
dosing regimen during part 1 or if DL-1b is the selected dosing regimen for part 2. 
•
Deleted a footnote in blood collection schedule for PDR001/(placebo) PK and IG table 
(Tables 7-10, 7-11, 7-12) regarding the dose reference ID for the end of treatment, 30 day 
safety and 150 day safety follow up visits since dose reference IDs are not applicable to 
these samples.
•
Added different sets of dose reference IDs for dabrafenib and trametinib in PK collection 
tables (Tables 7-13, 7-14, 7-15) to collect dosing date and time for the last dose taken 
before PK collection. Inserted a footnote to ensure collection of the date and time for 
dosing before and after PK sample collection (Tables 7-13, 7-14, 7-15).
•
Increased blood volume (10 mL to 12 mL) to be collected 
 for part 3 in 
Table 7-16 and Section 7.2.4.2.4 to accommodate two flow cytometry assays for 
biomarker analysis in part 3. 
•
Drug Safety and Epidemiology (DS&E) department at Novartis is now Chief Medical 
Office and Patient Safety (CMO&PS). This has been changed consistently throughout the 
documents (Sections 8.2.2, 8.4).
•
Corrected the definition of Full Analysis Set (FAS) and Safety Set in Section 10.1.1 to 
clarify that subjects in non-randomized part 1 and part 2 will be analyzed according to the 
study treatment they were assigned to (as opposed to treatment actually received).
•
 Inserted the following definitions of immunogenicity prevalence and incidence sets under 
‘Other analysis sets (Section 10.1.6)’. ‘The immunogenicity prevalence set includes all 
subjects in the full analysis set with a determinant baseline IG sample or at least one 
determinant post-baseline IG sample and the immunogenicity incidence set includes all 
subjects in the Immunogenicity prevalence set with a determinant baseline IG sample and 
at least one determinant post-baseline IG sample.’
•
Revised the definition of observation period (Section 10.5.3.1). The end of ‘on-treatment 
period’ was changed to ‘30 days after date of last actual administration of any study 
medication’ and the beginning of the ‘post treatment’ was changed to ‘at day 31 after last 
dose of study medication’. Inserted a paragraph stating that summaries for deaths, all AEs, 
and all SAEs collected up to 150 days after last administration of PDR001 will be 
reported.
•
Revised wording regarding part 2 biomarker cohort sample size (Section 10.8) by 
changing ‘up to 20 evaluable subjects’ to ‘approximately 20 evaluable subjects’.
•
Corrected errors in Table 14-6 (Section 14.2.3.1) and changed the dose level of dabrafenib 
from 35 mg BID to 350 mg BID, number of evaluable patients from 4 to 6, and number of 
DLTs from 0 to 1. 
As part of this amendment, minor editorial changes, to improve flow and consistency, and 
correction of spelling errors or typographical errors, have been made throughout the protocol.


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 1 (27-Jan-2017)
As of 24-Jan-2017, no patients have received study treatment in the trial and the original 
protocol has not been initiated at any study center globally.
Amendment rationale 
The primary purpose of this protocol amendment is to clarify that double barrier contraception 
methods are not classified as highly effective methods, per Clinical Trial Facilitation Group 
(CTFG) guidelines. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
The major change being made to the protocol due to this amendment is incorporated in the 
following section:
•
Section 5.3.3 (exclusion criterion #28): Removed double barrier contraception from the 
list of highly effective methods of contraception, and added a note to clarify this exclusion 
criterion.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are considered non-substantial and do not 
require IRB/IEC approval prior to implementation.
The changes herein affect the Informed Consent. Sites are required to update and send a revised 
Informed Consent that takes into account the changes described in this protocol amendment.


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Protocol summary
Title
A randomized, double-blind, placebo-controlled, phase III study comparing the combination 
of PDR001, dabrafenib and trametinib versus placebo, dabrafenib and trametinib in 
previously untreated patients with unresectable or metastatic BRAF V600 mutant 
melanoma
Study ID
CPDR001F2301
Brief title
Study of safety and efficacy of PDR001 in combination with dabrafenib and trametinib in 
patients with advanced melanoma
Sponsor and 
Clinical Phase
Novartis, Phase III
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
•
The purpose of this study is to evaluate safety and efficacy of the combination of an 
anti-PD-1 antibody (PDR001), a BRAF inhibitor (dabrafenib) and a MEK inhibitor 
(trametinib) in patients with BRAF V600 mutant, unresectable and metastatic 
melanoma.
•
A safety run-in part will be conducted to determine the recommended phase 3 regimen 
(RP3R) of PDR001 in combination with dabrafenib and trametinib. The randomized, 
placebo-controlled part of the study will compare the efficacy and safety of this triplet 
combination to placebo in combination with dabrafenib and trametinib in previously 
untreated patients with unresectable or metastatic BRAF V600 mutant melanoma.
•
A separate biomarker cohort will be run to explore changes in the immune 
microenvironment and biomarker modulations upon treatment with the combination of 
dabrafenib, trametinib and PDR001.
Primary 
Objectives
Part 1: Safety run-in
•
To determine the recommended regimen of PDR001 in combination with dabrafenib 
and trametinib for the randomized part (part 3)
Part 2: Biomarker cohort
•
To evaluate changes in PD-L1 levels and CD8+ cells upon treatment with PDR001 in 
combination with dabrafenib and trametinib
Part 3: Double-blind, randomized, placebo-controlled part
•
To compare the anti-tumor activity of PDR001 in combination with dabrafenib and 
trametinib versus placebo plus dabrafenib and trametinib as measured by PFS 
per investigator’s assessment according to Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1.
Key Secondary 
Objectives
Part 3: Double-blind, randomized, placebo-controlled part
•
To compare overall survival of PDR001 in combination with dabrafenib and trametinib 
versus placebo plus dabrafenib and trametinib
Other Secondary 
Objectives
Parts 1 & 2: Safety run-in and biomarker cohort
•
To determine safety and tolerability of PDR001 in combination with dabrafenib and 
trametinib
•
To evaluate preliminary anti-tumor activity of PDR001 in combination with dabrafenib 
and trametinib
•
To characterize pharmacokinetics (PK) of PDR001, dabrafenib and trametinib when 
administered in combination
•
To evaluate the prevalence and incidence of immunogenicity
Part 3: Double-blind, randomized, placebo-controlled part
•
To compare the anti-tumor activity of PDR001 in combination with dabrafenib and 
trametinib versus placebo plus dabrafenib and trametinib, as measured by ORR, DCR, 
DOR per investigator’s assessment according to RECIST 1.1
•
To evaluate safety and tolerability of PDR001 in combination with dabrafenib and 
trametinib versus placebo plus dabrafenib and trametinib


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•
To evaluate patient reported outcomes of PDR001 in combination with dabrafenib and 
trametinib versus placebo plus dabrafenib and trametinib
•
To characterize pharmacokinetics (PK) of PDR001, dabrafenib and trametinib when 
administered in combination 
•
To evaluate the prevalence and incidence of immunogenicity
•
To characterize the potential for PD-L1 expression to identify subjects with an 
enhanced response to PDR001 in combination with dabrafenib and trametinib versus 
placebo plus dabrafenib and trametinib
Study design
•
This study has been designed as a Phase III trial.
•
This study begins with an open-label safety run-in part and a biomarker cohort, 
followed by a double-blind, randomized, placebo-controlled Phase III part.
Population
Part 1: Safety run-in
Adult subjects with unresectable or metastatic melanoma with BRAF V600 mutation and 
ECOG performance status ≤ 1
Part 2: Biomarker cohort
Adult subjects with unresectable or metastatic melanoma with BRAF V600 mutation and 
ECOG performance status ≤ 2
Part 3: Double-blind, randomized, placebo-controlled part
Adult subjects with unresectable or metastatic melanoma with BRAF V600 mutation and 
ECOG performance status ≤ 2
Key Inclusion 
criteria
Part 1: Safety run-in
•
Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 
mutation
•
Aspartate transaminase (AST) < 2.5× ULN and Alanine transaminase (ALT) < 2.5× 
ULN
•
Measurable disease according to RECIST 1.1
•
ECOG performance status ≤ 1
Part 2: Biomarker cohort
•
Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 
mutation
•
At least two cutaneous or subcutaneous lesions or nodal lesions for tumor sample 
collection
•
Measurable disease according to RECIST 1.1
•
ECOG performance status ≤ 2
Part 3: Double-blind, randomized, placebo-controlled part
•
Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 
mutation
•
ECOG performance status ≤ 2
•
Measurable disease according to RECIST 1.1


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Key Exclusion 
criteria
Part 1: Safety run-in
•
Any history of CNS metastases
•
Subjects with uveal or mucosal melanoma
•
Prior systemic anticancer therapy for unresectable or metastatic melanoma
•
Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months 
prior to enrollment
•
Radiotherapy within 4 weeks prior to the first dose of study treatment
•
Active autoimmune disease, and/or history of autoimmune disease(s) that required 
treatment
Parts 2 & 3 : Biomarker cohort & double-blind, randomized, placebo-controlled part
•
Subjects with uveal or mucosal melanoma
•
Prior systemic anticancer therapy for unresectable or metastatic melanoma
•
Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months 
prior to enrollment
•
Radiotherapy within 4 weeks prior to the first dose of study treatment
•
Clinically active cerebral melanoma metastasis.
•
Active autoimmune disease, and/or history of autoimmune disease(s) that required 
treatment
Investigational 
and reference 
therapy
•
PDR001 in combination with dabrafenib and trametinib or placebo in combination with 
dabrafenib and trametinib
Efficacy 
assessments
•
Tumor assessment by investigator’s assessment per RECIST 1.1, measured at Cycle 
4 Day 1 (± 7 days), then every 8 weeks, until Cycle 22 Day 1 (± 7 days) when 
frequency will switch to every 12 weeks
Safety 
assessments
•
Physical examination
•
ECOG PS
•
Weight and vital signs
•
Ophthalmic examination
•
12-lead ECGs
•
ECHO/MUGA
•
Laboratory assessments, including hematology, chemistry, thyroid function, 
coagulation, urinalysis, and cytokine analysis
•
Monthly pregnancy testing for women of child-bearing potential
•
Adverse events (AEs), the severity, the relationship to study treatment and the 
seriousness
Other 
assessments
•
PK parameters such as but not limited to Ctrough and Ctroughss for PDR001, 
dabrafenib and trametinib.
•
Patient reported outcomes (PRO) assessment by the European Organization for 
Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL (EQ-
5D) questionnaire, and Melanoma Subscale of the FACT-M


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Data analysis
Part 1: Safety run-in
The primary variable is the incidence of dose-limiting toxicities (DLTs) during the first 8 
weeks (56 days) of PDR001 in combination with dabrafenib and trametinib. DLTs will be 
listed, and their incidence summarized by primary system organ class and preferred term 
and worst grade (CTCAE version 4.03). Listings and summaries will be based on the dose-
determining analysis set.
The dose determination part of this study will be guided by a Bayesian analysis of DLT 
data for the first 8 weeks (56 days) that subjects receive the combination of PDR001, 
dabrafenib, and trametinib. The Bayesian analysis to assess the triple combination will be 
based on a separate 10-parameter model for each dose regimen that comprises single-
agent toxicity parts and interaction parts to describe both two-way and three-way drug 
safety interactions. Details of the model are given in Section 10.4.2 and Appendix 2.
Dosing regimen decisions are guided by the escalation with overdose control principle. A 
dosing regimen may only be used for newly enrolled subjects if the risk of excessive 
toxicity at that dosing regimen is less than 25%. The starting dosing regimen is 400 mg i.v. 
Q4W PDR001, 150 mg BID dabrafenib, and 2 mg QD trametinib. For this dosing regimen, 
the prior risk of excessive toxicity is 12%, which satisfies the EWOC criterion. A full 
assessment of the prior risk to patients is given in Appendix 2.
Part 2: Biomarker cohort
Descriptive statistics of the primary endpoint, PD-L1 levels and CD8+ cells and changes 
from baseline, will be summarized by visit.
Part 3: Double-blind, randomized, placebo-controlled part
The primary endpoint of Progression-Free Survival (PFS), based on local (investigator) 
assessment of RECIST 1.1 criteria, is defined as the time from the date of randomization to 
the date of the first documented progression or death due to any cause.
The key secondary endpoint of Overall Survival (OS) is defined as the time from the date 
of randomization to the date of death due to any cause.
The following statistical hypotheses will be tested to address the primary efficacy objective 
for PFS:
H01 : θ1 ≥ 1 vs. HA1 : θ1 < 1
where θ1 is the PFS hazard ratio (HR) (PDR001 combined with dabrafenib and trametinib 
versus dabrafenib and trametinib). The primary efficacy analysis to test these hypotheses 
and compare the two treatment groups will consist of a stratified log-rank test at an overall 
one-sided 2.5% level of significance. The stratification will be based on the randomization 
stratification factors, i.e., (LDH level: < 1 x ULN vs ≥ 1 to < 2 x ULN vs ≥ 2 x ULN; ECOG 
PS: 0 vs 1 vs 2). Analyses will be based on the FAS population according to the 
randomized treatment group and strata assigned at randomization. The PFS distribution 
will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves, quartiles and 
associated 95% confidence intervals (CI) will be presented for each treatment group. The 
hazard ratio for PFS will be calculated, along with its 95% confidence interval, from a 
stratified Cox model using the same stratification factors as for the log-rank test.
The PFS analysis will be performed as a part of a two-look group sequential design using a 
Gamma alpha spending function to control the type 1 error probability with Gamma 
parameter = -9.7 (Hwang et al, 1990).
A similar hypothesis and model will be used to address the key secondary efficacy 
objective for OS. The OS analysis will be performed as part of a three-look group 
sequential design. At the time of the interim and final PFS analysis, interim OS analyses for 
a possible early significance claim for efficacy will be performed. The type I error probability 
for the interim and final OS analyses will be controlled by using a Lan-DeMets (O’Brien-
Fleming) alpha spending function. A hierarchical testing strategy will be used to control the 
overall type I error rate, where OS will only be formally tested and interpreted if the primary 
analysis of PFS is statistically significant.
Refer to Section 10.4.3 and Section 10.4.4 for details on censoring, as well as supportive 
and sensitivity analyses that will be performed for the primary and key secondary efficacy 
variables.
Key words
PDR001, dabrafenib, trametinib, melanoma, immunotherapy, combination treatment


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Melanoma is the most aggressive form of all skin cancers. Worldwide, it is expected that over 
232,000 people will be diagnosed with cutaneous melanoma each year and more than 55,000 
people are expected to die of this disease annually (Ferlay 2015). In adults, cutaneous melanoma 
is the fifth most common cancer in men and the seventh most common cancer in women in the 
United States (USA), with approximately 76,400 new cases and 10,100 deaths expected in 2016 
(SEER 2016). In Europe, the annual incidence of melanoma is somewhat lower than in the 
USA, but is the seventh most common cancer among women (Ferlay 2013, Siegel 2014). In 
Europe as a whole, approximately 100,300 cases were newly diagnosed and 22,000 patients 
died from this disease in 2012 (EUCAN 2012). The incidence of melanoma is increasing rapidly 
worldwide. This increase is the most rapid of any cancer with the exception of lung cancer in 
women (Jemal 2006).
Usually melanoma is diagnosed at an early stage in which surgical excision is curative in most 
cases. Patients who are at high-risk for developing metastatic disease may benefit from adjuvant 
therapy. The management of patients with unresectable or metastatic melanoma is more 
difficult, although recent advances have led to important improvements of clinical outcomes 
for this population. Many studies also showed elevated LDH was a negative prognostic factor 
for response and other efficacy outcomes (Sirott 1993, Eton 1998, Balch 2001). The key 
strategic approaches for these patients include immunotherapy with immune checkpoint 
inhibitors and/or targeted therapy that inhibits the mitogen-activated protein kinase (MAPK) 
pathway for BRAF V600 mutant melanoma (NCCN Guidelines® Melanoma V13 2016).
Immunotherapy
Under physiological conditions, immune checkpoints are crucial for the maintenance of self-
tolerance and autoimmunity. However, the expression of immune checkpoint proteins can be 
dysregulated by cancer cells which is an important immune resistance mechanism 
(Pardoll 2012). Immune checkpoints play a key role as negative regulators that restrain an 
effective anti-tumor response against melanoma (Pardoll 2012).
Cytotoxic T lymphocyte antigen 4 (CTLA-4) was the first checkpoint to be clinically targeted 
with ipilimumab. The inhibitory CTLA-4 receptor is expressed exclusively on T cells where it 
primarily regulates the amplitude of T cell activation in the early stages (Pardoll 2012). 
Ipilimumab (Yervoy®) is a monoclonal antibody to CTLA-4 and was the first drug to 
demonstrate a survival benefit in melanoma. The pivotal phase III study of ipilimumab showed 
an overall survival (OS) improvement in subjects with previously treated metastatic melanoma 
with HLA-A2*0201 genotype, as compared with an investigational peptide vaccine gp100 
(Hodi 2010). In a second phase III trial in treatment naive patients the combination of 
ipilimumab plus dacarbazine improved OS versus placebo plus dacarbazine (Robert 2011). 
Importantly, extended follow-up showed that ipilimumab resulted in long-term survival in 
approximately 20% of patients (Maio 2015). In 2011, ipilimumab was approved by the U.S. 
Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma 
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Programmed cell death receptor 1 (PD-1) is another inhibitory immune checkpoint receptor 
expressed by T cells. Its primary ligand 1 (PD-L1) is frequently expressed in the tumor 
microenvironment, including cancer cells and tumor-infiltrating macrophages. PD-1 has a 
second ligand (PD-L2), which is preferentially expressed by antigen-presenting cells 
(Pardoll 2012). Pembrolizumab (Keytruda®) and nivolumab (Opdivo®) are monoclonal 
antibodies that directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
Pembrolizumab received accelerated approval by the FDA based on response rate and durability 
of response for the treatment of patients with disease progression following ipilimumab, and if 
BRAF V600 mutation positive, a BRAF V600 inhibitor (FDA 2014). The approval was based 
on the results of an open-label, randomized cohort within a large, multi-stage, multiple cohort 
dose-finding and activity-estimating study (KEYNOTE-001). In the sub-study, patients with 
unresectable or metastatic melanoma which had prior treatment with ipilimumab or BRAF or 
MEK inhibitor if BRAF V600 positive were randomly assigned to pembrolizumab 2 mg/kg 
Q3W or 10 mg/kg Q3W. Anti-tumor activity was similar between the two doses with respect 
to both overall response rate (ORR) and duration of response (DOR) (Robert 2014). The 
KEYNOTE 002 study of pembrolizumab versus investigator-choice chemotherapy confirmed 
the benefits of pembrolizumab in ipilimumab-refractory melanoma patients (Ribas 2015). 
Importantly, pembrolizumab demonstrated statistically significant improvements in OS and 
progression free survival (PFS) for patients randomized to pembrolizumab as compared to 
ipilimumab in a phase III study (KEYNOTE-006) in previously treated and untreated 
unresectable or metastatic melanoma (Robert 2015). Two phase III studies have demonstrated 
efficacy for nivolumab: In CheckMate 037, nivolumab demonstrated significantly improved 
ORR, PFS and OS versus chemotherapy in ipilimumab-refractory patients (Weber 2015). In the 
second phase III study (CheckMate 066), nivolumab showed an improved ORR and PFS versus 
dacarbazine, among previously untreated patients without a BRAF V600 mutation 
(Robert 2015). No head to head trial has been done comparing pembrolizumab with nivolumab 
in melanoma.
Despite important clinical benefits, checkpoint inhibition is associated with a unique spectrum 
of side effects termed immune-related adverse events (irAEs). IrAEs include dermatologic, 
gastrointestinal, hepatic, endocrine, and other less common inflammatory events. IrAEs are 
more common with the anti-CTLA-4 antibody ipilimumab than with the anti-PD-1 agents 
pembrolizumab (Robert 2015) or nivolumab (Postow 2015). In general, treatment of moderate 
or severe irAEs requires interruption of the checkpoint inhibitor and the use of corticosteroid 
immunosuppression (NCCN Guidelines for Patients® Melanoma 2016).
The combination of CTLA-4 blockade with ipilimumab and PD-1 blockade with nivolumab has 
resulted in longer PFS and higher ORR than either agent alone at the expense of significantly 
increased toxicity (Larkin 2015, Postow 2015). Overall survival results from the phase III study 
(CheckMate 067) are pending.
Targeted therapy (see also Section 1.2.2)
MAPK pathways are evolutionarily conserved kinase modules that link extracellular signals to 
the machinery that controls fundamental cellular processes such as growth, proliferation, 
differentiation, migration and apoptosis (Dhillon 2007). This signaling pathway is an attractive 
therapeutic target because it is aberrantly activated in many human cancers. It can be activated 
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In 2011 the selective small molecule BRAF V600-inhibitor vemurafenib received FDA approval 
as the first molecular-targeted agent for unresectable or metastatic melanoma harboring BRAF 
V600E mutations. In the pivotal phase III study (BRIM-3) treatment with vemurafenib resulted 
in a significant improvement of PFS and OS compared to chemotherapy alone (Chapman 2011). 
In 2013, another BRAF V600 inhibitor, dabrafenib, was approved by the FDA based on 
significant improvement of clinical benefit compared to DTIC chemotherapy in the pivotal 
phase III study BREAK-3 (Hauschild 2012). Trametinib, a MEK inhibitor, successfully 
demonstrated clinical benefit in the same patient population in the pivotal phase III study 
(METRIC) and was also approved by the FDA at the same time (Flaherty 2012).
While monotherapy with either dabrafenib or trametinib represented a significant advance in 
the treatment of BRAF V600 mutated, unresectable or metastatic melanoma, responses were not 
observed in all patients; underscoring the fact that intrinsic mechanisms of resistance were in 
place and approximately half of the patients treated with a BRAF V600 or MEK inhibitor as 
monotherapy progressed within 5 to 7 months of starting treatment. Therefore, the combination 
of a selective and potent BRAF V600 and a MEK-inhibitor is favored to address specific 
molecular mechanisms of intrinsic and acquired resistance to a BRAF V600 inhibitor 
monotherapy (Nissan 2011). Data from the phase I/II study, BRF113220 established that the 
approved doses of dabrafenib and trametinib were safe when administered in combination, and 
additionally demonstrated a statistically significant and clinically meaningful improvement in 
several key efficacy endpoints when compared directly to dabrafenib monotherapy. These 
efficacy measures were also superior when indirectly compared to trametinib monotherapy. The 
superiority of the efficacy of the combination over BRAF V600 inhibitor monotherapy was 
subsequently confirmed across two randomized phase III studies where dabrafenib in 
combination with trametinib consistently demonstrated clinical benefit when compared to 
dabrafenib (COMBI-d) or vemurafenib monotherapy (COMBI-v). Statistically significant and 
clinically meaningful improvements were observed for OS, PFS, ORR, DOR and quality of life 
(QoL) with manageable adverse events profile (Long 2014, Robert 2014, Schadendorf 2015). 
Another combination of BRAF V600 and MEK inhibitor, vemurafenib and cobimetinib, also 
successfully demonstrated clinical benefit in BRAF V600-mutated metastatic melanoma as well 
as superior efficacy when compared with BRAF V600 inhibitor monotherapy with vemurafenib 
(Larkin 2014).
At present, the combination of immune checkpoint inhibitors or the combination of targeted 
therapy with or in sequence with immunotherapy are being investigated in different settings to 
further improve the clinical outcome for patients with unresectable or metastatic melanoma.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of PDR001
PDR001 is a high-affinity, ligand-blocking, humanized IgG4 antibody directed against PD-1 
that blocks the binding of PD-L1 and PD-L2. PD-1 is a critical immune checkpoint receptor 
that is expressed on CD4 and CD8 positive T cells upon activation (Freeman 2008). 
Engagement of PD-1 by its ligands, PD-L1 and PD-L2, transduces a signal that inhibits T-cell 
proliferation, cytokine production, and cytolytic function (Riley 2009). Monoclonal antibody 


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(mAb) inhibitors of immunological checkpoints, including PD-1 and PD-L1, have 
demonstrated significant antitumor activity in patients with various solid tumors. For further 
details please refer to the latest PDR0001 Investigator’s Brochure.
1.2.1.1
Non-clinical experience of PDR001
PDR001 binds specifically and with high affinity to human PD-1 and enhances interleukin-2 
(IL-2) production in in vitro lymphocyte stimulation assays. It does not cross react with rodent 
PD-1; therefore, toxicology studies were performed only in cynomolgus monkeys where there 
was acceptable cross reactivity with monkey PD-1. Repeat administration of PDR001 to 
monkeys was tolerated at all doses tested up to 100 mg/kg/week for 5 weeks in the GLP 
toxicology single-agent study. No drug-related in-life, mortality, organ weight changes, or 
macroscopic findings were noted. There were no PDR001-related effects seen in any of the 
safety pharmacology endpoints assessed (cardiovascular, neurobehavioral, and respiratory). 
Macrophage infiltrates into the splenic white pulp were observed in animals given 100 
mg/kg/week and mononuclear cell infiltrates, often associated with fibrosis, around the 
injection site blood vessel (saphenous vein) in a few animals given ≥25 mg/kg/week. These 
PDR001-related microscopic changes were fully reversible after an eight week recovery. 
Additionally, mostly low grade mononuclear infiltrates in the vascular and perivascular space 
in several tissues of main and recovery treated animals and in recovery controls were observed 
but with a slightly higher incidence in treated animals. No evidence of parenchymal damage 
was associated with the vascular/perivascular changes in any of the organs examined and the 
changes were not associated with any frank tissue injury. Dose-proportional exposure to 
PDR001 in each dose group was confirmed. Anti-drug antibodies (ADA) to PDR001 were 
observed in some PDR001 treated cynomolgus monkeys. A trend of reduced drug exposure was 
observed in these ADA-positive animals. Based on the toxicology studies with PDR001 as a 
single-agent, the Highest Non-Severely Toxic Dose (HNSTD) dose is 100 mg/kg. For further 
details, please refer to the latest PDR001 Investigator’s Brochure.
1.2.1.2
Clinical experience with PDR001
There are two ongoing studies with PDR001; [CPDR001X2101] and [CLAG525X2101C]. 
Sixty-four patients have received PDR001 either as a single-agent or in combination with 
LAG525 (an anti-LAG3 antibody).
In the first-in-human [CPDR001X2101] study, a total of 58 patients (as of cut-off date of 27-
Mar-2016) were exposed to PDR001 single-agent at 1 to 10 mg/kg on an every 2 weeks (Q2W) 
schedule or at 3 and 5 mg/kg every 4 weeks (Q4W) schedule. The patient population treated in 
this study included patients with a diverse range of advanced solid tumors, where the most 
frequent tumor types were renal (6 patients) and liposarcoma (3 patients). The median duration 
of exposure was 14 weeks (range 2–46) in a patient population that had been heavily pretreated 
(59% of the patients were previously exposed to ≥ 3 lines). The preliminary pharmacokinetic 
(PK) parameters from the study demonstrate approximately dose-proportional increases in 
exposure (C1D1 AUC0-336h) from 1 to 10 mg/kg with the half-life of PDR001 of 20 days for 
both schedules. Accumulation of approximately 2.1-3.4 –fold was observed with Q2W dosing 
and 1.6-2.2 –fold with Q4W dosing. No Dose Limiting Toxicities (DLTs) were reported. 
Population PK analysis indicated that the changes in exposure due to patient weight are minimal 


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across the anticipated weight range of 30 to 150 kg for the patient population. Therefore, a flat 
dosing scheme was selected. The recommended phase 2 dose (RP2D) therefore was established 
at 400 mg Q4W or 300 mg Q3 weeks. Adverse events (AEs), all grades, regardless of 
relationship to study drug, were reported in 58 patients (100%) overall, with the most frequent 
AEs (in ≥20% of patients) being nausea (40%), anemia (33%), fatigue (36%), diarrhea (29%), 
dyspnea (29%), vomiting (24%), abdominal pain (22%), decreased appetite (22%) and 
constipation (21%) which are consistent with the AEs reported in studies with other PD-1 
inhibitors and with the AEs commonly reported for patients with advanced solid malignancies 
(Opdivo (Nivolumab) USPI 2015, Keytruda (pembrolizumab) USPI 2015). The AE profile was 
similar across the different dose groups. The most frequent Grade 3/4 AEs (in ≥10% of patients) 
regardless of causality was anemia (15.5%). The most frequent AEs (≥10% of patients) 
suspected to study drug were fatigue (20.7%), diarrhea (15.5%), nausea (10.3%), and pruritus 
(10.3%). Grade 3/4 AEs related to study drug were rare, occurring in only 2 (3.4%) patients; 
one case of autoimmune colitis and another of hypophosphataemia. There were 4 deaths while 
on-treatment but none related to study drug.
As of cut-off date of 27-Mar-2016, serious adverse events (SAEs), all grades, regardless of 
relationship to study drug, were reported in 23 (39.7%) patients in study CPDR001X2101. Most 
of the SAEs were Grade 3 or 4 (22 out of 23). One SAE (Grade 3 autoimmune colitis) was 
suspected to be related to study treatment. This patient was treated with PDR001 at 10 mg/kg 
Q2W and the patient presented with sudden onset of diarrhea after four doses of treatment. 
Diagnosis of autoimmune colitis was confirmed by colonoscopy with biopsy. Treatment with 
PDR001 was interrupted and the patient’s diarrhea responded immediately to treatment with 
corticosteroids.
In terms of preliminary activity, the disease control rate across the wide range of tumor types 
was 41%, with one partial response in a patient with a metastatic, atypical pulmonary carcinoid 
tumor (Naing 2016). Although follow-up data are premature, preliminary data from the ongoing 
phase II portion of the study already showed confirmed responses per RECIST 1.1 in two of 16 
evaluable patients with unresectable or metastatic melanoma (cut-off date: 26 August 2016). 
As of 24 October 2016, a total of five investigator notifications due to serious, unexpected, 
possibly related adverse events have been issued during phase I and the ongoing phase II.
Updated information on clinical experience with PDR001 can be found in the latest 
Investigator's Brochure.
1.2.2
Overview of dabrafenib and trametinib
Dabrafenib (Tafinlar®) is an orally bioavailable, potent and selective RAF kinase inhibitor of 
human wild-type (WT) BRAF and CRAF enzymes as well as the mutant forms of the BRAF 
enzyme, BRAF V600E, BRAF V600K, and BRAF V600D. The mechanism of action of 
dabrafenib is consistent with competitive inhibition of ATP binding.
Dabrafenib was first approved by the FDA in 2013 as a single-agent oral treatment for 
unresectable or metastatic melanoma in adult patients with the BRAF V600E mutation. 
Dabrafenib is currently also approved in the EU, Switzerland, Canada, Australia and multiple 
other countries for the treatment of adult patients with unresectable or metastatic melanoma 
with a BRAF V600 mutation. Prior to initiation of dabrafenib, patients must have confirmation 


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of tumor BRAF V600 mutation. These approvals include the following limitation of use: 
dabrafenib is not indicated for the treatment of wild-type BRAF melanoma. The recommended 
dose of dabrafenib is 150 mg (two 75 mg capsules) twice daily (BID) (corresponding to a total 
daily dose of 300 mg).
Trametinib (Mekinist®) is a reversible and highly selective allosteric inhibitor of MEK1 and 
MEK2. MEK proteins are critical components of the MAPK pathway which is commonly 
hyperactivated in tumor cells. Oncogenic mutations in both BRAF and RAS signal through 
MEK1 or MEK2. Trametinib was first approved by the FDA on 2013 as a single-agent oral 
treatment for unresectable or metastatic melanoma in adult patients with BRAF V600 mutations. 
Trametinib is currently also approved in the EU, Canada, and Australia and multiple other 
countries for the treatment of adult patients with unresectable or metastatic melanoma. The 
recommended dose of trametinib is 2 mg once daily (QD).
Trametinib in combination with dabrafenib was first approved by the FDA in 2014 to treat 
unresectable or metastatic melanoma in adult patients with BRAF V600 mutations. The 
combination therapy is currently also approved in the EU, Australia, Chile, Canada, and 
multiple other countries.
1.2.2.1
Nonclinical experience with dabrafenib and trametinib combination
In vitro and in vivo preclinical data indicated increased anti-tumor activity by the combination 
of a BRAF V600-inhibitor dabrafenib and a MEK inhibitor trametinib. The combination of 
dabrafenib and trametinib has demonstrated enhanced anti-proliferative activity against a panel 
of BRAF-mutant cell lines in vitro, suggesting a synergistic effect of dabrafenib and trametinib 
in addressing primary resistance to each single agent. In addition, the combination was also 
effective in inhibiting the growth of dabrafenib- resistant BRAF-mutant melanoma cell clones 
indicating the potential ability of the combination therapy to overcome acquired resistance. This 
cell-line data are comparable to recently published in vitro results of other experimental BRAF- 
and MEK-inhibitor combinations (Corcoran 2010, Emery 2009). Moreover, the combination of 
dabrafenib and trametinib demonstrated improved activity in mouse xenograft models of BRAF 
mutant melanoma compared to either single agent. Furthermore, in skin toxicity studies 
performed in rats, the addition of trametinib to dabrafenib prevented the development of 
proliferative skin lesions observed following treatment with dabrafenib alone. These results 
suggest that the addition of a MEK inhibitor to a BRAF inhibitor may suppress the proliferative 
signals in normal skin cells which can lead to the development of hyperproliferative skin lesions 
including keratoacanthomas and cutaneous squamous-cell carcinomas frequently observed in 
clinical trials involving BRAF inhibitors (Flaherty 2010, Chapman 2011, Robert 2011). Similar 
results have been published with another combination of BRAF V600 and MEK inhibitors 
(Carnahan 2010).
1.2.2.2
Clinical experience with dabrafenib and trametinib combination
Dabrafenib and trametinib are approved as monotherapy or in combination for the treatment of 
adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation in the US, 
EU and over 20 other countries including Switzerland, Canada and Australia. For more details, 
please refer to the most current dabrafenib Investigator’s Brochure and the approved product 
information.


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1.2.2.2.1 Human pharmacokinetics
Dabrafenib is absorbed orally with median time to achieve tmax of 2 hours post-dose. Mean 
absolute bioavailability of oral dabrafenib is 95% (90% CI: 81 to 110%). Dabrafenib exposure 
(Cmax and AUC) increased in a dose proportional manner between 12 and 300 mg following 
single-dose administration, but the increase was less than dose proportional after repeat twice 
daily dosing. There was a decrease in exposure observed with repeat dosing, likely due to 
induction of its own metabolism. Mean accumulation AUC Day 18/Day 1 ratios was 0.73. 
Dabrafenib binds to human plasma protein and is 99.7% bound. The metabolism of dabrafenib 
is primarily mediated by cytochromes P450 (CYP) 2C8 and CYP3A4 to form hydroxy-
dabrafenib, which is further oxidized via CYP3A4 to form carboxy-dabrafenib. Carboxy-
dabrafenib can be decarboxylated via a non-enzymatic process to form desmethyl-dabrafenib. 
Mean metabolite to parent AUC ratios following repeat dose administration were 0.9, 11 and 
0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative 
potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to 
contribute to the clinical activity of dabrafenib; while the activity of carboxy-dabrafenib is not 
likely to be significant. Dabrafenib terminal half-life is 8 hours. Faecal excretion is the major 
route of elimination after oral dosing, accounting for 71% of a radioactive dose while urinary 
excretion accounted for 23% of radioactivity.
Trametinib is absorbed orally with median time to achieve peak concentrations (tmax) of 1.5 
hours post-dose. The mean absolute bioavailability of a single 2 mg tablet dose is 72%. The 
increase in exposure (Cmax and AUC) was dose proportional following repeat dosing. 
Trametinib accumulates with repeat daily dosing with a mean accumulation ratio of 6.0 
following a 2 mg once daily dose. Mean terminal half-life is 127 hours (5.3 days) after single 
oral dose administration. Steady-state was achieved by Day 15. In vitro and in vivo studies 
demonstrated that trametinib is metabolized predominantly via deacetylation alone or in 
combination with mono-oxygenation. The deacetylated metabolite was further metabolized by 
glucuronidation. The deacetylation is mediated by the carboxyl-esterases 1b, 1c and 2, with 
possible contributions by other hydrolytic enzymes. Drug-related material was excreted 
predominantly in the feces (≥ 81% of recovered radioactivity) and to a small extent in urine (≤ 
19%). Less than 0.1% of the excreted dose was recovered as parent in urine.
Repeated co-administration of dabrafenib 150 mg twice daily and trametinib 2 mg once daily 
resulted in a 16% increase in dabrafenib Cmax and a 23% increase in dabrafenib AUC. A small 
decrease in trametinib bioavailability, corresponding to a decrease in AUC of 12%, was 
estimated when dabrafenib is administered in combination with trametinib using a population 
pharmacokinetic analysis. These changes in dabrafenib or trametinib Cmax and AUC are 
considered not clinically relevant.
1.2.2.2.2 Drug-drug interactions
Dabrafenib induces CYP3A4- and CYP2C9-mediated metabolism and may induce other 
enzymes and transporters. Co-administration of dabrafenib and medicinal products which are 
affected by the induction of CYP3A4 or CYP2C9 such as hormonal contraceptives, warfarin or 
dexamethasone may result in decreased concentrations and loss of efficacy. If co-administration 
of these medications is necessary, monitor subjects for loss of efficacy or consider substitutions 
of these medicinal products.


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Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are likely to 
increase or decrease, respectively, dabrafenib concentrations. Alternative agents should be 
considered during administration with dabrafenib when possible. Use caution if strong 
inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, ritonavir, gemfibrozil) or inducers 
(e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) of CYP2C8 or 
CYP3A4 are coadministered with dabrafenib.
Trametinib is an inducer of CYP3A4 in vitro. However, trametinib’s efficacious dose of 2 mg 
once daily results in a low systemic maximal concentration (22.2 ng/mL or 0.036 μM), relative 
to its in vitro inhibition potency of CYP enzymes and transporters, rendering the risk of an 
inhibitory effect of trametinib on the PK of co-administered CYP or transporter substrates low.
Trametinib is eliminated primarily via deacetylation and possibly other hydrolases. There is 
little evidence from clinical studies for drug interactions mediated by carboxylesterases. 
Trametinib is also a substrate of P-gp and BSEP. However, due to its high passive permeability, 
these active transport processes are likely of limited relevance. Therefore, a clinically relevant 
effect of a co-administered P-gp or BSEP inhibitor on the PK of trametinib is unlikely.
No clinically relevant drug-drug interaction (DDI) was observed after repeat dosing dabrafenib 
150 mg twice daily and trametinib 2 mg once daily.
1.2.2.2.3 Clinical safety
Safety data pooled from the dabrafenib and trametinib combination arms of 2 completed phase 
III studies in subjects (N=559) with melanoma [MEK115306 and MEK116513] based on a cut-
off date of 13 March 2015 are provided below. Data are in comparison to the dabrafenib 
monotherapy arm (N=211) of Study MEK115306 and the vemurafenib monotherapy arm 
(N=349) of Study MEK116513. The safety population consists of all subjects who received at 
least 1 dose of study treatment.
The median duration of follow-up, defined as the time from study start to last contact or death, 
was 19 months for the combination therapy group, 15 months for the vemurafenib group, and 
16 months for the dabrafenib group.
Skin adverse effects were less frequent in the combination therapy group, especially the events 
linked to a paradoxical activation of the MAPK pathway, including both benign and malignant 
skin tumors. This finding is in accordance with preclinical models showing that the addition of 
MEK inhibitors may down regulate the BRAF inhibitor induced paradoxical activation of the 
MAPK pathway. Thus, secondary resistance and paradoxical activation of the MAPK pathway 
that occur with BRAF inhibitor monotherapy, which translate into rapid tumor relapses and 
emergence of skin cancers, respectively, were both improved by the combination therapy.
The incidences of subjects with any on-therapy AE, study treatment-related AE, SAEs, and 
study treatment-related SAE were similar between the treatment arms. The incidence of AEs 
leading to study treatment discontinuation, dose reductions, or dose interruptions was similar 
in the combination therapy group and the vemurafenib arm, and higher than in the dabrafenib 
monotherapy arm. The rate of fatal SAEs was higher in the combination therapy group 
compared to the two monotherapy groups. However, no subjects in the combination therapy 
group had fatal SAEs considered related to study treatment by the investigator.


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Common adverse events
The most commonly occurring AEs (≥20%) in subjects treated with dabrafenib alone were 
hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar 
erythrodysesthesia syndrome (PPES).
The most commonly occurring AEs (>20%) in subjects treated with trametinib alone were rash, 
diarrhea, and lymphedema.
The most commonly occurring AEs (>20%) in subjects treated with dabrafenib in combination 
with trametinib) were pyrexia, nausea, rash diarrhea, chills, headache, vomiting, hypertension, 
arthralgia, peripheral edema and cough and the most common Grade 3 or 4 AEs (5%) 
occurring in patients treated with the combination were hypertension and pyrexia.
The most common AEs leading to discontinuation (>1% of subjects) were pyrexia and ejection 
fraction decreased in the combination therapy group.
Adverse events leading to dose reduction or interruption of study treatment
Pyrexia, PPES, chills, fatigue, and headache were most frequent AEs leading to dose reduction 
of dabrafenib. The most common AEs leading to dose reduction (3% of subjects) were pyrexia 
and ejection fraction decreased in the combination therapy group. Of the most common events, 
dose reductions due to pyrexia were more common in the combination therapy group compared 
with each monotherapy arm.
Of the most common AEs leading to dose interruption, dose interruptions due to pyrexia were 
more common in the combination therapy group compared with either monotherapy arm.
The incidences of pyrexia and neutropenia were higher (10% difference) in the combination 
therapy group compared with either monotherapy arm. In addition, the incidences of diarrhea, 
hepatic events, hypertension and edema were higher (10% difference) in the combination 
therapy group compared with the dabrafenib monotherapy arm only, but similar to vemurafenib, 
and the incidence of bleeding events was higher in the combination therapy group compared 
with the vemurafenib monotherapy arm.
1.2.2.2.4 Clinical efficacy
Both dabrafenib and trametinib have proven anti-tumor activity as monotherapy in BRAF V600 
mutant metastatic melanoma (BREAK 3 and METRIC trials respectively).
Combining a BRAF V600 inhibitor with a MEK inhibitor addresses the limitations of single 
agent BRAF V600 inhibitors and results in a significant delay in the emergence of resistance, 
with a longer median PFS than with dabrafenib alone as well as a decreased incidence of BRAF 
V600 inhibitor induced skin tumors (Long 2014, Long 2015). The efficacy of dabrafenib and 
trametinib combination therapy for BRAF V600 mutation positive metastatic melanoma has 
been demonstrated in two pivotal randomized phase III studies (COMBI-d and COMBI-v) with 
patients harboring a BRAF V600 mutation.
Study MEK115306 [COMBI-d] was a two-arm, double-blind, randomized, phase III study 
comparing dabrafenib and trametinib combination therapy to dabrafenib monotherapy. Patients 
with histologically confirmed cutaneous melanoma that is either unresectable (Stage IIIC) or 


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metastatic (Stage IV), and BRAF V600E/K mutation positive were enrolled. The primary 
endpoint was investigator-assessed PFS for patients receiving the combination therapy 
compared with those receiving dabrafenib monotherapy. In this study, the median PFS was 11 
months in the dabrafenib and trametinib combination arm versus 8.8 months in the dabrafenib 
arm (p<0.001). The overall response rate was 69% in the dabrafenib and trametinib combination 
arm versus 53% in dabrafenib arm (p=0.001). Median OS was 25.1 months in the dabrafenib 
and trametinib combination arm versus 18.7 months in the dabrafenib only arm (p=0.011). 
Dabrafenib and trametinib combination therapy provided better preservation of health related 
quality of life (HRQoL) and pain improvements versus dabrafenib monotherapy (Robert 2015).
Study MEK116513 [COMBI-v] was a two-arm, open-label, randomized, phase III study 
comparing dabrafenib and trametinib combination therapy to vemurafenib monotherapy. 
Patients with histologically confirmed cutaneous melanoma that is either unresectable (Stage 
IIIC) or metastatic (Stage IV), and BRAF V600E/K mutation positive were enrolled. The 
primary endpoint was OS for patients receiving the combination therapy compared with those 
receiving vemurafenib only. Results from this study showed that the combination of dabrafenib 
and trametinib significantly (p<0.001) improved OS compared to vemurafenib monotherapy, 
and median OS was 25.6 months in the dabrafenib and trametinib combination arm versus 18 
months in the vemurafenib only arm. A statistically significant reduction of 34% in the risk of 
death among patients receiving combination therapy was observed in the study. The median 
PFS was 12.6 months in the dabrafenib and trametinib combination arm versus 7.3 months in 
the vemurafenib arm (p<0.001). The ORR was 64% in the dabrafenib and trametinib 
combination arm versus 51% in vemurafenib arm (p<0.001). In addition, an analysis of the 
patients’ HRQoL showed statistically significant and clinically meaningful improvements 
among those receiving the combination of dabrafenib and trametinib, compared to those 
receiving vemurafenib monotherapy (Long 2014, Robert 2015).
In these two randomized phase III studies, dabrafenib in combination with trametinib 
consistently demonstrated clinical benefit in BRAF V600 mutant metastatic melanoma when 
compared to BRAF V600 inhibitor monotherapy (dabrafenib or vemurafenib), that was 
established by statistically significant and clinically meaningful improvements in OS, PFS, 
ORR, DOR and quality of life without increased toxicity. In both studies, patients with elevated 
LDH at baseline consistently had a poorer clinical outcome in terms of PFS and OS compared 
to patients with normal LDH.
2
Rationale
2.1
Study rationale and purpose
Both immunotherapy with checkpoint inhibitors and targeted therapy are important in the 
management of BRAF V600-mutated unresectable or metastatic melanoma. Immunotherapy 
has gained much interest due to the promise of long-term disease control. To date, the main 
limitation of single agent immune checkpoint inhibitor therapy is that only a subset of patients 
respond, likely due to evasion of immunosurveillance and suppression of effector function in 
the tumor microenvironment. Strategies to further improve these response rates are needed 
(Wargo 2014). Combination immunotherapy with ipilimumab and nivolumab has resulted in 
longer PFS and higher ORR than either agent alone, however at the expense of significantly 


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increased toxicity (Larkin 2015, Postow 2015). While rapid and deep responses have been 
observed with the combination of BRAF V600 and MEK inhibitor therapies, most patients 
progress within a year and there are only a few complete responses. Thus, strategies to improve 
the durability of these responses are needed (Wargo 2014).
This randomized, double-blind, placebo-controlled, phase III study will evaluate the efficacy 
and safety of the combination of the anti-PD1 antibody PDR001 in combination with the BRAF 
V600 inhibitor dabrafenib and the MEK inhibitor trametinib in previously untreated BRAF 
V600 mutated melanoma. Based on preclinical and preliminary clinical data, it is expected that 
dabrafenib in combination with trametinib alter the immune microenvironment in a way that 
could be beneficial for combination with PD-1 inhibitors.
Preclinical data
Early data for the potential synergy of targeted therapy with immune checkpoint inhibitors in 
melanoma was based on observations that oncogenic BRAF can lead to immune escape in 
melanoma (Sumimoto 2006) and that blocking BRAF activity leads to increased expression of 
melanoma differentiation antigens in vitro (Kono 2006) through release of transcriptional 
repression and subsequent expression of MITF targets including MART-1, gp100, TRP-1 and 
TRP-2 (Boni 2010).
The effect of MAPK pathway inhibition on T cell activation and signaling was also studied in 
vitro. While BRAF V600 inhibitors did not show any adverse effects on T cell function and may 
even augment their function through paradoxical signaling through RAS-GTP (Callahan 2014), 
MEK inhibitors showed dose-dependent inhibition of T cell function in vitro (Boni 2010, Vella 
2014). The in vivo anti-tumor effect of trametinib was explored in a murine immunocompetent 
BALB/C syngeneic CT26 tumor model. In this study, trametinib monotherapy increased CD4+ 
tumor infiltrating lymphocytes (TILs) and did not negatively affect the prevalence of CD8+ 
TILs. Importantly the combination of trametinib with murine anti-PD-1 resulted in an effective 
anti-tumor response in the KRAS-mutant CT26 colorectal tumor syngeneic mouse model 
(Liu 2015). Another group showed that the addition of trametinib significantly improved the 
anti-tumor effect of anti-PD-1 in an immunocompetent mouse model of BRAF V600 mutant 
melanoma through improved effector T cell homing and preserved effector function, increased 
tumor antigen and MHC expression and cytokine release in the tumor microenvironment 
(Hu-Lieskovan 2015).
Clinical data
Additional supporting evidence for the potential synergy of BRAF V600 targeted therapy and 
checkpoint inhibitors comes from immune biomarker analysis of tumor samples from 16 
patients with metastatic melanoma treated with vemurafenib or dabrafenib plus trametinib. In 
these analysis BRAF V600 inhibition (1) was associated with increased melanoma antigen 
expression (MART, TYRP-1, TYRP-2, gp100), (2) significantly increased CD8+ TILs, (3) 
decreased expression of immunosuppressive cytokines in the tumor microenvironment, and (4) 
increased markers of T cell toxicity but also increased T cell exhaustion marker (TIM-3, PD-
1). Another important observation was that the antigen expression and CD8+ TILs were 
decreased at time of disease progression but could be restored through addition of dabrafenib 
and trametinib combination therapy (Frederick 2013, Wilmott 2012).


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A phase I, open-label, multi-center, dose-finding study (NCT01767454) in subjects with 
unresectable or metastatic melanoma and BRAF V600E/K mutations was undertaken to 
characterized the safety of dabrafenib and ipilimumab with and without trametinib. The study 
consisted of two treatment arms: a doublet combination treatment arm of dabrafenib and 
ipilimumab, and a triple combination treatment arm of dabrafenib, trametinib and ipilimumab, 
with the potential for expansion cohorts for each treatment arm. In the doublet combination 
treatment arm, the starting dose of dabrafenib was the recommended monotherapy dose of 150 
mg twice daily (BID). Ipilimumab was administered at the approved dose of 3 mg/kg every 3 
weeks for a total of 4 doses in this study. Cohorts in the doublet arm followed a 3+3 enrollment. 
The study was closed due to DLTs in 2 subjects in the triplet combination treatment arm, as 
both subjects developed colitis with colonic perforation that raised the possibility of added 
toxicity with the triplet combination over ipilimumab as a single agent. The majority of AEs 
reported in both the doublet and triplet combination treatment arms were consistent with the 
safety profile of one or more of the study treatments. More than 65% of the subjects in both 
combination treatment arms had Grade 3 or Grade 4 AEs. No fatal events were reported.
In study KEYNOTE-022 (NCT02130466), dabrafenib and trametinib are currently being 
evaluated in combination with pembrolizumab in a phase I/II study in BRAF V600 mutant 
melanoma (Ribas 2016). Based on the phase I results, the recommended regimen for phase II 
is pembrolizumab 2 mg/kg Q3W plus dabrafenib 150 mg BID with trametinib 2 mg QD. The 
double-blind, placebo-controlled, randomized phase II part is ongoing. Fifteen patients were 
treated with the triplet combination and 14 patients were evaluable for DLT from the first two 
parts. Three of the 14 patients had DLTs and all were laboratory abnormalities. One patient had 
Grade 4 neutropenia that lasted about 2 weeks and resolved with drug interruption and 
subsequently continued study treatment, one patient had Grade 4 ALT elevation that resolved 
in about 2 weeks and study treatments were discontinued, and one patient had elevated Grade 
3 ALT, AST and GGT elevation which were resolving and the patient was restarted on 
pembrolizumab alone. The adverse event profile was representative of the individual study 
agents. The recommended regimen was the labeled doses of each of the individual study 
medications. Preliminary efficacy data were promising with 5 patients achieving a confirmed 
response, 9 patients with an unconfirmed response and 13 of the 14 patients having a reduction 
in tumor size. The randomized portion of the study is ongoing, and as of 30 September 2016, 
89 of the proposed 120 patients have been accrued. The interim analysis will be conducted when 
the first 80 enrolled patients have had at least a 6-month follow-up (Long 2016).
Additionally, the combination of dabrafenib and trametinib with the anti-PD-L1 antibody 
durvalumab in BRAF V600 mutant melanoma was tested (NCT02027961). Two doses of 
durvalumab were tested. Initially 6 patients received the labeled dose of dabrafenib and 
trametinib and durvalumab (3 mg/kg Q2W) and 20 patients received 10 mg/kg of durvalumab 
Q2W. Both doses were tolerated and were manageable and the AE profile was representative 
of the individual AE profile of each study medication. Combining data from both doses, the 
ORR was 69.2% (95% CI: 48.2-85.7), median DOR was 67.1 weeks, and 55.6% of responders 
had an ongoing response at the time of the data cut-off. (Ribas 2015).
In this study, CPDR001F2301 (also called COMBI-i, NCT02967692), PDR001 in combination 
with dabrafenib and trametinib versus placebo in combination with dabrafenib and trametinib 
were evaluated in a phase I/II/III design in stage IIIC/IV BRAF-mutant melanoma in absence 


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of active brain metastases and prior systemic therapy for unresectable/metastatic disease. Safety 
and efficacy analyses for part 1 and 2 were presented at ASCO 2020. The analysis was based 
on the pooled patient population (N = 36) from parts 1 (n = 9) and 2 (n = 27), with a data cutoff 
of 19-Aug-2019. The treatment comprised of PDR001 400 mg q 4 weeks in combination with 
danrafenib 150 mg bid and trametinib 2 mg qd. Treatment with PDR001 in combination with 
dabrafenib and trametinib was continued until disease progression, death, unacceptable toxicity, 
loss to follow-up, or withdrawal of consent. At the time of data cutoff, median follow-up was 
24.3 months (range, 20.8-29.5 months), and treatment was ongoing in 10 patients. PDR001 in 
combination with dabrafenib and trametinib, exhibited an ORR of 78%, including a promising 
CR rate of 44%, in 36 patients with unresectable or metastatic BRAF-mutant melanoma. The 
treatment with PDR001 in combination with dabrafenib and trametinib seemed to be associated 
with a high frequency of durable responses with a 24-month DOR rate of 55% (median DOR 
not reached) and 24-month PFS and OS rates of 41% and 74%, respectively. No new safety 
signals had been observed; AEs were consistent with the individual toxicity profiles of each 
study drug.
At the time of final PFS analysis (data cut off 01-Jul-2020) for the randomized part 3, a total of 
532 patients were randomized to the treatment arms. The treatment comprised of PDR001 400 
mg q 4 weeks in combination with dabrafenib 150 mg bid and trametinib 2 mg qd or placebo 
in combination with dabrafenib 150 mg bid and trametinib 2 mg qd. The median follow-up from 
the time of randomization to the data cutoff was 27.2 months (range, 24.0-33.6 months). The 
primary endpoint was PFS based on investigator assessed response by RECIST v1.1.
The final PFS analysis showed that the study did not meet its primary endpoint of investigator-
assessed PFS. The combination of PDR001, dabrafenib and trametinib resulted in a limited 
benefit and did not significantly improve PFS vs placebo, dabrafenib and trametinib (median 
PFS, 16.2 months vs 12.0 months; HR=0.820 [95% CI, 0.655-1.027]; P = 0.042, one-sided). 
The OS analysis provided a HR=0.785 [95%CI (0.587, 1.047)] in favor of PDR001 in 
combination with dabrafenib and trametinib and median OS was not reached in either of the 
treatment arms. Since the primary endpoint was not met the key secondary endpoint OS was 
not formally statistically tested. Overall, no new safety concerns were identified and overall the 
AEs were manageable with dose interruptions and reductions. A higher number of dose 
modifications and discontinuations was observed in patients treated with PDR001 in 
combination with dabrafenib and trametinib (Nathan 2020). The safety data demonstrated that 
the treatment related AEs (TRAEs) all grades occurred in 98.5% vs. 87.5% of patients, and ≥ 
grade 3 in 54.7% vs. 33.3% of patients in the PDR001 in combination with dabrafenib and 
trametinib arm and placebo in combination with dabrafenib and trametinib arm respectively. 
Furthermore, AEs leading to discontinuation of all three drugs occurred in 15.7% vs. 9.1% of 
patients and AEs leading to discontinuation of any drug in 36.3% vs. 17.8 % of patients in the 
PDR001 in combination with dabrafenib and trametinib arm and placebo in combination with 
dabrafenib and trametinib arm, respectively. No treatment related deaths were reported in the 
PDR001 in combination with dabrafenib and trametinib arm. Two treatment related deaths were 
reported in the placebo in combination with dabrafenib and trametinib arm.
2.2
Rationale for the study design
This phase III study will evaluate the safety and efficacy of the investigational anti-PD-1 
antibody, PDR001 in combination with the approved doses of dabrafenib and trametinib in 




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evaluated to characterize the PK of PDR001, dabrafenib, and trametinib when administered in 
combination.
The number of PFS events required for the final PFS analysis (352) is sufficient to achieve 80% 
cumulative power to detect a significant difference between treatment groups based on the 
conservative assumption of a 5 months delayed treatment effect as observed in the KEYNOTE-
022 study (Ascierto et al., 2018b) and the subsequent effect is of the same magnitude as 
currently assumed (HR=0.60). However, since the KEYNOTE-022 study showing a 5 months 
delayed effect was of relatively small sample size, there is still some uncertainty over the exact 
duration of the delayed effect. Therefore, the design for this study incorporates an interim PFS 
analysis, which will allow a good chance to detect a clinical relevant benefit at an earlier 
timepoint if the delayed effect is in fact less than 5 months duration. The timing and significance 
boundary of this interim PFS analysis is chosen so that the efficacy threshold is only met when 
the PFS treatment effect is sufficient and clinically relevant (i.e. using a stringent significance 
level with very little penalty for the final PFS analysis). The final PFS analysis will serve as a 
safeguard in case the delayed effect is 5 months in duration as observed in KEYNOTE-022 
(Section 10.7, Section 10.8 and Section 10.9). 
2.3
Rationale for dose and regimen selection
Rationale for PDR001 dose (See also Section 1.2.1.2)
The dose of PDR001 selected for dose level 1 (DL1) in the safety run-in part (part 1) of this 
study is 400 mg Q4W, administered as an intravenous infusion. In study [CPDR001X2101], 
PDR001 single-agent was administered as an intravenous infusion over 30 minutes at doses 
ranging from 1 to 10 mg/kg on an every 2 weeks (Q2W) schedule or at 3 and 5 mg/kg every 4 
weeks (Q4W) schedules. Approximately dose proportional increase in exposure (C1D1 AUC0-
336) was observed with doses from 1 to 10 mg/kg and no DLTs were observed. Accumulation 
of approximately 2.1-3.4-fold was observed with Q2W dosing and 1.6-2.2-fold with Q4W 
dosing. Population PK analysis indicated that the changes in exposure due to patient weight 
differences are minimal across the anticipated weight range of 30 to 150 kg for the patient 
population. Therefore, a flat dosing scheme was selected. Two recommended phase II dosing 
regimens have been established: 300 mg Q3W and 400 mg Q4W flat dosing schedules. A flat 
dose of 400 mg Q4W or 300 mg Q3W is expected to achieve a mean steady-state Ctrough value 
higher than the ex vivo EC50 for antigen-stimulated IL-2 production, a translational biomarker 
for PD-1 blockade (Patnaik 2015). Based on the safety profile observed in study 
[CPDR001X2101] (Section 1.2) and the expected Ctrough values, 400 mg Q4W is expected to 
be a safe and efficacious dose. Subjects in the safety run-in part (part 1) will receive fixed dose 
combination of dabrafenib (150 mg BID) and trametinib (2 mg QD) and PDR001 400 mg every 
4 weeks. If this initial dose level (DL1) is not tolerated, the next dose level (DL-1a and DL-1b) 
will be tested in parallel (see Section 4.1.2). The cohorts DL-1a and DL-1b use different and 
independent strategies to improve the tolerability of the triplet combination. DL-1a aims to 
reduce drug exposure for PDR001 by increasing the interval for the PDR001 from Q4W to 
Q8W. DL-1b allows a run-in period of 28 days for the combination treatment with dabrafenib 
and trametinib with subsequent addition of PDR001. This allows optimal AE management for 
dabrafenib and trametinib combination prior to the administration of PDR001. The DLT 
observation period for DL-1b is 8 weeks from the initiation of the triplet treatment (Cycle 2 


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Day 1). As the strategies are independent and considered similar with regards to benefit/risk, 
they are tested in parallel. 
Rationale for dabrafenib dose
The dabrafenib dose is 150 mg BID (corresponding to a total daily dose of 300 mg) which is 
the approved dose for patients with unresectable or metastatic melanoma with BRAF V600E or 
V600K mutations.
Rationale for trametinib dose
Trametinib will be administered as 2 mg QD, which is the approved dose for patients with 
unresectable or metastatic melanoma with BRAF V600E or V600K mutations. 
Refer to Section 10.4.2 for details on how historical data were used to derive priors for the 
BLRM single agent (PDR001, dabrafenib, and trametinib) and interaction parameters, as well 
as for confirmation that the posterior probability of excessive toxicity for all 3 dosing regimens 
satisfy EWOC criteria (probability < 25%).
Rationale for combination dose
The approved doses of dabrafenib 150 mg twice daily (BID) and trametinib 2 mg once-daily 
(QD) will be used in all parts of the study as data from study BRF113220 showed decreased 
efficacy when lower doses of trametinib were used. Study BRF113220 was an open label study 
designed to assess the safety, pharmacokinetic and clinical activity of combination therapy with 
dabrafenib plus trametinib. Part C was a randomized phase 2 study in which subjects were 
randomly assigned in a 1:1:1 ratio to either receive 150 mg of dabrafenib BID plus trametinib 
QD, at a dose of either 1 mg or 2 mg, or dabrafenib 150 mg BID as monotherapy. The response 
rate and PFS of the dabrafenib 150 mg BID and trametinib 2 mg QD combination was superior 
to the other groups (Flaherty 2012, Long 2012). 
Lower doses of PDR001 would result in a reduction of the required Ctrough level, thus 400 mg 
Q4W should be the starting dose in combination with the approved doses of dabrafenib and 
trametinib. From simulations based on the population PK model, the dose of 400 mg Q4W is 
predicted to achieve mean steady-state Ctrough concentrations of approximately 31 μg/mL (90% 
CI: 22-42 μg/mL). Finally preliminary data from studies combining dabrafenib and trametinib 
with other anti-PD-1 or anti-PD-L1 antibodies have reported acceptable DLT rates in 
combination with the approved doses of dabrafenib and trametinib.
2.4
Rationale for choice of combination drugs
Please refer to Section 2.1 for the rationale for choice of combination drugs.
2.5
Rationale for choice of comparator drugs
The combination therapy of dabrafenib and trametinib is approved for the treatment of 
metastatic BRAF V600 mutated melanoma and is an accepted treatment standard for this patient 
population globally (NCCN Guidelines for Patients® Melanoma V1.2017, Cutaneous 
Melanoma: ESMO Clinical Practice Guidelines 2015, AWMF S13-Leitlinie Melanoma 2016) 
(Refer to Section 1.2.2).


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2.6
Risks and benefits
Both dabrafenib and trametinib have proven anti-tumor activity as monotherapy in BRAF V600 
mutant metastatic melanoma (BREAK-3 and METRIC trials respectively). Combining a BRAF 
V600 inhibitor with a MEK inhibitor addresses the limitations of single agent BRAF V600 
inhibitors and results in a significant delay in the emergence of resistance, with a longer median 
PFS than with dabrafenib alone as well as a decreased incidence of BRAF V600 inhibitor 
induced skin tumors (Long 2014, Long 2015). The efficacy of dabrafenib and trametinib 
combination therapy for BRAF V600 mutation positive unresectable or metastatic melanoma 
has been demonstrated in two large randomized, pivotal phase III studies (COMBI-d and 
COMBI-v) and is an accepted treatment option globally for the population studied (NCCN 
Guidelines for Patients® Melanoma V1.2017, Cutaneous Melanoma: ESMO Clinical Practice 
Guidelines 2015, AWMF S13-Leitlinie Melanoma 2016). As of June 2016, an estimated 9,600 
subjects, primarily with BRAF V600 mutated cancer, have received dabrafenib monotherapy or 
dabrafenib in combination with trametinib across the clinical development program.
PDR001 is an investigational humanized IgG4 monoclonal antibody specifically to anti-PD-1. 
This class of compound has demonstrated significant improvement in efficacy combined with 
tolerable and manageable safety profile, supporting recent regulatory approvals in melanoma, 
non-small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), bladder cancer, 
renal cancer and classical Hodgkin’s lymphoma (Opdivo® USPI 2015, Keytruda® USPI 2015).
Immune checkpoint inhibitors including anti-PD-1/PD-L1 may be associated with the 
occurrence of irAE. In general, irAE can potentially involve every organ system but 
gastrointestinal (colitis), dermatologic (rash), hepatic (hepatitis), pulmonary (pneumonitis), 
renal (nephritis) and endocrine toxicities (hypothyroidism, hyperthyroidism, diabetes, 
hypophysitis and hypopituitarism) are the most frequent and rarely CNS (encephalitis). These 
adverse effects are generally manageable but fatal events have been reported in some cases with 
checkpoint inhibitor compounds (Eggermont 2015, Friedman 2016, Hofmann 2016).
Based on the in vitro and in vivo preclinical, translational and preliminary clinical data it is 
expected that the addition of an anti-PD-1 antibody (like PDR001) to dabrafenib and trametinib 
may further relieve immunosuppression and allow a more robust anti-tumor response. 
Importantly, the combination of the approved anti-PD-1 antibody pembrolizumab with 
dabrafenib and trametinib showed a manageable toxicity profile in patients with BRAF V600-
mutant melanoma and a phase II study is ongoing (KEYNOTE-022). Drug-drug interactions 
(DDI) with dabrafenib and trametinib are not anticipated as PDR001 is a monoclonal antibody, 
and is not metabolized by CYP450 enzymes, or transported by P-gp or related ABC membrane 
transporters. The clinical relevance of cytokines impacting the levels of P-gp and CYP450 with 
administration of PDR001 is unknown but clinically significant effects are considered unlikely. 
In the case of nivolumab, another mAb targeting PD-1 with the same mechanism of action, the 
Clinical Pharmacology and Biopharmaceutics Review (Opdivo® USPI 2015) states a lack of 
CYP interaction via cytokine modulation up to a dose of 10 mg/kg in renal cell carcinoma (RCC) 
patients. In addition, in vitro and in vivo data suggests that CYP3A4 contributes maximally 50% 
to the elimination of dabrafenib and is not involved to a relevant level in the elimination of 
trametinib. In summary, the risk of DDI between dabrafenib, trametinib and PDR001 cannot be 
totally excluded, but it is anticipated to be low.


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This study incorporates routine safety monitoring and regularly scheduled safety assessments 
to identify and report any potential safety issues. All subjects must have safety evaluations for 
150 days after the last dose of study drug. Comprehensive dose modification, stopping rules 
and toxicity management plan for immune related events or drug related adverse events are 
provided in Section 6.3. Immune checkpoint inhibition is associated with a unique spectrum of 
side effects termed irAEs. Appropriate eligibility criteria and specific DLT definitions 
(Section 6.2.4), as well as specific dose modification and stopping rules along with adverse 
event management guidelines (Section 6.3.1), are included in this protocol. Recommended 
guidelines for prophylactic or supportive treatment for expected toxicities, including 
management of study-drug induced adverse events i.e., skin toxicity and diarrhea are provided 
in Section 6.3.1.
Based on the clinical experience with PDR001, which has been consistent with other 
monoclonal antibodies targeting PD-1, overlapping toxicities with trametinib and dabrafenib 
may include skin rash, diarrhea/ colitis, hepatic abnormalities, renal toxicity and pneumonitis. 
For these and other potential treatment-related adverse events of special interest, specific 
management and dose modification guidelines as well as stopping criteria are in place to 
safeguard patients (Section 6.3). In addition to following these guidelines, the risk to patients 
in this trial is further minimized by compliance with the eligibility criteria, study procedures 
and close clinical monitoring. Emerging safety data of this study will be monitored by an 
independent data monitoring committee (DMC).
In summary, the data from phase I-III studies on combination of dabrafenib and trametinib and 
phase I studies on monotherapy of PDR001 indicate that the majority of adverse events in 
patients receiving dabrafenib and trametinib combination or PDR001 as single agent have been 
manageable. Based on the available preclinical and clinical data, especially, the experience from 
phase I/II studies of dabrafenib and trametinib in combination with other anti PD-1/L1 mAbs, 
Novartis considers the potential risks of PDR001, dabrafenib and trametinib combination 
therapy are justified by the anticipated benefits that may be afforded to patients.
In addition, prior to enrollment, this protocol will undergo appropriate review by local and 
regional governance bodies including ethic committees and drug regulatory bodies.
Results from this study final PFS analysis are described in Section 2.1 Study rationale and 
purpose.
Immuno-oncology agents such as checkpoint inhibitors are associated with a distinct response 
kinetics. Based on this, separation of estimated survival curves might therefore occur 
significantly late after the start of treatment. Long-term survival has been observed with the use 
of checkpoint inhibitors therapies in certain cancer types, including melanoma (Hersh et al 2011, 
Garon et al 2015, Weber et al 2015, Samuel, 2016). In a Phase III trial of tremelimumab in 
metastatic melanoma, an early interim analysis showed no survival benefit and the study was 
terminated; however, extended follow-up showed delayed separation of the survival curves 
(Ribas et al 2013, Eroglu et al 2015). 
Based on this, this study will continue after the final PFS analysis, to collect valuable long-term 
survival and safety data. Unblinding of study treatment is mandatory and the decision to 
continue study treatment with PDR001 in combination with dabrafenib and trametinib should 


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be made by the physician on a case by case basis following medical judgement and considering 
the risk/benefit assessment upon discussion with the patient.
COVID-19 outbreak may have an impact on the Overall Survival and safety data if the period 
of COVID-19 outbreak is prolonged with lots of related deaths. However given that:
•
No confirmed COVID-19 cases have been observed up to the data cut-off (01-Jul-2020) of 
the primary endpoint analysis (which suggests potentially low risk of COVID related 
complications). 
•
The risk of deaths due to coronavirus is expected to be similar (i.e. equally spread) in both 
treatment arms
•
A sensitivity analysis of OS in follow-up analyses censoring for COVID-related deaths 
could be included to check the impact of the virus on this endpoint and estimate the 
treatment effect in the absence of virus
It is expected that the impact from the COVID-19 on follow-up OS analyses and safety will be 
minimal.
2.7
Rationale for public health emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities i.e., pandemic, 
epidemic or natural disaster; mitigation procedures to ensure participant safety and trial 
integrity are listed in relevant sections. Notification of the public health emergency should be 
discussed with Novartis prior to implementation of mitigation procedures, and 
permitted/approved by local or regional Health Authorities and Ethics Committees as 
appropriate.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Section 10.4.
Safety run-in (part 1)
To determine the recommended regimen of PDR001 in combination 
with dabrafenib and trametinib for the randomized part (part 3)
•
Incidence of DLTs during the first 8 weeks of treatment for each 
dose level associated with administration of PDR001 in 
combination of dabrafenib and trametinib.
Biomarker cohort (part 2)
To evaluate changes in PD-L1 levels and CD8+ cells upon treatment 
with PDR001 in combination with dabrafenib and trametinib
•
Descriptive statistics of PD-L1 levels and CD8+ cells and 
changes from baseline by visit
Double-blind, randomized, placebo-controlled (part 3)
To compare the anti-tumor activity of PDR001 in combination with 
dabrafenib and trametinib versus placebo plus dabrafenib and 
trametinib as measured by PFS per investigator’s assessment 
according to RECIST 1.1
•
Investigator assessed PFS (according to RECIST 1.1)
Key Secondary
Section 10.5.1.
Double-blind, randomized, placebo-controlled (part 3)
To compare overall survival of PDR001 in combination with 
dabrafenib and trametinib versus placebo plus dabrafenib and 
trametinib
•
Overall survival
Other Secondary
Section 10.5.1.
Safety run-in (part 1) and Biomarker cohort (part 2)
1)
To determine safety and tolerability of PDR001 in combination 
with dabrafenib and trametinib
•
Safety: Incidence and severity of AEs and SAEs, including 
changes in laboratory values, ECOG PS, vital signs, liver and 
cardiac parameters.
•
Tolerability: Dose interruptions, reductions, and dose intensity
2)
To evaluate preliminary anti-tumor activity of PDR001 in 
combination with dabrafenib and trametinib
•
PFS, OS, ORR, DOR, DCR by investigator’s assessment 
according to RECIST 1.1
3)
To characterize pharmacokinetics (PK) of PDR001, dabrafenib 
and trametinib when administered in combination
•
PK parameters such as, but not limited to, Ctrough and 
Ctroughss, for PDR001, dabrafenib and trametinib.
4)
To evaluate the prevalence and incidence of immunogenicity
•
ADA prevalence at baseline and ADA incidence on-treatment


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Objective
Endpoint
Analysis
Double-blind, randomized, placebo-controlled part (part 3)
1)
To compare the anti-tumor activity of PDR001 in combination 
with dabrafenib and trametinib versus placebo plus dabrafenib 
and trametinib as measured by ORR, DCR, DOR per 
investigator’s assessment according to RECIST 1.1
•
ORR, DOR and DCR by investigator’s assessment according to 
RECIST 1.1
2)
To evaluate safety and tolerability of PDR001 in combination 
with dabrafenib and trametinib versus placebo plus dabrafenib 
and trametinib
•
Safety: Incidence and severity of AEs and SAEs, including 
changes in laboratory values, ECOG PS, vital signs, liver 
assessments and cardiac assessments.
•
Tolerability: Dose interruptions, reductions, and dose intensity
3)
To evaluate patient reported outcomes of PDR001 in 
combination with dabrafenib and trametinib versus placebo plus 
dabrafenib and trametinib
•
Change from baseline in EORTC QLQ-C30, EQ-5D, and FACT-
M melanoma subscale
•
Time to 10 point definitive deterioration in overall quality of life 
score from EORTC QLQ-30.
4)
To characterize PK of PDR001, dabrafenib and trametinib when 
administered in combination
•
PK parameters such as but not limited to Ctrough and Ctroughss 
for PDR001, dabrafenib and trametinib.
5)
To evaluate the prevalence and incidence of immunogenicity
•
ADA prevalence at baseline and ADA incidence on-treatment
6)
To characterize the potential for PD-L1 expression to identify 
subjects with an enhanced response to PDR001 in combination 
with dabrafenib and trametinib versus placebo plus dabrafenib 
and trametinib
•
PFS by investigator’s assessment according to RECIST 1.1 and 
OS in subgroups defined by centrally assessed PD-L1 status.


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The study will continue after the final PFS analysis to further characterize the overall survival for PDR001 in combination with dabrafenib 
and trametinib versus dabrafenib and trametinib, and collect further safety data.


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4
Study design
4.1
Description of study design
This study has been designed as a phase III, multi-center study consisting of 3 parts.
•
Part 1: Safety run-in part (Figure 4-1)
•
Part 2: Biomarker cohort (Figure 4-2)
•
Part 3: Double-blind, randomized, placebo-controlled part (Figure 4-3)
Part 1: Safety run-in (Figure 4-1)
The safety run-in part will determine the recommended regimen of PDR001 in combination 
with dabrafenib and trametinib in previously untreated patients with BRAF V600 mutant 
unresectable or metastatic melanoma (AJCC Cancer Staging edition 7: Stage IIIC/IV).
The safety run-in part will consist of cohorts of approximately 6 newly enrolled subjects who 
will be treated at the specified dose regimen of PDR001 with fixed doses of dabrafenib 150 mg 
BID and trametinib 2 mg QD guided by the Bayesian Logistic Regression Model (BLRM) with 
EWOC criteria to determine the RP3R for part 3. Data from each cohort, including safety and 
PK data, will be reviewed by a Dose Level Review Team (DLRT) consisting of the Novartis 
team including at least one clinician, safety representative, and biostatistician, at least one 
investigator participating in the study who has enrolled subjects into the Safety run-in part of 
the study before the study can proceed to another dose level. The decision of the PDR001 
regimen will be based on the BLRM model with EWOC criteria as well as clinical judgement 
of the DLRT. If dose DL1 is tolerated, then this dosing regimen will be the RP3R. If DL1 is not 
tolerated, then fixed dose combinations will be explored in two parallel cohorts (DL-1a and DL-
1b), enrolling six additional subjects each provided that both dose levels are recommended 
based on results from BLRM with EWOC criteria. For the DL-1b cohort, subjects who do not 
tolerate and discontinue dabrafenib and/or trametinib during the first 4 weeks will be replaced. 
The primary objective of the safety run-in part is to determine the RP3R. At least 6 subjects, 
and up to approximately 18, will be enrolled in this part of the study. The starting dose (DL1) 
for PDR001 in part 1 is 400 mg Q4W in combination with the approved doses for dabrafenib 
and trametinib. DLTs from 2 complete cycles of treatment (28 days per cycle; a total of 56 days) 
will be assessed. Provisional dose levels and guidelines for safety run-in part are detailed in 
Section 6.2.
Part 2: Biomarker cohort (Figure 4-2)
The open-label, biomarker cohort will enroll approximately 20 patients with previously 
untreated BRAF V600 mutant unresectable or metastatic melanoma (AJCC Cancer Staging 
edition 7: Stage IIIC/IV). Part 2 will open when the fourth subject in dose level 1 (DL1) of part 
1 completes approximately 4 weeks of study treatment and less than 3 DLTs have been observed. 
It is possible for additional dosing regimens to be used based on emerging data from part 1, and 
recruitment may be suspended at any time.
Tumor tissue will be collected (1) at baseline, (2) after 2-3 weeks (C1D15 + 1 week window), 
(3) 8-12 weeks after initiation of PDR001 therapy and (4) at disease progression per RECIST 




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Figure 4-2
Part 2: Biomarker cohort overview of study design
Figure 4-3
Part 3: Double blind, randomized, placebo-controlled part overview of 
study design


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4.1.1
Screening phase
The screening phase begins once written informed consent is provided and ends after 28 days 
or when subject receives the first dose (part 1 and 2) or is randomized (part 3), whichever comes 
first.
Subjects must sign an informed consent form (ICF) prior to any study specific screening 
evaluations, within 28 days prior to the first dose of study treatment. Following completion of 
screening procedures and verifying subject eligibility based on assessments, the subject will be 
enrolled via the Interactive Response Technology (IRT) system. Laboratory results from the 
central laboratory will be used to determine subject’s eligibility to the study. However, the site 
does not need to wait for the results of centrally-analyzed laboratory assessments when an 
immediate clinical decision needs to be made and in those cases locally unscheduled testing 
may be performed and used for eligibility assessments. Refer to Section 7.1 for additional 
details.
4.1.2
Treatment phase
The treatment phase begins when the first dose of study treatment is administered to a subject 
and ends at disease progression by RECIST 1.1, unacceptable toxicity, start of a new anti-
neoplastic therapy, pregnancy, withdrawal of consent, lost to follow-up, physician’s decision, 
lost to follow-up, death, or study is terminated by the sponsor.
Subjects may continue study treatment beyond disease progression by RECIST 1.1 until disease 
progression as per response criteria for immunotherapy (if criteria stipulated in Section 6.1.5.1 
are fulfilled), unacceptable toxicity, start of new anti-neoplastic therapy, withdrawal of consent, 
physician’s decision, lost to follow-up, death, or study is terminated by the sponsor. In case of 
continuation of study treatment beyond disease progression by RECIST 1.1, the subject will 
continue tumor assessments as outlined in Section 7.
Part 1: Safety run-in
In the first cohort, 6 subjects will be treated with a fixed dose combination (dose level) of 
dabrafenib 150 mg BID, trametinib 2 mg QD, and PDR001 400 mg Q4W (see Table 6-1). If 
dose DL1 is tolerated, then this dosing regimen will be the RP3R. If DL1 is not tolerated, then 
fixed dose combinations will be explored in two parallel cohorts (DL-1a and DL-1b), enrolling 
six additional subjects each. For the DL-1b cohort, subjects who do not tolerate and discontinue 
dabrafenib and/or trametinib during the first 4 weeks will be replaced.
For each cohort, decisions regarding the dosing regimen of PDR001 will be based upon the 
Investigators and Novartis study personnel after review of the available safety data, as well as 
the recommendations from the BLRM incorporating the EWOC principle.
Part 2: Biomarker cohort
Subjects in the biomarker cohort will receive PDR001 400 mg Q4W in combination with 
dabrafenib 150 mg BID and trametinib 2 mg QD. Based on emerging data from part 1, it is 
possible for additional dosing regimens to be used in this part of the study, and recruitment may 
be suspended at any time. The proposed biomarker sampling timing is optimized to address the 


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modulation of the immune microenvironment and other biomarker endpoints over time with 
treatment.
Part 3: Double-blind, randomized, placebo-controlled part
Subjects will be randomly assigned (1:1) to receive either the RP3R identified in part 1 or 
placebo, dabrafenib 150 mg BID and trametinib 2 mg QD. Randomization will be stratified 
according to LDH level (< 1 x ULN vs. ≥1 to < 2 × ULN vs. ≥ 2 × ULN) and ECOG PS (0 vs. 
1 vs. 2).
Following the final PFS analysis:
•
Unblinding is mandated
•
Patients who have been unblinded may continue on the study
•
Decision on continuation of treatment with PDR001 in combination with dabrafenib and 
trametinib should be made on a case by case basis using medical judgement, individual 
benefit-risk assessment, and upon a documented discussion with the patient.
•
Placebo administrations to those patients randomized to the placebo arm will stop
4.1.3
End of treatment
Subjects should be scheduled for an End of Treatment (EOT) visit within 7 days after 
discontinuation of study treatment due to any reasons (Section 7.1).
4.1.4
Safety follow-up
All subjects will be followed for safety evaluations as outlined in detail in Section 7 and 
Section 3.
4.1.5
Efficacy follow-up 
Prior to the final PFS analysis:
All subjects who discontinue study treatment without disease progression by RECIST 1.1 will 
continue tumor assessments as outlined in Section 7 until documented disease progression by 
RECIST 1.1, withdrawal of consent, lost to follow-up or death irrespective of start of new anti-
neoplastic therapy. 
All subjects who continue treatment beyond disease progression per RECIST 1.1 
(see Section 6.1.5.1) will continue tumor assessments as outlined in Section 7 until confirmed 
progression per response criteria for immunotherapy, unacceptable toxicity, start of new anti-
neoplastic therapy, withdrawal of consent, physician’s decision, lost to follow-up, death or 
study is terminated by sponsor. 
Refer to Section 7.2.1.2 for details on additional tumor assessments to perform in order to 
confirm response or allow for central confirmation.
Following the final PFS analysis:
Efficacy data, other than overall survival, will no longer be collected. 


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All subjects who discontinue study treatment will immediately be followed for safety 
assessments and as part of the overall survival follow-up until death, lost to follow-up, or 
withdrawal of consent as described in Section 7. 
There will not be an efficacy follow-up phase. Standard local medical practice may be applied 
for tumor assessment. There is no requirement to record any tumor assessment results in the 
eCRF and imaging data must not be sent to the central imaging vendor.
Additional required data will be collected such as post-treatment anti-neoplastic therapies. See 
Section 7.2.1 for further details. 
4.2
Timing of interim analyses and design adaptations
An interim PFS analysis with possible early significance claim for efficacy will be conducted 
once approximately 260 PFS events have been observed.
Interim analyses of OS with early significance claim for efficacy will be conducted once 
approximately 260 PFS events (for the interim PFS analysis) have been observed and at the 
time of the final PFS analysis. Refer to Section 4.3, Section 10.4.2 and Section 10.7 for more 
details.
4.3
Definition of end of study
Following the final PFS analysis, which did not demonstrate a significant treatment benefit, the 
study will remain open for further follow-up to collect additional overall survival and safety 
data. Updated safety and descriptive analyses of overall survival will be performed. In the event 
that patients and physicians decide to continue treatment, PFS data will not be collected. 
The study will be closed when all subjects have either died, withdrawn consent, are lost to 
follow-up, or have had at least 5 years of follow-up (measured from the date of randomization).
At the end of the study, every effort will be made to continue provision of  study treatment 
outside this study, in alignment with local regulations, through an alternative setting (e.g., may 
include an extension phase to this study, a separate extension protocol, a rollover protocol, 
provision of the Novartis investigational product in a non-trial setting (known as post-study 
drug supply [PSDS]) when no further safety or efficacy data are required, or any other 
mechanism appropriate for the country (if the study drug is not commercially available and 
reimbursed in the local country)) to subjects who in the opinion of the investigator are still 
deriving clinical benefit from study treatment.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the subject should be seen as soon as possible for the EOT visit and the same assessments should 
be performed as described in Section 7 for a discontinued or withdrawn subject. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the subject’s interests. The investigator will 
be responsible for informing IRBs and/or ECs of the early termination of the trial.


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5
Population
5.1
Subject population
The investigator or designee must ensure that only subjects who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Subjects eligible for inclusion in this study have to meet all of the following criteria:
5.2.1
Specific inclusion criteria for safety run-in (part 1)
1. ECOG performance status ≤ 1
2. Aspartate transaminase (AST) < 2.5× ULN and Alanine transaminase (ALT) < 2.5× ULN
5.2.2
Specific inclusion criteria for biomarker cohort (part 2)
3. ECOG performance status ≤ 2
4. A total of at least two cutaneous or subcutaneous lesions or nodal lesions for tumor sample 
collection. Lesions situated in a previously irradiated area, or an area subject to other loco-
regional therapy (e.g., intralesional injections) cannot be considered for sample collection.
5.2.3
Specific inclusion criteria for double-blind, randomized, placebo-
controlled part (part 3)
5. ECOG performance status ≤ 2
5.2.4
Inclusion criteria for all subjects
6. ≥ 18 years of at the time of informed consent
7. Written informed consent must be obtained prior to any screening procedures
8. Histologically confirmed, unresectable or metastatic melanoma (stage IIIC or IV)
9. BRAF V600 mutation positive melanoma as assessed locally, or if local BRAF testing is 
unavailable, at a Novartis designated central reference laboratory (Section 7.1.2)
10. Measurable disease per RECIST 1.1.
11. Treatment-related toxicities (except alopecia) must ≤ Grade 1 at the time of randomization 
according to CTCAE version 4.03 (NCI 2009)
12. An adequate amount of tumor tissue (archived tumor tissue, or new biopsy if archived 
tissue is not available) must be available at the time of enrollment for central validation of 
BRAF V600 mutation and biomarker assessments (see Section 7.1.2 and Section 7.2.4 for 
testing details and requirements) 
13. Subject has adequate bone marrow and organ function as defined by the following 
laboratory values without continuous supportive treatment (such as blood transfusion, 
coagulation factors and/or platelet infusion, or red/white blood cell growth factor 
administration) as assessed by laboratory for eligibility:
•
Hematological
•
Absolute neutrophil count ≥ 1.5 × 109/L
•
Platelet count ≥ 100 × 109/L


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•
Hemoglobin ≥ 9 g/dL
•
Coagulation
•
PT/INR and PTT ≤ 1.5 x ULN. Subjects receiving anticoagulation treatment may 
be allowed to participate with INR established within the therapeutic range prior 
to randomization
•
Renal
•
Serum creatinine < 1.5 mg/dL
•
Hepatic
•
Total bilirubin ≤ 1.5 x ULN except for subjects with Gilbert’s syndrome who 
may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 
× ULN
•
Aspartate transaminase (AST) < 2.5 × ULN, except for subjects with liver 
metastasis, who are only included if the AST is < 5 × ULN
•
Alanine transaminase (ALT) < 2.5 × ULN, except for subjects with liver 
metastasis, who are only included if the ALT is < 5 × ULN
•
Albumin ≥ 2.5 g/dL
14. Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN) as 
assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
15. Able to swallow and retain oral medication and must not have any clinically significant 
gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome 
or major resection of the stomach or bowels
16. Subjects must avoid consumption of grapefruit, Seville oranges or products containing the 
juice of each during the entire study and preferably 7 days before the first dose of study 
medications, due to potential CYP3A4 interaction with the study medications. Orange 
juice is allowed.
5.3
Exclusion criteria
Subjects eligible for this study must not meet any of the following criteria:
5.3.1
Specific exclusion criteria for safety run-in (part 1)
1. Any history of CNS metastases
5.3.2
Specific exclusion criteria for the biomarker cohort (part 2) and the 
double-blind, randomized, placebo-controlled part (part 3)
2. Clinically active cerebral melanoma metastasis. Subjects with up to three cerebral 
metastases are eligible, if all lesions are stable and have been definitively treated with 
stereotactic radiation therapy, surgery or gamma knife therapy with no evidence of disease 
progression prior to enrollment as assessed by two consecutive assessments ≥ 6 weeks apart 
and have not required steroids for at least ≥ 4 weeks prior to enrollment (physiological doses 
of corticosteroids are allowed).
5.3.3
Exclusion criteria for all subjects
3. Subjects with uveal or mucosal melanoma


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4. Prior systemic anti-cancer treatment (e.g., checkpoint inhibitors, targeted therapy [e.g., 
BRAF and/or MEK inhibitors], chemotherapy, biologic therapy, tumor vaccine therapy, or 
any systemic investigational treatment) for unresectable or metastatic melanoma.
5. Prior loco-regional treatment with intralesional therapy (e.g., talimogene laherparepvec) for 
unresectable or metastatic melanoma in the last 6 month prior to start of study treatment.
6. Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior 
to start of study treatment (e.g., targeted therapy, immunotherapy [e.g., interferon], 
biochemotherapy, tumor vaccine).
7. Radiation therapy ≤ 4 weeks prior to start of study treatment (palliative radiotherapy to bone 
lesions allowed ≤ 2 weeks prior to start of study treatment).
8. Major surgery, open biopsy, or significant traumatic injury ≤ 2 weeks prior to start of study 
treatment. Minor surgical procedures should be completed 7 days prior to start of study 
treatment.
9. Active, known or suspected autoimmune disease or a documented history of autoimmune 
disease, including ulcerative colitis and Crohn’s disease (Subjects with vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement, psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll).
10. Systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any 
immunosuppressive therapy 7 days prior to planned date for first dose of study treatment. 
Topical, inhaled, nasal and ophthalmic steroids are allowed.
11. Current pneumonitis or interstitial lung disease.
12. History of organ transplant requiring use of immunosuppressive medication.
13. Taken an investigational drug ≤ 28 days or ≤ 5 half-lives (minimum 14 days) prior to start 
of study treatment, whichever is shorter.
14. History of severe hypersensitivity reactions to other monoclonal antibodies, which in the 
opinion of the investigator may pose an increased risk of serious infusion reaction.
15. Current use of a prohibited medication.
16. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred 
within 2 years prior to study treatment; completely resected basal cell and squamous cell 
skin cancers and any completely resected carcinoma in situ.
17. Active infection requiring systemic antibiotic therapy within 2 weeks prior to start of study 
treatment.
18. Known history of testing positive for Human Immunodeficiency Virus (HIV) infection. For 
Germany only: testing positive for HIV during screening using a local test. 
19. Subjects with active Hepatitis B infection (HbsAg positive) will be excluded.
Note: Subjects with antecedent of Hepatitis B (anti-HBc positive, HbsAg and HBV-DNA 
negative) are eligible.
20. Subjects with positive test for hepatitis C ribonucleic acid (HCV RNA)
Note: Subjects in whom HCV infection resolved spontaneously (positive HCV antibodies 
without detectable HCV-RNA) or those that achieved a sustained virological response after 
antiviral treatment and show absence of detectable HCV RNA ≥ 6 months (with the use of 


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IFN-free regimes) or ≥ 12 months (with the use of IFN-based regimes) after cessation of 
antiviral treatment are eligible
21. Any medical condition that would, in the investigator’s judgment, prevent the subject’s 
participation in the clinical study due to safety concerns, compliance with clinical study 
procedures or interpretation of study results.
22. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study 
treatment.
23. Uncorrectable 
electrolyte 
abnormalities 
(e.g., 
hypokalemia, 
hypomagnesemia, 
hypocalcemia), or long QT syndrome.
24. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically 
related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
25. Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test within 
72 hours prior to initiating study treatment. Note: Low levels of hCG may also be considered 
a tumor marker, therefore if low hCG levels are detected, another blood sample at least 4 
days later must be taken to assess the kinetics of the increase and transvaginal ultrasound 
must be performed to rule out pregnancy.
26. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy including:
•
Presence of predisposing factors to RVO or central serous retinopathy (e.g., 
uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled 
diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or
•
Visible retinal pathology as assessed by ophthalmic examination that is considered a 
risk factor for RVO or central serous retinopathy such as:
•
Evidence of new optic disc cupping;
•
Evidence of new visual field defects on automated perimetry;
•
Intraocular pressure >21 mmHg as measured by tonometry.
27. Cardiac or cardiac repolarization abnormality, including any of the following:
•
History or current diagnosis of cardiac disease indicating significant risk of safety for 
subjects participating in the study such as uncontrolled or significant cardiac disease, 
including any of the following:
•
Recent (within last 6 months) myocardial infarction (MI)
•
Unstable angina (within last 6 months),
•
Uncontrolled congestive heart failure (CHF)
•
Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree atrioventricular [AV] block 
without a pacemaker).
28. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 150-days after stopping treatment with PDR001/placebo, 2 weeks after 
stopping treatment with dabrafenib or 16 weeks after stopping treatment with trametinib, 
whichever is longer. Highly effective contraception methods include:


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a.
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment.
c.
Male sterilization (at least 6 months prior to screening). The vasectomized male partner 
should be the sole partner for that subject.
d. Placement of a non-hormonal intrauterine device (IUD) or intrauterine system (IUS) 
with a documented failure rate of less than 1% per year.
Notes: 
•
Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault 
caps) with a vaginal spermicidal agent (foam/gel/cream/suppository) are not considered 
highly effective methods of contraception.
•
Hormonal-based methods (e.g., oral contraceptives) are not considered as highly 
effective methods of contraception due to potential drug-drug interactions with 
dabrafenib.
•
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential.
29. Sexually active males unless they use a condom during intercourse while on treatment and 
for 150 days after stopping treatment with PDR001/placebo, 30 days after dabrafenib or 120 
days after trametinib, whichever is longer and should not father a child in this period. A 
condom is required to be used by vasectomized men as well during intercourse in order to 
prevent delivery of the drug via semen.
6
Treatment
6.1
Study treatment
For this study, the investigational drug is PDR001, and the study treatment is PDR001 or 
placebo in combination with dabrafenib 150 mg BID and trametinib 2 mg QD.
PDR001 will be supplied in vial in liquid or powder for solution for infusion pharmaceutical 
form. PDR001 (liquid or reconstituted powder) will be diluted in dextrose 5% in water (D5W). 
Due to incompatibility, 0.9% sodium chloride solution must not be used.
Placebo will be a D5W for infusion supplied by the site. 
Infusion must take place in a facility with appropriate resuscitation equipment available at the 
bedside and a physician readily available during the period of drug administration.


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Trametinib will be provided as 0.5 mg and 2 mg tablets, and dabrafenib as 50 mg and 75 mg 
capsules for oral administration.
All dosages prescribed and dispensed to subjects and all dose changes during the study must be 
recorded on the Dosage Administration Record (DAR) eCRF.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form and 
route of administration
Strength
Frequency 
and/or Regimen
Dose
PDR001
Powder for solution for infusiona 
100 mg
Q4W or Q8W
400 mg
PDR001
Liquid b in vial for i.v. infusion
100 mg
Q4W or Q8W
400 mg
Dabrafenib
Capsules for oral use
50 mg, 75 mg
BID
150 mg BID (300 
mg/day
Trametinib
Tablets for oral use
0.5 mg, 2 mg
QD
2 mg/day
a.
PDR001 powder for solution for infusion formulation will be used in the safety run-in (part 1) and biomarker 
cohort (part 2).
b.
PDR001 liquid formulation may be used for the double-blind, randomized part (part 3) once available.
6.1.1.1
Dosing regimen for Part 1: Safety run-in part
The safety run-in part of the study will determine the regimen of PDR001 in combination with 
dabrafenib and trametinib for the part 3 of the study. The starting dose for DL1 will be PDR001 
400 mg given as an intravenous infusion every 4 weeks, dabrafenib 150 mg orally twice daily 
and trametinib 2 mg orally once daily.
Table 6-2
Part 1 (safety run-in part): Provisional dose levels
Dose level
PDR001 infusion
Dabrafenib capsules 
Trametinib tablets 
Dose level 1 (DL1) a
400 mg Q4W
150 mg BID 
(300 mg/day)
2 mg QD
Dose level 1a (DL-1a)
400 mg Q8W
150 mg BID
(300 mg/day)
2 mg QD
Dose level 1b (DL-1b) b
400 mg Q4W 
(starting at C2D1)
150 mg BID
(300 mg/day)
2 mg QD
a.
Starting dose level. It is possible for additional and/or intermediate dose levels to be added during the 
course of the study based on emerging data.
b.
4 weeks of dabrafenib and trametinib only period followed by addition of 400 mg PDR001 Q4W starting at 
C2D1 (Day 29).


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6.1.1.2
Dosing regimen for Part 2: Biomarker cohort
Table 6-3
Part 2 (biomarker cohort): Dose and treatment schedule
Study treatments
Pharmaceutical form and route of 
administration
Dose
Frequency and/or regimen
PDR001
Powder for solution for infusion in vial 
for i.v. infusion
400 mg
Q4W
Dabrafenib
Capsules for oral use
150 mg
BID (300 mg/day)
Trametinib
Tablets for oral use
2 mg
QD
It is possible for dosing regimens to be added during the course of the study based on emerging data.
6.1.1.3
Dosing regimen for Part 3: Randomized part
The double-blind, randomized, placebo-controlled part of the study will enroll approximately 
500 patients in a 1:1 ratio to the following treatment arms:
•
Arm 1: PDR001 in combination with dabrafenib and trametinib
•
Arm 2: placebo in combination with dabrafenib and trametinib
The study treatment phase begins on C1D1 with the first administration of study treatment. 
Each cycle in both treatment arms is defined as 28 days.
Table 6-4
Part 3 (randomized part): Dose and treatment schedule
Study treatments
Pharmaceutical form and route of 
administration
Dose
Frequency and/or 
regimen
PDR001
Powder for solution for infusion or 
liquid a in vial for i.v. infusion
400 mg
To be determined in 
part 1 (safety run-in)
Dabrafenib
Capsules for oral use
150 mg
BID (300 mg/day)
Trametinib
Tablets for oral use
2 mg
QD
a. PDR001 liquid formulation may be used for the double blind, randomized part (part 3) once available.
6.1.1.4
PDR001 or placebo administration
PDR001 or placebo will be administered via intravenous infusion over 30 minutes (up to 2 
hours, if clinically indicated) once every 4 or 8 weeks as determined in part 1. Subjects should 
be provided instructions to notify study personnel if symptoms of infusion reaction occur after 
any PDR001 infusion. The dose may be interrupted up to 12 weeks. The safety assessments as 
outline in Section 7 should be performed.
Study visits with scheduled PK sampling should be scheduled in the morning so that a pre-dose 
PK blood sample can be collected. Scheduling these visits in the morning is especially important 
for Cycle 1 Day 1 and Cycle 3 Day 1 during which a post-dose (end-of-infusion) PK sample is 
to be collected.
Following final PFS analysis, and subsequent unblinding, placebo administrations to those 
patients randomized to the placebo arm will stop.
If there is a delay due to a logistical issue for administering PDR001 due to COVID-19 
pandemic then the participant should receive the infusion once it is feasible while continuing 


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therapy with dabrafenib and trametinib. Home delivery/administration is generally not 
recommended.
6.1.1.5
Dabrafenib and trametinib administration
Dabrafenib and trametinib will be provided by the sponsor to the investigative site or supplied 
locally as commercially available and labeled accordingly to comply with legal requirements 
of each country.
Dabrafenib and trametinib should be taken as follows:
•
Dabrafenib will be administered orally twice daily (BID) for Days 1-28 of a 28-day cycle.
•
Trametinib will be administered orally once daily (QD) for Days 1-28 of a 28-day cycle.
•
Subjects should be instructed to take the dabrafenib and trametinib concurrently in the 
morning, at approximately the same time every day. The second (evening) dose of 
dabrafenib (150 mg) should be administered approximately 12 (± 4) hours apart from the 
first dose (morning) of dabrafenib.
•
For Part 1, on days of coadministration with PDR001, dabrafenib and trametinib should be 
taken approximately 90 minutes after completion of PDR001 administration.
•
For Parts 2 and 3, on days of coadministration with PDR001, dabrafenib and trametinib 
should be taken prior to the start of infusion with PDR001.
•
Dabrafenib and trametinib should be taken with approximately 120-240 mL of water under 
fasting conditions, at least 1 hour before or 2 hours after a meal.
•
Subjects should be instructed to swallow whole capsules of dabrafenib and not chew or open 
them.
•
If a subject vomits after taking study drug, the subject should be instructed not to retake the 
dose and wait for the next scheduled dose. The occurrence and frequency of any vomiting 
during a treatment cycle must be noted in the AE section of the eCRF.
•
If a subject misses a dose, he/she should be instructed not to double the next regularly 
scheduled dose. However, subject may take the missed dose immediately if the next 
scheduled dose is at least 6 hours later for dabrafenib and 12 hours later for trametinib. 
Subject may then take the next dose at the scheduled time.
•
Subjects must avoid consumption of grapefruit, grapefruit hybrids, pomelos, star-fruit, 
Seville oranges or products containing the juice of each during the entire study and 
preferably 7 days before the first dose of study medications, due to potential CYP3A4 
interaction with the study medications.
•
Orange juice is allowed.
•
No herbal supplements are permitted.
•
Multivitamins are permitted.
During the COVID-19 pandemic that limits or prevents on-site study visits, delivery of 
trametinib and dabrafenib directly to a participant’s home is generally permitted in the event 


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the Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant’s health to administer the study treatment 
even without performing an on-site visit. Implementation will need to be discussed with 
Novartis. The dispatch of study drugs from the site to the participant’s home remains under the 
accountability of the Investigator. Each shipment/provisioning will be for a maximum of 3-
months supply, however the overall duration will be as required until discontinuation criteria 
are met. In this case, regular phone calls or virtual contacts (per existing protocol schedule, or 
more frequently if needed) will occur between the site and the participant for instructional 
purposes, safety monitoring, and discussion of the participant´s health status until the 
participants can again visit the site. 
6.1.2
Ancillary treatments
PDR001
Subjects should not receive pre-medication to prevent infusion reaction before the first infusion 
of study treatment. If a subject experiences an infusion reaction, he/she may receive pre-
medication on subsequent dosing days. The pre-medication should be chosen per institutional 
standard of care, at the discretion of the investigator.
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status. If a subject experiences a Grade 3 anaphylactic/anaphylactoid 
reaction, the subject will be discontinued from the study.
Guidelines on management of infusion reactions are provided in Table 6-20.
The CTCAE v4.03 (...//ctep.cancer.gov) category of “Infusion related reaction” should be used 
to describe study treatment related infusion reactions, unless the investigator considers another 
category, such as “allergic reaction,” “anaphylaxis,” or “cytokine release syndrome” more 
appropriate in a specific situation.
Dabrafenib and trametinib
Not applicable.
6.1.3
Rescue medication
Not applicable.
6.1.4
Guideline for continuation of treatment
Guidelines on management of common PDR001, dabrafenib or trametinib associated toxicities 
and dose modification instructions are provided in Section 6.3.
6.1.5
Treatment duration
Prior to the final PFS analysis:
For all parts, study treatment will continue until the subject experiences one of the following: 
disease progression per investigator’s assessment by RECIST 1.1 (and not meeting the criteria 


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in Section 6.1.5.1), unacceptable toxicity, pregnancy, treatment is discontinued at the discretion 
of the investigator or the subject, start of a new anti-neoplastic therapy, withdrawal of consent, 
lost to follow-up, death, or study is terminated by the sponsor.
Following the final PFS analysis:
Decision on continuation of treatment with PDR001 in combination with dabrafenib and 
trametinib should be made on a case by case basis using medical judgement, individual benefit-
risk assessment, and upon a documented discussion with the patient.
Participants who continue to derive clinical benefit from treatment based on investigator’s 
evaluation will be offered Post-Trial access (PTA). PTA means the provision of treatment to 
trial participants following their completion of this trial (EOT visit will be required prior to 
PTA). PTA will be provided until one of the following criteria are met: participant no longer 
derives clinical benefit, Investigator discontinues treatment, launch or reimbursement (where 
applicable) or the clinical program is discontinued for any other reason.
Mechanisms for provision of PTA may include an extension phase to this study, a separate 
extension protocol, a rollover protocol, managed access program, provision of the Novartis 
investigational product in a non-trial setting (known as post-study drug supply [PSDS]) when 
no further safety or efficacy data are required, or any other mechanism appropriate for the 
country (if the study drug is not commercially available and reimbursed in the local country).
The PTA mechanism must comply with local laws and regulations in the participating trial 
countries. If Novartis discontinues the PTA for this trial, Novartis will work with investigators 
to transition participants onto locally available alternative treatment, or standard of care.
6.1.5.1
Treatment beyond disease progression per RECIST 1.1
All subjects (including placebo arm in the randomized, double blind part 3) will be permitted 
to continue study treatment beyond disease progression per RECIST 1.1 provided they meet all 
the following criteria:
1. Informed consent for treatment beyond disease progression is provided by the subject
2. The continuation of treatment beyond progression will not delay an imminent intervention 
to prevent serious complications of disease progression (e.g., CNS metastases)
3. Subject exhibits adequate tolerance to study treatment
4. Subject remains with stable performance status
Subjects who meet the above criteria should continue study treatment and continue all study 
procedures as outlined in Section 7. Additional informed consent needs to be obtained for 
treatment beyond progression. The reasons for the subject continuing treatment beyond 
progression will be documented in the eCRF.
An additional tumor assessment must be performed to confirm response (CR or PR) no less 
than 4 weeks after the criteria for response are first met.
In case of clinical deterioration or suspicion of disease progression, a follow-up imaging 
assessment should be performed promptly rather than waiting for the next scheduled assessment. 
Subjects can be treated beyond progression until confirmed progression per response criteria 


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for immunotherapy, unacceptable toxicity, start of new anti-neoplastic therapy, withdrawal of 
consent, physician’s decision, lost to follow-up, death or study is terminated by sponsor.
Subsequent to disease progression per RECIST 1.1, at least two additional tumor assessments 
that are at least 4 weeks apart must be performed no less than 4 weeks after criteria for PD per 
RECIST 1.1 are first met. Tumor assessments after start of new anti-neoplastic therapy are 
recommended however not required.
6.2
Determination of recommended regimen for the randomized part 
of the study
6.2.1
Starting dose rationale
The starting dose of PDR001 is 400 mg IV Q4W in combination with 150 mg dabrafenib BID 
and 2 mg trametinib QD. Please refer to Section 2.3 for more details on the dose rationale.
6.2.2
Provisional dose levels
Table 6-5 describes the dose levels that may be evaluated during this trial. For the safety run-in 
period, the BLRM model will consider DLT data from the first 8 weeks of triple combination 
for each tested dose level.
Table 6-5
Provisional dose levels
Dose level 
(DL)
PDR001 IV
Dabrafenib
oral
Trametinib
oral
DLT
observation period
DL1 a
400mg Q4W
150mg BID (300 
mg/day)
2mg QD
8 wks
DL-1a
400mg Q8W
150mg BID (300 
mg/day)
2mg QD
8 wks
DL-1b b
400mg Q4W
starting at C2D1
150mg BID (300 
mg/day)
2mg QD
8 wks
Starting at C2D1
a. Starting dose level. It is possible for additional and/or intermediate dose levels to be added during the course 
of the study based on emerging data.
b. Dabrafenib and trametinib will be administered for 4 weeks initially, followed by addition of PDR001 400 mg 
Q4W at C2D1 (day 29)
6.2.3
Guidelines for determination of recommended regimen for part 3
For the purposes of determining the recommended dosing regimen for PDR001 in combination 
with dabrafenib and trametinib to be used in part 3, each cohort will consist of approximately 6 
newly enrolled subjects who will be treated at the specified dose level. The first cohort will be 
treated with the starting dose of PDR001 400 mg Q4W, dabrafenib 150 mg BID and trametinib 
2 mg QD.
To be considered ‘evaluable’ for dose regimen decisions, subjects must have received at least 
one dose of PDR001, received at least 50% of planned doses of dabrafenib and trametinib, and 
had safety assessments for a minimum of 8 weeks (56 days), or have a DLT within the first 8 
weeks (56 days) of study treatment. Dose regimen decisions will occur when the cohort of 
subjects has met these criteria.


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Dose regimen decisions will be made by Investigators and Novartis study personnel. Decisions 
will be based on a synthesis of all relevant data available from all dose levels evaluated in the 
ongoing study including safety information, DLTs, all CTCAE v4.03 ≥ Grade 2 toxicity data 
during the first 8 weeks (56 days) of triple combination treatment, and pharmacokinetic data 
from evaluable subjects. The recommended dose for the next cohort of subjects will be guided 
by the BLRM with EWOC principle.
The adaptive Bayesian methodology provides an estimate of DLT rates for all dose levels of 
the combination of PDR001, dabrafenib, and trametinib and incorporates all DLT information 
at all dose levels for this estimation.
If the first 2 subjects in a cohort experience a DLT, further enrollment to that cohort will stop, 
the BLRM will be updated with this new information, and re-evaluation of the available safety, 
and pharmacokinetic data will occur. By incorporating information gained at the preceding dose 
levels, additional subjects may be enrolled into the current dose level only if the combination 
still meets the EWOC criteria. Alternatively, if recruitment to the same dose level may not 
resume, a new cohort of subjects may be recruited to a lower dose combination, as agreed by 
Investigators and Novartis personnel, and if the BLRM predicts that the risk for this lower dose 
combination to exceed toxicity remains below 25% (EWOC). Re-escalation may then occur if 
data in subsequent cohorts supports this (EWOC criteria are satisfied) and Investigators and 
Novartis personnel agree.
The recommended dose regimen is identified when the following conditions are met:
1. at least 6 subjects have been treated at this dose and observed for 8 weeks (56 days)
2. this dose satisfies the EWOC criteria
3. the selected regimen is recommended either per the model or by review of all clinical data 
by Novartis and Investigators in a teleconference.
6.2.3.1
Implementation of dose escalation decisions
Not applicable.
6.2.3.2
Intra-patient dose escalation
Not applicable.
6.2.4
Definition of dose limiting toxicities in the safety-run in part (part 1)
A DLT is defined as (1) an adverse event or abnormal laboratory value assessed as unrelated to 
disease, disease progression, inter-current illness, or concomitant medications that occurs 
within the 8 weeks (56 days) of treatment with PDR001 in combination with dabrafenib and 
trametinib and (2) meets any of the predefined criteria in Table 6-6. NCI CTCAE v4.03 
(http/ctep.cancer.gov) will be used for grading of DLTs and adverse events in this protocol.


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Table 6-6
Criteria for defining dose-limiting toxicities
TOXICITY
DLT CRITERIA (NCI CTCAE v4.03 will be used for grading)
Hematological

Grade 4 anemia

Grade 4 neutropenia (for > 7 consecutive days) or Grade 4 febrile neutropenia

Grade 4 thrombocytopenia (of any duration).

Grade 3 thrombocytopenia with clinically significant bleeding regardless of 
duration or requirement of platelet transfusion
Hepato-biliary

Grade 4 bilirubin elevation

For subjects with normal baseline AST and ALT values:

AST or ALT > 8.0 × ULN

For subjects with normal baseline AST and ALT and normal baseline bilirubin 
value:

AST or ALT > 3.0 × ULN combined with total bilirubin > 2.0 × ULN without 
evidence of cholestasis

For subjects with abnormal baseline AST or ALT or abnormal baseline bilirubin 
value:

[AST or ALT > 2 × baseline AND > 3.0 × ULN] OR [AST or ALT > 8.0 x 
ULN], combined with [TBIL > 2 × baseline AND > 2.0 × ULN] without 
evidence of cholestasis
Gastrointestinal

Nausea and vomiting ≥ Grade 3 for > 3 days despite optimal anti-emetic 
therapy.

≥ Grade 3 diarrhea for > 5 days despite optimal antidiarrheal treatment (which 
could include steroids).
Pancreas

Symptomatic serum amylase or lipase elevation, medical intervention required 
(Pancreatitis Grade 3 or higher)
Hypertension

≥ Grade 3 hypertension related to the study medication if it persists > 7 days 
despite optimal anti-hypertensive treatment

Grade 4 hypertension of any duration
Cardiac

≥ Grade 3 cardiac event that is symptomatic or requires medical intervention
Pneumonitis

Grade 2 pneumonitis if it persists > 7 days despite treatment with 
corticosteroids.

≥ Grade 3 pneumonitis of any duration
Immune-related 
toxicities (except 
pneumonitis)

Grade 3 immune-related toxicities that persist > 14 days with same severity 
despite treatment with corticosteroids.

Grade 4 immune related toxicities of any duration

≥ Grade 3 infusion related reaction
Other Adverse Events

Other clinically significant adverse events:

≥ Grade 3 adverse events that has not been previously identified for 
dabrafenib/trametinib and/or PDR001.

≥ Grade 3 AEs that are known to occur with dabrafenib, trametinib and/or 
PDR001, but cannot be controlled using the recommended product-
specific management guidelines or leads to 50% of planned exposure of 
study medications

 Other clinically significant toxicities, including a single event or multiple 
occurrences of the same event that lead to a dosing delay of > 12 weeks 
should be considered to be DLTs by the Investigators and Novartis, even if 
not Grade 3 or higher.


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TOXICITY
DLT CRITERIA (NCI CTCAE v4.03 will be used for grading)
Events which will NOT be considered as DLT for the purpose of this protocol:
•
Clinically insignificant laboratory values ≤ Grade 2. For laboratory values ≥ Grade 3, the maximum 
allowable time limit for correction of electrolyte abnormalities to ≤ Grade 1 is 72 hr.
•
Cutaneous squamous cell carcinoma (CuSCC), basal cell carcinoma, and new primary melanoma which 
are manageable with surgical excision alone
The investigator must notify Novartis within less than 24 hours of any unexpected CTCAE 
v4.03 ≥ Grade 3 AEs or laboratory abnormalities.
Dose modification during DLT observation period
If a subject experiences a DLT, during the DLT observation period, then treatment with 
dabrafenib, trametinib and PDR001 must be interrupted and the subject may be discontinued 
from the study depending on the severity of the DLT. However, following resolution of the 
DLT to CTCAE v4.03 Grade 1 or baseline value, the subject may continue to receive study 
treatment at a reduced dose level, if appropriate, at the discretion of the investigator.
6.3
Dose modifications and reductions
Adverse events of special interest (AESI) include AEs of a potential irAE that are associated 
with PDR001 treatment. An irAE may be experienced by subjects treated with PDR001 due to 
its mechanism of action and predicted based on the reported experience with other 
immunotherapies that have a similar mechanism of action. Investigators must be vigilant and 
carefully identify AEs that may be suggestive of potential irAEs as their appearance may be 
sub-clinical and early diagnosis is critical for its adequate management and resolution.
An irAE is typically low grade and self-limited, often occurring after multiple doses, and most 
frequently involving the GI tract (diarrhea/colitis), skin (rashes), liver (hepatitis), lung 
(pneumonitis), kidneys (nephritis) and endocrine systems (a variety of endocrinopathies) and 
rarely CNS (encephalitis). Serological, immunological and histological assessments should be 
performed as deemed appropriate by the investigator, to verify the potential immune-related 
nature of the AE, and exclude a neoplastic, infectious or metabolic origin of the AE.
Severe grade or persistent lower grade irAEs typically require interrupting or permanently 
discontinuing treatment and administration of systemic steroids or other non-corticosteroid 
immunosuppressive medication when systemic steroids are not effective. Early recognition of 
irAEs and initiation of treatment are critical to reduce the risk of complications, since the 
majority of irAEs are reversible with the use of steroids and other immune suppressants.
In some cases, it may be unclear to determine if an adverse event is immune related or not, thus 
the following dose reduction guidelines should be followed.
The following sections address the specific instructions for mandatory dose modifications and 
recommended management for AEs considered suspected to be related to study treatment. For 
subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions or 
modifications are mandated in order to allow subjects to continue study treatment.
No dose reductions are allowed for PDR001. Dose interruption for PDR001/placebo includes 
delaying or withholding the treatment for any reason as well as an interruption of treatment 
during an infusion. All dose interruptions and the reason for the dose interruption must be 


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recorded on the Dosage Administration Record eCRF. Three dose reductions for dabrafenib 
and two dose reductions for trametinib are permitted. If more dose reductions of dabrafenib and 
trametinib are required, the subject must be permanently discontinued from that specific study 
treatment. Dose modification steps for PDR001 or placebo, dabrafenib and trametinib in 
Table 6-7 must be followed for the AEs presented in Section 6.3.
Table 6-8 provides a list of AEs of special interest and relevant sections where detailed dose 
modification and management requirements for relevant AEs and/or irAEs can be found. All 
AEs are to be graded according to NCI-CTCAE v4.03, unless otherwise specified. Investigators 
should refer to the current PDR001 Investigator’s Brochure and the dabrafenib and trametinib 
local prescribing information for additional information regarding the background of each drug 
and the management of other AEs or potential safety-related issues not specifically mentioned 
in this protocol.
Trial participants with confirmed active COVID-19 infection or presenting with symptoms 
indicative of COVID-19 infection which may include but not limited to fever, cough, difficulty 
breathing, sore throat, pneumonia, loss of sense of smell, or taste or feeling unwell with flu like 
symptoms may interrupt study treatment based on the risk benefit assessment; in case of 
suspected COVID-19 infection, testing for COVID-19 is recommended as per local guidelines.
Should a patient require treatment for COVID-19 infection, the investigator should assess the 
risks and benefits of continued study drug treatment during this time. The investigator may 
consider holding study treatment until the patient is stable to restart because of potential drug 
to drug interaction. Additionally, the concomitant medications are to be documented in the 
relevant eCRF.
Trial participants who have been exposed to someone infected by COVID-19 and/or who 
develop symptoms indicative of potential COVID-19 infection (see above) should contact the 
Investigator and discuss the next steps; these may include self-quarantine, or may require further 
testing/follow-up as appropriate. Administration of the study treatment may be delayed based 
on the risk benefit assessment until the trial participant completes the quarantine and remains 
asymptomatic and/or COVID-19 infection has been ruled out. Investigators are recommended 
to follow the local health authority guidelines for prevention against COVID-19.


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Table 6-7
Dose modification steps for PDR001/placebo, dabrafenib and 
trametinib
Dose modification for PDR001 or placebo a
Starting dose level
Dose level - 1
PDR001 or placebo
400 mg Q4W 
400 mg Q8W (only if DL-1a is 
determined to be the dose regimen)
Not applicable
Dose reduction for dabrafenib a, b
Starting dose level
Dose level - 1
Dose level - 2
Dose level - 3
Dabrafenib
150 mg BID
(300 mg/day)
100 mg BID
(200 mg/day)
75 mg BID
(150 mg/day)
50 mg BID
(100 mg/day)
Dose reduction for trametinib a, b
Starting dose level
Dose level - 1
Dose level - 2
Dose level - 3
Trametinib
2 mg QD
1.5 mg QD
1.0 mg QD
-
Q4W: once in every 4 weeks; BID: twice daily; QD: once daily
a. Dose modification should be based on the worst toxicity demonstrated at the last dose.
b. Dose reduction below 50 mg BID for dabrafenib and 1.0 mg QD for trametinib are not allowed.
Table 6-8
Reference of AEs and toxicity management guidelines
Adverse Events
PDR001
dabrafenib
trametinib
Guideline
Diarrhea/colitis
X
X
X
Section 6.3.3.1
Table 6-9.
Abnormal liver enzyme test
X
X
X
Section 6.3.3.2
Table 6-10.
Skin rash
X
X
X
Section 6.3.3.3
Table 6-11.
Serious skin reaction
X
X
X
Section 6.3.3.4
Nephritis
X
X
X
Section 6.3.3.5
Table 6-12
Pneumonitis
X
X
X
Section 6.3.3.6
Table 6-13
Encephalitis
X
X
X
Section 6.3.3.7
Table 6-14
Endocrine events
X
X
X
Section 6.3.3.8
Table 6-15
Hand foot skin reaction
X
X
X
Section 6.3.3.9
Table 6-16
Neutropenia and thrombocytopenia
X
X
X
Section 6.3.3.10
Table 6-17
Adverse events including abnormal 
laboratory related AEs
X
X
X
Section 6.3.3.11
Table 6-18
Asymptomatic amylase and/or lipase 
elevation
X
X
X
Section 6.3.3.11
Table 6-18
Others
X
X
X
Section 6.3.3.12
Table 6-19
Infusion reaction and cytokine release 
syndrome
X
Section 6.3.4
Table 6-20
General
X
X
Section 6.3.5  
Table 6-21


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Adverse Events
PDR001
dabrafenib
trametinib
Guideline
LVEF
X
X
Section 6.3.5.1
Table 6-22
Hypertension
X
X
Section 6.3.5.2
Table 6-23
New malignancies
X
X
Section 6.3.5.3.
Pyrexia syndrome
X
X
Section 6.3.5.4
Table 6-24
Visual changes
X (Uveitis)
X (RVO)
Section 6.3.5.5
Table 6-25
RPED
X
Section 6.3.5.5
Table 6-26
Hyperglycemia
X
Section 6.3.5.6
Hemorrhage
X
X
Section 6.3.5.7
Thromboembolic events
X
Section 6.3.5.8
Hemophagocytic lymphohistiocytosis
X
X
Section 6.3.5.9
“X” indicates study treatment (s) that may need to be modified. 
6.3.1
General dose modification instructions for PDR001 or placebo
No dose reductions are allowed for PDR001. Dose interruption for PDR001/placebo includes 
delaying or withholding the treatment for any reason as well as an interruption of treatment 
during an infusion. Subjects with adverse events suspected to be related to PDR001 or placebo 
including those of potential immune-mediated etiology (irAE) (see definition in Section 6.3) 
must be permanently discontinued from PDR001 or placebo if (1) the AE doesn’t recover to ≤ 
Grade 1 or baseline within 12 weeks and/or (2) the dose of steroids (for the management of 
irAE) remains > 10 mg/day prednisone or equivalent for >12 weeks. 
The 12 week timeframe will begin from the time the irAE reaches a grade that leads to 
PDR001/placebo interruption.
Subjects who discontinue the study for a study related adverse event or an abnormal laboratory 
value must be followed as described in Section 7.
6.3.2
General dose modification instructions for dabrafenib and trametinib:
If treatment related toxicities occur that are specific to combination treatment of dabrafenib and 
trametinib, then both treatments should be simultaneously dose reduced, interrupted or 
discontinued with the exceptions shown below:
Exception where dose modification is necessary for only dabrafenib:
•
Uveitis (Table 6-25)
Exception where dose modifications are necessary for only trametinib:
•
Retinal vein occlusions (RVO) (Table 6-25) and retinal pigment epithelial detachment 
(RPED) (Table 6-26)
•
Left ventricular ejection fraction (LVEF) reduction (Table 6-22)


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If a subject’s dose of dabrafenib and trametinib has been reduced per the dose modification 
instructions, re-escalation of the subject’s dose is recommended provided the following criteria 
are met:
•
a period of 4 weeks of treatment has passed since restarting dosing at the lower dose level 
and there is no recurrence of the AE
•
the subject is deriving clinical benefit
For dabrafenib and/or trametinib related adverse events: if following an interruption of 
dabrafenib and trametinib, an AE doesn’t recover to ≤ Grade 1 or baseline within 4 weeks, 
dabrafenib and trametinib must be discontinued.
6.3.3
Dose modification and management guideline for adverse events 
common to PDR001, dabrafenib and trametinib
Adverse events that have been reported with PDR001, dabrafenib or trametinib include, but are 
not limited to diarrhea/colitis, abnormal liver enzymes, skin rash, nephritis, pneumonitis, 
encephalitis, and endocrinopathies. It is possible that these and /or other adverse events may be 
exacerbated when PDR001, dabrafenib and trametinib are combined. Therefore, it is important 
to note that the management guidelines for the combination of PDR001, dabrafenib and 
trametinib may differ for a given AE from the management guidelines for each agent or 
combination treatment of dabrafenib and trametinib.
6.3.3.1
Mandatory dose modifications and recommended clinical 
management guidelines for diarrhea/colitis 
Guidelines for dose modification and management for diarrhea and colitis considered to be 
related to study treatment by the investigator are provided in Table 6-9.
Table 6-9
Mandatory dose modifications and recommended clinical 
management guidelines for diarrhea/colitis
CTCAE v4.03
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1 diarrhea (increase of 
<4 stools per day over 
baseline; mild increase in 
ostomy output compared to 
baseline)
OR
Grade 1 colitis 
(asymptomatic;
clinical or diagnostic 
observations only;
intervention not indicated)
OR
Grade 2 diarrhea (increase of 
4 - 6 stools per day over 
baseline; moderate
increase in ostomy output
compared to baseline)
OR
•
Diet: stop all lactose containing 
products; eat small meals, BRAT 
diet (banana, rice, apples, toast)
•
Hydration: 8-10 large glasses of 
clear liquids per day (e.g., 
Gatorade or broth)
•
Loperamide: initially 4 mg, 
followed by 2 mg every four 
hours or after every unformed 
stool; maximum 16 mg/day. 
Continue until diarrhea free for 
12 hours;
•
Diarrhea > 24hr: loperamide 2 
mg every two hours; maximum 
16 mg/day. Consider adding oral 
antibiotics.
•
Diarrhea > 48hr: loperamide 2 
mg every two hours; maximum 
16 mg/day. Consider other 
•
Continue PDR001/placebo, 
dabrafenib and trametinib at the 
same dose level.
•
If diarrhea is Grade 2, despite 
loperamide at 2 mg every two 
hours for > 48hr:
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib 
until ≤ Grade 1, and then 
reinstate PDR001, 
dabrafenib and trametinib at 
the same dose level.


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management guidelines
Mandatory dose modification 
requirements
Grade 2 colitis (abdominal 
pain; mucus or blood in stool)
second-line therapies for 
diarrhea (e.g., octreotide, oral 
diphenoxylate, and oral 
antibiotics)
•
If Grade 2 and no improvement 
in 5 days consider oral steroids
•
If Grade 2 diarrhea persists >1 
week consider gastroenterologist 
consultation and endoscopy to 
evaluate for colitis
•
If Grade 2 persists for 5 days and 
worsening of symptoms or 
diffuse ulcerations and bleeding 
seen on endoscopy, commence 
oral steroids at a dose 0.5 to 1 
mg/kg/day prednisone 
equivalents and continue until 
symptoms improve to Grade 1. If 
no improvement occurs, manage 
as per Grade 3. Steroids can be 
tapered as per Section 6.3.4.1.
•
Lower GI endoscopy and biopsy 
should be considered and may 
assist in determining the duration 
of steroid taper based on the 
evidence of macroscopic and 
microscopic inflammation.
Grade 3 diarrhea (increase of 
≥7 stools per day over 
baseline; incontinence;
hospitalization indicated;
severe increase in ostomy
output compared to baseline; 
limiting self-care ADL)
OR
Grade 3 colitis (severe 
abdominal pain;
change in bowel habits;
medical intervention 
indicated;
peritoneal signs)
•
Clinical evaluation and 
hospitalization mandatory; rule 
out bowel perforation and 
intravenous hydration.
•
Consider consultation with 
gastroenterologist and 
confirmation biopsy with lower GI 
endoscopy.
•
In addition to symptomatic 
treatment (diet, hydration, 
loperamide, antibiotics if 
indicated); initiate immediate 
treatment with intravenous 
steroids (methylprednisolone 
1mg/kg/day) followed by high 
dose oral steroids (1 to 2 
mg/kg/day prednisone 
equivalents)
•
When symptoms improve to ≤ 
Grade 1, steroid taper should be 
started and continued over no 
less than 4 weeks as per 
Section 6.3.4.1.
•
Taper over 6 to 8 weeks in 
subjects with diffuse and severe 
ulceration and/or bleeding.
•
If no improvement in 2-3 days: 
consider initiating infliximab 5 
mg/kg and continue steroids. 
1st occurrence
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until ≤ 
Grade 1, and then reinstate 
PDR001 treatment (after 
appropriate steroid tapering) and 
reduce dabrafenib and trametinib 
to the next lower dose level per 
Table 6-7. Re-escalation of the 
subject’s dose is recommended if 
criteria in Section 6.3.2 are met.
•
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 12 weeks since a grade 
3 event has been identified, 
otherwise PDR001 must be 
permanently discontinued.
2nd occurrence
•
Permanently discontinue 
PDR001/placebo.
•
Interrupt dabrafenib and 
trametinib until ≤ Grade 1, and 
then reduce dabrafenib and 
trametinib to the next lower dose 
per Table 6-7. Re-escalation of 
the subject’s dose is 
recommended if criteria in 
Section 6.3.2 are met.
3rd occurrence


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Mandatory dose modification 
requirements
(Infliximab is contraindicated in 
subjects with sepsis or a 
perforation). Upon symptomatic 
relief initiate a prolonged steroid 
taper over 45 to 60 days.
•
If symptoms worsen during 
steroid reduction, initiate a re-
tapering of steroids starting at a 
higher dose followed by a more 
prolonged taper and administer 
infliximab.
•
If symptoms persist despite the 
above treatment, a surgical 
consult should be obtained.
•
Permanently discontinue 
dabrafenib and trametinib.
Grade 4: Life-threatening
consequences; urgent
intervention indicated
•
Same as Grade 3
•
Permanently discontinue 
PDR001/placebo, dabrafenib and 
trametinib.
6.3.3.2
Mandatory dose modifications and recommended clinical 
management guidelines for abnormal liver enzyme test
Guidelines for dose modification and management of abnormal liver enzyme functions 
considered to be related to study treatment by the investigator are provided in Table 6-10.
In addition to the instructions below, subjects with normal baseline transaminases and bilirubin 
who experience sudden elevations even within Grade 1, should be monitored more closely.
Table 6-10
Mandatory dose modifications and recommended clinical 
management guidelines for abnormal liver enzyme test
Abnormal liver enzyme tests/hepatitis
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 2: AST or ALT >3× 
ULN to ≤ 5× ULN and/or 
bilirubin > 1.5× ULN to ≤ 3× 
ULN
•
Monitor hepatic laboratory tests 
more frequently(every 2-3 days) 
until returned to baseline values
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until ≤ 
Grade 1, and then reinstate 
PDR001/placebo, dabrafenib and 
trametinib at the same dose level.
Grade 3 or 4: AST or ALT > 
5× ULN and/or bilirubin > 3× 
ULN
•
Monitor hepatic laboratory tests 
more frequently (every 2-3 days) 
until return to baseline values.
•
Consider appropriate 
consultation* with hepatologist 
and liver biopsy to establish 
etiology of hepatic injury, if 
necessary
•
If after 2-3 days new liver 
assessment shows worsening of 
laboratory test consider to initiate 
treatment with high dose steroids 
(1 to 2 mg/kg/day prednisone or 
equivalents)
•
Permanently discontinue 
PDR001/placebo only if causality 
is suspected to be related to 
PDR001/placebo **
•
If lab results show worsening, 
follow the management and dose 
modification (instructions below)
1st occurrence
•
Interrupt dabrafenib and 
trametinib until recovery to ≤ 
Grade 1 or baseline
•
Reduce dabrafenib and 
trametinib to the next lower 
dose level per Table 6-7. Re-
escalation of the subject’s 


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Abnormal liver enzyme tests/hepatitis
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
•
Add prophylactic antibiotics for 
opportunistic infections
•
Start steroid taper as outlined in 
Section 6.3.4.1 if symptoms 
improve to Grade ≤1
•
If serum transaminase levels do 
not decrease 48 hours after 
initiation of systemic steroids, oral 
mycophenolate mofetil 500 mg 
every 12 hours may be given.
•
Infliximab is not recommended 
due to its potential for 
hepatotoxicity
dose is recommended if 
criteria in Section 6.3.2 are 
met.
•
If no recovery to ≤ Grade 2 
within 10 weeks, 
permanently discontinue 
dabrafenib and trametinib.
2nd occurrence
•
Interrupt dabrafenib and 
trametinib until ≤ Grade 1.
•
Reduce dabrafenib and 
trametinib to the next lower 
dose level per Table 6-7. Re-
escalation of the subject’s 
dose is recommended if 
criteria in Section 6.3.2 are 
met.
3rd occurrence
•
Permanently discontinue 
dabrafenib and trametinib
*Rule out viral hepatitis and other potential causes of liver injury
**For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increase by ≥ 
50% relative to baseline and last for at least 1 week then the patient should be discontinued
Note: For additional information on follow-up of potential drug induced liver injury cases, refer to 
Section 6.3.6.2.
6.3.3.3
Mandatory dose modifications and recommended clinical 
management guidelines for skin rash 
Guidelines for dose modification and management of skin rash considered to be related to study 
treatment by the investigator are provided in Table 6-11.
Table 6-11
Mandatory dose modifications and recommended clinical 
management guidelines for rash
Rash Events (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1: Rash covering < 
10% body surface area
•
Initiate prophylactic and 
symptomatic treatment 
measures.
•
Consider use of topical 
corticosteroids or urea containing 
creams in combination with oral 
antipruritics or moderate strength 
topical steroid (hydrocortisone 
2.5% cream or fluticasone 
propionate 0.5% cream)
•
Reassess after 2 weeks
•
Continue PDR001/placebo, 
dabrafenib and trametinib at the 
same dose.
Grade 2: 10-30% of body 
surface area
•
If tolerable, as per Grade 1
•
If tolerable, continue 
PDR001/placebo, dabrafenib and 
trametinib at the same dose.


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Rash Events (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
•
If intolerable, initiate systemic 
steroids (0.5 to 1 mg/kg/day 
prednisone or equivalents)
•
If symptoms persist or recur 
consider skin biopsy.
•
If intolerable:
1st occurrence
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until ≤ 
Grade 1, and then reinstate 
PDR001 treatment (after 
appropriate steroid tapering) and 
reduce dabrafenib and trametinib 
to the next dose level per 
Table 6-7. Re-escalation of the 
subject’s dose is recommended if 
criteria in Section 6.3.2 are met.
•
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 12 weeks since a 
Grade 3 event has been 
identified, otherwise PDR001 
must be permanently 
discontinued.
Grade 3: More than 30% of 
body surface area
•
Obtain a skin biopsy and 
dermatology consult.
•
Initiate therapy with high dose 
steroids (1 to 2 mg/kg/d 
prednisone or equivalents)
1st occurrence
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until ≤ 
Grade 1, and then reinstate 
PDR001 treatment (after 
appropriate steroid tapering), and 
reduce dabrafenib and trametinib 
to the next dose level per 
Table 6-7. Re-escalation of the 
subject’s dose is recommended if 
criteria in Section 6.3.2 are met.
•
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 12 weeks since a grade 
3 event has been identified, 
otherwise PDR001 must be 
permanently discontinued.
2nd occurrence
•
Permanently discontinue 
PDR001/placebo.
•
Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline. Once recovered, 
reduce dabrafenib and trametinib 
to the next dose level per 
Table 6-7. Re-escalation of the 
subject’s dose is recommended if 
criteria in Section 6.3.2 are met.
3rd occurrence
•
Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline. Once recovered, 
reduce dabrafenib and trametinib 
to the next dose level per 
Table 6-7. Re-escalation of the 


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Rash Events (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
subject’s dose is recommended if 
criteria in Section 6.3.2 are met.
4th occurrence
•
Permanently discontinue 
PDR001/placebo, dabrafenib and 
trametinib.
Grade 4: Life-threatening
•
Same as Grade 3
•
Permanently discontinue 
PDR001/placebo, dabrafenib and 
trametinib.
6.3.3.4
Mandatory dose modifications and recommended clinical 
management of serious skin reactions 
Withhold trametinib for intolerable or severe skin toxicity. Resume trametinib at reduced doses 
in subjects with improvement or recovery from skin toxicity within 3 weeks. In cases of 
Stevens-Johnson syndrome and toxic epidermal necrolysis, permanently discontinue dabrafenib, 
trametinib and PDR001 and institute supportive care as per institutional guidelines.
6.3.3.5
Mandatory dose modifications and recommended clinical 
management guidelines for nephritis 
 Guidelines for does modification and management of nephritis considered to be related to study 
treatment by the investigator are provided in Table 6-12.
Table 6-12
Mandatory dose modifications and recommended clinical 
management guidelines for renal function alterations
NCI-CTCAE v4.03
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1 (Creatinine > ULN to 
≤ 1.5× ULN)
•
Monitor creatinine weekly
•
If creatinine return to baseline 
resume routine creatinine 
monitoring per protocol
•
Promote hydration and cessation 
of nephrotoxic drugs.
•
Continue PDR001/placebo, 
dabrafenib and trametinib at the 
same dose.
Grade 2 (Creatinine > 1.5× to 
≤ 3× ULN
•
Monitor creatinine every 2 to 3 
days
•
Initiate 0.5 to 1 mg/kg/day 
prednisone equivalents
•
If worsening or no improvement: 
increase to 1 to 2 mg/kg/day 
prednisone equivalents
•
Consult with specialist and 
consider renal biopsy 
•
Promote hydration and cessation 
of nephrotoxic drugs.
1st occurrence
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until ≤ 
Grade 1 or baseline and then 
reinstate PDR001 treatment and 
dabrafenib and trametinib at the 
same dose.
•
AE resolution to ≤ Grade 1 must 
occur within a period of 12 
weeks since Grade 2 event has 
been identified. Otherwise, 
PDR001/placebo must be 
permanently discontinued.
2nd occurrence:


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Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
•
Permanently discontinue 
PDR001/placebo.
•
Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline. Once recovered, 
reduce dabrafenib and trametinib 
to the next dose level per 
Table 6-7. Re-escalation of the 
subject’s dose is recommended 
if criteria in Section 6.3.2 are 
met.
3rd occurrence:
•
Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline. Once recovered, 
reduce dabrafenib and trametinib 
to the next dose level per 
Table 6-7. Re-escalation of the 
subject’s dose is recommended 
if criteria in Section 6.3.2 are 
met.
4th occurrence
•
Permanently discontinue 
dabrafenib and trametinib.
Grade 3 (Creatinine > 3.0 to < 
6×ULN)
•
Monitor creatinine every 1 to 2 
days.
•
Start 1 to 2 mg/kg/day 
prednisone equivalents
•
Consult with nephrologist. 
•
Promote hydration and cessation 
of nephrotoxic drugs.
1st occurrence:
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until ≤ 
Grade 1 or baseline and then 
reinstate PDR001 then reduce 
dabrafenib and trametinib to the 
next lower dose per Table 6-7. 
Re-escalation of the subject’s 
dose is recommended if criteria 
in Section 6.3.2 are met.
•
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 12 weeks since the 
Grade 3 event has been 
identified, otherwise 
PDR001/placebo must be 
permanently discontinued
2nd occurrence:
•
Permanently discontinue 
PDR001/placebo.
•
Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline and then reduce 
dabrafenib and trametinib to the 
next lower dose per Table 6-7. 
Re-escalation of the subject’s 
dose is recommended if criteria 
in Section 6.3.2 are met.
3rd occurrence:


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Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
•
Interrupt dabrafenib and 
trametinib until ≤ Grade 1 or 
baseline and then reduce 
dabrafenib and trametinib to the 
next lower dose per Table 6-7. 
Re-escalation of the subject’s 
dose is recommended if criteria 
in Section 6.3.2 are met.
4th occurrence:
•
Permanently discontinue 
dabrafenib and trametinib.
Grade 4: Creatinine > 6× ULN
•
Monitor creatinine daily.
•
Initiate steroids with 1 to 2 
mg/kg/day prednisone 
equivalents
•
Consult with specialist and 
recommend renal biopsy. 
•
Promote hydration and cessation 
of nephrotoxic drugs.
•
Permanently discontinue 
PDR001/placebo, dabrafenib 
and trametinib.
6.3.3.6
Mandatory dose modifications and recommended clinical 
management guidelines for pneumonitis 
Guidelines for dose modification and management of pneumonitis considered to be related to 
study treatment by the investigator are provided in Table 6-13.
Table 6-13
Mandatory dose modifications and recommended clinical 
management guidelines for pneumonitis
Pneumonitis (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1: Radiographic 
changes only- 
Asymptomatic
•
CT scan (high-resolution with 
lung windows) recommended, 
with serial imaging to monitor for 
resolution or progression- re-
image at least every 3 weeks
•
Monitor for symptoms every 2-3 
days - Clinical evaluation and 
laboratory work-up for infection
•
Monitoring of oxygenation via 
pulse oximetry recommended
•
Consultation of pulmonologist 
recommended.
•
Continue dabrafenib and trametinib 
at the same dose.
•
Interrupt PDR001/placebo, until 
recovery to baseline.
•
Once recovered, reinitiate 
PDR001/placebo at the same 
schedule.
•
If worsens, treat as Grade 2 or 
3-4.
•
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 12 weeks since Grade 
1 event has been identified, 
otherwise PDR001 /placebo 
must be permanently 
discontinued
Grade 2: Symptomatic-
medical intervention 
indicated; limits 
instrumental ADLs
•
CT scan (high-resolution with 
lung windows)
1st occurrence:
•
Interrupt PDR001/placebo, and 
trametinib until recovery to ≤ Grade 


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Pneumonitis (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
•
Monitor symptoms daily, 
consider hospitalization
•
Clinical evaluation and 
laboratory work up for infection
•
Consult pulmonologist
•
Pulmonary function tests - if 
normal at baseline, repeat every 
8 weeks
•
Bronchoscopy with biopsy 
and/or BAL recommended
•
Symptomatic therapy including 
corticosteroids if clinically 
indicated (systemic 
corticosteroids at a dose of 1 to 
2 mg/kg/day prednisone or 
equivalent as clinically 
indicated).
1 or baseline. Dabrafenib may 
continue at the same dose.
•
Once recovered, reinstate 
PDR001/placebo at same 
schedule and reduce trametinib 
to the next lower dose per 
Table 6-7. Re-escalation of the 
subject’s dose is recommended 
if criteria in Section 6.3.2 are 
met.
•
If no recovery to ≤ Grade 1 
within 4 weeks, permanently 
discontinue trametinib. 
Dabrafenib may continue.
•
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 12 weeks since Grade 
2 event has been identified, 
otherwise.PDR001/placebo 
must be permanently 
discontinued.
•
If worsens treat as Grade 3 or 4.
2nd occurrence:
•
Permanently discontinue 
PDR001/placebo.
•
Interruption of trametinib until 
recovery to Grade 1 or baseline. 
Dabrafenib may continue at the 
same dose.


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Pneumonitis (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 3: Severe 
symptoms; limits self-care 
ADLs; oxygen indicated
•
CT scan (high-resolution with 
lung windows)
•
Clinical evaluation and 
laboratory work-up for infection
•
Consult pulmonologist
•
Pulmonary function tests-if < 
normal, repeat every 8 weeks 
until ≥ normal
•
Bronchoscopy with biopsy 
and/or BAL if possible
•
Treat with intravenous steroids 
(methylprednisolone 125 mg) as 
indicated. When symptoms 
improve to ≤ Grade 1, a high 
dose oral steroid (prednisone 1 
to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 
hours).
•
If IV steroids followed by high 
dose oral steroids does not 
reduce initial symptoms within 
48 to 72 hours, consider non-
corticosteroid 
immunosuppressive medication 
(e.g., infliximab, 
cyclophosphamide, IVIG or 
mycophenolate mofetil).
•
Permanently discontinue 
PDR001/placebo.
•
Interrupt trametinib until recovery to 
Grade ≤1 or baseline. Dabrafenib 
may continue.
•
Once recovered, trametinib may 
be restarted at the next lower 
dose per Table 6-7. Re-
escalation of the subject’s dose 
is recommended if criteria in 
Section 6.3.2 are met.
•
If no recovery to Grade ≤ 1 or 
baseline within 4 weeks, 
permanently discontinue 
trametinib. Dabrafenib may 
continue.
Grade 4: Life- threatening 
respiratory compromise
•
Same as Grade 3
•
Same as Grade 3
6.3.3.7
Mandatory dose modifications and recommended clinical 
management guidelines for encephalitis 
Guidelines for dose modification and management of encephalitis considered to be related to 
study treatment by the investigator are provided in Table 6-14.
Table 6-14
Mandatory dose modifications and recommended clinical 
management guidelines for encephalitis
Encephalitis
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1: Asymptomatic or 
mild symptoms
•
Continue PDR001/placebo, 
dabrafenib and trametinib at the 
same dose.


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Encephalitis
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 2: New onset of 
moderate symptoms, limiting 
instrumental ADL
•
Consider consulting with 
neurologist
•
Treat with 0.5 to 1 mg/kg/day 
prednisone equivalents
1st occurrence:
•
Interrupt PDR001/placebo, until 
recovery to ≤ Grade 1 or 
baseline.
•
Once recovered, restart 
PDR001/placebo at the 
same dose.
•
AE resolution to ≤ Grade 1 
or baseline must occur within 
a period of 12 weeks since 
Grade 2 event has been 
identified, otherwise 
PDR001/placebo must be 
permanently discontinued.
If it worsens, treat as Grade 3 – 
4.
2nd occurrence:
•
Permanently discontinue 
PDR001/placebo.
•
Continue dabrafenib and 
trametinib at the same dose.
3rd occurrence:
•
Permanently discontinue 
dabrafenib and trametinib.
Grade 3 or 4: New onset of 
severe symptoms, limiting 
self-care ADL, life-threatening
•
Recommend consultation with 
neurologist.
•
Treat with 1 to 2 mg/kg/day 
prednisone equivalents.
1st occurrence:
•
Permanently discontinue 
PDR001/placebo.
•
Interrupt dabrafenib and 
trametinib until recovery to ≤ 
Grade 1 or baseline. Once 
recovered, reduce dabrafenib 
and trametinib at the next dose 
level per Table 6-7. Re-
escalation of the subject’s dose is 
recommended if criteria in 
Section 6.3.2 are met.
2nd occurrence:
•
Permanently discontinue 
dabrafenib and trametinib.


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6.3.3.8
Mandatory dose modifications and recommended clinical 
management guidelines for endocrine events 
Guidelines for does modification and management of endocrine events considered to be related 
to study treatment by the investigator are provided in Table 6-15.
Table 6-15
Mandatory dose modifications and recommended clinical 
management guidelines for endocrine events
Endocrine events (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Asymptomatic, intervention 
not indicated (hyperthyroidism 
or hypothyroidism)
•
If TSH <0.5x LLN, or TSH >2x ULN, 
or consistently out of range in 2 
subsequent measurements, include 
free T4 at subsequent cycles as 
clinically indicated
•
Consider endocrinologist consult
•
If hypophysitis is considered, 
pituitary gland imaging should be 
considered (MRIs with gadolinium 
and selective cuts of the pituitary can 
show enlargement or heterogeneity 
and confirm the diagnosis)
•
Repeat labs in 1 to 3 weeks/MRI in 1 
month if laboratory abnormalities 
persist but normal lab/pituitary scan
•
Continue PDR001/placebo, 
dabrafenib and trametinib at 
the same dose.
Symptomatic endocrinopathy 
(e.g., hypophysitis, adrenal 
insufficiency, hypothyroidism, 
hyperthyroidism)
•
Consider Endocrinology consultation
•
Rule out infection and sepsis with 
appropriate cultures and imaging
•
Treat with an initial dose of 
methylprednisolone 1 to 2 mg/kg 
intravenously followed by oral 
prednisone 1 to 2 mg/kg per day.
•
Replacement of appropriate 
hormones may be required as the 
steroid dose is tapered
•
Hypophysitis with clinically significant 
adrenal insufficiency and 
hypotension, dehydration, and 
electrolyte abnormalities (such as 
hyponatremia and hyperkalemia) 
constitutes adrenal crisis
•
Consider hospitalization and 
intravenous methylprednisolone 
should be initiated.
1st occurrence:
•
Interrupt PDR001/placebo, 
until symptomatic recovery to 
mild or no symptoms.
•
Once recovered, restart 
PDR001/placebo.
•
AE resolution to mild or 
no symptoms must 
occur within a period of 
12 weeks since 
symptomatic 
endocrinopathy event 
has been identified, 
otherwise 
PDR001/placebo must 
be permanently 
discontinued.
2nd occurrence:
•
Permanently discontinue 
PDR001/placebo and may 
continue dabrafenib and 
trametinib at the same dose.


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6.3.3.9
Mandatory dose modifications and recommended clinical 
management guidelines for hand-foot reaction (palmar-plantar 
erythrodysesthesia)
In general, management of hand-foot skin reactions include:
•
Prevention/prophylaxis: promote sunscreen use and avoidance of unnecessary sun exposure, 
use alcohol-free emollient creams, topical steroids and antibiotics as needed.
•
Pruritic lesions: cool compresses and oral antihistamines
•
Fissuring lesions: Monsel’s solution, silver nitrate or zinc oxide cream
•
Desquamation: thick emollients and mild soap
•
Paronychia: antiseptic bath, local potent corticosteroids, antibiotics, surgery as needed
•
Infected lesions: topical or systemic antibiotics
•
Measures for PPES should include:
•
Lifestyle modification: avoidance of hot water, traumatic activity, constrictive footwear, 
or excessive friction on the skin and the use of thick cotton socks and gloves, and shoes 
with padded insoles
•
Symptomatic treatments: apply moisturizing creams frequently, topical keratolytics 
(e.g., urea 20-40% cream, salicylic acid 6%, tazarotene 0.1% cream, fluorouracil 5% 
cream), clobetasol propionate 0.05% ointment for erythematous areas, topical lidocaine 
2%, and / or systemic pain medication such as nonsteroidal anti-inflammatory drugs, 
codeine, and pregabalin for pain.
Guidelines for does modification for hand foot skin reaction considered to be related to study 
treatment by the investigator are provided in Table 6-16.
Table 6-16
Mandatory dose modifications and recommended clinical 
management guidelines for hand foot skin reaction (palmar-plantar 
erythrodysesthesia)
Hand foot skin reaction
Grade
Recommended adverse 
event management 
guidelines
Mandatory dose modification requirements
Grade 1: Numbness, 
dysesthesia, paresthesia, 
tingling, painless swelling, 
erythema or discomfort of 
the hands or feet which 
does not disrupt the 
subject’s normal activities
•
Recommend topical 
therapy for symptomatic 
relief.
•
Continue PDR001/placebo, dabrafenib and 
trametinib at the same dose.


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Hand foot skin reaction
Grade
Recommended adverse 
event management 
guidelines
Mandatory dose modification requirements
Grade 2: Painful erythema 
and swelling of the hands 
or feet and/or discomfort 
affecting the subject’s 
normal activities
•
Recommend topical 
therapy for symptomatic 
relief
•
Continue treatment and if no improvement 
within 7 days, see below.
•
No improvement within 7 days or 2nd 
or 3rd occurrence:
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until 
toxicity resolves to ≤ Grade 1 or 
baseline.
•
Reduce dabrafenib and trametinib 
at the next lower dose per 
Table 6-7. Re-escalation of the 
subject’s dose is recommended if 
criteria in Section 6.3.2 are met.
4th occurrence:
•
Discontinue PDR001/placebo, dabrafenib 
and trametinib.
Grade 3: Moist 
desquamation, ulceration, 
blistering or severe pain of 
the hands or feet, or 
severe discomfort that 
causes the subject to be 
unable to work or perform 
activities of daily living
•
Recommend topical 
therapy for symptomatic 
relief
1stoccurrence:
•
Interrupt PDR001/placebo, dabrafenib and 
trametinib until toxicity resolves to ≤ Grade 
1 or baseline.
•
Once recovered, reinstate 
PDR001/placebo, and reduce dabrafenib 
and trametinib to the next dose level per 
Table 6-7. Re-escalation of the subject’s 
dose is recommended if criteria in 
Section 6.3.2 are met.
2nd occurrence:
•
Interrupt PDR001/placebo, dabrafenib and 
trametinib until toxicity recovers to ≤ Grade 
1 or baseline.
•
Once recovered, reinstate 
PDR001/placebo, and reduce 
dabrafenib and trametinib to the next 
dose level per Table 6-7. Re-
escalation of the subject’s dose is 
recommended if criteria in 
Section 6.3.2 are met.
3rd occurrence:
•
Discontinue PDR001/placebo, dabrafenib 
and trametinib.


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6.3.3.10 Mandatory dose modifications and recommended clinical 
management guidelines for neutropenia and thrombocytopenia
Guidelines for dose modification for neutropenia and thrombocytopenia suspected to be related 
to study treatment by the investigator are provided in Table 6-17.
Table 6-17
Mandatory dose modifications and recommended clinical 
management guidelines for neutropenia and thrombocytopenia
Neutropenia and thrombocytopenia suspected AEs (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Neutropenia
Grade 1, 2
NA
•
Continue PDR001/placebo, 
dabrafenib and trametinib at the 
same dose.
Grade 3, 4
•
Monitor blood test more 
frequently (every 7 days for 
Grade 3, and 3-5 days for Grade 
4).
1st occurrence:
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until 
toxicity recovers to ≤ Grade 2 or 
baseline.
•
Restart PDR001/placebo at 
the same regimen, and 
reduce dabrafenib and 
trametinib at the next dose 
level. Re-escalation of the 
subject’s dose is 
recommended if criteria in 
Section 6.3.2 are met.
2nd occurrence:
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until 
toxicity recovers to ≤ Grade 2 or 
baseline.
•
Restart PDR001/placebo at 
the same regimen, and 
reduce dabrafenib and 
trametinib at the next dose 
level. Re-escalation of the 
subject’s dose is 
recommended if criteria in 
Section 6.3.2 are met.
•
AE resolution to ≤ Grade 2 or 
baseline must occur within a 
maximum period of 12 weeks 
since Grade 3 or 4 event has 
been identified, otherwise 
PDR001/placebo must be 
permanently discontinued.
3rd occurrence:
•
Permanently discontinue 
PDR001/placebo and interrupt 
dabrafenib and trametinib until 
toxicity recovers to ≤ Grade 2 or 
baseline.


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Neutropenia and thrombocytopenia suspected AEs (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
•
Once recovered, reduce 
dabrafenib and trametinib to 
the next dose level. Re-
escalation of the subject’s 
dose is recommended if 
criteria in Section 6.3.2 are 
met.
4th occurrence:
•
Permanently discontinue 
dabrafenib and trametinib
Febrile Neutropenia
•
Apply Institutional guidelines
•
Follow modification guide for 
neutropenia Grade 4 (above).
Thrombocytopenia
Grade 1, 2, 3 without 
clinically significant bleeding
•
Grade 3: monitor blood test more 
frequently (every 7 days)
•
Continue PDR001/placebo, 
dabrafenib and trametinib at the 
same dose.
Grade 3 with clinically 
significant bleeding
Grade 4
•
Grade 3: monitoring blood test 
more frequently (every 3-5 days)
1st occurrence:
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until 
toxicity resolves to ≤ Grade 2 or 
baseline.
•
Restart PDR001/placebo, 
dabrafenib and trametinib at 
same dose.
2nd occurrence:
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until 
toxicity resolves to ≤ Grade 2 or 
baseline.
•
Restart dabrafenib and 
trametinib at the next lower 
dose per Table 6-7 and 
restart PDR001/placebo. Re-
escalation of the subject’s 
dose is recommended if 
criteria in Section 6.3.2 are 
met.
•
AE resolution to ≤ Grade 2 or 
baseline must occur within a 
maximum period of 12 weeks 
since Grade 3 with clinically 
significant bleeding or Grade 
4 event has been identified, 
otherwise PDR001/placebo 
must be permanently 
discontinued.
3rd occurrence:
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until 
toxicity resolves to ≤ Grade 2 or 
baseline.
•
Restart dabrafenib and 
trametinib at another lower 


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Neutropenia and thrombocytopenia suspected AEs (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
dose per Table 6-7. Re-
escalation of the subject’s 
dose is recommended if 
criteria in Section 6.3.2 are 
met.
4th occurrence:
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until 
toxicity resolves to ≤ Grade 2 or 
baseline.
•
Permanently discontinue 
dabrafenib and trametinib.
6.3.3.11 Mandatory dose modifications and recommended clinical 
management guidelines for adverse events including abnormal 
laboratory related AEs
Guidelines for dose modification for adverse events including abnormal laboratory related AEs 
suspected to be related to study treatment by the investigator are provided in Table 6-18.
Table 6-18
Mandatory dose modifications and recommended clinical 
management guidelines for adverse events including abnormal 
laboratory related AEs
Non-Hematologic AEs (except Grade 2 alopecia, Grade 2 fatigue) and abnormal laboratory related AEs 
(except neutropenia, thrombocytopenia) (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1-2 tolerable
•
Monitor closely.
•
Provide supportive care 
according to institutional 
standards.
•
Continue PDR001/placebo, dabrafenib 
and trametinib at the same dose.


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Non-Hematologic AEs (except Grade 2 alopecia, Grade 2 fatigue) and abnormal laboratory related AEs 
(except neutropenia, thrombocytopenia) (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 2 intolerable or
Grade 3
•
Monitor closely
•
Provide supportive care 
according to institutional 
standards
1st or 2nd occurrence:
•
Interrupt PDR001/placebo, dabrafenib 
and trametinib until toxicity recovers to ≤ 
Grade 1 or baseline.
•
Restart PDR001/placebo, 
dabrafenib and trametinib at the 
same dose.
•
AE resolution to ≤1 Grade or 
baseline must occur within a 
maximum period of 12 weeks since 
intolerable Grade 2 or Grade 3 
event has been identified, otherwise 
PDR001 must be permanently 
discontinued.
3rd occurrence:
•
Permanently discontinue 
PDR001/placebo. Interrupt dabrafenib 
and trametinib until toxicity recovers to ≤ 
Grade 1 or baseline.
•
Restart dabrafenib and trametinib at the 
next lower dose per Table 6-7. Re-
escalation of the subject’s dose is 
recommended if criteria in Section 6.3.2 
are met.
4th occurrence:
•
Permanently discontinue dabrafenib and 
trametinib.


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Non-Hematologic AEs (except Grade 2 alopecia, Grade 2 fatigue) and abnormal laboratory related AEs 
(except neutropenia, thrombocytopenia) (NCI-CTCAE v4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 4
•
Monitor closely
•
Provide supportive care 
according to institutional 
standards
1st occurrence:
•
Interrupt PDR001/placebo and 
dabrafenib and trametinib.
•
Permanently discontinue 
PDR001/placebo. If benefit risk 
assessment support treatment 
continuation, re-start PDR001/placebo. 
Dabrafenib and trametinib may be 
reinitiated at the next lower dose per 
Table 6-7. Re-escalation of the subject’s 
dose is recommended if criteria in 
Section 6.3.2 are met. 
•
For asymptomatic amylase and/or 
lipase* elevation, if AE resolves to ≤ 
Grade 1 or baseline within 4 weeks, 
subject can resume treatment with 
PDR001/placebo, otherwise 
PDR001/placebo must be permanently 
discontinued. 
2nd occurrence:
•
Permanently discontinue 
PDR001/placebo, dabrafenib and 
trametinib.
•
For asymptomatic amylase and/or 
lipase* elevation, if AE resolves to ≤ 
Grade 1 or baseline within 4 weeks, 
subject can resume treatment with 
PDR001/placebo only if subject is 
deriving benefit and after approval by 
both the investigator and the Medical 
Monitor, otherwise PDR001/placebo 
must be permanently discontinued. 
Dabrafenib and trametinib may be 
reinitiated at the next lower dose per 
Table 6-7. Re-escalation of the subject’s 
dose is recommended if criteria in 
Section 6.3.2 are met.
•
Asymptomatic amylase and/or lipase 
elevation in the absence of clinical 
evidence of pancreatitis. This includes 
negative radiographic evaluation as well 
as absence of clinical symptoms of 
pancreatitis.
6.3.3.12 Mandatory dose modifications and recommended clinical 
management guidelines for other adverse events of special interest 
Guidelines for mandatory dose modifications and clinical management of “other” AEs are 
provide in Table 6-19. Under the category of “other” are several AEs of special interest that 
must be managed specifically. “Other” AEs included in this section are: autoimmune 
neuropathy, demyelinating polyneuropathy, Guillain-Barre, myasthenia Gravis-like syndrome, 


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non-infectious myocarditis, non-infectious pericarditis, pancreatitis and, rapid onset of Grade 3 
fatigue in the absence of disease progression.
Table 6-19
Mandatory dose modifications and recommended clinical 
management guidelines for other AEs of special interest
Other: Autoimmune neuropathy, demyelinating polyneuropathy, Guillane-Barré, Myasthenia Gravis- 
like syndrome, Non-infectious myocarditis, pericarditis, pancreatitis (for asymptomatic amylase and/or 
lipase elevations refer to Table 6-18), and Grade 3 Fatigue with rapid onset in absence of disease 
progression
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Mild (Grade 1)
•
Provide symptomatic treatment
•
Continue PDR001/placebo, 
dabrafenib and trametinib at the 
same dose.
Moderate (Grade 2) or Grade 
1 that does not improve with 
symptomatic treatment
•
Provide symptomatic treatment.
•
Systemic corticosteroids may be 
indicated.
•
Recommend biopsy for 
confirmation of diagnosis.
•
A specialist should be consulted.
1st occurrence:
•
Interrupt PDR001/placebo and 
dabrafenib and trametinib until 
recovery to ≤ Grade 1 or 
baseline.
•
Restart PDR001/placebo at 
the same schedule.
•
Continue dabrafenib and 
trametinib at the same 
dose.
•
AE resolution to ≤ Grade 1 
or baseline must occur 
within a period of 12 weeks 
since event has been 
identified, otherwise 
PDR001/placebo must be 
permanently discontinued.
2nd occurrence:
•
Permanently discontinue 
PDR001/placebo.
•
Interrupt dabrafenib and 
trametinib until recovery to ≤ 
Grade 1 or baseline, dabrafenib 
and trametinib may be reduced 
to the next lower dose per 
Table 6-7. Re-escalation of the 
subject’s dose is recommended 
if criteria in Section 6.3.2 are 
met.
3rd occurrence:
•
Interrupt dabrafenib and 
trametinib until toxicity resolves 
to ≤ Grade 1 or baseline, then 
reduce dabrafenib and 
trametinib to the next lower 
dose level per Table 6-7. Re-
escalation of the subject’s dose 
is recommended if criteria in 
Section 6.3.2 are met.
4th occurrence:


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Other: Autoimmune neuropathy, demyelinating polyneuropathy, Guillane-Barré, Myasthenia Gravis- 
like syndrome, Non-infectious myocarditis, pericarditis, pancreatitis (for asymptomatic amylase and/or 
lipase elevations refer to Table 6-18), and Grade 3 Fatigue with rapid onset in absence of disease 
progression
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
•
Permanently discontinue 
dabrafenib and trametinib.
Severe (Grade 3)
•
All management for moderate 
irAEs
•
Initiate systemic corticosteroids 
(prednisone or equivalent) at a 
dose of 1-2 mg/kg QD.
1st occurrence:
•
Interrupt PDR001/placebo, 
dabrafenib and trametinib until 
recovery to ≤ Grade 1 or 
baseline
•
Restart PDR001/placebo at 
the same schedule.
•
Dabrafenib and trametinib 
may be reduced to the next 
lower dose per Table 6-7. 
Re-escalation of the 
subject’s dose is 
recommended if criteria in 
Section 6.3.2 are met.
•
AE resolution to ≤ Grade 1 
or baseline must occur 
within a maximum period of 
12 weeks since a Grade 3 
event has been identified, 
otherwise PDR001/placebo 
must be permanently 
discontinued.
2nd occurrence:
•
Permanently discontinue 
PDR001/placebo and consider 
reducing dabrafenib and 
trametinib to the next lower 
dose per Table 6-7. Re-
escalation of the subject’s dose 
is recommended if criteria in 
Section 6.3.2 are met.
3rd occurrence:
•
Permanently discontinue 
dabrafenib and trametinib.
Grade 4
•
Refer to management of severe 
AEs
•
Permanently discontinue 
PDR001.
6.3.4
Mandatory dose modifications and recommended clinical 
management guidelines for infusion reactions
Acute infusion reactions (which can include cytokine release syndrome, angioedema, or 
anaphylaxis) are different from allergic/hypersensitive reactions, although some of the 
manifestations are common to both AEs. Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion.


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Table 6-20
Mandatory dose modifications and recommended clinical 
management guidelines for infusion reaction and cytokine release 
syndromes
Infusion reaction and cytokine release syndrome (NCI-CTCAE v4.03)
Grade
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Grade 1 infusion reaction or Grade 
1 cytokine release syndrome: 
mild/mild transient reaction; 
infusion interruption not indicated; 
intervention not indicated.
Increase monitoring of vital signs 
as medically indicated until the 
patient is deemed medically stable 
in the opinion of the investigator.
•
Continue PRD001/placebo
•
Continue dabrafenib and 
trametinib at the same dose 
level.
Grade 2 infusion reaction or Grade 
2 cytokine release syndrome: 
therapy or infusion
interruption indicated but responds 
promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 hr
•
Stop Infusion
•
Additional appropriate medical 
therapy may include but is not 
limited to:
•
IV fluids
•
Antihistamines
•
NSAIDS
•
Acetaminophen
•
Narcotics
•
Increase monitoring of vital 
signs as medically indicated 
until the patient is deemed 
medically stable in the opinion 
of the investigator.
•
If symptoms resolve within 
one hour of stopping drug 
infusion, the infusion may be 
restarted at 50% of the 
original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held 
until symptoms resolve and 
the patient should be re-
premedicated for the next 
scheduled dose.
•
Patient may be premedicated 
1.5 hr (± 30 minutes) prior to 
infusion of PDR001 with:
•
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine).
•
Acetaminophen 500-1000 
mg PO (or equivalent 
dose of analgesic).
1st occurrence:
•
Continue PRD001/placebo 
treatment with premedication
2nd occurrence:
•
Despite premedication or 
prolongation of infusion, 
consider permanent 
discontinuation of 
PDR001/placebo.
Grade 3 infusion reaction or grade 
3 cytokine release syndrome: 
prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for clinical sequelae 
•
Stop Infusion
•
Additional appropriate medical 
therapy may include but is not 
limited to:
•
IV fluids
•
Antihistamines
•
NSAIDS
•
Acetaminophen
•
Narcotics
•
Permanently discontinue 
PDR001/placebo


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Infusion reaction and cytokine release syndrome (NCI-CTCAE v4.03)
Grade
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
(e.g., renal impairment, pulmonary 
infiltrates)
Grade 4:
Grade 4 infusion reaction: Life-
threatening consequences; urgent 
intervention indicated
OR
Grade 4 cytokine release 
syndrome: Life-threatening 
consequences; pressor or 
ventilatory support indicated
•
Oxygen
•
Pressors
•
Corticosteroids
•
Epinephrine
•
Increase monitoring of vital 
signs as medically indicated 
until the patient is deemed 
medically stable in the opinion 
of the investigator. 
Hospitalization may be 
indicated.
6.3.4.1
Guidance for corticosteroids tapering for management of immune-
related AEs
Reduce prednisone dose by 2.5 to 5.0 mg decrements every 3–7 days until physiologic dose (5 
to 7.5 mg of prednisone per day) is reached. Consider to complete tapering over a period of at 
least 4 weeks. Slower tapering of corticosteroids therapy may be recommended if the adverse 
event is not showing improvement. Once corticosteroid tapering is achieved at a level of ≤ 10 
mg of prednisone/day (or equivalent), PDR001 can be restarted as indicated in the dose 
modification tables.
6.3.5
Dose modification and management guideline for adverse events 
suspected to be related to dabrafenib and/or trametinib 
Continue PRD001/placebo.
For adverse events of special interest reported only for dabrafenib and/or trametinib, general 
guidelines for dose modification in Table 6-21 should be followed for dabrafenib and trametinib.
In general, if an AE resolves to Grade 1 or baseline at the reduced dose level, and no additional 
toxicities are seen after 4 weeks of study treatment at the reduced dose, the dose may be 
increased to the previous dose level.
A dose reduction below 50 mg BID for dabrafenib or below 1 mg QD for trametinib is not 
allowed. If a dose reduction below 50 mg BID for dabrafenib is required, dabrafenib will be 
permanently discontinued but these subjects will be allowed to continue trametinib. If a dose 
reduction below 1.0 mg QD for trametinib is required, then trametinib will be permanently 
discontinued, but these subjects will be allowed to continue dabrafenib.


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Table 6-21
General guidelines for dose modification for adverse events 
suspected to be related to dabrafenib and/or trametinib treatment 
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Grade 1 or Grade 2 tolerable
•
Monitor closely.
•
Provide supportive care 
according to institutional 
standards.
•
Continue dabrafenib and 
trametinib at the same dose 
level.
Grade 2 (intolerable) or
Grade 3
•
Monitor closely.
•
Provide supportive care 
according to institutional 
standards.
•
Interrupt dabrafenib and 
trametinib (except for cuSCC, 
keratoacanthoma, new primary 
melanoma, and basal cell 
carcinoma)
•
When toxicity resolves to ≤ 
Grade 1 or baseline, restart 
dabrafenib and trametinib 
reduced by one dose level per 
Table 6-7.
•
If the Grade 2 (intolerable) or 
Grade 3 toxicity recurs, interrupt 
dabrafenib and trametinib.
•
When toxicity resolves to Grade 
1 or baseline, restart dabrafenib 
and trametinib reduced by 
another dose level per Table 6-7. 
Re-escalation of the subject’s 
dose is recommended if criteria 
in Section 6.3.2 are met.
Grade 4
•
Monitor closely.
•
Provide supportive care 
according to institutional 
standards.
•
Interrupt dabrafenib and 
trametinib.
•
Restart with dabrafenib and 
trametinib reduced by one dose 
level per Table 6-7 once toxicity 
resolves to ≤ Grade 1 or baseline 
or permanently discontinue 
dabrafenib and trametinib at the 
discretion of investigator.
6.3.5.1
Mandatory dose modification and management guideline for changes 
in LVEF suspected to be related to dabrafenib and/or trametinib 
treatment
Decreases of left-ventricular-ejection-fraction (LVEF) have been observed in subjects receiving 
trametinib monotherapy and in combination with dabrafenib. Therefore, ECHOs must be 
performed to assess cardiac ejection fraction in regular intervals as outlined in the Visit 
Evaluation Schedule (Table 7-1, Table 7-2 and Table 7-3). Dose modification guidance and 
stopping criteria for LVEF decrease are provided in Table 6-22.


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Table 6-22
Mandatory dose modification and recommended clinical management 
for changes in LVEF suspected to be related to dabrafenib and/or 
trametinib treatment
Left Ventricular Ejection Fraction decrease (NCI-CTCAE v4.03)
LVEF-drop (%) &
clinical symptoms
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
Asymptomatic:
Absolute decrease of >10% 
in LVEF compared to 
baseline and ejection fraction 
below the institution’s LLN
•
Report as SAE.
•
Closely monitoring LVEF via 
ECHO, repeat ECHO within 2 
weeks*.
•
If the LVEF recovers within 4 
weeks (defined as LVEF ≥LLN 
and absolute decrease ≤10% 
compared to baseline)
•
Repeat ECHO 2, 4, 8 and 12 
weeks after re-start; continue 
in intervals of 12 weeks 
thereafter.
•
If repeat LVEF does not recover 
within 4 weeks.
•
Consult with cardiologist
•
Repeat ECHO after 2, 4, 8, 
12, and 16 weeks or until 
resolution
•
Interrupt trametinib.
•
If the LVEF recovers, restart 
trametinib reduced by one dose 
level per Table 6-7 and continue 
dabrafenib at the same dose 
level.
•
More than two occurrence, 
permanently discontinue 
trametinib.
•
Permanently discontinue 
trametinib if repeat LVEF does 
not recover within 4 weeks.
Symptomatic:
Resting LVEF 39-20%
or >20% absolute reduction 
from baseline
resting LVEF <20%
•
Report as SAE.
•
Consult with cardiologist.
•
Repeat ECHO after 2, 4, 8, 12, 
and 16 weeks or until resolution.
•
Permanently discontinue 
trametinib.
•
Interrupt dabrafenib
•
Restart dabrafenib if LVEF 
recovers including resolution of 
symptoms.
* If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later.
6.3.5.2
Mandatory dose modification and management guideline for 
hypertension suspected to be related to dabrafenib and/or trametinib 
treatment
Increases in blood pressure have been observed in subjects receiving trametinib. For adequate 
monitoring and management of hypertension, all blood pressure assessments should be 
performed under the following optimal conditions:
•
the subject has been seated with back support, ensuring that legs are uncrossed and flat on 
the floor
•
the subject is relaxed comfortably for at least 5 minutes
•
restrictive clothing has been removed from the cuff area and the right cuff size has been 
selected
•
the subject’s arm is supported so that the middle of the cuff is at heart level
•
the subject remains quiet during the measurement.
In subjects with an initial blood pressure reading within the hypertensive range, a second 
reading should be taken at least 1 minute later, with the 2 readings averaged to obtain a final 
blood pressure measurement. The averaged value should be recorded in the eCRF.


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Persistent hypertension is defined as an increase of systolic blood pressure (SBP) > 140 mm Hg 
and/or diastolic blood pressure (DBP) > 90 mm Hg in three consecutive visits with blood 
pressure assessments from two readings collected as described above. Visits to monitor 
increased blood pressure can be scheduled independently from the per- protocol visits outlined 
in the Visit Evaluation Schedule (Section 7.1). Ideally, subsequent blood pressure assessments 
should be performed within one week.
Asymptomatic hypertension is defined as an increase of SBP >140 mm Hg and/or DBP >90 
mmHg in the absence of headache, light-headedness, vertigo, tinnitus, episodes of fainting or 
other symptoms indicative of hypertension.
For subjects experiencing an increase in systolic and/or diastolic blood pressure that is persistent 
and may be associated with the study treatment, recommendations for dose modifications and 
management of hypertension are described below in Table 6-23.
Table 6-23
Mandatory dose modification and recommended clinical management 
for hypertension suspected to be related to dabrafenib and/or 
trametinib treatment
Hypertension (NCI-CTCAE 4.03)
Severity
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
(Scenario A)
•
Asymptomatic and 
persistent a SBP of >140 
and <160 mmHg, or 
DBP >90 and <100 
mmHg, or
•
Clinically significant 
increase in DBP of 20 
mmHg (but still below 
100 mmHg).
•
Adjust current or initiate new 
antihypertensive medication.
•
Titrate antihypertensive 
medication(s) during the next 2 
weeks as indicated to achieve 
well-controlled b BP
•
If BP is not well controlled within 2 
weeks, recommended to refer to a 
specialist and go to scenario (B).
•
Continue dabrafenib and 
trametinib at the same dose.
(Scenario B)
•
Asymptomatic SBP ≥160 
mmHg, or DBP ≥100 
mmHg, or
Failure to achieve well-
controlled BP within 2 weeks 
in Scenario A
•
Adjust current or initiate new 
antihypertensive medication(s).
•
Titrate antihypertensive 
medication(s) during the next 2 
weeks as indicated to achieve 
well-controlled BP.
•
Interrupt dabrafenib and 
trametinib if clinically indicated.
•
Once BP is well controlled, 
restart dabrafenib and trametinib 
reduced by one dose level per 
Table 6-7.
•
Symptomatic c 
hypertension or
•
Persistent SBP ≥160 
mmHg, or DBP ≥100 
mmHg, despite 
antihypertensive 
medication and dose 
reduction of study 
treatment.
•
Adjust current or initiate new 
antihypertensive medication(s)
•
Titrate antihypertensive 
medication during the next 2 
weeks as indicated to achieve 
well-controlled BP.
•
Referral to a specialist for further 
evaluation and follow-up is 
recommended
•
Interrupt dabrafenib and 
trametinib.
•
Once BP is well controlled, 
restart dabrafenib and trametinib 
reduced by one dose level per 
Table 6-7.
•
Refractory hypertension 
unresponsive to above 
interventions or 
hypertensive crisis.
•
Continue follow-up per protocol.
•
Permanently discontinue 
dabrafenib and trametinib.


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Hypertension (NCI-CTCAE 4.03)
Severity
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
a.
Hypertension detected in two separate readings during up to three consecutive visits.
b.
Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate 
readings during up to three consecutive visits.
c.
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-
headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled within 
the normal range.
6.3.5.3
Mandatory dose modification and management guideline for new 
malignancies suspected to be related to dabrafenib and/or trametinib 
treatment
New cutaneous malignancies:
Cutaneous squamous cell carcinoma (CuSCC), keratoacanthomas (KA) and new primary 
melanomas have been observed in subjects treated with dabrafenib and dabrafenib/trametinib 
combination therapy. These treatment-related lesions should be surgically removed according 
to institutional practices. Dose modification or interruption of study treatment is not required 
for cuSCC, KA, or new primary melanoma, however cuSCC and new primary melanoma should 
be reported as a SAE. In addition, a biopsy of the lesion should be taken, where possible, and 
submitted for further analyses and a summary of the results submitted to Novartis.
Subjects should be instructed to immediately inform their physician if new lesions develop. 
Skin examination should be performed prior to initiation of study treatment and throughout 
therapy as detailed in the Visit Evaluation Schedule. Monitoring should continue every month 
for 6 months following discontinuation of dabrafenib or until initiation of another anti-
neoplastic therapy.
New non-cutaneous malignancies:
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling in 
BRAF wild type cells with RAS mutations when exposed to BRAF inhibitors, which may lead 
to increased risk of non-cutaneous malignancies in subjects treated with dabrafenib. Cases of 
RAS-driven malignancies have been seen with BRAF inhibitors, including dabrafenib. Subjects 
should be monitored as clinically appropriate. Consider the benefits and risks before continuing 
treatment with dabrafenib in subjects with a non-cutaneous malignancy harboring a RAS 
mutation. No dose modification of trametinib is required when taken in combination with 
dabrafenib.
Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent 
malignancies should continue for up to 6 months or until initiation of another anti-neoplastic 
therapy.
New cutaneous and non-cutaneous malignancies that are reported to the Investigator should be 
reported as an SAE. A biopsy of the new malignancy should be taken, where possible, and 
submitted for further analyses including RAS mutation status. Testing of these biopsies may 
include analysis of genomic alterations, which include but not limited to DNA, RNA and protein 


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analysis of these biopsy specimens, and would analyze the biological pathways known to be 
associated with, and relevant to, BRAF-mutant tumor activation.
6.3.5.4
Mandatory dose modification and recommended clinical management 
for pyrexia syndrome suspected to be related to dabrafenib and/or 
trametinib treatment
Episodes of pyrexia syndrome have been observed in subjects receiving dabrafenib 
monotherapy or in combination with trametinib. The pyrexia syndrome is defined as treatment-
related fever (≥ 38°C) or chills/rigors/night sweats or flu-like symptoms. In a minority of cases 
the pyrexia was accompanied by symptoms such as severe rigors/chills, dehydration, 
hypotension, dizziness or weakness and required hospitalization. The incidence and severity of 
pyrexia syndrome are increased when dabrafenib is used in combination with trametinib 
compared to dabrafenib monotherapy.
Dabrafenib and trametinib must be interrupted promptly at the very first symptom of pyrexia or 
its associated prodrome (chills or rigors or night sweats or flu-like symptoms) and should be 
restarted upon improvement of symptoms at the same dose if symptom free at least 24 hours.
Subjects should be instructed on the importance of immediately reporting febrile episodes. In 
the event of a fever, the subject should be instructed to take non-steroidal anti-pyretics as 
appropriate to control fever. The use of oral corticosteroids should be considered in those 
instances in which anti-pyretics are insufficient. In subjects experiencing pyrexia associated 
with rigors, severe chills, dehydration or hypotension, serum creatinine and other evidence of 
renal function should be monitored carefully during and following severe events of pyrexia.
Pyrexia accompanied by hypotension, dehydration requiring intravenous fluids, renal 
insufficiency and/or severe (≥ Grade 3) rigors/chills in the absence of an obvious infectious 
cause should be reported as a SAE.
Guidelines for dose modification and management for pyrexia syndrome considered to be 
related to dabrafenib are provided in Table 6-24. 
Table 6-24
Mandatory dose modification and recommended clinical management 
for pyrexia syndrome suspected to be related to dabrafenib and/or 
trametinib treatment
Pyrexia
Occurrence
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
1st occurrence and 
subsequent occurences 
•
Educate patient about pyrexia 
syndrome and to immediately 
interrupt dabrafenib and 
trametinib at the very first 
symptom of pyrexia or its 
associated prodrome (chills or 
rigors or night sweats or flu-like 
symptoms).
•
Clinical evaluation for infection 
and hypersensitivity a
•
Laboratory work-up a
•
Administer anti-pyretic treatment 
•
Dabrafenib and trametinib must 
be interrupted promptly at the 
very first symptom of pyrexia or 
its associated prodrome (chills, 
rigors, night sweats or flu-like 
symptoms) and should be 
restarted upon improvement of 
symptoms at the same dose if 
symptom free at least 24 hours.
•
If pyrexia cannot be managed 
with interruption, dose reduction 
per Table 6-7 must be considered 
if clinically indicated. For re-


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Pyrexia
Occurrence
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
with non-steroidal anti-
inflamatory drugs (NSAID) 
and/or
paracetamol b 
•
Recommend oral corticosteroids 
(i.e., prednisone 10 mg) for at 
least 5 days or as clinically 
indicated.
•
Optimize oral corticosteroid dose 
as clinically indicated for 
recalcitrant pyrexia. 
•
Oral hydration should be 
encouraged in subjects without 
evidence of dehydration. 
Intravenous hydration is 
recommended in subjects 
experiencing pyrexia 
complicated by 
dehydration/hypotension.
escalation, refer to Section 6.3.2.
•
Note: proactive intermittent 
dosing is not allowed.
a. For subjects experiencing pyrexia, a clinical evaluation and laboratory work-up is mandatory for each event; 
thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; laboratory work-
up should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-reactive protein (CRP), 
liver-function tests, blood culture, and urine culture.
b. Anti-pyretic treatment should be started immediately at the first occurrence and prophylactic anti-pyretic 
treatment is recommended. Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-pyretic 
medication according to institutional standards. Prophylactic anti-pyretic treatment is recommended to be 
discontinued after three days in the absence of pyrexia.
6.3.5.5
Mandatory dose modification and management guideline for visual 
changes suspected to be related to dabrafenib and/or trametinib 
treatment
Episodes of visual changes have been observed in subjects receiving trametinib, dabrafenib or 
the combination of dabrafenib/trametinib. An ophthalmologist should be consulted if changes 
in vision develop. However, if the visual changes are clearly unrelated to study treatment (e.g., 
allergic conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic 
examination.
Treatment with dabrafenib has been associated with the development of uveitis, including iritis. 
Monitor subjects for visual signs and symptoms (such as, change in vision, photophobia and 
eye pain) during therapy. Permanently discontinue dabrafenib for persistent ≥ Grade 2 uveitis 
(including iritis and iridocyclitis) of > 6 weeks duration. No dose modification of trametinib is 
required when taken in combination with dabrafenib.
In subjects treated with trametinib, special attention should be given to retinal findings (e.g., 
RPED) or retinovascular abnormalities (i.e., branch or central RVO). Treatment emergent cases 
of RVO and RPED should be reported as SAEs.
Guidelines for dose modification and management for visual changes and/or ophthalmic 
examination findings considered to be related to dabrafenib and/or trametinib are provided in 
Table 6-25 and Table 6-26.


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Table 6-25
Mandatory dose modification and recommended clinical management 
for visual changes and/or ophthalmic examination findings suspected 
to be related to dabrafenib and/or trametinib treatment
Visual changes (Eye disorders – Other, CTCAE Version 4.03)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification requirements
Grade 1 a
•
Consult ophthalmologist within 7 
days of onset
•
If dilated fundus examination cannot be 
performed within 7 days of onset, interrupt 
trametinib until RPED and RVO can be 
excluded by retina 
specialist/ophthalmologist. Continue 
dabrafenib.
•
If RPED and RVO excluded, continue (or 
restart) trametinib at the same dose level.
•
If RPED suspected or diagnosed: see 
RPED dose modification in Table 6-26; 
report as SAE if diagnosed.
•
If RVO diagnosed: Permanently 
discontinue trametinib and report as SAE.
Grade 2 and
Grade 3
•
Consult ophthalmologist 
immediately
•
Interrupt trametinib. Dabrafenib may be 
continued at the same dose b.If RPED and 
RVO excluded, restart trametinib at the 
same dose level.
•
If RPED diagnosed, see RPED dose 
modification in Table 6-26; report as SAE.
•
If RVO diagnosed: Permanently 
discontinue trametinib and report as 
SAE.
Grade 4
•
Consult ophthalmologist 
immediately
•
Interrupt trametinib. Dabrafenib may be 
continued at the same dose b.If RPED and 
RVO excluded, should consider restarting 
trametinib at same or reduced dose after 
discussion with study medical monitor.
•
If RVO or RPED diagnosed, permanently 
discontinue trametinib and report as SAE.
a. If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required.
b. Permanently discontinue dabrafenib for ≥ Grade 2 uveitis (including iritis and iridocyclitis) of > 6 weeks 
duration.
Table 6-26
Mandatory dose modification and recommended clinical management 
for retinal pigment epithelial detachments (RPED) suspected to be 
related to trametinib treatment
Retinal pigment epithelial detachments (RPED)
Grade
Recommended adverse event 
management guidelines
Mandatory dose modification 
requirements
•
Grade 1 (Asymptomatic; 
clinical or diagnostic 
observations only)
•
If RPED worsens follow 
instructions below.
•
Continue treatment with retinal 
evaluation monthly until 
resolution.
•
Grade 2-3 RPED 
(Symptomatic with mild 
to moderate decrease in 
visual acuity).
•
Retinal evaluation monthly.
•
Interrupt trametinib.
•
If improved to ≤ Grade 1, restart 
trametinib at a lower dose per 
Table 6-7.


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6.3.5.6
Monitoring guideline for hyperglycemia suspected to be related to 
dabrafenib treatment
Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral therapy can 
occur with dabrafenib. Monitor serum glucose levels as clinically appropriate during treatment 
with dabrafenib in subjects with pre-existing diabetes or hyperglycemia.
Advise subjects to report symptoms of severe hyperglycemia such as excessive thirst or any 
increase in the volume or frequency of urination.
6.3.5.7
Mandatory dose modification and management guideline for 
hemorrhage
Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or 
organ, can occur when dabrafenib is administered with trametinib. Permanently discontinue 
dabrafenib and trametinib for all Grade 4 hemorrhagic events and for any persistent Grade 3 
hemorrhagic events. Withhold dabrafenib and trametinib for Grade 3 hemorrhagic events; if 
improved, resume at the next lower dose level. 
6.3.5.8
Mandatory dose modification and management guideline 
thromboembolic events
Advise patients to immediately seek medical care if they develop symptoms of deep vein 
thrombosis (DVT) or pulmonary embolism (PE), such as shortness of breath, chest pain, or arm 
or leg swelling. If any signs or symptoms of venous thromboembolism are present, the subject 
will undergo specific laboratory and medical imaging studies to confirm it. The medical 
imaging study or studies selected will depend on the anatomic site or organ of involvement 
(e.g., Doppler ultrasound, venography, ventilation perfusion lung scan, angiography, MRI). If 
the diagnosis is confirmed, appropriate medical care according to standard local clinical practice 
should be initiated immediately. 
Permanently discontinue trametinib for life threatening PE. Withhold trametinib for 
uncomplicated venous thromboembolism for up to 3 weeks; if improved, trametinib may be 
resumed at a lower dose level.
6.3.5.9
Guideline dose modification and management for hemophagocytic 
lymphohistiocytosis (HLH) 
In post marketing experience, hemophagocytic lymphohistiocytosis (HLH), has been observed 
with dabrafenib and trametinib combination therapy. Since post-marketing adverse drug 
reactions are reported from a population of uncertain size, the exact frequency of HLH in 
patients receiving dabrafenib and trametinib is unknown. HLH is a rare, life-threatening 
condition caused by an overactive, abnormal response of the immune system (Kikuchi et al 
2022). HLH is associated with a constellation of multiple clinical and laboratory features that 
may include fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, high 
serum ferritin, multilineage cytopenias and hemophagocytosis. If HLH is suspected, treatment 
should be interrupted. If HLH is confirmed, treatment should be permanently discontinued and 
appropriate management of HLH per institutional standards should be initiated.


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6.3.6
Follow-up for toxicities
6.3.6.1
Follow up on potential immune related adverse events
The emergence of irAE may be anticipated based on the mechanism of action of 
immunomodulatory therapies.
Serologic, histologic (tumor sample) and immunological assessments should be performed as 
deemed appropriate by the Investigator to verify the immune-related nature of the AE and to 
exclude alternative explanations. Recommendations (Section 6.3) have been developed to assist 
investigators in assessing and managing the most frequently occurring irAEs.
Subjects whose treatment is interrupted or permanently discontinued due to an irAE, AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 30 days, and 
subsequently at approximately 30-day intervals (or more frequently if required by institutional 
practices, or if clinically indicated), until resolution or stabilization of the event, whichever 
comes first. Appropriate clinical experts should be consulted as deemed necessary.
If an AE is suspected to be immune-related the relevant immunological assessments (e.g., 
rheumatoid factor, anti-DNA Ab, etc.) should be performed. If cytokine release syndrome is 
suspected, the assessments outlined in Section 7.2.2.6.8 must be performed. All subjects must 
be followed-up for irAEs, AEs and SAEs for 150 days following the last dose of 
PDR001/placebo. However, if the subject begins post treatment antineoplastic medication 
before the 150-Day safety visit the collection of new SAEs and AEs unrelated to study 
medication will stop and thereafter only suspected SAEs and suspected AEs will continue to be 
collected to Day 150. If SAEs suspected to be related to study medication occur beyond Day 
150, information should also be collected.
6.3.6.2
Follow up on potential drug-induced liver injury (DILI) cases
Subjects with transaminase increase combined with an elevation of total bilirubin (TBIL) may 
be indicative of potential DILI; these events should be considered as clinically important.
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBIL 
value; subjects meeting any of the following criteria will require further follow-up as outlined 
below:
•
For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN
•
For subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in subjects without bone metastasis, or elevation 
of ALP liver fraction in subjects with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).


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In the absence of cholestasis, these subjects should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g., biliary tract) 
may be warranted.
4. Additional testing for other hepatotropic viral infection (e.g., CMV, EBV, Adenovirus, HSV, 
HHV6, HIV), autoimmune hepatitis or liver biopsy may be considered as clinically 
indicated or after consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.4
Concomitant medications
The investigator must instruct the subject to notify the study site of any new medication(s) 
he/she takes after start of study participation. All prescription medications, OTC drugs and 
significant non-drug therapies (including physical therapy, herbal/natural medications and 
blood transfusions) taken within 28 days or 5 half-lives, whichever is shorter, including 
vitamins taken within one week prior to dosing must be recorded on the ‘Prior and Concomitant 
Medications’ or ‘Surgical and Medical Procedures’ eCRF. Prior antineoplastic therapies 
including medications, radiotherapy, and surgery are to be recorded on the separate ‘Prior 
Antineoplastic Therapy eCRF’ page during screening. Medication entries must be specific to 
trade name, dose and units, frequency and route of administration, start and discontinuation 
dates, and reason for therapy. For medications administered one time, the frequency column 
may reflect “once”.
Administration of certain concomitant medications may lead to the requirement for subject to 
be discontinued. Discussions regarding discontinuation of subjects requiring concomitant 
medication will be discussed with Novartis on a case by case
6.4.1
Permitted concomitant therapy
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g., such as anti-emetics, anti-diarrhea) and safety of the subject are allowed except those 
prohibited in Section 6.4.3.
Subjects are permitted to use the following medications during study treatment:


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•
Antivirus medications to manage HBV or HCV infection and/or prevent reactivation (e.g., 
tenofovir); supportive care.
•
Medications to prevent or treat nausea or vomiting.
•
Anti-diarrheal medications (e.g., loperamide) for subjects who develop diarrhea.
•
Pain medication to allow the subject to be as comfortable as possible.
•
Bone targeted therapies (e.g., bisphosphonates, denosumab) to treat bone metastases or to 
prevent skeletal related events. 
•
Any radiotherapy must be listed on the ‘Concomitant Antineoplastic Therapy - 
Radiotherapy’ eCRF.
•
Immunosuppressive agents to treat suspected irAEs.
•
Nutritional support or appetite stimulants (e.g., megestrol).
•
Oxygen therapy and blood products or transfusions.
•
Limited-field palliative radiotherapy to non-target lesion(s) may be allowed after 
documented discussion with Novartis study physician as concomitant therapy such as local 
therapies administered during the study treatment. In case of palliative radiotherapy, the 
subject should interrupt dabrafenib and trametinib for fractionated radiotherapy and 
stereotactic radiosurgery before and after radiotherapy as outlined below (Anker CJ et al, 
2016).
•
Interrupt dabrafenib and trametinib ≥ 3 days before and after fractionated radiation 
•
Interrupt dabrafenib and trametinib ≥ 1 day before and after stereotactic radiosurgery 
(SRS)
•
Inactivated vaccines.
•
The subject must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications 
or the Procedures and Surgical and Medical Procedures eCRF.
6.4.2
Permitted concomitant therapy requiring caution and/or action
6.4.2.1
PDR001
•
Anticoagulation and anti-aggregation agents are permitted if the subjects are already at 
stable doses for > 2 weeks at the time of first dose of PDR001 and INR should be monitored 
as clinically indicated per investigator’s discretion. However, ongoing anticoagulant 
therapy should be temporarily discontinued to allow tumor biopsy sample collection 
according to the institutional guidelines. 
6.4.2.2
Dabrafenib
6.4.2.2.1 Effect of other drugs on dabrafenib
Based on in vitro studies, dabrafenib was shown to be primarily metabolized by CYP2C8 and 
CYP3A4. Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are 
likely to increase or decrease, respectively, dabrafenib concentrations. Alternative agents 


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should be considered during administration with dabrafenib when possible. Use caution if 
strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, ritonavir, gemfibrozil) or 
inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP2C8 
or CYP3A4 are co-administered with dabrafenib.
6.4.2.2.2 Effect of dabrafenib on other drugs
Dabrafenib induces CYP3A4- and CYP2C9- mediated metabolism and may induce other 
enzymes including CYP2B6, CYP2C8, CYP2C19 and UDP glucuronosyltransferases (UGT). 
Dabrafenib may also induce transporters (e.g., P-glycoprotein (P-gp)). Co-administration of 
dabrafenib and medicinal products which are affected by the induction of CYP3A4 or CYP2C9 
such as hormonal contraceptives, warfarin or dexamethasone may result in decreased 
concentrations and loss of efficacy. If co-administration of these medications is necessary, 
monitor subjects for loss of efficacy or consider substitutions of these medicinal products. Use 
caution if co-administration of CYP2C or CYP3A4 substrates with narrow therapeutic index is 
required. Refer to the Tafinlar label for further information.
6.4.2.3
Trametinib
Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the 
pharmacokinetics of other medicinal products via interactions with CYP enzymes or 
transporters.
6.4.3
Prohibited concomitant therapy
6.4.3.1
PDR001/placebo
During the course of the study, subjects must not receive other additional investigational drugs, 
devices, chemotherapy, or any other therapies that may be active against cancer or modulate 
the immune responses. However, limited-field palliative radiotherapy to non-target lesion(s) 
may be allowed as concomitant therapy. Such local therapies administered during the study 
treatment must be entered into the CRF. Additionally, no other therapeutic monoclonal 
antibodies and no immunosuppressive medication may be administered while on this study 
unless given for the management of immune toxicity.
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed except 
for the treatment of (recurrent) pyrexia, infusion reactions, irAEs, and for prophylaxis against 
imaging contrast dye allergy or replacement-dose steroids in the setting of adrenal insufficiency 
(providing this is ≤ 10 mg/day prednisone or equivalent), or transient exacerbations of other 
underlying diseases such as COPD requiring treatment for ≤ 3 weeks. If systemic corticosteroids 
are required for the control of infusion reactions, pyrexia or irAEs, it must be tapered and be at 
non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) before the next 
administration of study treatment. 
The use of live vaccines is not allowed through the whole duration of the study. Inactivated 
vaccines are allowed.
There are no prohibited therapies during the post-treatment follow-up period.


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6.4.3.2
Dabrafenib and trametinib
The following medications or non-drug therapies are prohibited while on treatment in this study:
•
Other anti-cancer therapies
•
Other investigational drugs
Although not contraindicated/prohibited, certain medications drugs should be used with caution 
due to potential drug-drug interactions (see Section 6.4.2.2).
6.4.4
Use of bisphosphonates (or other concomitant agents)
Localized radiotherapy and treatment with bisphosphonates for pre-existing, painful bone/liver 
metastases is permitted for non-target lesions. The radiotherapy must be listed on the 
‘Concomitant Antineoplastic Therapy – Radiotherapy’ eCRF.
6.5
Subject numbering, treatment assignment or randomization
6.5.1
Subject numbering
Each subject is identified in the study by a 7-digit Subject Number (Subject No.), that is 
assigned when the subject is first enrolled for screening and is retained as the primary identifier 
for the subject throughout his/her entire participation in the trial.
•
The Subject No. consists of the 4-digit Center Number (Center No.) (as assigned by Novartis 
to the investigative site) with a sequential 3-digit patient number suffixed to it, so that each 
subject is numbered uniquely across the entire database.
•
Upon signing the informed consent form, the subject is assigned to the next sequential 
Subject No. available to the investigator through the Oracle Clinical RDC interface.
•
The investigator or designated staff will contact the IRT and provide the requested 
identifying information for the subject to register them into the IRT.
•
Once assigned, the Subject No. must not be reused for any other subject and the Subject No. 
for that individual must not be changed, even if the subject is re-screened.
•
If the subject fails to be randomized or start treatment for any reason, the reason will be 
entered into the Screening Disposition page.
•
IRT must be notified within 2 days that the subject was not randomized.
6.5.2
Treatment assignment or randomization
In Part 1 and 2 of this study, the assignment of a subject to a particular cohort will be coordinated 
by the sponsor via IRT.
In Part 3 of this study, subjects will be randomized via IRT in a ratio of 1:1 to one of the 2 
treatment arms (Section 4 and Section 6.1):
•
Arm 1: PDR001 in combination with dabrafenib and trametinib
•
Arm 2: Placebo in combination with dabrafenib and trametinib
Randomization will be stratified by LDH level (< 1 x ULN vs. ≥ 1 to < 2 x ULN vs. ≥ 2 x ULN) 
and ECOG PS (0 vs. 1 vs. 2).


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Random permuted blocks scheme will be used for this study.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication randomization list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to medication packs containing each of the study 
treatments.
Prior to dosing, all subjects who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the subject. The randomization number will not be communicated to the caller.
6.5.3
Treatment blinding
Parts 1 & 2: Safety run-in and biomarker cohort
Not applicable.
Part 3: Double-blind, randomized, placebo-controlled part:
Patients, investigator, site personnel and data analysts will remain blinded to the identity of the 
treatment from the time of randomization until database lock using the following methods: (1) 
Randomization data are kept strictly confidential until the time of unblinding and will not be 
accessible by anyone else involved in the study except for the unblinded pharmacist, unblinded 
CRAs, independent biostatistician and programmer who will perform DMC analysis and the 
PK bioanalyst. (2) Any potential visible difference in treatments will be concealed by the use 
of a non-translucent, opaque sleeve. (3) To the best extent possible the order of assessments 
will match the one used at each dosing visit, thus normalizing the process to all subjects. 
Randomization data are strictly confidential and will be accessible only to authorized personnel 
until unblinding of the trial after database lock. The study bioanalyst will receive a copy of the 
randomization schedule to facilitate analysis of the samples. The unblinded pharmacist, 
unblinded CRA, independent biostatistician and programmer and bioanalyst will keep treatment 
allocation information confidential until clinical database lock.
To limit the impact of unblinding on the scientific validity of the study results, individual patient 
unblinding will be prohibited, except for medical emergencies, (Section 8.3), for regulatory 
reporting purposes, or if it is critical to determine subsequent therapy after disease progression. 
Except in these cases, documented approval by the Novartis study physician is required prior 
to unblinding a subject's treatment assignment. In case of unblinding, all data is required to be 
captured in the eCRF prior to unblinding. Data after unblinding will continue to be collected as 
per protocol. The date of any unblinding and the reason will also be collected.


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IMPORTANT: Due to the difference in preparation methods between the active and placebo 
treatments, an unblinded pharmacist/designee who is independent of the investigational staff 
will be required. This unblinded pharmacist will receive the appropriate treatment allocations. 
Appropriate measures must be taken by the unblinded pharmacist to ensure that the 
investigational staff remains blinded throughout the study. The unblinded pharmacist must not 
administer the drug to the subject nor have any contact with the study participants. Please refer 
to the Pharmacist Instruction Manual.
Following the final PFS analysis:
•
Unblinding is mandated and does not require notification to Novartis study physician
•
Patients who have been unblinded may continue on the study
•
Decision on continuation of treatment with PDR001 in combination with dabrafenib and 
trametinib can be made on a case by case basis using medical judgement, individual 
benefit-risk assessment, and upon a documented discussion with the patient.
•
Placebo administrations to those patients randomized to the placebo arm will discontinue 
while dabrafenib and trametinib may continue for the same patients.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the subject or caregiver to take 
dabrafenib and trametinib as per protocol. These study drug(s) will be dispensed to the subject 
by authorized site personnel only. All dosages prescribed to the subject and all dose changes 
during the study must be recorded on the Dosage Administration Record eCRF.
Dabrafenib and trametinib with instructions for administration will be provided to subjects for 
self-administration at home, until their next scheduled study visit.
PDR001/placebo will be administered intravenously as a 30 minute infusion (up to 2 hours, if 
clinically indicated). Subjects should be provided instructions how to notify study personnel if 
symptoms of infusion reaction occur after any PDR001 infusion. Further instructions for the 
preparation and dispensation of PDR001 are described in the Pharmacist Instruction Manual.
Placebo will be a Dextrose 5% in water (D5W) infusion supplied by the site.
Study drugs must be received at the study site by a designated person, handled and stored safely 
and properly, and kept in a secure location to which only the unblinded pharmacist, unblinded 
CRA, or unblinded designated staff have access. Upon receipt, the study drugs should be stored 
according to the instructions specified on the drug labels. Storage conditions must be adequately 
monitored and appropriate temperature logs maintained as source data. Appropriate 
documentation of the subject specific dispensing process must be maintained. Bulk medication 
labels will be in the local language, will comply with the legal requirements of each country, 
and will include storage conditions for the drug but no information about the subject.
Note: To maintain the blind, the investigational treatments will be prepared by an unblinded 
pharmacist/designee, and the bags will be covered by a non-translucent, opaque sleeve. Only 
study personnel blinded to treatment allocation must administer PDR001 or placebo.
All drug supplies are to be used only for this protocol and not for any other purpose. Unless 
specifically instructed by Novartis, the Investigator must not destroy any drug labels, or any 


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partly used or unused drug supply. Only after receiving a written authorization by Novartis, the 
Investigator/designee will send all the unused and partly used drug supplies as well as the empty 
containers to the address provided at the time of authorization for destruction.
As per Section 2.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of study treatment directly to a participant's home may be permitted (if allowed by 
Local or Regional Health Authorities and Ethics Committees as appropriate) in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant's health to administer the study treatment 
even without performing an on-site visit. The dispatch of study treatment from the site to the 
participant’s home remains under the accountability of the Investigator. In this case, regular 
phone calls or virtual contacts will occur between the site and the participant for instructional 
purposes, safety monitoring, investigation of any adverse events, ensuring participants continue 
to benefit from treatment, and discussion of the participant's health status until the participants 
can resume visits at the study site.
6.6.1
Study treatment packaging and labeling
PDR001 will be provided as global clinical open label supply and will be packed and labeled 
under the responsibility of Novartis, Drug Supply Management.
PDR001 in different formulations may be used once available.
PDR001 (powder for solution for infusion or liquid in vial) will be provided as global clinical 
open label supply and will be packed and labeled under the responsibility of Novartis, Drug 
Supply Management.
Dabrafenib and trametinib will be either sourced as local commercial supply or provided as 
global clinical open label supply. Global clinical open label supply will be provided in bottles.
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions.
Novartis Drug Supply Management supplied treatments will also contain a unique medication 
number (corresponding to study treatment and strength).
Responsible site personnel will identify the study treatment package(s) to dispense by the 
medication number(s) assigned by IRT to the subject. If the label has 2 parts (base plus tear-off 
label), immediately before dispensing the package to the subject, site personnel will detach the 
tear-off part of the label from the package and affix it to the subject’s source document.
Table 6-27
Packaging and labeling
Study treatments
Supply
Storage
PDR001
Centrally supplied by 
Novartis
Refer to study treatment label
Dabrafenib 
(DRB436)
Novartis or locally
Refer to study treatment label or local product 
information
Trametinib 
(TMT212)
Novartis or locally
Refer to study treatment label or local product 
information


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6.6.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the latest PDR001 Investigator’s Brochure, 
Dabrafenib Investigator’s Brochure, and Trametinib Investigator’s Brochure.
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each subject visit and 
information provided by the subject and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each subject 
visit. Dose changes of dabrafenib and trametinib and interruptions of PDR001, dabrafenib and 
trametinib must be specifically documented in the subject source documents and eCRF.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the CRA 
(parts 1 and 2) or by the unblinded CRA (part 3) during site visits and at the completion of the 
study. Subjects will be asked to return all unused study treatment and packaging on a regular 
basis, at the end of the study or at the time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
Disposal and destruction
Any waste material should be disposed of in accordance with local regulations and according 
to institutional guidelines. If local regulations disallow storage of empty or pierced vials at the 
site, the site is able to destroy the vials as per local requirements and procedures. Documentation 
regarding the local regulations and the destruction of the empty vials will be provided to the 
Sponsor to ensure full drug accountability. 
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 (Safety run-in part), Table 7-2 (Biomarker cohort) and Table 7-3 (Randomized part) 
list all of the assessments and indicates with an “X” (or otherwise specified) the visits when 
they are performed. All data obtained from these assessments must be supported in the subject’s 


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source documentation. The table indicates which assessments produce data to be entered into 
the database (D) or remain in source documents only (S) (“Category” column).
Every effort must be made to follow the schedule of assessments within the windows outlined 
in the protocol.
•
For Cycle 1, all assessments have a ± 3 day window unless otherwise indicated.
•
After Cycle 1, all assessments have a ± 7 day window, unless otherwise indicated.
Additional assessment may be performed as clinically indicated.
If study drug is being held due to toxicity, then the scheduled visits and assessments should still 
be performed per protocol (except dose administration), unless otherwise specified.
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented. Phone calls, virtual contacts (e.g. teleconsult) 
or visits by site staff/home nursing service to the participant´s home depending on local 
regulations and capabilities, can replace on-site study visits, for the duration of the pandemic 
until it is safe for the participant to visit the site again.
Physical assessments may be performed by another medical professional; the process for 
assuring investigator oversight, including communication to confirm patient safety and any 
treatment must be documented. In addition, any certified source documents should be provided 
by the medical professional to the investigator. 
Safety laboratory testing may be performed locally and used for decision making for patients 
who cannot come to the study site. All local lab reports must be collected and filed in the patient 
medical record or chart. 
As per Section 2.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g., tele consultation) or visits by site staff/home 
nursing staff to the participant´s home, can replace on-site study visits, for the duration of the 
disruption until it is safe for the participant to visit the site again. If the Investigator delegates 
tasks to an off-site healthcare professional, the Investigator must ensure the individual(s) is/are 
qualified and appropriately trained to perform assigned duties. The Investigator must oversee 
their conduct and remain responsible for the evaluation of the data collected.


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Table 7-1
Visit evaluation schedule: Safety run-In part (Part 1) – visit schedule updated and applicable following final PFS 
analysis 
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Day 1
End of 
Study 
Treatment 
(EoT)
30- Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150 Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
8
15
1
8
15
1
15
1
Obtain Informed Consent
Study ICF
D
7.1.2
X
Pharmacogenetic ICF
D
7.2.4.2.1
X
IRT Registration-
Enrollment
S
7.1.2.1
X
Treatment beyond 
progression ICF
D
6.1.5.1
X (subjects who meet the criteria outlined in 
Section 6.1.5.1)
Patient History
Demography
D
7.1.2.3
X
Inclusion/exclusion
D
5.2, 5.3
X
Past and current 
medical conditions 
including 
cardiovascular 
medical history and 
risk factors
D
7.1.2.3
X


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Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Day 1
End of 
Study 
Treatment 
(EoT)
30- Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150 Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
8
15
1
8
15
1
15
1
Diagnosis and extent 
of cancer
D
7.1.2.3
X
Alcohol History
D
7.1.2.3
X
Smoking History
D
7.1.2.3
X
HIV History (Note: for 
Germany only, a 
mandatory HIV test is 
required during 
screening using a 
local test)
S
7.1.2.3
X
Prior antineoplastic 
therapies (meds, 
surgery, radiation)
D
7.1.2.3
X
Prior/concomitant 
medications
D
7.1.2.3
From 30 days prior to starting study treatment until 150 day safety follow-up or start of new antineoplastic 
medication, whichever occurs first. If new antineoplastic medication is started then only medications relative 
to the AEs/SAEs that are reported should be collected.
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
7.1.2.3
X
X
X
X
X
X
X


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Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Day 1
End of 
Study 
Treatment 
(EoT)
30- Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150 Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
8
15
1
8
15
1
15
1
Enrollment
Drug Supply (IRT)
S
7.1.2.1
X
Disposition 
Assessment (at the 
end of each study 
phase)
D
7.1.4
X
X
X
Physical Examination
Physical Examination 
(complete)
S
7.2.2.1
X
As clinically indicated
Physical Examination 
(short)
S
7.2.2.1
X
X
X
X
X
30 days from the last dose 
of PDR001 and every 
month for 6 months from 
the last dose of dabrafenib
Performance Status 
(ECOG)
D
7.2.2.4
X
X
X
X
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X


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Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Day 1
End of 
Study 
Treatment 
(EoT)
30- Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150 Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
8
15
1
8
15
1
15
1
Ophthalmic 
examination
D
7.2.2.5
X
X
As clinically indicated
12-lead ECG for DL1
D
7.2.2.7.1
X
X
As clinically indicated
X 
12-lead ECG for DL-
1a or DL-1b
D
7.2.2.7.1
X
X
As clinically 
indicated
X
Cardiac function 
(MUGA or ECHO)
D
7.2.2.7.2
X
X
C4D1 and 
every 12 
weeks and 
as clinically 
indicated
X 
Laboratory Assessments
Hematology for DL1
D
7.2.2.6.1
X
X
X
X
X
X
X
X
X
X
X
Hematology for DL-1a
D
7.2.2.6.1
X
X
X
X
X
X
X
X
X and at 
C4D15
X
X
Hematology for DL-1b
D
7.2.2.6.1
X
X
X
X
X
X
X
X
X
X
X
Chemistry for DL1
D
7.2.2.6.1
X
X
X
X
X
X
X
X
X
X
X
Chemistry for DL-1a
D
7.2.2.6.1
X
X
X
X
X
X
X
X
X and at 
C4D15
X
X
Chemistry for DL-1b
D
7.2.2.6.1
X
X
X
X
X
X
X
X
X
X
X


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Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Day 1
End of 
Study 
Treatment 
(EoT)
30- Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150 Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
8
15
1
8
15
1
15
1
Thyroid function- TSH
D
7.2.2.6.3
X
X
X
X
X
X
X
Thyroid Panel- Free 
T3 and Free T4
D
7.2.2.6.3
X
Only if TSH 
is abnormal
Coagulation
D
7.2.2.6.4
X
C1D1, every 2 cycles for the first 12 cycles and every 3 
cycles thereafter as clinically indicated
As clinically 
indicated
Urinalysis 
(microscopy or 
macroscopic)
S
7.2.2.6.5
X
X
X
X
X
X
X
Urine pregnancy test
S
7.2.2.6.6 
X
X
X
X
X
X
Serum Pregnancy
S
7.2.2.6.6 
X
X
X
X
Hepatitis Testing
D
7.2.2.6.7 
X
As Clinically indicated
For Germany only: 
local HIV Testing 
S
7.2.2.6.9 
X


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Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Day 1
End of 
Study 
Treatment 
(EoT)
30- Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150 Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
8
15
1
8
15
1
15
1
Imaging
Tumor evaluation per 
RECIST 1.1
D
7.2.1
X
Following final PFS analysis; tumor evaluations per RECIST 1.1 
are no longer required. Investigators are directed to follow local 
procedures for the frequency and modality of tumor 
assessments
Chest, abdomen and 
pelvis CT or MRI (with 
contrast 
enhancement)
D
7.2.1
X
Following final PFS analysis; chest, abdomen and pelvis CTor 
MRI assessments are no longer required. Investigators are 
directed to follow local procedures for the frequency and 
modality of tumor assessments
Brain imaging (CT or 
MRI)
D
7.2.1
X
Following final PFS analysis; brain imaging assessments are no longer required. Investigators are directed to 
follow local procedures.
Whole body bone 
scan
D
7.2.1
Following final PFS analysis; whole body bone scan assessments are no longer required. Investigators are directed 
to follow local procedures.
Localized bone CT, 
MRI or X-ray
D
7.2.1
Following final PFS analysis; localized bone CT MRI or X-ray assessments are no longer required. Investigators are 
directed to follow local procedures.
CT or MRI of other 
metastatic sites (e.g., 
neck)
D
7.2.1
Following final PFS analysis; CT or MRI of other metastatic sites are no longer required. Investigators are directed 
to follow local procedures.


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Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Day 1
End of 
Study 
Treatment 
(EoT)
30- Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150 Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
8
15
1
8
15
1
15
1
Color Digital 
Photography 
(including a metric 
ruler) for cutaneous 
lesions
D
7.2.1
X
Following final PFS analysis; colour digital photography 
assessments are no longer required. Investigators are directed 
to follow local procedures for the frequency and modality of 
tumor assessments
Body Fluid/Tissue
D
7.2.1
Needle aspiration, biopsy or any other form of collection (e.g., paracentesis, punctuation) performed for any reason
Safety
Adverse events
D
7.2.2, 8.1
Suspected AEs up to Day 150; non-suspected AEs up to Day 150 or start of new post treatment anti-
neoplastic medication, whichever is sooner.
Monitoring of new cutaneous malignancies should continue every month for 6 months following 
discontinuation of dabrafenib or until initiation of another antineoplastic therapy (refer to Section 6.3.5.3).
Serious adverse 
events
D
8.2.2
Suspected SAEs up to Day 150 and beyond; non-suspected SAEs up to Day 150 or start of new post 
treatment anti-neoplastic medication, whichever is sooner.
Biomarkers




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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Day 1
End of 
Study 
Treatment 
(EoT)
30- Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150 Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
8
15
1
8
15
1
15
1


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Day 1
End of 
Study 
Treatment 
(EoT)
30- Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150 Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
8
15
1
8
15
1
15
1
Study Administration
PDR001 infusion
D
6.1.1.1
DL1: PDR001 400mg IV every 4 weeks
DL-1a: PDR001 400mg IV every 8 weeks
DL-1b: at C2D1, PDR001 400mg IV every 4 weeks
Trametinib/Dabrafenib 
combination
D
6.1.1.1
Trametinib orally once daily and Dabrafenib orally twice 
daily for Days 1-28 of a 28-day cycle
PK sampling of 
PDR001 (for DL1 or 
DL-1a)
D
7.2.3.1.1
PK sampling of 
PDR001 (for DL-1b)
D
7.2.3.1.1
PK sampling of 
trametinib and 
dabrafenib
D
7.2.3.1.2
Immunogenicity (IG) 
sampling (For DL1 
and DL-1a)
D
7.2.3.1.1
Immunogenicity (IG) 
sampling (for DL-1b)
D
7.2.3.1.1 
Following final PFS analysis data cut-off date 01-Jul-2020; PK and IG samples will no longer be collected or sent to 
central labs.
Survival Follow-up
D
7.1.8 
X


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Protocol No. CPDR001F2301
Table 7-2
Visit evaluation schedule: Biomarker cohort (Part 2) – visit schedule updated and applicable following final PFS 
analysis 
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Cycle 3
Subsequent Cycles
Day 1
End of Study Treatment 
(EoT)
30-Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150-Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
15
1
15
1
15
1
Obtain Informed Consent
Study ICF
D
7.1.2
X
Pharmacogenetic ICF
D
7.2.4.2.1
X
IRT Registration
S
7.1.2.1
X
Treatment beyond 
progression ICF
D
6.1.5.1
X (subjects who meet the criteria 
outlined in Section 6.1.5.1)
Patient History
Demography
D
7.1.2.3
X
Inclusion/exclusion
D
5.2, 5.3
X
Past and current medical 
conditions including 
cardiovascular medical history 
and risk factors
D
7.1.2.3
X
Diagnosis and extent of 
cancer
D
7.1.2.3
X
Alcohol History
D
7.1.2.3
X


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Cycle 3
Subsequent Cycles
Day 1
End of Study Treatment 
(EoT)
30-Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150-Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
15
1
15
1
15
1
Smoking History
D
7.1.2.3
X
HIV History (Note: for 
Germany only, a mandatory 
HIV test is required during 
screening using a local test)
S
7.1.2.3
X
Prior antineoplastic therapies 
(meds, surgery, radiation)
D
7.1.2.3
X
Prior/concomitant 
medications;
D
7.1.2.3
From 30 days prior to starting study treatment until 150 Day safety follow-up or start of new 
antineoplastic medication, whichever is sooner. If new antineoplastic medication is started then only 
medications relative to the AEs/SAEs that are reported should be collected
Antineoplastic therapies since 
discontinuation of study 
treatment
D
7.1.2.3
X
X
X
X
X
X
X
Enrollment
Drug Supply (IRT)
S
7.1.2.1
X
Disposition Assessment (at 
the end of each study phase)
D
7.1.4
X
X
X
Physical Examination
Physical Examination 
(complete)
S
7.2.2.1
X
As clinically indicated


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Cycle 3
Subsequent Cycles
Day 1
End of Study Treatment 
(EoT)
30-Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150-Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
15
1
15
1
15
1
Physical Examination (short)
S
7.2.2.1
X
X
X
X
X
30 days from the last dose 
of PDR001 and every 
month for 6 months from 
the last dose of dabrafenib
Performance Status (ECOG)
D
7.2.2.4
X
X
X
X
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
Ophthalmic examination
D
7.2.2.5
X
X
As clinically indicated
12-lead ECG if DL1 is 
determined to be the regimen
D
7.2.2.7.1
X
X
As clinically indicated
X
12-lead ECG if DL-1a or DL-
1b is determined to be the 
regimen
D
7.2.2.7.1
X
X
As 
clinically 
indicated
X
Cardiac function (MUGA or 
ECHO)
D
7.2.2.7.2
X
X
X C4D1, 
every 12 
weeks 
and as 
clinically 
indicated
X


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Cycle 3
Subsequent Cycles
Day 1
End of Study Treatment 
(EoT)
30-Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150-Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
15
1
15
1
15
1
Laboratory Assessments
Hematology
D
7.2.2.6.1
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.6.2
X
X
X
X
X
X
X
X
X
X
Thyroid function-TSH
D
7.2.2.6.3
X
X
X
X
X
X
X
Thyroid Panel- FreeT3 and 
Free T4
D
7.2.2.6.3
X
Only if 
TSH is 
abnormal
Coagulation
D
7.2.2.6.4
X
C1D1, every 2 cycles for the first 12 
cycles and every 3 cycles thereafter as 
clinically indicated
As clinically indicated
Urinalysis (microscopy and 
macroscopic)
S
7.2.2.6.5
X
X
X
X
X
X
X
Serum Pregnancy Test
S
7.2.2.6.6
X
X
X
X
Urine Pregnancy Test
S
7.2.2.6.6
X
X
X
X
X
X
Hepatitis testing
D
7.2.2.6.7
X
As clinically indicated
For Germany only: local HIV 
testing 
S
7.2.2.6.9
X


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Cycle 3
Subsequent Cycles
Day 1
End of Study Treatment 
(EoT)
30-Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150-Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
15
1
15
1
15
1
Imaging
Tumor evaluation per RECIST 
1.1
D
7.2.1
X
Following final PFS analysis; tumor evaluation per RECIST 1.1 
assessments are no longer required. Investigators are directed to 
follow local procedures for the frequency and modality of tumor 
assessments.
Chest, abdomen and pelvis 
CT or MRI (with contrast 
enhancement)
D
7.2.1
X
Following final PFS analysis; chest, abdomen and pelvis CT or MRI 
assessments are no longer required. Investigators are directed to 
follow local procedures for the frequency and modality of tumor 
assessments 
Brain imaging (CT or MRI)
D
7.2.1
X
Following final PFS analysis; brain imaging assessments are no longer required. Investigators are 
directed to follow local procedures.
Whole body bone scan
D
7.2.1
Following final PFS analysis; whole body bone scan assessments are no longer required. Investigators are 
directed to follow local procedures.
Localized bone CT, MRI or X-
ray
D
7.2.1
Following final PFS analysis; localized bone CT, MRI or X-ray assessments are no longer required. 
Investigators are directed to follow local procedures.
CT or MRI of other metastatic 
sites (e.g., neck)
D
7.2.1
Following final PFS analysis; CT or MRI of other metastatic sites are no longer required. Investigators are 
directed to follow local procedures.


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Cycle 3
Subsequent Cycles
Day 1
End of Study Treatment 
(EoT)
30-Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150-Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
15
1
15
1
15
1
Color Digital Photography 
(including a metric ruler) of 
skin lesions
D
7.2.1
X
Following final PFS analysis; color digital photography of skin lesion 
assessments are no longer required. Investigators are directed to 
follow local procedures for the frequency and modality of tumor 
assessments
Body Fluid/Tissue
D
7.2.1
Needle aspiration, biopsy or any other form of collection (e.g., paracentesis, punctuation) performed for any 
reason
Safety
Adverse events
D
7.2.2, 
8.1
Suspected AEs up to Day 150; non-suspected AEs up to Day 150 or start of new post treatment anti-
neoplastic medication, whichever is sooner.
Monitoring of new cutaneous malignancies should continue every month for 6 months following 
discontinuation of dabrafenib or until initiation of another antineoplastic therapy (refer to
Section 6.3.5.3).
Serious adverse events
D
8.2
Suspected SAEs up to Day 150 and beyond; non-suspected SAEs up to Day 150 or start of new post 
treatment anti-neoplastic medication, whichever is sooner.


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Cycle 3
Subsequent Cycles
Day 1
End of Study Treatment 
(EoT)
30-Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150-Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
15
1
15
1
15
1
Biomarkers
Newly acquired tumor tissue 
for central BRAF V600 
mutation testing, assessment 
of IO markers and potential 
companion diagnostic bridging 
study. Sampling schedule if 
DL1 or DL-1a is determined to 
be the regimen.
Note: if local BRAF V600 
mutation result is not 
available, the sample 
collected at 
screening/baseline will be 
used for screening and should 
be sent for central testing by 
Day -20
D
7.2.4.1.1
X
X
X 
(Anytime 
during 
Cycle 3)
Unscheduled: At disease progression and/or at a 
subsequent PD per response criteria for immunotherapy if 
subject continues treatment post progression, prior to the 
start of new antineoplastic therapy


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Cycle 3
Subsequent Cycles
Day 1
End of Study Treatment 
(EoT)
30-Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150-Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
15
1
15
1
15
1
Newly acquired tumor tissue 
for central BRAF V600 
mutation testing, assessment 
of immunemarkers and 
potential companion 
diagnostic bridging study. 
Sampling schedule if DL-1b is 
determined to be the regimen.
D
7.2.4.1.1
X
X
X
(Anytime 
during 
Cycle 4)
Unscheduled: At disease progression and/or at a 
subsequent PD per response criteria for immunotherapy if 
subject continues treatment post progression, prior to the 
start of new antineoplastic therapy


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Cycle 3
Subsequent Cycles
Day 1
End of Study Treatment 
(EoT)
30-Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150-Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
15
1
15
1
15
1


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period 
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Cycle 3
Subsequent Cycles
Day 1
End of Study Treatment 
(EoT)
30-Day Safety Follow Up
60-Day Safety Follow Up
90-Day Safety Follow Up
120-Day Safety Follow Up
150-Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to
-1
1
15
1
15
1
15
1
Optional Tumor biopsy on 
treatment
D
7.2.4.1.2
Anytime – depending on investigator 
assessment
Study Administration
PDR001 infusion
D
6.1.1.2
PDR001 400mg IV every 4 weeks
(It is possible for additional dosing 
regimens to be used based on emerging 
data from part 1.)
Trametinib/ Dabrafenib 
combination
D
6.1.1.2
Trametinib orally once daily and 
Dabrafenib orally twice daily every 28 
days
PK sampling of PDR001 (if 
DL1 or DL-1a is determined to 
be the regimen)
D
7.2.3.1.1
Following final PFS analysis data cut-off date 01-Jul-2020; PK and IG samples will no longer be collected or 
sent to central labs.
PK sampling of PDR001 (if 
DL-1b is determined to be the 
regimen)
D
7.2.3.1.1
PK sampling of trametinib and 
dabrafenib
D
7.2.3.1.2
Immunogenicity (IG) sampling
D
7.2.3.1.1
Following final PFS analysis data cut-off date 01-Jul-2020; PK and IG samples will no longer be collected or 
sent to central labs.
Survival Follow-up
D
7.1.8
X


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Table 7-3
Visit evaluation schedule: Double-blind, randomized, placebo-controlled part (Part 3) – visit schedule updated 
and is applicable following final PFS analysis 
Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1
Obtain Informed Consent
Study ICF
D
7.1.2
X
Pharmacogenetic ICF
D
7.2.4.2.1
X
IRT Registration-
Randomization
7.1.2.1
X
Treatment beyond progression 
ICF
D
6.1.5.1
X (subjects who meet the criteria 
outlined in Section 6.1.5.1)
Patient History
Demography
D
7.1.2.3
X
Inclusion/exclusion
D
5.2, 5.3
X
Past and current medical 
conditions including 
cardiovascular medical history 
and risk factors
D
7.1.2.3
X
Diagnosis and extent of cancer
D
7.1.2.3
X
Alcohol History
D
7.1.2.3
X
Smoking History
D
7.1.2.3
X


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1
HIV History (Note: for Germany 
only, a mandatory HIV test is 
required during screening using a 
local test)
S
7.1.2.3
X
Prior antineoplastic therapies 
(meds, surgery, radiation)
D
7.1.2.3
X
Prior/concomitant medications
D
7.1.2.3
From 30 days prior to starting study treatment until 150 Day safety follow-up or start of new 
antineoplastic medication, whichever is sooner. If new antineoplastic medication is started then 
only medications relative to the AEs/SAEs that are reported should be collected
Antineoplastic therapies since 
discontinuation of study treatment
D
7.1.2.3
X
X
X
X
X
X
Enrollment
Drug Supply (IRT)
S
7.1.2.1
X
End of Phase Disposition
D
7.1.4
X
X
X
Patient Reported Outcomes
PRO questionnaires should be administered at beginning of the scheduled study visit, prior to any tests performed, treatments administered or receipt of test results.
EORTC QLQ-C30
D
7.2.5.1
X
Following final PFS analysis; PRO assessments will no longer be collected.
EQ-5D-5L
D
7.2.5.2
X
Following final PFS analysis; PRO assessments will no longer be collected.
FACT-M subscale (16 questions)
D
7.2.5.3
X
Following final PFS analysis; PRO assessments will no longer be collected.


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1
Physical Examination
Physical Examination (complete)
S
7.2.2.1
X
As clinically indicated
Physical Examination (short)
S
7.2.2.1
X
X
X
X
30 days from the last dose 
of PDR001/placebo and 
every month for 6 months 
from the last dose of 
dabrafenib
Performance Status (ECOG)
D
7.2.2.4
X
X
X
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
Ophthalmic examination
D
7.2.2.5
X
X
As clinically indicated
12-lead ECG if DL1 is determined 
to be the regimen
D
7.2.2.7.1
X
X
As clinically 
indicated
X 
12-lead ECG if DL-1a or DL-1b is 
determined to be the regimen
D
7.2.2.7.1
X
C3D1, and as 
clinically 
indicated
X


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Amended Protocol Version 07 (Clean)
Protocol No. CPDR001F2301
Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1
Cardiac function (MUGA or 
ECHO)
D
7.2.2.7.2
X
X
C4D1 and every 
12 weeks and as 
clinically 
indicated
X
Laboratory Assessments
Hematology
D
7.2.2.6.1
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.6.2
X
X
X
X
X
X
X
X
Thyroid function-TSH
D
7.2.2.6.3
X
X
X
X
X
X
Thyroid Panel Free T3 and Free 
T4
D
7.2.2.6.3
X
Only if TSH is 
abnormal
Coagulation
D
7.2.2.6.4
X
C1D1, every 2 cycles for the first 12 
cycles and every 3 cycles thereafter 
as clinically indicated
As clinically indicated
Urinalysis (microscopy and 
macroscopic)
S
7.2.2.6.5
X
X
X
X
X
X
Serum Pregnancy Test
S
7.2.2.6.6
X
X
X
X
Urine Pregnancy Test
S
7.2.2.6.6
X
X
X
X
X
Hepatitis testing
D
7.2.2.6.7
X
As clinically indicated


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Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1
For Germany only: local HIV 
Testing
S
7.2.2.6.9
X
Imaging
Tumor evaluation per RECIST 1.1
D
7.2.1
X
Following final PFS analysis; tumor evaluation per RECIST 1.1 
assessments are no longer required. Investigators are directed to follow 
local procedures for the frequency and modality of tumor assessments.
Chest, abdomen and pelvis CT or 
MRI (with contrast enhancement)
D
7.2.1
X
Following final PFS analysis; chest, abdomen and pelvis CT or MRI 
assessments are no longer required. Investigators are directed to follow 
local procedures for the frequency and modality of tumor assessments.
Brain imaging (CT or MRI)
D
7.2.1
X
Following final PFS analysis; brain imaging assessments are no longer required. Investigators 
are directed to follow local procedures.
Whole body bone scan
D
7.2.1
Following final PFS analysis; whole body bone scan assessments are no longer required. Investigators 
are directed to follow local procedures.
Localized bone CT, MRI or X-ray
D
7.2.1
Following final PFS analysis; localized bone CT, MRI or X-ray assessments are no longer required. 
Investigators are directed to follow local procedures.


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Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1
CT or MRI of other metastatic 
sites (e.g., neck)
D
7.2.1
Following final PFS analysis; CT or MRI of other metastatic sites are no longer required. Investigators 
are directed to follow local procedures.
Color Digital Photography 
(including a metric ruler) of skin 
lesions
D
7.2.1
X
Following final PFS analysis; colour digital photography of skin lesions 
assessments are no longer required. Investigators are directed to follow 
local procedures for the frequency and modality of tumor assessments.
Body Fluid/Tissue
D
7.2.1
Needle aspiration, biopsy or any other form of collection (e.g., paracentesis, punctuation) performed for 
any reason
Safety
Adverse events
D
7.2.2, 8.1
Suspected AEs up to Day 150; non-suspected AEs up to Day 150 or start of new post treatment 
anti-neoplastic medication, whichever is sooner. 
Monitoring of new cutaneous malignancies should continue every month for 6 months following 
discontinuation of dabrafenib or until initiation of another antineoplastic therapy (refer to 
Section 6.3.5.3).
Serious adverse events
D
8.2
Suspected SAEs up to Day 150 and beyond; non-suspected SAEs up to Day 150 or start of new 
post treatment anti-neoplastic medication, whichever is sooner.


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Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1
Biomarkers
Tumor tissue (archival or new) for 
central BRAF V600 mutation 
testing, assessment of IO markers 
and potential companion 
diagnostic bridging study.
Note: if local BRAF V600 mutation 
result is not available, sample will 
be used for screening and should 
be sent for central testing by Day -
20
D
7.2.4.1.1
X


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Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1


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Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1


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Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1
Study Administration
PDR001 or placebo infusion
D
6.1.1
Regimen as determined by Safety 
Run In as one of the below 
options:
DL1: PDR001 400mg IV every 4 
weeks
DL-1a: PDR001 400mg IV every 8 
weeks
DL-1b: at C2D1, PDR001 400mg IV 
every 4 weeks
Trametinib/Dabrafenib 
combination
D
6.1.1
Trametinib orally once daily and 
Dabrafenib orally twice daily
PK sampling of PDR001 or 
placebo infusion (if DL1 or DL-1a 
is determined to be the regimen)
D
7.2.3.1.1
PK sampling of PDR001 or 
placebo infusion (if DL-1b is 
determined to be the regimen)
D
7.2.3.1.1
PK sampling of trametinib and 
dabrafenib
D
7.2.3.1.2
Following final PFS analysis data cut-off date 01-Jul-2020; PK and IG samples will no longer be 
collected or sent to central labs.


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Treatment (Cycle = 28 days)
Follow-Up Period
Category
Protocol Section
Screening/Baseline
Cycle 
1
Cycle 
2
Subsequent cycles
Day 1
End of Study Treatment 
(EoT)
30 Day Safety Follow Up
60- Day Safety Follow Up
90- Day Safety Follow Up
120- Day Safety Follow Up
150- Day Safety Follow Up
End of Post Treatment 
Follow Up
Survival Follow Up
Day of cycle
-28 
to -1
1
15
1
15
1
1
Immunogenicity (IG) sampling (if 
DL1 or DL-1a is determined to be 
the regimen)
D
7.2.3.1.1
Immunogenicity (IG) sampling (if 
DL-1b is determined to be the 
regimen)
D
7.2.3.1.1
Survival Follow-up
D
7.1.8
X


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7.1.1
Molecular pre-screening
Not applicable.
7.1.2
Screening
Written informed consent/assent must be obtained prior to any screening procedures. Screening 
assessments to confirm eligibility into the study should be performed as per visit evaluation 
schedule between Day-28 and Day-1. Serum pregnancy test must be conducted within 72 hours 
prior to start of study treatment and must be confirmed negative before the first dose of study 
treatment. Physical examinations and laboratory assessments performed as part of the screening 
evaluations will not require to be repeated prior to dosing if performed within 7 days prior to 
the first dose of study treatment. Laboratory results from the central laboratory will be used to 
determine subject’s eligibility. However, the site does not need to wait for the results of 
centrally-analyzed laboratory assessments when an immediate clinical decision needs to be 
made and in those cases locally unscheduled testing may be performed and used for eligibility 
assessments.
The cardiac eligibility criteria should be assessed with the local ECG report.
A subject who has a laboratory test result(s) that does not satisfy the entrance criteria may have 
the test(s) repeated. These test(s) may be repeated as soon as the investigator believes the re-
test result(s) is/are likely to be within the acceptable range to satisfy the entrance criteria, but 
should be completed within approximately 3 weeks of the original screening visit date. In this 
case, the subject will not be required to sign another ICF, and the original subject ID number 
assigned by the investigator will be used. In the event that the laboratory test(s) cannot be 
performed within 3 weeks of the original screening visit, or the re-test(s) do not meet the 
entrance criteria, or other eligibility criteria have changed and are not met anymore, the subject 
is considered a screen failure.
A new ICF will need to be signed if the investigator chooses to re-screen the subject after a 
subject has screen failed, however, the subject ID number will remain the same. All required 
screening activities must be performed when the subject is re-screened for participation in the 
study. An individual subject may only be re-screened once for the study. Once the number of 
subjects screened and enrolled is likely to ensure target enrollment, the Sponsor may close the 
study to further screening. In this case, the subjects who screen failed will not be permitted to 
re-screen.
Subjects will be enrolled based on local BRAF V600 mutation result as part of study inclusion 
criteria 9 (applicable to all study cohorts). The BRAF V600 mutation will be assessed using a 
validated tissue-based molecular test for BRAF V600 mutations. Immunohistochemistry is not 
an accepted method and liquid biopsy based BRAF V600 results cannot be used to enroll 
patients. The eCRF page for methods of local BRAF mutation testing must be completed for 
subjects whose tumor sample was tested by a local institutional assay. Verification of locally 
documented BRAF V600 mutation result must be completed prior to randomization. If the local 
lab uses a non-FDA approved BRAF V600 assay (FDA approved tests for BRAF V600 
mutations include: biomerieux THxID® BRAF Detection Kit and Roche Cobas 4800 BRAF 




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7.1.2.3
Subject demographics and other baseline characteristics
The data to be collected on subject characteristics at screening includes:
•
Demography (age, gender, childbearing potential, race and ethnicity, or as allowed by local 
regulations)
•
Past and current medical conditions including cardiovascular medical history and risk 
factors
•
Diagnosis and extent of cancer using AJCC edition 7 and 8
•
Alcohol history
•
Smoking history
•
HIV history (for Germany only: HIV test is required during screening using a local test)
•
Prior antineoplastic therapies (medications, radiation, surgeries)
•
Prior and current concomitant medications, surgical and medical procedures and significant 
non-drug therapies
Note: All other medications taken within 28 days or 5 half-lives, whichever is shorter before 
the first dose of study treatment is administered must be recorded on the Prior and current 
concomitant medication eCRF page and updated on an ongoing basis if there is new change to 
the medication.
Assessments to be performed at screening/baseline include;
•
Physical examination (e.g., performance status (ECOG), height, weight, vital signs, 
ophthalmic and skin examination)
•
Cardiovascular assessments (e.g., ECG, ECHO or MUGA)
•
Laboratory assessments (e.g., hematology, chemistry, thyroid function, coagulation, 
urinalysis, serum pregnancy test, hepatitis B, C test, and 
)
•
Tumor assessment (RECIST 1.1, color digital photography (including metric ruler for skin 
lesions)
•
Biomarker assessments in 
 tumor tissue
7.1.3
Treatment period
•
Study treatment will begin on Day 1 of Cycle 1.
•
Study treatment will continue until the subject experiences any of the following: disease 
progression according to RECIST 1.1 as determined by investigator, unacceptable toxicity 
that precludes further treatment, pregnancy, start of a new anti-cancer therapy, 
discontinuation at the discretion of the Investigator or subject, lost to follow-up, death, or 
study termination by the sponsor. 
•
Subjects may continue study treatment beyond disease progression by RECIST 1.1 until 
disease progression per response criteria for immunotherapy (if criteria stipulated in 
Section 6.1.5.1 are fulfilled), unacceptable toxicity, start of new anti-neoplastic therapy, 
withdrawal of consent, physician’s decision, lost to follow-up, death, or study is terminated 
by the sponsor. In case of continuation of study treatment beyond disease progression by 
RECIST 1.1, the subject will continue tumor assessments as outlined in Section 7.


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Visit frequency
•
Safety run-in part: visits will be scheduled for C1D1, (C1D8 for DL1 and DL-1a only), 
C1D15, C2D1, (C2D8 for DL-1b only), C2D15, C3D1, C3D15, C4D1, (C4D15 for DL-1a 
only), C5D1, and every 4 weeks thereafter. For details of assessment, refer to Table 7-1.
•
Biomarker cohort: visits will be scheduled for C1D1, C1D15, C2D1, C2D15, C3D1, C3D15, 
C4D1, and every 4 weeks thereafter. For details of assessment, refer to Table 7-2.
•
Randomized part: visits will be scheduled for C1D1, C1D15, C2D1, C2D15, C3D1, and 
every 4 weeks thereafter. For details of assessment, refer to Table 7-3.
Windows for scheduling assessments
•
Every effort must be made to follow the schedule of assessments within the windows outline 
in the protocol.
•
For Cycle 1, all assessments have a ± 3 day window, unless otherwise indicated.
•
After Cycle 1, all assessments have a ± 7 day window, unless otherwise indicated.
•
Subjects who discontinue study treatment must have an End of Treatment (EOT) visit 
performed ≤ 7 days after stopping study treatment.
7.1.4
Discontinuation of study treatment
Subjects may voluntarily discontinue from the study treatment for any reason at any time. If a 
subject decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g., telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the subject’s chart and on the appropriate eCRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, or become lost to follow-up for any other reason.
The investigator may discontinue study treatment for a given subject if, he/she believes that 
continuation would be detrimental to the subject’s well-being.
Study treatment must be discontinued under the following circumstances:
•
Emergence of specific adverse events or laboratory abnormalities under some 
circumstances as outlined in Section 6.3.
•
Pregnancy (pregnancy will be followed for outcome)
•
Use of prohibited treatment
•
Any protocol deviation that results in a significant risk to the subject’s safety
Subjects who become pregnant during the trial must be withdrawn (Section 8.4). Subjects who 
become pregnant must cease all tumor assessments regardless of whether or not they developed 
Progressive Disease according to investigator.
Subjects who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Section 7.2. If they fail to return for these 
assessments for unknown reasons, every effort (e.g., telephone, email, and letter) should be 
made to contact them as specified in Section 7.1.9.
Subjects who discontinue study treatment should be scheduled for an EOT visit as soon as 
possible and within 7 days of the last dose of study treatment, at which time all of the 


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assessments listed for the EOT visit will be performed. If a subject is discontinued from 
treatment at a study visit, the assessments performed at that visit will be considered as EOT 
assessments and do not need to be repeated. An End of Treatment Disposition eCRF page 
should be completed, giving the date and reason for stopping treatment. Subjects who 
discontinue due to disease progression should have an EOT visit and have disease progression 
biomarker samples collected.
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
In some circumstances subjects may be allowed to continue to receive study treatment beyond 
disease progression as per RECIST 1.1 criteria (Section 6.1.4). These subjects will continue 
assessments as outlined in Section 7, and will complete the EOT visit only after permanent 
discontinuation of study treatment. 
The physician can decide to discontinue the study treatment based on the risk benefit assessment 
following a discussion with the patient. 
Following final PFS analysis and results, subjects who discontinue treatment, for any reason, 
must continue to be followed for safety assessments and as part of the overall survival follow-
up until death, lost to follow-up, or withdrawal of consentas described in Section 7. 
Patients who have accepted to move to Post-Trial Access (PTA), as per local regulation, will 
perform the end of treatment visit. Upon completion of this visit, no further safety and survival 
follow-up will be conducted under this protocol for these patients.
7.1.4.1
Replacement policy
Part 1: Safety run-in
If a subject is considered as non-evaluable for the Dose-Determining Set (DDS), a new subject 
will be enrolled until at least the minimum number of 6 evaluable subjects is achieved within 
the cohort.
Part 2: Biomarker cohort
If not possible to collect at least three tumor biopsies (at screening, C1D15 and one additional 
biopsy on treatment), a new subject will be enrolled to allow for a sufficient number of 
evaluable subjects for the biomarker studies.
Part 3: Double-blind, randomized, placebo-controlled part
Subjects will not be replaced.
7.1.5
Withdrawal of study consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject does not want to participate in the study 
any longer, and does not allow any further collection of personal data.


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If a subject withdraws consent, the investigator should make a reasonable effort (e.g., telephone, 
e-mail, letter) to understand the primary reason for the subject’s decision to withdraw his/her 
consent and record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communication or follow up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and Rest of World (RoW): All biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements.
7.1.6
Follow up for safety evaluations
All subjects must be followed for safety up to 150 days after the last dose of PDR001/placebo. 
After the 30-day onsite safety follow-up visit, subjects will be followed (via telephone call or 
onsite visit if subject happens to be visiting the site) at 60, 90, 120 and 150 days after the last 
dose of PDR001/placebo (Appendix 3). 
In case where individual drug components of the study treatment are discontinued at different 
times, subjects must be followed for safety evaluation up to 150 days following the last dose of 
PDR001/placebo or up to 30 days after the last dose of dabrafenib or 120 days after the last 
dose of trametinib, whichever is longer. In addition, subjects will be followed for skin related 
toxicity every month for 6 months from the last dose of dabrafenib.
All safety assessments should be completed outlined in Section 7.1. However, if the subject 
begins post treatment antineoplastic medication before the 150-Day safety follow-up visit the 
collection of new SAEs and AEs unrelated to study medication will stop and thereafter only 
suspected AEs and suspected SAEs will continue to be collected up to Day 150. Suspected 
SAEs will continue to be collected beyond the 150-Day safety visit. Data collected should be 
added to the appropriate eCRF pages. For female subjects of child bearing potential, a 
pregnancy test will be performed at the time points listed in Section 7.1.
Data collected should be added to the Adverse Events eCRF and the Concomitant Medications 
eCRF.
Following the final PFS analysis and results, safety assessments will continue per protocol 
schedules outlined in Table 7-1, Table 7-2 and Table 7-3.


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For subjects who transferred to Post-Trial Access (PTA), no further safety follow-ups will be 
performed. 
7.1.7
Follow up for efficacy evaluations - 
Prior to the final PFS analysis (not applicable after primary end point interim analysis):
All subjects who discontinue study treatment without disease progression by RECIST 1.1 will 
continue tumor assessments as outlined in Section 7.1 until documented disease progression by 
RECIST 1.1, withdrawal of consent, lost to follow-up, or death irrespective of start of new anti-
neoplastic therapy. 
All subjects who continue treatment beyond disease progression per RECIST 1.1 
(see Section 6.1.5.1) will continue tumor assessments as outlined in Section 7 until confirmed 
progression per response criteria for immunotherapy, unacceptable toxicity, start of new anti-
neoplastic therapy, withdrawal of consent, physician’s decision, lost to follow-up, death or 
study is terminated by sponsor. 
Refer to Section 7.2.1.2 for details on additional tumor assessments that should be performed 
to confirm response or allow for further central analysis.
Following the final PFS analysis:
Efficacy data, other than overall survival, will no longer be collected. 
All subjects who discontinue study treatment will immediately be followed for safety 
assessments and as part of the overall survival follow-up until death, lost to follow-up, or 
withdrawal of consent as described in Section 7. 
There will not be an efficacy follow-up phase. Standard local medical practice may be applied 
for tumor assessment. There is no requirement to record any tumor assessment results in the 
eCRF and imaging data must not be sent to the central imaging vendor.
Additional required data will be collected such as post-treatment anti-neoplastic therapies. See 
Section 7.2.1 for further details. 
7.1.8
Survival follow-up
Subjects will enter the survival follow-up period once they complete the safety follow-up period. 
Subjects will then be contacted by telephone every 12 weeks to follow-up on their survival 
status. Any new antineoplastic medications that have been started since the last contact date 
will also be collected during these phone calls. 
Following the final PFS analysis, which did not demonstrate a significant treatment benefit, the 
study will remain open for further follow-up to collect additional survival and safety data. 
Updated safety and descriptive analyses of overall survival will be performed.
For subjects who transferred to Post-Trial Access (PTA), no further survival follow-ups will be 
performed.


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7.1.9
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the subject, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the subject, e.g., dates of telephone calls, 
registered letters, etc. A subject should not be considered lost to follow-up until due diligence 
has been completed. Subjects lost to follow up should be recorded as such on the appropriate 
Disposition eCRF.
7.2
Assessment types
7.2.1
Efficacy assessments 
Prior to the final PFS analysis:
Tumor response will be assessed locally according to the Novartis guideline version 3.2 based 
on RECIST 1.1 (Appendix 1). The imaging assessment collection plan is presented in 
Table 7-4. Details of the central review process will be described in the independent review 
charter.
Imaging data will be centrally collected and centrally checked for quality by an imaging CRO 
designated by Novartis. The local investigator’s assessment will be used for the primary 
endpoint analysis and for treatment decision making. Central review of the imaging data using 
RECIST 1.1 and tumor response criteria based on guidelines for immunotherapy (e.g., 
Seymour 2017) will be performed for sensitivity analysis and completed prior to planned 
database locks for the interim and final PFS/interim OS analyses. 
Information regarding prior interventions (e.g., radiotherapy), pre-existing radiographic 
findings that mimic metastatic disease at baseline/screening and prior interventions should be 
transmitted to the imaging CRO via the Baseline Clinical Form along with the baseline images. 
Sites must ensure the data entered on the form is consistent with the data entered in the clinical 
database.
Clinical data (e.g., physical exam, biopsy results, surgical procedures and pathology data (e.g., 
histology, cytology, fluid collections)) captured at baseline and on-study will be transmitted to 
the imaging CRO for review by a medical oncologist. Sites must ensure the data entered on the 
baseline form is consistent with the data entered in the clinical database.
Following the final PFS analysis:
Efficacy data, other than overall survival, will no longer be collected. 
All subjects who discontinue study treatment will immediately be followed for safety 
assessments and as part of the overall survival follow-up until death, lost to follow-up, or 
withdrawal of consent as described in Section 7. 
There will not be an efficacy follow-up phase. Standard local medical practice may be applied 
for tumor assessment. There is no requirement to record any tumor assessment results in the 
eCRF and imaging data must not be sent to the central imaging vendor.


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Additional required data will be collected such as post-treatment anti-neoplastic therapies. 
Table 7-4
Imaging assessment collection plan for Parts 1, 2, 3 
Procedure
Screening/Baseline
(Day -28 to Day -1)
During Treatment/Follow-up 
(± 7 day window)
Chest, abdomen and pelvis CT or 
MRI (with contrast enhancement)
Mandated
•
During treatment: C4D1 (± 7 
days), every 8 weeks, then from 
C22D1 (± 7 days) every 12 
weeks
•
End of Treatment (EOT): if a 
scan was not conducted within 
30 days prior to end of study 
treatment.
•
Efficacy follow-up: Every 12 
weeks starting from the last 
assessment until documented 
disease progression per 
RECIST 1.1 (unless meeting 
criteria for treatment beyond 
progression), withdrawal of 
consent, lost to follow-up, or 
death irrespective of start of 
new anti-neoplastic therapy
•
Refer to Section 7.2.1.2 for 
details on additional tumor 
assessments to perform in 
order to confirm response or 
allow for further central 
analysis.
•
Brain imaging (CT or MRI)
Mandated 
•
If lesions were documented at 
baseline or if clinically indicated, 
follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis.
Whole body bone scan
If clinically indicated
•
If clinically indicated
Localized bone CT, MRI or X-ray
For any lesions identified on the 
whole body bone scan that are 
not visible on the chest, abdomen 
and pelvis CT or MRI
•
If lesions were documented at 
baseline or if clinically indicated, 
follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis
Color digital photography (with 
scale/ruler) of skin lesions
For any skin lesions present
•
If skin lesions were documented 
at baseline or present on study, 
follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis.
CT or MRI of other metastatic 
sites (e.g., neck)
If clinically indicated
•
If lesions were documented at 
baseline or if clinically indicated, 
follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis.
During a Public Health emergency as declared by Local or Regional authorities i.e., pandemic, epidemic, or 
natural disaster, that limits or prevents on-site study visits, the collection of images may be modified by 
Novartis and will be communicated to the investigator


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7.2.1.1
Baseline imaging assessments
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1).
Any imaging assessments already completed during the regular work-up of the subject within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after 
randomization cannot be considered baseline images. The following assessments are required 
at screening/baseline:
•
Chest, abdomen and pelvis CT or MRI
•
Brain CT or MRI
•
Whole body bone scan, if clinically indicated
•
Localized bone CT, MRI or x-ray, for any lesions identified on the whole body bone scan 
that are not visible on the chest, abdomen and pelvis CT or MRI
•
Color photography, including a metric ruler to measure the size of the lesion, for any skin 
lesions present 
•
CT or MRI of other metastatic sites (e.g., neck), if clinically indicated
If a subject is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed.
Contrast enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then 
MRI without contrast or CT with/without contrast is acceptable.
If clinically indicated, a whole body bone scan must be performed per institutional standard of 
care [e.g., Tc-99 bone scan, whole body bone MRI, Fluorodeoxyglucose positron emission 
tomography (FDG-PET) or sodium fluoride (NaF) PET]. Localized CT, MRI or X-rays must 
be acquired for all skeletal lesions identified on the screening whole body bone scan, which are 
not visible on the chest, abdomen and pelvis CT/MRI.
If clinically indicated, CT or MRI of other areas (e.g., neck) of disease as appropriate should be 
performed.
If skin lesions are present at screening, color photography should be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can be 
determined from the photograph.
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion.
Chest x-rays and ultrasound should not be used to measure tumor lesions.


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7.2.1.2
Post-baseline imaging assessments
Prior to the final PFS analysis: 
Imaging assessments as described in Table 7-4 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing. Imaging 
assessments for response evaluation will be performed at Cycle 4 Day 1 (± 7 days) and every 8 
weeks during the first 18 months from the first dose of study treatment, and then from Cycle 22 
Day 1 (± 7 days), every 12 weeks thereafter until disease progression per RECIST 1.1, and/or 
response criteria for immunotherapy, death, lost to follow-up or withdrawal of consent. Imaging 
assessments should be scheduled using the randomization date as the reference date (not the 
date of the previous tumor assessment), and should be respected regardless of whether treatment 
with study treatment is temporarily withheld or unscheduled assessments performed.
An additional tumor assessment must be performed to confirm response (CR or PR) no less 
than 4 weeks after the criteria for response are first met. 
Subsequent disease progression per RECIST 1.1:
•
For subjects who discontinue study treatment without disease progression per RECIST 1.1, 
imaging assessments will be performed until disease progression per RECIST 1.1, death, 
lost to follow-up or withdrawal of consent. Subsequent to disease progression per RECIST 
1.1, at least two additional tumor assessments that are at least 4 weeks apart are 
recommended (for further central analysis) no less than 4 weeks after criteria for PD are 
first met. While tumor assessments after start of new anti-neoplastic therapy should be 
performed up to and including disease progression per RECIST 1.1, tumor assessments after 
start of new anti-neoplastic therapy post-progression are recommended however not 
required.
•
For subjects who continue treatment beyond progression, at least two additional tumor 
assessments that are at least 4 weeks apart must be performed (for further central analysis) 
no less than 4 weeks after criteria for PD per RECIST 1.1 are first met. Tumor assessments 
after start of new anti-neoplastic therapy are recommended however not required.
•
For subjects who discontinue treatment due to disease progression per RECIST 1.1, at least 
two additional tumor assessments that are at least 4 weeks apart are recommended (for 
further central analysis) no less than 4 weeks after the criteria for PD are first met. Tumor 
assessments after start of new anti-neoplastic therapy are recommended however not 
required.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment.
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, by the same 
local radiologist/physician throughout the study so that the comparison is consistent. The same 
is true for any new lesions that occur after start of treatment. They should be imaged using the 
same modality at each subsequent time point. New cutaneous lesions need to be color 


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photographed including a metric ruler to measure the size of the lesion. If an off-schedule 
imaging assessment is performed because progression is suspected, subsequent imaging 
assessments should be performed in accordance with the original imaging schedule.
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of IV contrast media. At the discretion of the 
Investigators, FDG-PET scans may be performed to document progressive disease per RECIST 
1.1 (Appendix 1).
All study imaging (including any off-schedule imaging studies) should be submitted to the 
designated imaging CRO for quality control.
Following the final PFS analysis:
Efficacy data, other than overall survival, will no longer be collected. 
All subjects who discontinue study treatment will immediately be followed for safety 
assessments and as part of the overall survival follow-up until death, lost to follow-up, or 
withdrawal of consent as described in Section 7. 
There will not be an efficacy follow-up phase anymore. Standard local medical practice may be 
applied for tumor assessment. There is no requirement to record any tumor assessment results 
in the eCRF anymore and imaging data must not be sent to the central imaging vendor anymore.
Additional required data will be collected such as post-treatment anti-neoplastic therapies. 
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, performance status, laboratory 
examinations, ECGs, cardiac imaging as well as collecting of the adverse events at every visit. 
For details on AE collection and reporting, refer to Section 8.
More frequent examinations may be performed at the investigator’s discretion, if clinically 
indicated.
During the COVID-19 pandemic that limits or prevents on-site study visits regular phone or 
virtual calls will occur (per existing protocol schedule or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until the participant can again visit 
the site.
Trial participants with confirmed active COVID-19 infection or presenting with symptoms 
indicative of COVID-19 infection such as fever, cough, difficulty breathing, sore throat, 
pneumonia, loss of sense of smell, or taste or feeling unwell with flu like symptoms may 
interrupt study treatment based on the risk benefit assessment; in case of suspected COVID-19 
infection, testing for COVID-19 is recommended as per local guidelines.
The investigator should assess the risks and benefits should a patient require treatment for 
COVID-19 infection, and the investigator may consider holding study treatment until the patient 
is stable to restart because of potential drug to drug interaction. All concomitant medications 
should be documented and all cases of patients with COVID-19 infection should be recorded 
in the eCRF.


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Trial participants who have been exposed to someone infected by COVID-19 and/or who 
develop symptoms indicative of potential COVID-19 infection should contact the Investigator 
and discuss the next steps; these may include self-quarantine, or may require further 
testing/follow-up as appropriate. Administration of the study treatment may be delayed based 
on the risk benefit assessment until the trial participant completes the quarantine and remains 
asymptomatic and/or COVID-19 infection has been ruled out. Investigators are recommended 
to follow the local health authority guidelines for prevention against COVID-19.
As per Section 2.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur for safety monitoring and discussion of the participant´s 
health status until it is safe for the participant to visit the site again.
7.2.2.1
Physical examination
A complete physical examination will be performed at screening and later as clinically indicated 
and will include the examination of general appearance, skin, neck (including thyroid), eyes, 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological assessments. If indicated based on medical history and/or symptoms, rectal, 
external genitalia, breast, and pelvic exams will be performed.
A short physical exam will be performed as per schedule in Table 7-1, Table 7-2 and 
Table 7-3 and will include the examination of general appearance, skin (including a full skin 
exam every 8 weeks), and vital signs (blood pressure and pulse).
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the subject’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the subject’s CRF.
7.2.2.2
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature and will be measured at screening and at subsequent time 
points as specified in Table 7-1, Table 7-2 and Table 7-3.
7.2.2.3
Height and weight
Height will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1, Table 7-2 and Table 7-3.
7.2.2.4
Performance status
Performance status will be assessed as described in the Table 7-1, Table 7-2 and Table 7-3. 
More frequent examinations may be performed at the investigator’s discretion, if medically 
indicated. ECOG Performance status scale will be used as described in the Table 7-5.


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Table 7-5
ECOG performance status scale
Score
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 housework, 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
7.2.2.5
Ophthalmic examination
A standard ophthalmic examination by an ophthalmologist will be performed as per schedule 
in Table 7-1, Table 7-2 and Table 7-3. The exam will include best corrected visual acuity, 
tonometry, slit lamp biomicroscopic examination, visual field examination, and dilated indirect 
fundoscopy with special attention to retinal abnormalities (dilation only required if clinically 
indicated). Optical coherence tomography is recommended at scheduled visits, and mandated 
if retinal abnormalities are suspected. Other types of ancillary testing including color fundus 
photography and fluorescein angiography are also recommended if clinically indicated.
7.2.2.6
Laboratory evaluations
A central laboratory will be used for analysis of scheduled hematology, biochemistry, and other 
blood specimens collected as part of safety monitoring (as detailed in Table 7-6), except 
urinalysis and pregnancy tests. The frequency of the assessments is indicated in the relevant 
Visit Evaluation Schedule (Table 7-1, Table 7-2 and Table 7-3).
For assessment of subjects’ eligibility to the study, laboratory results from the central laboratory 
will be used. However, the site does not need to wait for the results of centrally-analyzed 
laboratory assessments when an immediate clinical decision needs to be made and in those cases 
locally unscheduled testing may be performed and used for eligibility assessments.
Local laboratory assessments may be performed if medically indicated or when the treating 
physician cannot wait for central laboratory results for decision making. In this particular 
situation, the blood sample obtained at the same time point should be submitted to the central 
laboratory for analysis in parallel with local analysis.
The results of the local laboratory will be recorded in the eCRF if the following criteria are met:
•
a treatment decision was made based on the local results, or
•
there are no concomitant central results available
Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in a separate Laboratory manual.
The CRA will obtain the local laboratory reference ranges and a copy of the laboratory 
certification for all laboratory results that are entered into the eCRF.
As per Section 2.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 


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if participants cannot visit the site for protocol specified safety lab assessments, an alternative 
Lab (local) collection site may be used.
Table 7-6
Clinical laboratory parameters collection plan for all 3 parts
Test Category
Test Name
Hematology
Hemoglobin, Platelets, White blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands, Other)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, Lactate dehydrogenase (LDH), Calcium, 
Magnesium, Phosphorus, Sodium, Potassium, Chloride, Creatinine, Creatine kinase, 
Direct Bilirubin, Total Bilirubin, Total Cholesterol, Blood Urea Nitrogen (BUN) or Urea, 
Uric Acid, Amylase, Lipase, Glucose (fasting or non-fasting)
Thyroid
At baseline: TSH (Thyroid Stimulation Hormone), Free T3 and Free T4
At the subsequent visits as indicated in Table 7-1, Table 7-2 and Table 7-3: TSH only.
If TSH is abnormal, central lab will test Free T3 and Free T4
Coagulation
International normalized ratio (INR), Activated partial thromboplastin time (APTT)
Urinalysis
Local Laboratory: Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, 
Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
If dipstick is abnormal then perform local laboratory Microscopic Panel (Red Blood 
Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells)
Pregnancy Test
A serum pregnancy test must be performed at screening (at the local laboratory) ≤ 72 
hours before first dose of study treatment, at EOT, at 30-day and 150 day safety follow-
up.
A local laboratory urine pregnancy test must be performed at day 1 of every cycle 
beginning with cycle 2, and at home every 30-days after the 30-day safety follow-up 
visit until 120-day follow-up.
Hepatitis markers
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR
Virology
For Germany only: Local HIV testing at screening
7.2.2.6.1 Hematology
Hematology assessments listed in Table 7-6 will be measured according to the relevant Visit 
Evaluation Schedule (Table 7-1, Table 7-2 and Table 7-3). More frequent hematology testing 
may also be performed as medically necessary. Additional results from unscheduled 
hematology lab evaluations should be recorded on the appropriate Unscheduled Visit eCRF.
7.2.2.6.2 Clinical chemistry
Blood chemistry assessments listed in Table 7-6 will be measured according to the relevant 
Visit Evaluation Schedule (Table 7-1, Table 7-2 and Table 7-3).
More frequent clinical chemistry testing may also be performed as medically necessary. 
Additional results from unscheduled clinical chemistry lab evaluations should be recorded on 
the appropriate Unscheduled Visit eCRF.
It should be noted in the subject’s eCRF if the subject was fasting at the time of blood sampling.
7.2.2.6.3 Thyroid function
Thyroid function assessments outlined in Table 7-6 will be performed according to the relevant 
Visit Evaluation Schedule (Table 7-1, Table 7-2 and Table 7-3).
Thyroid function will be performed at:


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•
Screening/baseline: TSH, Free T3, Free T4
•
Day 1 of subsequent cycles, EoT, 30-day safety follow-up: TSH only
•
If TSH is abnormal, central lab will test Free T3 and Free T4.
7.2.2.6.4 Coagulation
Coagulation assessments listed in Table 7-6 will be performed according to the relevant Visit 
Evaluation Schedule (Table 7-1, Table 7-2 and Table 7-3).
7.2.2.6.5 Urinalysis
Urinalysis panel outlined in Table 7-6 will be assessed according to the relevant Visit 
Evaluation Schedule (Table 7-1, Table 7-2 and Table 7-3).
Abnormal findings will be followed up with a microscopic evaluation and/or additional 
assessments as clinically indicated. A microscopic evaluation (WBC/HPF, RBC/HPF, and any 
other evaluations depending on macroscopic findings) need only to be performed if the 
urinalysis result is significantly abnormal.
7.2.2.6.6 Pregnancy and assessments of fertility
Women of child-bearing potential will have serum pregnancy tests within 72 hours prior to the 
first dose of study treatment. Monthly urine pregnancy tests will then be required to be 
performed on day 1 of every cycle beginning with cycle 2, followed by a serum pregnancy test 
at the End of Treatment visit, 30-Day and 150-Day Safety follow-up visit. After the 30-Day 
Safety Follow-up visit, women of child-bearing potential will perform at-home urine pregnancy 
testing every 30 days using kits provided until the 120-Day follow-up telephone call visit. Every 
effort must be made for the women of child bearing potential to return to the site for the final 
pregnancy test. However, if the subject is unable to return then the subject will administer the 
urine pregnancy test at home using the kit provided. For all pregnancy tests performed at home, 
the site personnel will follow-up with the subject via telephone call to collect the date and the 
test results and document the information in the subject’s source documents. If the subject 
returns to the site for the serum pregnancy test at the 150 day safety follow up the results must 
be documented in the subject’s source documents.
Women of child-bearing potential will be instructed to contact the site immediately at any time 
during the study (on-treatment or during follow-up) should they have a positive pregnancy test.
As per Section 2.7, during a Public Health emergency declared by Local or Regional authorities’ 
i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, if 
participants cannot visit the site to have serum pregnancy tests, urine pregnancy test kits may 
be used. Relevant participants can perform the urine pregnancy test at home and report the result 
to the site. It is important that participants are instructed to perform the urine pregnancy test 
first and only if the test result is negative proceed with the administration of the study treatment. 
A communication process should be established with the participant so that the site is informed
and can verify the pregnancy test results (e.g., following country specific measures).


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7.2.2.6.7 Hepatitis marker
Hepatitis panels listed in Table 7-6 will be performed at screening and as clinically indicated 
while on study treatment.
HBV-DNA serology (including HBV-DNA, HBsAg, HBsAb, HBcAb) and HCV RNA-PCR 
test will be performed at baseline screening (≤ 28 days prior to start of study treatment) and as 
clinically indicated (hepatitis markers should be evaluated for precautionary safety monitoring 
of viral re-activation while on study treatment).
During the screening period, subjects must be screened for HBV and HCV (current or past 
history of infection). Careful medical history must be taken for all subjects to look for risk 
factors (family history of HBV and HCV, intravenous drug abuse, unprotected sex, dialysis, 
blood transfusions, etc.), and any past or present HBV symptoms (e.g., jaundice, dark urine, 
light colored stools, right upper quadrant pain).
Hepatitis B
At screening, all subjects will be tested for:
•
HBV-DNA level
•
Hepatitis B surface antigen (HBsAg)
•
Hepatitis B core antibody (HBcAb)
•
Hepatitis B surface antibody (HBsAb)
Hepatitis C
At screening, all subjects will be tested for quantitative HCV RNA-PCR.
After start of the study treatment and until 150-day safety follow-up, testing for HBV and HCV 
should be performed if clinically indicated (for example: rule out viral causality in case of DILI).
7.2.2.6.8 Cytokine analysis
Samples for cytokine analysis listed in Table 7-6 will be collected at the following time points:
•
Screening/Baseline
•
On an ad-hoc basis in case a subject has an adverse event suspected to be a cytokine 
release syndrome. In such case, this assessment should be performed at the following time 
points:
•
within 5 hours (or as soon as possible) after the occurrence of the adverse event,
•
one week after the occurrence of the adverse event.
Samples for cytokine panel at screening will be stored below -70°C.
7.2.2.6.9 HIV testing
For subjects in Germany only, a local test for HIV must be performed at screening according to 
the relevant Visit Evaluation Schedule (Table 7-1, Table 7-2, or Table 7-3).


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7.2.2.7
Cardiac assessments
7.2.2.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed according to the relevant Visit Evaluation Schedule 
(Table 7-1, Table 7-2 and Table 7-3).
Standard 12 lead ECG (single or triplicate) will be performed after the subject has been resting 
for approximately 10 min prior to each ECG collection time point according to the relevant 
assessment schedule (Table 7-7). Additional, unscheduled, ECGs may be performed at the 
discretion of the investigator at any time during the study as clinically indicated. Unscheduled 
ECGs with clinically significant findings should be collected in triplicate.
Triplicate ECGs should be recorded approximately 2 minutes apart. The mean QTcF value 
should be calculated from each of the triplicate ECGs assessments. All ECGs need to be 
collected and copies kept in the medical record for central review, if requested by the sponsor. 
Table 7-7
ECG collection plan for safety run-in (part 1), biomarker cohort (part 
2), and randomized part (part 3)
Cycle
Day
Time
ECG Type
Number of ECG
Screening/baseline
-28 to -1
Anytime
12 Lead
3
2 a
1
1 hr after PDR001 (or 
placebo) administration
12 Lead
3
3 b
1
1 hr after PDR001 (or 
placebo) administration
12 Lead
3
Unscheduled
As clinical 
indicated
Anytime
12 Lead
1 (3 if clinically 
significant)
End of treatment
Anytime
12 Lead
1 
a. Part 1: DL1 cohort only; Parts 2 & 3: if DL1 is determined to be the regimen
b. Part 1: DL-1a or DL-1b cohort only; Parts 2 & 3: if DL-1a or DL-1b is determined to be the regimen
Twelve (12)-lead ECGs will be obtained using an ECG machine that automatically calculates 
heart rate and measures PR, QRS, QT, and QTcF intervals. All ECG assessments will be 
performed in the supine position. ECG data will be read and interpreted locally.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
eCRF page. Each ECG tracing should be labeled with the study number, subject initials (where 
regulations permit), subject number, date, and kept in the source documents at the study site.
Clinically significant abnormalities present when the subject signed informed consent should 
be reported on the Medical History eCRF page. Clinically significant findings must be 
discussed with Novartis prior to enrolling the subject in the study. New or worsened clinically 
significant findings occurring after informed consent must be recorded on the Adverse Events 
eCRF page.
7.2.2.7.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram
Decreases of the LVEF have been observed in subjects receiving trametinib. Therefore, 
ECHO/MUGAs must be performed to assess cardiac ejection fraction in regular intervals 
according to the relevant schedule (Table 7-1, Table 7-2 or Table 7-3).




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Table 7-8
Parts 1 & 2 Safety run-in and biomarker cohorts: Blood (serum) 
collection schedule for PDR001 PK and IG
Cycle
Day
Scheduled time 
point (hours)
Dose 
reference ID
PK Sample 
number
IG Sample 
number
1
1
Predose/0 hr a
1
101
201
1
1
End-of-Infusion a 
(within 2 hr)
1
102
1
8
Anytime a
1
103
1
15
Anytime a
1
104
2
1
672 (±24h) hr / 0 hr 
pre-C2D1 dose
1/2 b
105
202
2
15
Anytime
2
106
3
1
672 (±24h) hr / 0 hr 
pre-C3D1 dose
2/3 b
107
203
3
1
End-of-Infusion (within 
2 hr)
3
108
4
1
672 (±24h) hr / 0 hr 
pre-C4D1 dose
3/4 b
109
204
5
1
Predose/0 hr
5
110
205
6
1
Predose/0 hr
6
111
206
7
1
Predose/0 hr
7
112
207
8
1
Predose/0 hr
8
113
208
9
1
Predose/0 hr
9
114
209
10
1
Predose/0 hr
10
115
210
11
1
Predose/0 hr
11
116
211
12
1
Predose/0 hr
12
117
212
Every 6 Cycle after 
C12D1
1
Predose/0 hr
13+
118+
213+
EOT
-
Anytime
N/A
197
297
30-day safety 
follow-up visit c
-
Anytime
N/A
198
298
150-day safety 
follow-up visit c
-
Anytime
N/A
199
299
Unscheduled and at 
the time of 
progression or AE
N/A
Anytime
N/A
1001+
2001+
a PK and immunogenicity samples for PDR001 will not be collected during Cycle 1 for the DL-1b dosing 
regimen during Part 1, or if DL-1b is the selected dosing regimen for Part 2, and at Cycle 1 Day 8 for Part 2. 
b The first Dose Reference ID (DRID) is for last dose the patient received prior to the collection of the PK 
sample, while the second DRID is for the current dose
c If PDR001 is permanently discontinued prior to dabrafenib and/or trametinib, 30 day and 150 day safety follow 
up visits should be based on the last dose of PDR001.
•
All predose samples must be collected within 30 min before the infusion begins
•
An unscheduled PK samples and immunogenicity sample should be collected up on confirmed disease 
progression.
•
Unscheduled PK and immunogenicity samples may be collected at any time if clinically indicated or at the 
Investigator’s discretion and must be sequentially numbered as 1001, 1002, 1003, etc. for PK samples, 
and 2001, 2002, 2003, etc. for immunogenicity samples.
•
After the primary Clinical Study Report (CSR) data cut-off date 01-Jul-2020 is reached, no additional PK 
and IG samples will be collected for the subjects still on-going on the study.


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Table 7-9
Part 3 Double-blind, randomized, placebo-controlled part: Blood 
(serum) collection schedule for PDR001/placebo PK and IG
Cycle
Day
Scheduled time 
point (hours)
Dose 
reference ID
PK Sample 
number
IG Sample 
number
1
1
Pre-C1D1 dose a
1
301
401
1
1
End-of-Infusion a 
(within 2 hr)
1
302
2
1
Predose/0 hr
2
303
402
3
1
Predose/0 hr
3
304
403
3
1
End-of-Infusion
(within 2 hr)
3
305
4
1
Predose/0 hr
4
306
404
5
1
Predose/0 hr
5
307
405
6
1
Predose/0 hr
6
308
406
7
1
Predose/0 hr
7
309
407
8
1
Predose/0 hr
8
310
408
9
1
Predose/0 hr
9
311
409
10
1
Predose/0 hr
10
312
410
11
1
Predose/0 hr
11
313
411
12
1
Predose/0 hr
12
314
412
Every 6 Cycle after 
C12D1
1
Predose/0 hr
13+
315+
413+
EOT 
-
Anytime
N/A
397
497
30-day safety 
follow-up visit b.
-
Anytime
N/A
398
498
150-day safety 
follow-up visit b.
-
Anytime
N/A
399
499
Unscheduled and 
at the time of 
progression or AE
N/A
Anytime
N/A
3001+
4001+
a If DL-1b is the selected dosing regimen for the randomized part (part 3), PK and IG samples for PDR001 will 
not be collected during Cycle 1.
b.If PDR001/placebo is permanently discontinued prior to dabrafenib and/or trametinib, 30 day and 150 day 
safety follow up visits should be based on the last dose of PDR001/placebo.
•
All predose samples must be collected within 30 min before the infusion begins
•
An unscheduled PK samples and IG samples should be collected up on confirmed disease progression.
•
Unscheduled PK and IG samples may be collected at any time if clinically indicated or at the Investigator’s 
discretion and must be sequentially numbered as 3001, 3002, 3003, etc. for PK samples, and 4001, 4002, 
4003, etc. for IG samples.
•
After the primary CSR data cut-off date 01-Jul-2020 is reached, no additional PK and IG samples will be 
collected for the subjects still on-going on the study.
7.2.3.1.2 Pharmacokinetic sampling for dabrafenib and trametinib
PK blood sampling schedule for dabrafenib and trametinib is outlined in Table 7-10.


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Table 7-10
Part 1 & 2 Safety run-in and biomarker cohorts: Pharmacokinetic 
blood (plasma) collection schedule for trametinib and dabrafenib
Cycle
Day
Scheduled 
time point 
(hours)
Trametinib
Dose 
reference 
ID 
Dabrafenib
Dose 
reference 
ID 
Trametinib
Dose 
reference 
ID
Dabrafenib
Dose 
reference 
ID
PK 
Sample 
number
Refers to the last dose 
taken before PK 
collection
Refers to the dose taken 
on the day of PK 
collection
1
1
Predose/0 hr
31
61
701
1
15
Predose/0 hr
321
621
32
62
702
1
15
Between 1 and 
3 hr post-dose
32
62
703
2
1
Predose/0 hr
331
631
33
63
704
2
15
Predose/0 hr
341
641
34
64
705
3
1
Predose/0 hr
351
651
35
65
706
3
1
Between 2 and 
12 hr post-dose
35
65
707
4
1
Predose/0hr
361
661
36
66
708
4
1
Between 2 and 
12 hr post-dose
36
66
709
5
1
Predose/0 hr
371
671
37
67
710
6
1
Predose/0 hr
381
681
38
68
711
7
1
Predose/0 hr
391
691
39
69
712
8
1
Predose/0 hr
401
701
40
70
713
9
1
Predose/0 hr
411
711
41
71
714
10
1
Predose/0 hr
421
721
42
72
715
11
1
Predose/0 hr
431
731
43
73
716
12
1
Predose/0 hr
441
741
44
74
717
Every 6 
Cycle after 
C12D1
1
Predose/0 hr
451+
751+
45+
75+
718+
EOT
1
Anytime
N/A
N/A
N/A
N/A
799
Unscheduled
N/A
Anytime
N/A
N/A
N/A
N/A
7001+
•
All predose samples must be collected prior to dosing on PK day. For pre-dose samples, the date and time 
of the last dose taken before PK collection and the date and time of the first dose taken after PK collection 
should be recorded in Dose Administration Record (DAR) for dabrafenib and trametinib CRF page. An 
unscheduled PK sample should be collected up on confirmed disease progression.
•
Unscheduled PK sample may be collected at any time if clinically indicated or at the Investigator’s 
discretion and must be sequentially numbered as 7001, 7002, 7003, etc.
•
After the primary CSR data cut-off date 01-Jul-2020 is reached, no additional PK samples will be collected 
for the subjects still on-going on the study.


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Table 7-11
Part 3 Double-blind, randomized, placebo-controlled part: 
Pharmacokinetic blood (plasma) collection schedule for trametinib 
and dabrafenib
Cycle
Day
Scheduled 
time point 
(hours)
Trametinib
Dose 
reference 
ID 
Dabrafenib
Dose 
reference ID 
Trametinib
Dose 
reference 
ID 
Dabrafenib
Dose 
reference ID 
PK 
Sample 
number
Refers to the last dose 
taken before PK 
collection
Refers to the dose taken 
on the day of PK 
collection
1
1
Predose/0 hr
31
61
801
2
1
Predose/0 hr
321
621
32
62
802
2
1
Between 1 
and 3 hr post-
dose
32
62
803
3
1
Predose/0 hr
331
631
33
63
804
3
1
Between 2 
and 12 hr 
post-dose
33
63
805
4
1
Predose/0 hr
341
641
34
64
806
4
1
Between 2 
and 12 hr 
post-dose
34
64
807
5
1
Predose/0 hr
351
651
35
65
808
6
1
Predose/0 hr
361
661
36
66
809
7
1
Predose/0 hr
371
671
37
67
810
8
1
Predose/0 hr
381
681
38
68
811
9
1
Predose/0 hr
391
691
39
69
812
10
1
Predose/0 hr
401
701
40
70
813
11
1
Predose/0 hr
411
711
41
71
814
12
1
Predose/0 hr
421
721
42
72
815
Every 6 
Cycle after 
C12D1
1
Predose/0 hr
431+
731+
43+
73+
816+
EOT
1
Anytime
N/A
N/A
N/A
N/A
899
Unscheduled
N/A
Anytime
N/A
N/A
N/A
N/A
8001+
•
All predose samples must be collected prior to dosing on PK day. For pre-dose samples, the date and time 
of the last dose taken before PK collection and the date and time of the first dose taken after PK collection 
should be recorded in DAR for dabrafenib and trametinib CRF page. An unscheduled PK sample should 
be collected up on confirmed disease progression.
•
Unscheduled PK sample may be collected at any time if clinically indicated or at the Investigator’s 
discretion and must be sequentially numbered as 3001, 3002, 3003, etc.
•
After the primary CSR data cut-off date 01-Jul-2020 is reached, no additional PK samples will be collected 
for the subjects still on-going on the study.
7.2.3.2
Analytical method
Bioanalysis for PK and IG assessment will employ the validated assays:
1. The assay to quantify PDR001 is a validated LC/MS assay.




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Biomarker sample collection plan
Sample Type
Volume
Visit
Time Point
Tumor samples
assessment of IO markers 
and a potential companion 
diagnostic bridging study
(Core, excisional and 
incisional biopsies are 
acceptable. Fine needle 
aspirates are not acceptable 
sample types.)
must be submitted.
should be sent for 
testing by Day -20.
2.
If an archival sample is 
being submitted, then 
samples collected 
within 3 months prior 
to study treatment 
initiation is strongly 
recommended.
3.
If slides are being 
provided, only freshly 
cut slides are 
acceptable. Slide cut 
date must be provided 
on the requisition form.
Screening
Anytime during Screening 
prior to study treatment on 
C1D1.
Cycle 1 Day 15 
(Part 3)
C1D15 + 7 day window
Cycle 3 
(Part 1)
(Part 3 only if DL1 or 
DL-1a is determined 
to be the regimen)
Anytime
Cycle 4 
(Part 3 only if DL-1b 
is determined to be 
the regimen)
Anytime
Optional
Newly acquired tumor biopsy
(Core, excisional and 
incisional biopsies are 
acceptable. Fine needle 
aspirates are not acceptable 
sample types.)
Please refer to the lab 
manual
Unscheduled (at 
disease progression 
and/or at a 
subsequent PD per 
response criteria for 
immunotherapy if 
subject continues 
treatment post 
progression).
At the time of disease 
progression, prior to the 
start of new antineoplastic 
therapy


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Biomarker sample collection plan
Sample Type
Volume
Visit
Time Point
Tumor samples
Cycle 4 Day 1 
(Part 3 only if DL-1b 
is determined to be 
the regimen)
Pre-dose
10 mL
Unscheduled (at 
disease progression 
and/or at a 
subsequent PD per 
response criteria for 
immunotherapy if 
subject continues 
treatment post 
progression).
At the time of disease 
progression, prior to the 
start of new antineoplastic 
therapy




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Biomarker sample collection plan
Sample Type
Volume
Visit
Time Point
Cycle 3 (if DL1 or DL-
1a is determined to 
be the regimen)
Cycle 4 (if DL-1b is 
determined to be the 
regimen)
Anytime
Newly acquired tumor biopsy 
must be provided for 
assessment of IO markers.
(Core, excisional and 
incisional biopsies are 
acceptable. Fine needle 
aspirates are not acceptable 
sample types.)
manual
Unscheduled (at 
disease progression 
and/or at a 
subsequent PD per 
response criteria for 
immunotherapy if 
subject continues 
treatment post 
progression).
At the time of disease 
progression prior to the 
start of new antineoplastic 
therapy
Optional
Newly acquired tumor biopsy 
for IO assessment
(Core, excisional and 
incisional biopsies are 
acceptable. Fine needle 
aspirates are not acceptable 
sample types.)
Please refer to the lab 
manual
Anytime
Depending on investigator assessment
Blood samples


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Biomarker sample collection plan
Sample Type
Volume
Visit
Time Point
7.2.4.1
Biomarker assessments in tumor tissue
7.2.4.1.1 Mandatory tumor sample collection
A mandatory newly acquired biopsy (preferred) or an archival specimen obtained at or since 
the time of diagnosis (within 3 months prior to study treatment start is strongly recommended) 
must be provided during screening prior to the first dose of study treatment.






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7.2.4.2.7 Optional additional biomarkers assessments upon adverse event
If FFPE tissue is obtained as part of the evaluation of an AE that is suspected to be treatment-
related (e.g., skin biopsy for rash), Novartis may request that remaining tissue to be submitted 
for central evaluation to gain further understanding of the AE, or other safety findings 
associated with that AE. For these reasons, additional analyses (similar to the ones described 
above for the baseline, on treatment and at disease progression biopsies) may be conducted on 
this material. In addition, an unscheduled blood sample collection may be requested in case of 
suspected adverse events and once the suspected adverse event is resolved.


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7.2.5
Patient reported outcomes 
The European Organization for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, version 3.0), the EuroQoL 5-level instrument (EQ-5D-5L, 
tablet version), and the Melanoma Subscale of the Functional Assessment of Cancer Therapy–
Melanoma (FACT-M) will be used to evaluate patient-reported outcome measures of health-
related quality-of-life, functioning, disease symptoms, treatment-related side effects, and global 
health status. The EORTC QLQ-C30, EQ-5D-5L and Melanoma Subscale of the FACT-M are 
recognized as reliable and valid measures (Aaronson 1993, Rabin 2001, Cormier 2008) 
frequently used in clinical trials of patients with advanced or metastatic cancer.
As per Section 2.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
Clinical Outcomes Assessment (COA) data may be collected remotely (no longer applicable 
per protocol amendment 06).
Prior to the final PFS analysis:
All patient-reported outcomes (PRO) data will be collected using an electronic tablet device. 
All PRO assessments should be administered in the patients’ local language according to the 
Visit Evaluation Schedule in Table 7-3, prior to any tests, treatments or receipt of results from 
any test to avoid biasing the patient’s perspective. 
Patients should be given sufficient space and time to complete all study questionnaires and all 
administered questionnaires should be reviewed for completeness. If missing responses are 
noted, patients should be encouraged to complete any missing responses. Attempts should be 
made to collect responses to all questionnaires for all patients, including from those who 
discontinue prior to the study evaluation completion visit, however, if patients refuse to 
complete questionnaires, this should be documented in study source records. Patient’s refusal 
to complete study questionnaires are not protocol deviations.
Completed questionnaires, including both responses to the questions and any unsolicited 
comments written by the patient, should be reviewed and assessed by the investigator before 
the clinical examination for responses which may indicate potential AEs or SAEs. This review 
should be documented in study source records.
If an AE or SAE is confirmed then the physician should record the event as instructed in 
Section 8 of this protocol. Investigators should not encourage the patients to change responses 
reported in questionnaires.
Following primary PFS analysis
PRO data will no longer be collected and any additional data will not be analysed.
7.2.5.1
EORTC QLQ-C30
The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-
item measures. These include five functional scales (physical, role, emotional, cognitive and 
social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items 


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(dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global 
health status/QoL scale (Aaronson 1993).
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Thus, a high score for a functional scale represents a high / 
healthy level of functioning; a high score for the global health status / QoL represents a high 
QoL, but a high score for a symptom scale / item represents a high level of symptomatology / 
problems. All scoring will follow the scoring procedures defined by the EORTC Scoring 
Manual (Fayers 2001).
7.2.5.2
EQ-5D-5L
The EQ-5D-5L (tablet version) is a standardized measure of health utility that provides a single 
index value for one’s health status. The EQ-5D-5L is frequently used for economic evaluations 
of health care and has been shown to be a valid and reliable instrument (The EuroQol Group 
1990, Rabin 2001). The EQ-5D-5L contains one item for each of five dimensions of Health 
Related QoL (HRQoL) (i.e., mobility, self-care, usual activities, pain or discomfort, and anxiety 
or depression). Response options for each item vary from having no problems (e.g., “…no 
problems walking about”), moderate problems (e.g., “…some problems walking about”), or 
extreme problems (e.g., “…unable to walk about”). Subject responses to the five dimensions of 
HRQoL reflect a specific health state that corresponds to a population preference weight for 
that state on a continuous scale of 0 (death) to 1 (perfect health). A visual analog scale (ranging 
from 0 to 100) is also included to capture subject’s rating of their overall health status. Higher 
scores of the EQ-5D-5L represent better health states. All scoring and handling of data will 
follow the User’s Guide defined by the EuroQoL Group (Reenen 2015).
7.2.5.3
Functional Assessment of Cancer Therapy–Melanoma (FACT-M)
The Functional Assessment of Cancer Therapy–Melanoma (FACT-M) quality of life 
questionnaire consists of the FACT-General (FACT-G) plus the Melanoma Subscale and the 
Melanoma Surgery Subscale, which complement the general scale with items specific to quality 
of life (QoL) in melanoma. Higher scores on all the FACT-M scales indicate a higher quality 
of life. In psychometric testing FACT-M questionnaire has been shown to be a reliable and 
valid instrument for subjects with melanoma that can be used for the assessment of QoL in 
clinical trials (Cormier 2008). For the purpose of this study the 16 items that comprise the 
Melanoma Subscale of the FACT-M are used.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after subject’s signed informed consent 
has been obtained.
Subjects whose BRAF V600 mutation status is known will sign the main study ICF.


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Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the subject’s CRF. Adverse event monitoring should 
be continued for at least:
•
150 days following the last dose of PDR001/placebo
•
until the start of a new post-treatment antineoplastic medication if sooner than the 150 
days mentioned above. If a subject starts a post-treatment antineoplastic therapy, then only 
adverse events suspected to be related to study treatment should be collected out to 150 
days after discontinuation of PDR001/placebo.
•
30 days after the last dose of dabrafenib or 120 days after the last dose of trametinib, if the 
subject continued the combination partner more than 150 days after the last dose of 
PDR001/placebo)
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event.
Adverse events will be assessed and graded according to the CTCAE v4.03 
(...//ctep.cancer.gov).
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the subject 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the subject during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine:
1. The severity grade (CTCAE v4.03 Grade 1-5)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
and which seriousness criteria have been met


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7. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For Grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the eCRF noting 
the start date when the event improved from having been Grade 3 or Grade 4.
For safety run-in part, any AE that constitutes a DLT should be reported like a Grade 3 and 4 
adverse event.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a 
serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g., anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE v4.03 does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such.


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8.1.3
Adverse events of special interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure, and a list of Medical Dictionary 
for Regulatory Activities (MedDRA) preferred terms to flag as AESI’s will be included in the 
SAP.
AESI for dabrafenib include:
•
Hypersensitivity
•
Pyrexia
•
cuSCC including keratoacanthoma
•
Non-cutaneous treatment emergent malignancies
•
New primary melanoma
•
pre-renal and intrinsic renal failure
•
Uveitis
•
Hyperglycemia
•
Pancreatitis
•
Neutropenia (in combination with trametinib)
AESI for trametinib include:
•
Skin related toxicities
•
Ocular events
•
Cardiac related events
•
Hepatic disorders
•
Pneumonitis/interstitial lung disease
•
Bleeding events
•
Diarrhea
•
Hypertension
•
Edema
•
Hypersensitivity
•
Deep vein thrombosis/pulmonary embolism
AESI for PDR001 include:
•
Endocrinopathies 
•
Pneumonitis
•
Colitis
•
Hepatitis


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•
Nephritis
•
Encephalitis
•
Rash
•
Infusion reaction
•
Other immune disorders
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:
•
Is fatal or life-threatening
•
Results in persistent or significant disability/incapacity
•
Constitutes a congenital anomaly/birth defect
•
Is medically significant, i.e., defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
•
Requires inpatient hospitalization or prolongation of existing hospitalization,
•
Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:
•
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
•
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent
•
Social reasons and respite care in the absence of any deterioration in the subject’s 
general condition
•
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
For subjects with known BRAF V600 mutation status who sign the main study ICF, SAE 
collection starts at time of main study informed consent whether the subject is a screen failure 
or not.
To ensure subject safety, every SAE, regardless of suspected causality, occurring after the 
subject has provided informed consent and until at least 30 days after the subject has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence and 
until
•
at least 150 days following the last dose of PDR001/placebo (or all patients in a double 
blind study)
•
30 days after the last dose of dabrafenib or 120 days after the last dose of trametinib, if the 
subject continued the combination partner more than 150 days after the last dose of 
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•
the start of a new post-treatment antineoplastic medication if sooner that the 150 days 
mentioned above. If a subject starts a post-treatment antineoplastic therapy, then only 
SAEs suspected to be related to study treatment should be collected out to 150 days after 
discontinuation of PDR001/placebo. SAEs suspected to be related to PDR001/placebo will 
continue to be collected beyond the 150-Day safety visit.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any SAEs experienced after the reporting period described above should only be reported to 
Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the subject continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. If the SAE is 
confirmed as Suspected Unexpected Serious Adverse Reaction (SUSAR) according to the 
Reference Safety Information in the IB, drug safety will be unblinded to the treatment according 
to the Novartis SOP for unblinding. Novartis may need to issue an Investigator Notification 
(IN), to inform all investigators involved in any study with the same drug that this SAE has 
been reported. In this case the subject will be unblinded to the treatment. SUSARs will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries.
8.3
Emergency unblinding of treatment assignment
Parts 1 & 2: Safety run-in and biomarker cohort
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Part 3: Double-blind, randomized, placebo-controlled part
Emergency unblinding decisions must only be undertaken by the investigator when it is 
essential for effective treatment of the subject. Most often, study treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study subject who 
presents with an emergency condition. Emergency code breaks are performed using the IRT. 
When the investigator/designee contacts the IRT to unblind a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to unblind the subject. The 
investigator/designee will then receive details of the drug treatment for the specified subject 
and a fax confirming this information. The system will automatically inform the Novartis 
monitor for the site and the Study Lead that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the subject how to contact his/her 
backup in cases of emergency when he/she is unavailable. The protocol number, study treatment 
name if available, subject number, and instructions for contacting the local Novartis CPO will 
be provided to the subject in case emergency unblinding is required at a time when the 
investigator and backup are unavailable. However, if a mechanism is already in place to ensure 
that the investigator and/or back-up can always be reached in case of emergency then the 
procedure above is not required.
Following the final PFS analysis:
•
Unblinding is mandated and does not require notification to Novartis study physician
•
Patients who have been unblinded may continue on the study
•
Decision on continuation of treatment with PDR001 in combination with dabrafenib and 
trametinib can be made on a case by case basis using medical judgement, individual 
benefit-risk assessment, and upon a documented discussion with the patient.
•
Placebo administrations to those patients randomized to the placebo arm will stop
If a subject is unblinded, he/she must be followed for survival, as applicable per Section 7.1.7 
and Section 7.1.8.
8.4
Pregnancies
To ensure subject safety, each pregnancy occurring while the subject is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. Follow-ups will be done one month after the estimated date of 
delivery and 3 and 12 months after the estimated date of delivery for live births only.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis CMO&PS. Pregnancy follow-up should be recorded on 
the same form and should include an assessment of the possible relationship to the study 
treatment any pregnancy outcome. Any SAE experienced during pregnancy must be reported 
on the SAE Report Form.


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Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed.
8.6
Data Monitoring Committee
This study will institute a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will be constituted prior to the randomization 
of the first subject. The DMC will be responsible to review safety data approximately every 3-
6 months (after the first randomized subject has started study treatment). This includes but does 
not limit the role of the DMC to evaluate these data and to provide recommendations to the 
sponsor to continue modify or stop the study early. The DMC will be informed and convened 
quickly in the event of unexpected results that raise concerns to permit DMC evaluation and 
input.
It is expected that the DMC will consist at a minimum of two physicians with appropriate 
disease area qualifications and one statistician. There will be a meeting with the DMC 
describing their roles and responsibilities and discussing potential data format and process 
issues prior to the finalization of DMC charter and the interim SAP. 
It is envisioned that the DMC may make the following types of recommendations, namely:
•
No safety issues, ethical to continue the study as planned
•
Serious safety concerns precluding further study treatment, regardless of efficacy
•
Recommendation to continue the study but proposing an amendment to the protocol (e.g., 
incorporate an additional safety assessments)
Furthermore, the DMC will be responsible for reviewing the efficacy results from the interim 
PFS analysis (at which point the first interim OS data will be analyzed as well), as well 
overseeing the safety data accruing in the trial at regular intervals. The interim PFS analysis 
will be performed by an independent external statistician. The results will be made available to 
the DMC who will then make a recommendation to the Sponsor. Details will be provided in the 
DMC charter. If the unblinded results are not made available at this point, the study will proceed 
as normal and the final PFS analysis will be performed by the Sponsor's clinical team when the 
approximate target number of events has been observed.
8.7
Steering Committee
The steering committee will be established comprising investigators participating in the trial, 
i.e. not being members of the DMC and Novartis representatives from the Clinical Trial Team.


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The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:
•
What protected health information (PHI) will be collected from subjects in this study
•
Who will have access to that information and why
•
Who will use or disclose that information
•
The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g., has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.


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The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
subject’s file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
Designated investigational site staff will enter the information required by the protocol into the 
appropriate eCRF and/or designated laboratory requisition forms. Field monitors will review 
the eCRFs and laboratory paper requisition forms for accuracy and completeness and instruct 
site personnel to make any required corrections or additions. One copy of the requisition form 
will be forwarded to each analytical laboratory with the respective sample(s) by the field 
monitor or by the designated investigational site staff; and one copy will be retained at the 
investigational site.
PK and biomarker (blood, serum, plasma and/or tissue) samples obtained during the course of 
the study will be collected and shipped by the site to a Novartis designated laboratory for sample 
management and/or analysis. The Laboratory results will be sent electronically to Novartis.
ECG data will be collected via 12-lead digital ECG machines and reviewed by the site 
investigator. ECG data should be entered in to the eCRFs.
Radiological imaging and photography data will be acquired by the sites and interpreted locally. 
Additionally, radiological and photography data will be transmitted by the sites to a CRO 
designated by Novartis to undergo quality checks and central review. The decision regarding 
subject management will remain with the local investigator.
Data entered into IRT will be transferred electronically to Novartis as described in the Data 
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9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
MedDRA terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). Data that will be processed centrally include:
•
IRT data including information regarding screening, drug assignment and discontinuation
•
Centrally analyzed laboratory data including clinical, PK, tumor biomarker and safety 
parameters
•
Central imaging review (if required)
Randomization codes and data about all study treatments dispensed to the subject and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The system 
will be supplied by a vendor(s), who will also manage the database. The data will be sent 
electronically to Novartis personnel (or designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be determined 
after return of all code break reports and unused drug supplies to Novartis personnel (or 
designated CRO). The occurrence of any protocol violations will be determined. After these 
actions have been completed and the data has been verified to be complete and accurate, the 
database will be declared locked and the treatment codes will be unblinded and made available 
for data analysis. Authorization is required prior to making any database changes to locked data, 
by joint written agreement between the Global Head of Biostatistics and Data Management and 
the Global Head of Clinical Development.
10
Statistical methods and data analysis
For the safety run-in (part 1) and biomarker cohort (part 2), efficacy and safety analyses will be 
conducted on all subject data at the time that each part is completed. For the randomized part 
of the study (part 3), the final PFS efficacy and safety analysis will be performed after observing 
approximately 352 PFS events. 
As the rate of events may decrease with longer follow-up, achieving the target number of events 
for the final PFS analysis might be challenging to obtain within a reasonable period of follow-
up. To allow for this scenario the data cutoff date for the final PFS analysis will be chosen at 
the time when the target number of approximately 352 PFS events has been observed or at 
approximately 24 months after the last patient has been randomized, whichever occurs first. 
In addition, an interim PFS analysis for the primary endpoint will be performed after 
approximately 260 events have been reported. The primary CSR will be produced after the final 


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PFS analysis (or after the interim PFS analysis if the test of the PFS endpoint is significant and 
Novartis decides to make the unblinded results publicly available) and will summarize data 
from all 3 parts of the study.
The additional data for any patients continuing to receive study treatment past this time, as 
allowed by the protocol, will be further summarized in a final study report once these patients 
complete the study.
Categorical data will be presented as contingency tables (frequencies and percentages). For 
continuous data summary statistics of mean, standard deviation, median, minimum, and 
maximum will be presented. For selected parameters, 25th and 75th percentiles will also be 
presented.
Screen failure subjects are those who signed the informed consent, but never started the study 
treatment for any reason. For these subjects, the eCRF data collected will not be included in 
analyses, but will be reported in CSR as separate listings.
Following final PFS analysis, which did not demonstrate a significant treatment benefit benefit, 
the study will remain open for further follow-up to collect additional survival and safety data. 
Updated safety and descriptive analyses of overall survival will be performed.
10.1
Analysis sets
10.1.1
Full Analysis Set
Parts 1 & 2: Safety run-in and biomarker cohort
For each part, the full analysis set (FAS) and safety set are defined in the same way and comprise 
all subjects to whom study treatment has been assigned and who received at least one dose of 
any study treatment (i.e. at least one dose of any component of PDR001 (including incomplete 
infusion), dabrafenib, or trametinib). Subjects will be analyzed according to the study treatment 
they have been assigned to. 
Part 3: Double-blind, randomized, placebo-controlled part
The FAS comprises all subjects to whom study treatment has been assigned by randomization, 
regardless of whether or not treatment was administered. According to the intent to treat 
principle, subjects will be analyzed according to the treatment and strata they have been 
assigned to during the randomization procedure. This population will be the primary population 
for efficacy analyses.
10.1.2
Safety set
Parts 1 & 2: Safety run-in and biomarker cohort
See definition of FAS.
Part 3: Double-blind, randomized, placebo-controlled part
The Safety Set includes all subjects who received at least one dose of study treatment (i.e. at 
least one dose of any component of PDR001 or placebo (including incomplete infusion), 
dabrafenib, or trametinib). Subjects will be analyzed according to the study treatment received, 
where treatment received is defined as the randomized treatment if the subject took at least one 


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dose of that treatment or the first treatment received if the randomized treatment was never 
received.
10.1.3
Per-Protocol set
Parts 1 & 2: Safety run-in and biomarker cohort
Not applicable.
Part 3: Double-blind, randomized, placebo-controlled part
The Per-Protocol Set (PPS) will only be used for sensitivity analyses on the primary variables. 
The PPS consists of a subset of the subjects in the FAS who are compliant with requirements 
of the clinical study protocol (CSP).
Oncology standards for protocol deviations potentially leading to exclusion from the PPS are:
•
type of indication different from those required by the CSP (e.g., incorrect 
histology/cytology, not refractory, not metastatic, different grade of cancer, etc.)
•
if prior therapy does not match with CSP requirements in terms of number and types of 
previous therapy regimens
•
missing or incomplete documentation of stage of disease (as required in the CSP)
•
if ECOG performance status at least 2 categories worse than protocol-defined inclusion 
criteria
•
another anti-neoplastic therapy administered after start of study treatment and prior to first 
tumor assessment
•
study treatment received different from treatment assigned by randomization
Full specifications of deviations leading to exclusion will be described in the Study Specific 
Document (SSD) document.
10.1.4
Dose-determining analysis set
Part 1: Safety run-in
The Dose-Determining Set (DDS) includes all subjects who received at least one dose of study 
treatment who either 1) met the minimum exposure criterion and had sufficient safety 
evaluations, or 2) experienced a DLT during the first 8 weeks (56 days) of PDR001 in 
combination with dabrafenib and trametinib dosing.
A subject meets the minimum exposure criterion if the subject receives at least 1 dose of 
PDR001, and takes at least 50% of the planned cumulative doses of dabrafenib and trametinib 
within the first 8 weeks (56 days) of treatment. Subjects who do not experience a DLT during 
the first 8 weeks are considered to have sufficient safety evaluations if they have been observed 
for at least 8 weeks following the first dose of PDR001 in combination with dabrafenib and 
trametinib, and are considered by both the Sponsor and Investigators to have enough safety data 
to conclude that a DLT did not occur. Patients who do not meet the minimum exposure criterion 
due to an AE will be counted as having a DLT. Patients who do not meet the minimum exposure 
criterion for reasons other than AE’s (e.g., rapid disease progression or non-compliance) will 


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not be included in the DDS. Parts 2 & 3: Biomarker cohort and double-blind, randomized, 
placebo-controlled part
Not applicable.
10.1.5
Pharmacokinetic analysis set
The following analysis sets will be derived separately for each of the 3 parts. The PDR001 
pharmacokinetic analysis set (PAS-PDR001) includes all subjects who provide at least one 
evaluable PDR001 PK concentration. For a concentration to be evaluable, subjects are required 
to:
•
Received one of the planned treatments of PDR001 prior to sampling
•
For pre-dose samples, have the samples collected before the next dose administration
•
For end-of-infusion samples, have the samples collected within 2 hours post infusion
The dabrafenib and trametinib Pharmacokinetic analysis set (PAS-D+T) includes all subjects 
who provide at least one evaluable dabrafenib or trametinib PK concentration. For a 
concentration to be evaluable, subjects are required to:
•
Receive a dose of dabrafenib and trametinib prior to sampling
•
For pre-dose samples, have the samples collected before the next dose administration
•
For post-dose samples, do not vomit within 4 hours after the dosing of dabrafenib and 
trametinib
10.1.6
Other analysis sets
The Immunogenicity prevalence set includes all subjects in the FAS with a determinant baseline 
IG sample or at least one determinant post-baseline IG sample.
The Immunogenicity incidence set includes all subjects in the Immunogenicity prevalence set 
with a determinant baseline IG sample and at least one determinant post-baseline IG sample.
Additional details, including definition of determinant, will be provided in the SAP.
10.1.6.1 Efficacy/evaluable set
Not applicable.
10.2
Subject demographics/other baseline characteristics
Parts 1 & 2: Safety run-in and biomarker cohort
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by dose cohort for the FAS. Relevant medical histories and current 
medical condition at baseline will be summarized separately by system organ class and 
preferred term, by dose cohort.
Part 3: Double-blind, randomized, placebo-controlled part
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group and for all subjects for the FAS and safety set. 


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Relevant medical histories and current medical at baseline will be summarized separately by 
system organ class and preferred term, by treatment group and for all subjects.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The safety set will be used to summarize treatment data. Categorical data will be summarized 
as frequencies and percentages. For continuous data, mean, standard deviation, median, 25th 
and 75th percentiles, minimum, and maximum will be presented.
Parts 1 & 2: Safety run-in and biomarker cohort
The duration of exposure to PDR001, dabrafenib, and trametinib as well as the dose intensity 
(computed as the ratio of actual cumulative dose received and actual duration of exposure) and 
the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity) 
will be summarized by means of descriptive statistics using the safety set. The duration of 
exposure will also be presented for the study treatment by arm.
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by dose cohort, and all dosing data will be 
listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by dose cohort.
Part 3: Double-blind, randomized, placebo-controlled part
The duration of exposure to PDR001 (or matching placebo), dabrafenib, and trametinib as well 
as the dose intensity (computed as the ratio of actual cumulative dose received and actual 
duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity 
and planned dose intensity) will be summarized by means of descriptive statistics using the 
safety set. The duration of exposure will also be presented for the study treatment by arm.
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group and for all subjects, 
and all dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the ATC classification system, by 
treatment group and for all subjects.
10.4
Primary objective
Part 1: Safety run-in
The primary objective is to determine the recommended regimen of PDR001 in combination 
with dabrafenib and trametinib for the randomized part (part 3)
Part 2: Biomarker cohort
The primary objective is to evaluate changes in PD-L1 levels and CD8+ cells upon treatment 
with PDR001 in combination with dabrafenib and trametinib.


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Part 3: Double-blind, randomized, placebo-controlled part
The primary objective is to evaluate and compare PFS per RECIST 1.1 of PDR001 in 
combination with dabrafenib and trametinib versus dabrafenib and trametinib plus placebo.
10.4.1
Variables
Part 1: Safety run-in
The primary variable is the incidence of DLTs during the first 8 weeks (56 days) of treatment 
for each dose level associated with administration of PDR001 in combination of dabrafenib and 
trametinib.
Part 2: Biomarker cohort
The primary variable is PD-L1 levels and CD8+ cells and changes from baseline.
Part 3: Double-blind, randomized, placebo-controlled part
The primary efficacy variable is PFS, defined as the time from the date of randomization to the 
date of the first documented progression per RECIST 1.1 or death due to any cause. PFS will 
be assessed via local review according to RECIST 1.1 (see Appendix 1 for further details). 
Censoring conventions are provided below in Section 10.4.3.
Local scans will be sent to a blinded, independent central reviewer who will provide 
assessments using both RECIST 1.1 and tumor response criteria based on guidelines for 
immunotherapy, and these centrally reviewed data will be used for sensitivity analysis.
10.4.2
Statistical hypothesis, model, and method of analysis
Part 1: Safety run-in
Identification of recommended regimen
Estimation of the recommended regimen will be based upon the estimation of the probability 
of DLT in the first 8 weeks (56 days) for subjects in the DDS. A lower recommended regimen 
may be identified based on other safety and PK data from the current study (Section 6.2.3).
Bayesian adaptive approach
The dose determination part of this study will be guided by a Bayesian analysis of DLT data 
for the first 8 weeks (56 days) that subjects receive the combination of PDR001, dabrafenib, 
and trametinib. The Bayesian analysis to assess the triple combination will be based on a 
separate 10-parameter model for each dose regimen that comprises single-agent toxicity parts 
and interaction parts to describe both two-way and three-way drug safety interactions. Single 
agent toxicity is modelled using logistic regression for the probability of a subject experiencing 
a DLT against log-dose. The odds of a DLT for each dose regimen are then calculated under no 
interaction for the three single agent toxicities, and interaction is accounted for by adjusting 
these odds with additional model parameters (odds multipliers). Details of the model are given 
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Assessment of subject risk
After each cohort of subjects, the posterior distribution for the risk of DLT for new subjects at 
combination doses of interest will be evaluated. The posterior distributions will be summarized 
to provide the posterior probability that the risk of DLT for each dose regimen lies within the 
following intervals:
•
Under-dosing: [0, 16%)
•
Targeted toxicity: [16%, 33%)
•
Excessive toxicity: [33%, 100%]
The escalation with overdose control (EWOC) principle
Dosing regimen decisions are guided by the escalation with overdose control principle 
(Rogatko 2007). A dosing regimen may only be used for newly enrolled subjects if the risk of 
excessive toxicity at that dosing regimen is less than 25%.
Prior distributions
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
single-agent PDR001, dabrafenib, and trametinib model parameters. The MAP prior for the 
logistic model parameters for this study is the conditional distribution of the parameters given 
the historical data (Spiegelhalter 2004, Neuenschwander 2010, Neuenschwander 2014). MAP 
priors are derived from hierarchical models, which take into account possible differences 
between the studies. For dabrafenib and trametinib, 100% MAP priors will be used. For 
PDR001, this is then robustified by creating a mixture prior including both a component derived 
from the MAP prior and a weakly informative robustification component. This robustification 
allows for the possibility that the dose/toxicity relationship for PDR001 in combination differs 
substantially from that of the single agent. A full description of the application of the MAP 
approach to derive the prior distributions of the single agent PDR001, dabrafenib, and 
trametinib model parameters for each dose regimen is given in Appendix 2.
The prior distributions for the interaction parameters were based upon prior understanding of 
possible drug safety interactions. These priors allow for the possibility of either synergistic or 
antagonistic interaction, and are fully described in Appendix 2.
Additional DLT information from completed studies assessing the combination of dabrafenib 
and trametinib (i.e. Phase I study BRF113220, Phase III study MEK115306 (COMBI-d), and 
Phase III study MEK116513 (COMBI-v)) are included using discounted weighting. Full details 
of the discounted weighting approach are described in Appendix 2.
Starting dose
The starting dosing regimen is 400 mg i.v. Q4W PDR001, 150 mg BID dabrafenib, and 2 mg 
QD trametinib (Section 6.2.1). For this dosing regimen, the prior risk of excessive toxicity is 
12%, which satisfies the EWOC criterion. A full assessment of the prior risk to subjects for all 
dosing regimens is given in Appendix 2. Historical data were reviewed to account for modified 
DLT criteria (protocol amendment 2). Prior specifications for the BLRM were not impacted, 
and therefore the starting dose of Part 1 remained unchanged. 


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Listing of DLT’s
DLTs will be listed, and their incidence summarized by primary system organ class and 
preferred term and worst grade (CTCAE v4.03). Listings and summaries will be based on the 
DDS.
Part 2: Biomarker cohort
Descriptive statistics of the primary endpoint, PD-L1 levels and CD8+ cell values and changes 
from baseline, will be summarized by visit.
Part 3: Double-blind, randomized, placebo-controlled part
The following statistical hypotheses will be tested to address the primary efficacy objective for 
PFS (based on investigator assessment of RECIST 1.1 criteria):
H01 : θ1 ≥ 1 vs. HA1 : θ1 < 1
where θ1 is the PFS hazard ratio (PDR001 combined with dabrafenib and trametinib versus 
dabrafenib and trametinib plus placebo). The primary efficacy analysis to test these hypotheses 
and compare the two treatment groups will consist of a stratified log-rank test at an overall one-
sided 2.5% level of significance. The stratification will be based on the randomization 
stratification factors, i.e., (LDH level: < 1 x ULN vs ≥1 to < 2 x ULN vs ≥ 2 x ULN; ECOG 
PS: 0 vs 1 vs 2).
Analyses will be based on the FAS population according to the randomized treatment group 
and strata assigned at randomization. The PFS distribution will be estimated using the Kaplan-
Meier method, and Kaplan-Meier curves, quartiles and associated 95% confidence intervals 
will be presented for each treatment group. The hazard ratio for PFS will be calculated, along 
with its 95% confidence interval, from a stratified Cox model using the same stratification 
factors as for the log-rank test.
The PFS analysis will be performed as part of a two-look group sequential design using a 
conservative Gamma alpha spending function with Gamma parameter = -9.7 (Hwang, Shih and 
DeCani, 1990). Analyses will be based on the FAS population according to the randomized 
treatment group and strata assigned at randomization. The PFS distribution will be estimated 
using the Kaplan-Meier method, and Kaplan-Meier curves, quartiles and associated 95% 
confidence intervals will be presented for each treatment group. The hazard ratio for PFS will 
be calculated, along with its 95% confidence interval, from a stratified Cox model using the 
same stratification factors as for the log-rank test.
If the interim PFS analysis is significant, the subsequent planned final PFS analysis will still be 
performed to obtain more mature PFS data and additional follow-up PFS analyses may also be 
performed earlier than planned final PFS analysis at the request of health authorities or to 
facilitate health authority interactions. 
The data cutoff date for the final PFS analysis will occur at the time when the target number of 
approximately 352 PFS events has been observed or at approximately 24 months after the last 
patient has been randomized, whichever occurs first. 


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10.4.3
Handling of missing values/censoring/discontinuations
Part 1: Safety run-in
Subjects who are ineligible for the DDS will be excluded from the primary analysis (incidence 
of DLT during first 8 weeks of PDR001 in combination with dabrafenib and trametinib), 
although their data will be used for all remaining analyses.
Other missing data will simply be noted as missing on appropriate tables/listings.
Part 2: Biomarker cohort
Missing data will simply be noted as missing on appropriate tables/listings.
Part 3: Double-blind, randomized, placebo-controlled part
In the primary analysis, PFS will be censored at the date of the last adequate tumor assessment 
if no PFS event is observed prior to the analysis cut-off date.
PFS events documented after the initiation of new anti-neoplastic therapy (i.e. RECIST 1.1 
documented disease progression or death) will be considered for the primary analysis provided 
tumor assessments continue after initiation of new cancer therapy.
If a PFS event is observed after two or more missing or non-adequate tumor assessments, then 
PFS will be censored at the last adequate tumor assessment before the PFS event. If a PFS event 
is observed after a single missing or non-adequate tumor assessment, the actual date of event 
will be used (RECIST 1.1 in Appendix 1).
10.4.4
Supportive and sensitivity analyses
Parts 1 & 2: Safety run-in and biomarker cohort
Not applicable.
Part 3: Double-blind, randomized, placebo-controlled part
As a supportive analysis, PFS based on RECIST 1.1 criteria as per blinded independent central 
review will be analyzed using a stratified Cox model, with the same analysis conventions as the 
primary efficacy analysis (based on investigator assessment), and the treatment effect will be 
summarized by the hazard ratio with its 95% confidence interval. Kaplan-Meier curves, 
quartiles and associated 95% confidence intervals will be presented for each treatment group.
Similarly, the above analysis will be performed for PFS based on tumor response criteria based 
on guidelines for immunotherapy as per blinded independent central review.
As sensitivity analyses for PFS and OS in the FAS, the hazard ratio and 95% confidence interval 
will be obtained from:
•
An unstratified and covariate unadjusted Cox model
•
A stratified and covariate adjusted Cox model that may include the following covariates: 
gender, age group (< 65, ≥ 65 years), LDH group (< 1 x ULN, ≥1 to < 2 x ULN, ≥ 2 x 
ULN), ECOG PS (0, 1, 2), sites of disease at baseline (< 3, ≥ 3), stage at screening (IIIC or 
IVM1a vs IVM1b or IVM1c), BRAF mutation (V600E, V600K), and prior adjuvant 
checkpoint inhibitor therapy (yes, no). A final list of covariates of interest will be defined 
in the SAP.


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•
PFS and OS will also be analyzed based on the PPS, using the same analysis conventions 
as in the primary efficacy analysis (with the exception of the log-rank test, which will not 
be performed).
If the primary PFS analysis is statistically significant, subgroup analyses to assess the 
homogeneity of the treatment effect across demographic and baseline disease characteristics 
will be performed. The following subgroups may be considered: gender (male, female), age 
group (< 65, ≥ 65 years), LDH group (< 1 x ULN, ≥1 to < 2 x ULN, ≥ 2 x ULN), ECOG PS (0, 
1, 2), sites of disease at baseline (<3, ≥ 3), stage at screening (IIIC or IVM1a vs IVM1b or 
IVM1c), BRAF mutation (V600E, V600K), and prior adjuvant checkpoint inhibitor therapy 
(yes, no). An additional subgroup will be derived for those who experienced at least 1 immune-
related AE (yes, no). A final list of subgroups of interest will be defined in the SAP.
The number of subjects censored for PFS and OS and reasons for censoring will be summarized 
by treatment group using descriptive statistics.
Additional key supportive analyses for PFS and OS will be performed to take into account 
delayed treatment effect leading to non-proportional hazards. Due to the expected non-
proportional hazards the treatment effect will be estimated by means of a restricted mean 
survival time (RMST) approach (Uno et al., 2014).
The RMST and 95% CIs will be estimated for each treatment group separately and the treatment 
effect will be derived as the difference in the treatment group RMSTs with the 95% CI for the 
difference also being provided. Additional supportive analyses will include methods that 
provide alternative tests and treatment effect estimates in the presence of non-proportional 
hazards, e.g. weighted log-rank test with Fleming-Harrington class of weight (Fleming & 
Harrington, 1991), landmark analyses, piece-wise Cox regression to obtain HR by period. 
Details of all these analyses will be outlined in the SAP.
Additional supportive 
 analyses may be conducted to support the primary 
objective of the safety run-in, biomarker cohort, or randomized part, if appropriate, and the 
details of these analyses will be defined in the SAP.
10.5
Secondary objectives
Part 1: Safety run- in and Part 2: Biomarker cohort
The secondary objectives for these parts of the study are to determine the safety and tolerability, 
evaluate preliminary anti-tumor activity, characterize the pharmacokinetics, and evaluate the 
prevalence and incidence of immunogenicity of PDR001 in combination with dabrafenib and 
trametinib.
Part 3: Double-blind, randomized, placebo-controlled part
The secondary objectives in this part of the study are to compare the two treatment groups with 
respect to OS, tumor related efficacy variables (ORR, DOR, and DCR based on RECIST 1.1), 
safety and tolerability, quality of life, pharmacokinetics, and immunogenicity.
OS is identified as the key secondary endpoint. A hierarchical testing strategy will be used to 
control the overall type I error rate, where OS will only be formally tested and interpreted if the 
primary analysis of PFS is statistically significant.


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10.5.1
Key secondary objectives
Part 1: Safety run-in and Part 2: Biomarker cohort
Not applicable.
Part 3: Double-blind, randomized, placebo-controlled part
The key secondary objective is to determine whether treatment with PDR001 in combination 
with dabrafenib and trametinib prolongs OS compared with dabrafenib and trametinib plus 
placebo. OS is defined as the time from date of randomization to date of death due to any cause. 
If a patient is not known to have died, then OS will be censored at the latest date the patient was 
known to be alive (on or before the cut-off date).
The following statistical hypotheses will be tested to address the key secondary efficacy 
objective for OS:
H02 : θ2 ≥ 1 vs. H12 : θ2 < 1
where θ2 is the OS hazard ratio (PDR001 combined with dabrafenib and trametinib versus 
dabrafenib and trametinib plus placebo). The analysis to test these hypotheses and compare the 
two treatment groups will consist of a stratified log-rank test at an overall one-sided 2.5% level 
of significance. The stratification will be based on the randomization stratification factors, i.e., 
(LDH level: < 1 x ULN vs ≥ 1 to < 2 x ULN vs ≥ 2 x ULN; ECOG PS: 0 vs 1 vs 2).
OS analyses will be conducted as a part of a three-look group sequential design using a Lan-
DeMets (O’Brien-Fleming) alpha spending function. Analyses will be based on the FAS 
population according to the randomized treatment group and strata assigned at randomization. 
The OS distribution will be estimated using the Kaplan-Meier method, and Kaplan-Meier 
curves, quartiles and associated 95% confidence intervals will be presented for each treatment 
group. The hazard ratio for OS will be calculated, along with its 95% confidence interval, using 
a stratified Cox model.
OS data will be presented at each analysis but will be formally tested hierarchically as follows:
If PFS is statistically significant at the interim PFS analysis:
Interim OS data will be tested at the time of the interim and final PFS analyses. 
A final (inferential) analysis for OS is planned when approximately 245 deaths have occurred 
(or earlier if specifically requested by health authorities).
If PFS is not statistically significant at the interim PFS analysis:
Interim OS data will not be tested at the time of the interim PFS analysis.
If PFS is statistically significant at the final PFS analysis:
Interim OS data will be tested at the time of the final PFS analysis. If OS is not statistically 
significant at this stage, a final OS analysis will be planned after approximately 245 deaths.
If PFS is not statistically significant at the final PFS analysis:
Interim OS data will not be tested and there will also not be testing of OS data at the planned 
final OS analysis.


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In the case of statistically significant interim or final OS results, additional OS estimates at 
relevant annual milestones up to 5 years will be summarized.
Following final PFS analysis, which did not demonstrate a significant treatment benefit, the 
study will remain open for further follow-up to collect additional survival and safety data. 
Updated safety and descriptive analyses of overall survival will be performed.
10.5.2
Other secondary efficacy objectives 
Not applicable after final PFS analysis 
Part 1: Safety run-in and Part 2: Biomarker cohort
The secondary objectives in these parts of the study are to determine the safety and tolerability, 
evaluate preliminary anti-tumor activity, characterize the pharmacokinetics, and evaluate the 
prevalence and incidence of immunogenicity of PDR001 in combination with dabrafenib and 
trametinib.
The incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as well 
as changes in laboratory values, ECOG PS, vital signs, and liver and cardiac parameters will be 
summarized. For all safety and tolerability descriptive analyses, the safety set will be used. All 
listings and tables will be presented by dose cohort (for part 1) and overall (for part 2). Refer to 
Section 10.5.3 for more details.
To assess preliminary clinical activity, descriptive statistics for PFS, OS, ORR, DCR, and DOR 
will be summarized by dose cohort (for part 1) and overall (for part 2), using the local review 
result where applicable. For definitions of these endpoints, refer to Section 10.4, Section 10.5, 
and the text in Section 10.5.1 for the randomized part of the study. As a supportive analysis, 
results as per blinded independent central review using RECIST 1.1 and tumor response criteria 
based on guidelines for immunotherapy will also be presented by dose cohort (for part 1) and 
overall (for part 2). For details on how censoring will be handled, the same methods described 
in Section 10.4.3 will be applied.
Refer to Section 10.5.3 for details on the analysis of secondary PK objectives and Section 10.5.4 
for details on the analysis of secondary immunogenicity objectives.
Part 3: Double-blind, randomized, placebo-controlled part
Other secondary objectives in this part of the study are to compare the two treatment groups 
with respect to tumor related efficacy variables (ORR, DOR, and DCR based on RECIST 1.1), 
safety and tolerability, quality of life, and pharmacokinetics. No multiplicity adjustments are 
planned for other secondary endpoints.
Overall response rate (ORR) is defined as the proportion of subjects with confirmed best overall 
response (BOR) of complete response (CR) or partial response (PR), as per local review. ORR 
will be evaluated according to RECIST 1.1 (Appendix 1). Complete and partial responses must 
be confirmed by repeat assessments that should be performed not less than 4 weeks after the 
criteria for response are first met. ORR based on local review will be calculated based on the 
FAS. ORR and its 95% confidence interval will be presented by treatment group. The Cochran-
Mantel-Haenszel chi-square test, stratified by the randomization stratification factors, will be 
used to compare ORR between the two treatment groups, at the one-sided 2.5% level of 


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significance. As a supportive analysis, ORR as per blinded independent central review (using 
RECIST 1.1 as well as tumor response criteria based on guidelines for immunotherapy) will be 
presented by treatment group, along with 95% confidence intervals.
Duration of response (DOR) only applies to subjects whose best overall response is complete 
response (CR) or partial response (PR) based on tumor response data per local review. DOR 
will be evaluated according to RECIST 1.1 (Appendix 1). The start date is the date of first 
documented response of CR or PR (i.e., the start date of response, not the date when response 
was confirmed), and the end date is defined as the date of the first documented progression or 
death due to underlying cancer. Subjects continuing without progression or death due to 
underlying cancer will be censored at the date of their last adequate tumor assessment. DOR 
based on RECIST 1.1 will be listed and summarized by treatment group for all subjects in the 
FAS with confirmed BOR of CR or PR, as well as for the subgroup of FAS subjects with 
confirmed BOR of CR only.
DCR is defined as the proportion of subjects with CR or PR or subjects with stable disease (SD) 
lasting for a duration of at least 24 weeks as per local review. CR, PR and SD are defined 
according to RECIST 1.1 (see Appendix 1 for details). DCR will be calculated based on the 
FAS. DCR and its 95% confidence interval will be presented by treatment group. As a 
supportive analysis, DCR as per blinded independent central review (using RECIST 1.1 as well 
as tumor response criteria based on guidelines for immunotherapy) will be presented by 
treatment group, along with 95% confidence intervals.
In order to characterize the potential for PD-L1 expression to identify subjects with an enhanced 
response to PDR001, PFS and OS analyses will be performed by PD-L1 subgroup (positive, 
negative) where a positive status is defined as having ≥ 1% expression and a negative status is 
defined as having < 1% expression as determined by immunohistochemistry. Additionally PD-
L1 subgroups will also be assessed using ≥ 5% and ≥ 10% as cut-offs for PD-L1 positivity.
Refer to Section 10.5.3 for details on the analysis of secondary safety and tolerability objectives, 
Section 10.5.4 for secondary PK objectives, Section 10.5.5 for secondary immunogenicity 
objectives and Section 10.5.8 for secondary quality of life objectives.
10.5.3
Safety objective(s)
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used and data will be presented separately for each 
part; no pooled safety analyses are planned. For the safety run-in part and biomarker cohort, 
listings and tables for each part will be presented by dose cohort. For the randomized part, all 
listings will be presented by treatment group and tables will be presented by treatment group 
and all subjects.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of subject’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after the date of 
last actual administration of any study medication
3. post-treatment period: starting at day 31 after last dose of study medication.


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If dates are incomplete in a way that clear assignment to pre-, on-, or post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period. Additional 
details to address incomplete AE and/or dosing dates will be addressed in the SAP.
Additional summaries will be displayed to report deaths, all AEs, AEs related to study treatment, 
all SAEs and SAEs related to study treatment collected up to 150 days after last administration 
of PDR001/placebo.
Following final PFS analysis, which did not demonstrate a significant treatment benefit, the 
study will remain open for further follow-up to collect additional survival and safety data. 
Updated safety and descriptive analyses of overall survival will be performed.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE v4.03 
grades), type of adverse event, and relation to study treatment.
Serious adverse events, non-serious adverse events, and adverse events of special interest (AESI; 
see Section 8.1.3) during the on-treatment period will be tabulated. The list of AESI’s will also 
include relevant events for dabrafenib and trametinib which will be defined in the SAP.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those starting during the post-treatment period will be flagged.
10.5.3.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI CTCAE version 
4.03. The calculation of CTCAE v4.03 grades will be based on the observed laboratory values 
only, clinical assessments will not be taken into account.
CTCAE v4.03 Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be applicable.
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following listing/summaries will be generated separately for hematology, and biochemistry 
tests:
•
Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v4.03
•
Worst post-baseline CTCAE v4.03 grade (regardless of the baseline status). Each subject 
will be counted only once for the worst grade observed post-baseline.
•
Shift tables using CTCAE v4.03 grades to compare baseline to the worst on-treatment 
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For laboratory tests where grades are not defined by CTCAE v4.03,
•
Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the SAP.
10.5.3.4 Other safety data
Data from other tests, such as ECG and vital signs, will be listed and summarized accordingly. 
Notable values will be flagged in the listing. Definitions of notably abnormal results will be 
specified in the SAP.
ECG
12-lead ECGs including PR, QRS, QT, and QTcF intervals and heart rate will be obtained for 
each subject during the study. ECG data will be read and interpreted locally.
Categorical analysis of QT/QTc interval data based on the number of subjects meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these subjects will be produced by treatment group.
Vital signs
Data on vital signs will be tabulated and listed, and notable values will be flagged.
10.5.3.5 Supportive analyses for secondary objectives
Not applicable.
10.5.3.6 Tolerability
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions and dose reductions. Reasons for dose interruptions and dose reduction will be 
listed and summarized (see Section 10.3).
10.5.4
Pharmacokinetics
The respective PAS for each study drug will be used in the pharmacokinetic data analysis. 
Descriptive statistics (n, m (number of non-zero concentrations), mean, CV%, SD, median, 
geometric mean, geometric CV%, minimum and maximum) for PDR001, dabrafenib and 
trametinib concentrations will be presented at each scheduled time point by treatment. Pre-dose 
concentrations collected before dose administration on Day 1 of Cycle 2+ are Ctrough for 
PDR001. In the cases where dosing of PDR001 starts at Cycle 2 only, Ctrough are considered 
to be pre-dose concentrations collected before dose administration on Day 1 of Cycle 3+. Pre-
dose concentrations collected before dose administration on Day 15 of Cycle 1+ are Ctrough 
for dabrafenib and trametinib. All concentration data for PDR001, dabrafenib, and trametinib 
will be displayed graphically by treatment.


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Following final PFS analysis data cut-off date 01-Jul-2020, PK samples will no longer be 
collected or sent to the central laboratory.
10.5.4.1 Data handling principles
Missing values for any PK parameters or concentrations will not be imputed and will be treated 
as missing.
Below the limit of quantitation (BLQ) values will be set to zero by the Bioanalyst, and will be 
displayed in the listings as zero and flagged. BLQ values will be treated as missing for the 
calculation of the geometric means and geometric CV%.
10.5.4.2 Population pharmacokinetic analysis
The pharmacokinetics of dabrafenib and trametinib will be determined using a non-linear mixed 
effects modeling approach. Population pharmacokinetic parameters including CL/F, V/F, and 
absorption rate constant (ka) will be estimated, if data permit. Dependent on the final structural 
pharmacokinetic model, additional pharmacokinetic parameters may also be estimated. Sources 
of variability in pharmacokinetic parameters will be investigated during population modeling.
If data permit, a mixed-effects model may be applied to the serum PDR001 concentration-time 
data to generate post hoc estimates of pharmacokinetic parameters using NONMEM to 
characterize PDR001 exposure in subjects with advanced melanoma.
If there are sufficient data for analysis, the details of the population pharmacokinetic analyses 
will be provided in a separate SAP, and the results may be reported in a separate population 
pharmacokinetic report. Data from this and other studies may be pooled for analysis.
10.5.5
Immunogenicity
Immunogenicity will be characterized descriptively by tabulating ADA prevalence at baseline 
and ADA incidence on-treatment.
Following final PFS analysis data cut-off date 01-Jul-2020, IG samples will no longer be 
collected or sent to the central laboratory.
10.5.6
Biomarkers
There may be circumstances when a decision is made to stop sample collection, or not perform 
or discontinue the analysis of blood / archival tumor samples / fresh tumor biopsies due to either 
practical or strategic reasons (e.g., issues related to the quality and/or quantity of the samples 
or issues related to the assay). Under such circumstances, the number of samples may be 
inadequate to perform a rigorous data analysis and the available data will only be listed and 
potentially summarized.






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missing at random assumption for the missing data if deemed appropriate. Details will be 
specified in the SAP.
Time to definitive 10 point deterioration in the global health status will be assessed for each 
treatment group. The time to definitive 10 point deterioration is defined as the time from the 
date of randomization to the date of event, which is defined as at least 10 points relative to 
baseline worsening of the corresponding scale score or death due to any cause. If a subject has 
not had an event, time to deterioration will be censored at the date of the last adequate PRO 
assessment. The distribution will be presented descriptively using Kaplan-Meier curves. 
Summary statistics from Kaplan-Meier distributions will be determined, including the median 
time to definitive 10 point deterioration along with two-sided 95% confidence interval. 
Additionally, time to definitive deterioration with different cut-off definitions (e.g., 5 points, 15 
points) may be specified in the RAP as deemed appropriate. A stratified Cox regression will be 
used to estimate the hazard ratio (HR), along with two-sided confidence interval.
Following primary PFS analysis and protocol amendment version 06 PRO data will no longer 
be collected and any additional data will not be analysed
10.7
Interim analysis
Part 1: Safety run-in
No formal interim analysis is planned for this part of the trial. However, the safety run-in design 
foresees that decisions based on the current data are taken before the end of the study. More 
precisely, after each cohort of subjects the next dose will be chosen depending on the observed 
data (based on safety, PK, tolerability data, guided by the recommendations from the BLRM of 
DLT using EWOC, and recommendations from participating investigators). Details of this 
procedure and the process for communication with Investigators are provided in Section 6.2.3.
Part 2: Biomarker cohort
No formal interim analysis is planned for this part of the trial.


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10.7.1
Progression-Free Survival
An interim PFS analysis is planned after approximately 260 events, which will allow for an 
early significance claim for a superior PFS result. If PFS is significant at this analysis an interim 
analysis of OS will also be performed at this time.
The timing and significance boundary of this interim PFS analysis has been chosen so that the 
efficacy threshold is met only when the PFS treatment effect is sufficiently large and clinically 
relevant (i.e. using a stringent significance level at interim PFS analysis with a small penalty 
for the final PFS analysis). The final PFS analysis, if performed at 352 events, will provide an 
80% cumulative power to detect a statistically significant result if the delayed effect is indeed 
5 months long as observed in KEYNOTE-022 and followed by an effect as currently assumed 
(i.e. HR=0.60).
A Gamma alpha spending function will be used to control the type 1 error probability with 
Gamma parameter = -9.7 (Hwang, Shih and DeCani, 1990). EAST version 6.4 will be used to 
determine the critical thresholds for the analysis based on the actual number of observed events 
at the time of the analysis. This particular Gamma alpha spending function was selected due to 
its conservative nature to ensure that statistical significance at interim PFS analysis will only 
be declared for a clinically relevant PFS treatment effect.
The exact nominal p-values that will need to be observed to declare statistical significance at 
the time of these analyses for PFS will depend on the number of PFS events that have been 
observed at the time of these analyses and for the final PFS analysis the α already spent at the 
time of the interim PFS analysis.
If the number of PFS events at the interim anlaysis is exactly 260 then a significant result will 
be obtained if p-value <0.00198 (or equivalently if HR<0.700). Similarly assuming 260 events 
have previously been observed at the interim, if there are exactly 352 events at the final PFS 
analysis then a significant result will be obtained if p-value <0.02483 (or equivalently if 
HR<0.811). The interim PFS analysis will be performed by an external independent 
statistician. This will include an analysis of the primary PFS endpoint plus other critical efficacy 
endpoints and safety data. The results will be made available to the DMC who will then make 
a recommendation to Novartis (see Section 8.6).
The DMC recommendation at the interim PFS analysis will be based on whether the predefined 
efficacy threshold for primary endpoint PFS by investigator was met and will also take into 
account PFS results by central radiology review. The details on criteria used will be provided 
in the DMC charter.
If the DMC recommendation is to consider making the unblinded results available, key Novartis 
personnel will review the (unblinded) interim data and make the final decision on what steps to 
take. Full details of this decision-making process including who will have access to the 
unblinded results will be specified in the DMC Charter.
The projected timing of the interim and final PFS analysis based on current study data is 
summarized in Table 10-1. However, note that due to the limited follow-up the predictions for 
timing of analyses is highly uncertain. Indeed, doublet data from two pivotal randomized Phase 


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III studies (MEK115306 [COMBI-d]) and MEK116513 [COMBI-v]) indicate that there could 
be a rapid reduction in the event rate with longer follow-up which would lead to the targeted 
events occurring much later than predicted from the current study data alone. 
Table 10-1
Estimated timelines for interim and final PFS analyses
Months after randomization of the 
first patient (prediction based on 
actual study data at Protocol 
Amendment 5 )
# PFS
Events (information 
fraction)
Cumulative PFS Power against a 
hazard ratio of 1 for first x months 
and a hazard ratio 0.60 after x 
months
x = 3 months
Delayed Effect
x = 5 months 
Delayed 
Effect
19
260 (74%)
41.5%
15.5%
25
352 (100%)
93.8%
80.6%
Calculated using EAST 6.4
10.7.2
Overall Survival (OS)
Interim analyses for OS are planned at the time of the interim and final PFS analyses. A 
hierarchical testing procedure will be adopted and the statistical tests for OS will be performed 
only if the primary efficacy endpoint PFS is statistically significant.
A maximum of three analyses are planned for OS; 
1. at the time of the interim analysis for PFS (provided PFS is significant),.
2. at the time of the final analysis for PFS (provided interim or final PFS is significant), 
3. a final analysis for OS when approximately 245 deaths are expected (expected 
approximately 36 months from date of first patient to be randomized according to a 
prediction analysis using actual study data, although at this point this prediction based on 
limited study follow-up is still highly uncertain).
An α-spending function according to Lan-DeMets (O’Brien-Fleming) as implemented in EAST 
(6.4) (Lan and DeMets 1983), along with the testing strategy outlined below will be used to 
maintain the overall type I error probability. This guarantees the protection of the 2.5% overall 
level of significance across the repeated testing of the OS hypotheses in the interim and the final 
analysis (Glimm 2010).
The trial allows for an early significance claim for efficacy for a superior OS result, provided 
the primary endpoint PFS has already been shown to be statistically significant favoring the test 
treatment arm. Further, the exact nominal p-values that will need to be observed to declare 
statistical significance at the time of these analyses for OS will depend on the number of OS 
events that have been observed at the time of these analyses and the α for OS already spent at 
the time of earlier analyses. 
At the time of final PFS analysis, both PFS and interim OS analyses will be performed by the 
Sponsor's clinical team. Investigators and patients will remain blinded to study treatment 
(unless OS reaches significance at any of the PFS analyses) and all patients will continue to be 
followed for OS until study closure.


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Following final PFS analysis, which did not demonstrate a significant treatment benefit, the 
study will remain open, until definition for end of study is met (Section 4.3), for further follow-
up so that updated descriptive safety and overall survival analyses will be performed.
10.8
Sample size calculation
Part 1: Safety run-in
No formal statistical power calculations to determine sample size were performed for this part 
of the study. In the case that the starting dose (PDR001 400 mg i.v. every 4 weeks with the 
fixed dose combination of 150 mg BID dabrafenib and 2 mg QD trametinib) is confirmed to be 
safe and tolerated, the safety run-in part is expected to enroll 6 evaluable subjects (i.e. who met 
the minimum exposure criterion and had sufficient safety evaluations during the first 8 weeks 
of PDR001 in combination with dabrafenib and trametinib dosing). Otherwise, up to 18 
additional subjects are foreseen to be enrolled to assess additional cohorts.
Part 2: Biomarker cohort
No formal statistical power calculations to determine sample size were performed for this part 
of the study. Approximately 20 evaluable subjects (i.e. who have at least one tumor biopsy at 
screening and at least two during triple combination therapy) will be enrolled in this cohort.
Part 3: Double-blind, randomized, placebo-controlled part
The sample size calculation is based on the primary variable PFS. The hypotheses to be tested 
and details of the testing strategy are described in Section 10.4.2.
Based on data from two pivotal randomized Phase III studies (MEK115306 [COMBI-d]) and 
MEK116513 [COMBI-v]), the median PFS time in the control arm is expected to be 11 months. 
Ignoring delayed treatment effect, it would be expected that the experimental treatment 
response would result in a hazard ratio of 0.60 (which corresponds to an increase in median 
PFS to 18.33 months under the exponential model assumption). Given knowledge of a potential 
delayed treatment effect, it is hypothesized that there will be no difference between treatment 
arms until 5 months after the start of treatment for PFS. Therefore, it is assumed that the HR 
between the groups will be equal to 1 for the first 5 months. Thereafter, exponential survival 
distributions are assumed, with an HR of 0.60. This will result in an overall HR=0.739 
(Kalbfleisch 1981) at the time of the final PFS analysis (given the assumed 5 month delayed 
treatment effect, this equates to median PFS times of 15.0 and 11 months in the PDR001 in 
combination with dabrafenib and trametinib combination arm and the dabrafenib and trametinib 
plus placebo group, respectively).
In order to ensure 80% power for PFS using the above assumptions for HR=1 for the first 5 
months and HR=0.60 thereafter, it is calculated that a total of 352 PFS events need to be 
observed. This calculation was made using the software package EAST 6.4 and assumes 
analysis by a one-sided log-rank test at the overall 2.5% level of significance where subjects 
are randomized to the two treatments in a 1:1 ratio. 
The calculation also assumes a two-look group sequential design (i.e. that there will be an 
interim PFS analysis performed after 260 events (73.9% of total)) with a Gamma alpha spending 
function used to control the type 1 error probability, with Gamma parameter = -9.7 (Hwang, 
Shih and DeCani, 1990).


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It should be noted that the cumulative 80% power refers to the overall HR of 0.739 that 
combines both the period of no effect and the subsequent delayed effect period and this 
represents ‘alternative hypothesis’ value.
Based on predictions using actual blinded PFS data from the 532 patients randomized to part 3 
of the study which were available at the time of Protocol Amendment 5, the 352 PFS events are 
expected to occur approximately 25 months after the randomization date of the first subject. 
The data cutoff for interim PFS analysis (260 events) is expected to occur approximately 19 
months after the first patient was randomized. It should be noted that those future predictions 
are associated with reletively high level of uncertainty since they are based on the data with 
limited follow up. 
The total of approximately 352 PFS events targeted for the final anlaysis represent a large 
percentage of the patients randomized in the study (66.2%) and therefore the rate of PFS events 
is likely to decrease with longer follow-up. In addition, formation of a plateau in the PFS 
Kaplan-Meier curve might occur in the combination arm with PDR001 based on patterns seen 
in studies with other immune therapy agents and might lead to additional delay in the event 
accrual. 
For those reasons it might actually take significantly longer to obtain the targeted number of 
PFS event and this is why the final anlaysis cutoff will be chosen based on both event numbers 
and calendar time. 
10.9
Power for analysis of key secondary variables
OS, as the key secondary variable, will be formally statistically tested, provided that the primary 
variable PFS is statistically significant. The hypotheses to be tested and details of the testing 
strategy are provided in Section 10.5.1 and Section 10.7.1.
Based on data from two pivotal randomized Phase III studies (MEK115306 [COMBI-d]) and 
MEK116513 [COMBI-v]), the median OS time in the control arm is expected to be 25 months. 
Ignoring delayed treatment effect, it would be expected that the experimental treatment 
response would result in a hazard ratio of 0.60 (which corresponds to an increase in median OS 
to 41.67 months under the exponential model assumption). Given knowledge of a potential 
delayed treatment effect, it is hypothesized that there will be no difference between treatment 
arms until 5 months after the start of treatment for OS. Therefore, it is assumed that the HR 
between the groups will be equal to 1 for the first 5 months. Thereafter, exponential survival 
distributions are assumed, with an HR of 0.60. This will result in an overall HR=0.693 
(Kalbfleisch 1981) at the time of final analysis (given the assumed 5 month delayed treatment 
effect, this equates to median OS times of 38.3 and 25 months in the PDR001 in combination 
with dabrafenib and trametinib combination arm and the dabrafenib and trametinib plus placebo 
group, respectively). 
In order to ensure 80% power for OS using the above assumptions for HR=1 for the first 5 
months and HR=0.60 thereafter, it is calculated that a total of 245 deaths need to be observed. 
This calculation assumes analysis by a one-sided log-rank test at the overall 2.5% level of 
significance, subjects randomized to the two treatments in a 1:1 ratio, and a 3-look group 
sequential design with a Lan-DeMets (O’Brien-Fleming) alpha spending function 


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At the moment it is inappropriate to give the number of deaths and information fractions 
expected at the interim OS analyses due to the high uncertainty of event predictions for both 
PFS (which directly determines the timing of the interim OS analyses) and for OS itself. 
These calculations were made using the software package EAST 6.4.
It should be noted that the cumulative 80% power refers to the overall HR of 0.693 that 
combines both the period of no effect and the subsequent delayed effect period and this 
represents ‘alternative hypothesis’ value.
At the final OS analysis 245 deaths will need to be observed. The final OS analysis is expected 
to be performed after approximately 36 months from the date of first subject randomized based 
on a prediction analysis using actual study data. However, note that this prediction is also 
associated with high uncertainty as described above.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the subject source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.


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Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study.
As per Section 2.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g., the presence of an impartial witness, sign/dating separate 
informed consent forms (ICFs) by trial participant and person obtaining informed consent, etc.).
Additional consent form
Sub-studies 
 will have a separate 
consent form or an option (check box) under the study main ICF covering those studies. This 
form will be adapted for each Study based on a standard template used globally for all Studies. 
These informed consent forms will be submitted for ethical approval together with the Study 
Protocol and the main informed consent form of the Study. If a subject opts not to participate 
in the optional assessments, this in no way affects the subject’s ability to participate in the main 
research study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g., www.clinicaltrials.gov before study 
start. In addition, results of interventional clinical trials in adult subjects are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric subjects within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted.
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present their writing of a publication, either directly from Novartis or through the professional 
medical writing agency. Author(s) maybe requested to present poster or oral presentation at 
scientific congress; however, there will be no honorarium provided for such presentations.


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As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial nature by all authors, including medical writing and 
editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com.
Publication section text for Novartis-sponsored Phase I healthy volunteer studies:
In general, Phase I healthy volunteer studies will not be registered on publicly accessible 
database. However, Novartis will comply with local country regulations for trial registration 
and results posting, as needed.
According to Novartis policy, authors of publication will not receive remuneration for their 
writing of a publication, either directly from Novartis or through the professional medical 
writing agency. Author(s) may be requested to present poster or oral presentation at scientific 
congress; however, there will be no honorarium provided for such presentations.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study CRF is the primary data collection instrument for the 
study. The investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported in the CRFs and all other required reports. Data reported on the CRF, that are 
derived from source documents, should be consistent with the source documents or the 
discrepancies should be explained. All data requested on the CRF must be recorded. Any 
missing data must be explained. Any change or correction to a paper CRF should be dated, 
initialed, and explained (if necessary) and should not obscure the original entry. For electronic 


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CRFs an audit trail will be maintained by the system. The investigator should retain records of 
the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and subject records
The investigator must ensure anonymity of the subjects; subjects must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and subject 
enrollment log must be kept strictly confidential to enable subject identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of subjects at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for subject safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any subject 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 


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according to local regulations (e.g., UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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13
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Long GV, Stroyakovskiy D, Gogas H, et al (2014). Combined BRAF and MEK inhibition 
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with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J 
Clin Oncol; 33(10):1191-1196
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previously untreated BRAF V600-mutant unresectable or metastatic melanoma. ESMO oral 
presentation #LBA43.
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Melanoma Version 1.2017. Source URL 
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information on controls in clinical trials. Clin Trials; 7:5-18
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I Combination Trials in Oncology. Statistical Methods in Drug Combination Studies
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patients treated with ipilimumab? J Immunother Cancer; 2:17
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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown


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14.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
14.1.2.1 Definitions
14.1.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.
•
Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 14.1.3.2.8.
Measurable lesions (both nodal and non-nodal)
•
Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g., the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.
•
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.
•
Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.


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•
Cystic lesions:
•
Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
•
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
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.
•
Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g., longest diameter <10 mm with CT/MRI or pathological lymph nodes with  
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
14.1.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v.) contrast.
The following considerations are to be made when evaluating the tumor:
•
All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.
•
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.
•
For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.
•
A change in methodology can be defined as either a change in contrast use (e.g., keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a major change in technique (e.g., from 
CT to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. However, 
another response assessment than the Novartis calculated UNK response may be accepted 


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from the investigator or the central blinded reviewer if a definitive response assessment 
can be justified, based on the available information.
•
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
•
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
•
No FDG-PET at baseline with a positive FDG-PET at follow-up:
•
If new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up 
assessments by CT will be needed to determine if there is truly progression occurring at 
that site. In all cases PD will be the date of confirmation of new disease by CT (or some 
other conventional technique such as MRI) rather than the date of the positive PET scan. 
If there is a positive PET scan without any confirmed progression at that site by CT, then a 
PD cannot be assigned.
•
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD.
•
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT is preferable.
•
Physical exams: Evaluation of lesions by physical examination is accepted when 
lesions are superficial, with at least 10mm size, and can be assessed using calipers.
•
Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by 
the protocol. It is, however, a possible alternative to clinical measurements of 
superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. US 
might also be useful to confirm the complete disappearance of superficial lesions 
usually assessed by clinical examination.
•
Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for 
objective tumor evaluation has not yet been fully and widely validated. Their uses in 
this specific context require sophisticated equipment and a high level of expertise that 
may only be available in some centers. Therefore, the utilization of such techniques 
for objective tumor response should be restricted to validation purposes in specialized 
centers. However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained.
•
Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g., CA-125 for ovarian 
cancer, PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) 
can be integrated as non-target disease. If markers are initially above the upper 
normal limit they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared.
•
Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 


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confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).
•
Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.1.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:
•
Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline
•
Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g., clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.1.2.1.1.
•
Nodal target: See Section 14.1.2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
•
Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
14.1.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. These 


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evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-3) as well as the presence or absence of new lesions.
14.1.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.


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14.1.2.4.2
Determination of target lesion response
Table 14-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis to 
< 10 mm.1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded 
at or after baseline (nadir). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.2
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have 
not been assessed or have been assessed using a different method than 
baseline.3
1.
SOD for CR may not be zero when nodal lesions are part of target lesions
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR
In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgment based on the available information (see Notes on 
target lesion response and methodology change in Section 14.1.2.2).
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following 
possibilities:
•
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
•
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.
•
For those patients who have only one target lesion at baseline, the reappearance of the target 
lesion which disappeared previously, even if still small, is considered a PD.
•
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 


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100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.
•
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.
•
Lesions split: In some circumstances, disease that is measurable as a target lesion at baseline 
and appears to be one mass can split to become two or more smaller sub-lesions. When this 
occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of the two 
split lesions should be added together and the sum recorded in the diameter field on the case 
report form under the original lesion number. This value will be included in the sum of 
diameters when deriving target lesion response. The individual split lesions will not be 
considered as new lesions, and will not automatically trigger a PD designation.
•
Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of diameters 
for target lesions. On the case report form, the diameter of the “merged lesion” should be 
recorded for the size of one of the original lesions while a size of “0”mm should be entered 
for the remaining lesion numbers which have coalesced.
•
The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.
•
Since lesions less than 10 mm are considered normal, a CR for target lesion response should 
be assigned when all nodal target lesions shrink to less than 10 mm and all non-nodal target 
lesions have disappeared.
•
Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions.
•
Following a CR, a PD can subsequently only be assigned for target lesion response if either 
a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm and 
there is at least 20% increase in sum of the diameters of all nodal target lesions relative to 
nadir with at least 5 mm increase in the absolute sum of the diameters.
•
A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g., a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression in 
which case the investigator might assign an SD target lesion response; however, this should 
be done with caution and conservatively as the response categories have well defined 
criteria.


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14.1.2.4.3
Determination of non-target lesion response
Table 14-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned 
a non-target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions 
have not been assessed or have been assessed using a different method than 
baseline2.
1.
The assignment of PD solely based on change in non-target lesions in light of target lesion response of 
CR, PR or SD should be exceptional. In such circumstances, the opinion of the investigator or central 
reviewer does prevail.
2.
It is recommended that the investigator and/or central reviewer should use expert judgment to assign a 
Non-UNK response wherever possible (see notes section for more details)
Notes on non-target lesion response
•
The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned.
•
The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions returned 
to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or there are 
any abnormal nodal lesions (i.e.  10 mm) the response can only be ‘Non-CR/Non-PD’ 
unless there is unequivocal progression of the non-target lesions (in which case response is 
PD) or it is not possible to determine whether there is unequivocal progression (in which 
case response is UNK).
•
Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable disease 
at baseline. If there is unequivocal progression of non-target lesion(s), then at least one of 
the non-target lesions must be assigned a status of “Worsened”. Where possible, similar 
rules to those described in Section 14.1.2.4.2 for assigning PD following a CR for the non-
target lesion response in the presence of non-target lesions nodal lesions should be applied.


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14.1.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF page.
•
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion
•
If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.2.5).
•
A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to  10 mm for the first time in the study plus 5 
mm absolute increase. FDG-PET: can complement CT scans in assessing progression 
(particularly possible for ‘new’ disease). See Section 14.1.2.2.
14.1.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 14-3.
Table 14-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1.
This overall lesion response also applies when there are no non-target lesions identified at baseline.
2.
Once confirmed PR was achieved, all these assessments are considered PR.
3.
As defined in Section 14.1.2.4.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.


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14.1.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.1.3.1 Best overall response
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). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.
•
For non-randomized trials where response is the primary endpoint, confirmation is needed.
•
For trials intended to support accelerated approval, confirmation is needed
•
For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:
•
CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required
•
PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required
•
SD = at least one SD assessment (or better) > 12 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).
•
PD = progression  12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).


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•
UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 12 weeks or early progression within the first 12 weeks)
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 8 
week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g., if the assessment occurs every 6 weeks with a time 
window of ± 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment.
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g., PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:
•
Investigator overall lesion response
•
Central Blinded Review overall lesion response
•
Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)


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The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR, or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g., populations based on an ITT approach).
14.1.3.2 Time to event variables
The protocol should state which of the following variables is used in that study.
14.1.3.2.1
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g., in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 


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patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint.
14.1.3.2.2
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
14.1.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
14.1.3.2.4
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
14.1.3.2.5
Duration of response
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 


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a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by Morgan 
(1988).
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates… If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
14.1.3.2.6
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 14.1.3.2.4. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.


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•
at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)
•
at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
14.1.3.2.7
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g., X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:
•
Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:
•
Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).
•
Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.
•
Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.


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•
Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.3.2.7).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.
•
Date of discontinuation is the date of the end of treatment visit.
•
Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.
•
Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.1.3.2.8
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 14.1.3.2.6, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics April 2005) 
as a reference, the following analyses can be considered:


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Table 14-4
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next 
scheduled assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly 
one missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or 
more missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. clinical 
progression based on investigator 
claim
(1) Ignore clinical progression and follow 
situations above
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
As per above 
situations
Progressed
F
New anticancer therapy given
(1) Ignore the new anticancer therapy and 
follow situations above (ITT approach)
(2) Date of last adequate assessment prior to 
new anticancer therapy
(3) Date of secondary anti-cancer therapy
(4) Date of secondary anti-cancer therapy
As per above 
situations
Censored
Censored
Event
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)
1.
=Definitions can be found in Section 14.1.3.2.6.
2.
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 14.1.3.2.6.
3.
=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment 
as defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.
•
(C1) taking the actual progression or death date, in the case of only one missing 
assessment.
•
(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.


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Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g., CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy.
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the SAP.
In some specific settings, local treatments (e.g., radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g., by assigning the dates for censoring 
and events only at scheduled visit dates. The latter could be handled by replacing in 
Table 14-4 the “Date of last adequate assessment” by the “Date of previous scheduled 
assessment (from baseline)”, with the following definition:
•
Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
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14.1.4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g., on incomplete dates).
14.1.4.1 Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
14.1.4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment.
Patients may discontinue study treatment for any of the following reasons:
•
Adverse event(s)
•
Lost to follow-up
•
Physician decision
•
Pregnancy
•
Protocol deviation
•
Technical problems
•
Subject/guardian decision
•
Progressive disease
•
Study terminated by the sponsor
•
Non-compliant with study treatment
•
No longer requires treatment
•
Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
Death is a reason which “must” lead to discontinuation of patient from trial.
14.1.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:


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Adverse event
•
Lost to follow-up
•
Physician decision
•
Pregnancy
•
Protocol deviation
•
Technical problems
•
Subject/guardian decision
•
Death
•
Progressive disease
•
Study terminated by the sponsor
14.1.4.4 Medical validation of programmed overall lesion response
In order to be as objective as possible the RECIST programmed calculated response assessment 
is very strict regarding measurement methods (i.e. any assessment with more or less sensitive 
method than the one used to assess the lesion at baseline is considered UNK) and not available 
evaluations (i.e. if any target or non-target lesion was not evaluated the whole overall lesion 
response is UNK unless remaining lesions qualified for PD). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) at Novartis or external experts. In addition, 
data review reports will be available to identify assessments for which the investigators’ or 
central reader’s opinion does not match the programmed calculated response based on RECIST 
criteria. This may be queried for clarification. However, the investigator or central reader’s 
response assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.1.4.5 Programming rules
The following should be used for programming of efficacy results:
14.1.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)


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When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.1.4.5.2
Incomplete assessment dates
All investigation dates (e.g., X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.1.3.2.6). If all measurement dates have 
no day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.1.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.1.4.5.4
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
14.1.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.1.4.5.6
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:
•
Alive
•
Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:
•
Ongoing without event
•
Lost to follow-up
•
Withdrew consent
•
Adequate assessment no longer available*
•
Event documented after two or more missing tumor assessments (optional, see Table 14-4)


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•
Death due to reason other than underlying cancer (only used for TTP and duration of 
response)
•
Initiation of new anti-cancer therapy
* Adequate assessment is defined in Section 14.1.3.2.6. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:
•
This may be when there has been a definite decision to stop evaluation (e.g., 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).
•
The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g., withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.
•
This reason will also be used to censor in case of no baseline assessment.


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14.1.5
References (available upon request)
Dent S, Zee (2001). application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009). New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008). Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988). Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000). New Guidelines to Evaluate the Response 
to Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16


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14.2
Appendix 2: The Bayesian logistic regression model, prior, and 
dosing regimen recommendations in hypothetical scenarios


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14.2.1
Introduction
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical data, and the results of the Bayesian analyses and respective dosing decisions for 
hypothetical data scenarios.
14.2.2
Statistical model
For each of the k dosing regimens (k = 1, 2, 3), a separate statistical model will comprise of 
single-agent toxicity parts and interaction parts to describe both two-way and three-way drug 
safety interactions.
•
Model 1 will incorporate DLT data from the first 8 weeks of triple combination treatment 
in cohort 1 (400 mg i.v. PDR001 Q4W + 150 mg BID dabrafenib + 2 mg QD trametinib)
•
Model 2 will incorporate DLT data from the first 8 weeks of triple combination treatment 
in cohort -1a (400 mg i.v. PDR001 Q8W + 150 mg BID dabrafenib + 2 mg QD 
trametinib)
•
Model 3 will incorporate DLT data from the first 8 weeks of triple combination treatment 
in cohort -1b (4 weeks run-in of 150 mg BID dabrafenib + 2 mg QD trametinib, followed 
by 400 mg i.v. PDR001 Q4W + 150 mg BID dabrafenib + 2 mg QD trametinib)
14.2.2.1 Single agent parts
Let 1k (d1) be the risk of DLT for dabrafenib given as a single agent BID at dose d1 for the kth 
model (k = 1, 2, 3); 2k (d2) be the risk of DLT for trametinib given as a single agent QD at dose 
d2 for the kth model; and 3k (d3) be the risk of DLT for PDR001 given as a single agent Q4W 
at dose d3 for the kth model. These single agent dose-DLT models are logistic:
where 150 mg, 2 mg, and 400 mg are used to scale the doses of dabrafenib, trametinib, and 
PDR001, respectively. Hence, for the kth model, α1k, α2k, and α3k (>0) are the single agent odds 
of a DLT at 150 mg BID, 2 mg QD, and 400 mg Q4W, respectively; and β1k, β2k, and β3k (>0) 
are the increase in the log-odds of a DLT by a unit increase in log-dose.
14.2.2.2 Interaction
Under no interaction, the risk of a DLT for the kth model (k = 1, 2, 3) at dose d1 of dabrafenib, 
dose d2 of trametinib, and dose d3 of PDR001 is:
To allow for interaction between dabrafenib, trametinib, and PDR001, odds multipliers are 
introduced:


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η12k
Two-way interaction between dabrafenib and trametinib
η13k
Two-way interaction between dabrafenib and PDR001
η23k
Two-way interaction between trametinib and PDR001
η123k
Three-way interaction between dabrafenib, trametinib, and PDR001
The risk of DLT for combination dose (d1, d2, d3) is then given by:
where odds() =  / (1 - ); ƞijk is the kth model log-odds ratio between the interaction and no 
interaction model at the reference dose for treatments i and j and a zero dose of the third 
treatment; and (ƞ12k + ƞ23k + ƞ32k + ƞ123k) is the kth model log-odds ratio between the interaction 
and no interaction model, at the reference dose for all three treatments. Here ƞijk = 0 corresponds 
to no interaction, with ƞijk > 0 and ƞijk < 0 representing synergistic and antagonistic toxicity, 
respectively.
14.2.3
Prior specifications
The Bayesian approach requires the specification of prior distributions for all model parameters 
which include, for the kth model (k = 1, 2, 3), the single agent parameters log(α1k) and log(β1k) 
for dabrafenib, log(α2k) and log(β2k) for trametinib, log(α3k) and log(β3k) for PDR001, and 
interaction parameters ƞ12k, ƞ13k, ƞ23k, and ƞ123k. A meta-analytic-predictive (MAP) approach is 
used to derive a prior distribution for the single agent model parameters based upon available 
DLT data. For dabrafenib and trametinib, 100% MAP priors will be used. For PDR001, this is 
then robustified by creating a mixture prior including both a component derived from the MAP 
prior and a weakly informative robustification component. This robustification allows for the 
possibility that the dose/toxicity relationship for PDR001 in combination differs substantially 
from that of the single agent.
14.2.3.1 Prior distribution for the logistic parameters
Description of the meta-analytic-predictive (MAP) approach
The aim of the MAP approach is to derive a prior distribution from the logistic parameters 
(log(α*), log(β*)) of the new trial using DLT data from historical studies.
Gp
The corresponding probability of a DLT is πds. The model specifications for the derivation of 
the MAP prior are as follows:
rds | πds ~Bin(πds, nds)
logit(πds) = log(αs) + βs log (d/dref)
(log(αs), log(βs)) | µ, ψ ~ BVN(µ, ψ), s = 1,…, S
(log(α*), log(β*)) | µ, ψ ~ BVN(µ, ψ)


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where dref is the reference dose. The parameters µ = (µ1, µ2) and ψ are the mean and between-
trial covariance matrix for the logistic parameters, the latter with standard deviations τ1 and τ2 
and correlation ρ. The parameters τ1 and τ2 quantify the degree of between-trial heterogeneity. 
The following priors are used for these parameters:
•
normal priors for µ1 and µ2,
•
log-normal priors for τ1 and τ2, and
•
a uniform prior for ρ
The MAP prior for single agent model parameters in the new trial, (log(α*), log(β*)), is the 
predictive distribution
(log(α*), log(β*)) | (rds, nds: s = 1,…, S)
Since the predictive distribution is not available analytically, MCMC is used to simulate values 
from this distribution. This is implemented using JAGS version 4.1.0.
Single agent dabrafenib:
The prior distributions for the kth model (k = 1, 2, 3) of dabrafenib single agent BLRM model 
parameters (log(α1k), log(β1k)) are based 100% on MAP.
MAP component for dabrafenib
For the MAP model for dabrafenib, reference dose dref = 150 mg (BID) is used, and data from 
S = 1 history study are available.
Weakly informative normal priors are assumed for µ11k and µ12k, with means corresponding to 
an assumed 10% risk of DLT at the reference dose of 150 mg, and a double in dose leading to 
a doubling in the odds of a DLT, respectively. Priors for τ11k and τ12 are assigned such that (1) 
their medians correspond to moderate between-trial heterogeneity, and (2) their uncertainty (95% 
prior interval) cover plausible between-trial standard deviations (Neuenschwander 2014).
The prior distributions for the model used for deriving the MAP priors for dabrafenib are 
specified in Table 14-5.
Table 14-5
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single agent dabrafenib model parameters
Parameter
Prior distribution
µ11k
N(mean = logit(0.1), sd = 2)
µ12k
N(mean = logit(0.5), sd=1)
11k
log-normal(mean = 0.250, sd = log(2)/1.96)
12k
log-normal(mean = 0.125, sd = log(2)/1.96)
ρ1k
uniform(-1,1)
Historical data for dabrafenib
The dose-DLT data of dabrafenib single agent from the following clinical study are considered 
as relevant information (Table 14-6). Only BID dosing data from this study were used to derive 
the prior distribution for the BLRM parameters (log(α1k), log(β1k)) for model k (k = 1, 2, 3).


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•
BRF112680: open-label, multi-center, phase I dose-escalation study to investigate the 
safety, pharmacokinetics, and pharmacodynamics of dabrafenib in subjects with solid 
tumors or BRAF-mutation positive melanoma
The DLT observation window in the phase I dose escalation part of this trial was 3 weeks.
Table 14-6
Historical data from dabrafenib single agent clinical study
Dose level
Number of evaluable patients
Number of DLTs
35 mg BID
4
0
70 mg BID
4
0
100 mg BID
6
0
150 mg BID
6
0
200 mg BID
7
1
350 mg BID
6
1
Single agent trametenib:
The prior distributions for the kth model (k = 1, 2, 3) of trametinib single agent BLRM model 
parameters (log(α2k), log(β2k)) are based 100% on MAP.
MAP component for trametinib
For the MAP model for trametinib, reference dose dref = 2 mg (QD) is used, and data from S = 
1 history study are available.
Weakly informative normal priors are assumed for µ21k and µ22k, with means corresponding to 
an assumed 10% risk of DLT at the reference dose of 2 mg, and a double in dose leading to a 
doubling in the odds of a DLT, respectively. Priors for τ21k and τ22k are assigned such that (1) 
their medians correspond to moderate between-trial heterogeneity, and (2) their uncertainty (95% 
prior interval) cover plausible between-trial standard deviations.
The prior distributions for the model used for deriving the MAP priors for trametinib are 
specified in Table 14-7.
Table 14-7
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single agent trametinib model parameters
Parameter
Prior distribution
µ21k
N(mean = logit(0.1), sd = 2)
µ22k
N(mean = logit(0.5), sd=1)
21k
log-normal(mean = 0.250, sd = log(2)/1.96)
22k
log-normal(mean = 0.125, sd = log(2)/1.96)
ρ2k
uniform(-1,1)
Historical data for trametinib
The dose-DLT data of trametinib single agent from the following clinical study are considered 
as relevant information (Table 14-8) and were used to derive the prior distribution for the 
BLRM parameters (log(α2k), log(β2k)) for model k (k = 1, 2, 3).


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•
MEK111054: open-label, multi-center, phase I dose-escalation study to investigate the 
safety, pharmacokinetics, and pharmacodynamics of trametinib in subjects with solid 
tumors or BRAF-mutation positive melanoma
The DLT observation window in the phase I dose escalation part of this trial was 4 weeks.
Table 14-8
Historical data from trametinib single agent clinical study
Dose level
Number of evaluable patients
Number of DLTs
2.5 mg QD
9
0
3 mg QD
12
0
4 mg QD
3
1
Single agent PDR001 Q4W:
The prior distributions for the kth model (k = 1, 2, 3) of PDR001 Q4W single agent BLRM 
model parameters (log(α3k), log(β3k)) are a mixture of two components: a MAP component and 
a robustification component used to allow for a dose/toxicity relationship for PDR001 in a 
combination that differs substantially from that in single agent. The components form a mixture 
prior with respective weights (0.95, 0.05).
MAP component for PDR001 for model 1 (dosing regimen 1)
For the MAP model for dosing regimen 1 of PDR001, reference dose dref = 400 mg (Q4W) is 
used, and data from S = 1 historical study are available.
Weakly informative normal priors are assumed for µ311 and µ321, with means corresponding to 
an assumed 10% risk of DLT at the reference dose of 400 mg, and a double in dose leading to 
a doubling in the odds of a DLT, respectively. Priors for τ311 and τ321 are assigned such that (1) 
their medians correspond to moderate between-trial heterogeneity, and (2) their uncertainty (95% 
prior interval) cover plausible between-trial standard deviations.
The prior distributions for the model used for deriving the MAP priors for dosing regimen 1 of 
PDR001 are specified in Table 14-9.
Table 14-9
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single agent PDR001 model parameters for model 1 
(dosing regimen 1)
Parameter
Prior distribution
µ311
N(mean = logit(0.1), sd = 2)
µ321
N(mean = logit(0.5), sd=1)
311
log-normal(mean = 0.250, sd = log(2)/1.96)
321
log-normal(mean = 0.125, sd = log(2)/1.96)
ρ31
uniform(-1,1)
MAP component for PDR001 for model 2 (dosing regimen -1a)
For the MAP model for dosing regimen -1a of PDR001, reference dose dref = 400 mg (Q4W) is 
used, and data from S = 1 historical study are available.


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Weakly informative normal priors are assumed for µ312 and µ322, with means corresponding to 
an assumed 10% risk of DLT at the reference dose of 400 mg, and a double in dose leading to 
a doubling in the odds of a DLT, respectively. Priors for τ312 and τ322 are assigned such that (1) 
their medians correspond to substantial between-trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations. As less is information is 
known about Q8W versus Q4W dosing of PDR001, substantial between-trial heterogeneity is 
assumed for PDR001 in dosing regimen -1a. The prior distributions for the model used for 
deriving the MAP priors for dosing regimen -1a of PDR001 are specified in Table 14-10.
Table 14-10
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single agent PDR001 model parameters for model 2 
(dosing regimen -1a)
Parameter
Prior distribution
µ312
N(mean = logit(0.1), sd = 2)
µ322
N(mean = logit(0.5), sd=1)
312
log-normal(mean = 0.50, sd = log(2)/1.96)
322
log-normal(mean = 0.25, sd = log(2)/1.96)
ρ32
uniform(-1,1)
MAP component for PDR001 for model 3 (dosing regimen -1b)
For the MAP model for dosing regimen -1b of PDR001, reference dose dref = 400 mg (Q4W) is 
used, and data from S = 1 historical study are available.
Weakly informative normal priors are assumed for µ313 and µ323, with means corresponding to 
an assumed 10% risk of DLT at the reference dose of 400 mg, and a double in dose leading to 
a doubling in the odds of a DLT, respectively. Priors for τ313 and τ323 are assigned such that (1) 
their medians correspond to substantial between-trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations. As less is information is 
known about Q4W dosing of PDR001 after a 4 week run-in of dabrafenib and trametinib versus 
immediate Q4W dosing, substantial between-trial heterogeneity is assumed for PDR001 in 
dosing regimen -1b. The prior distributions for the model used for deriving the MAP priors for 
dosing regimen -1b of PDR001 are specified in Table 14-11.
Table 14-11
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single agent PDR001 model parameters for model 3 
(dosing regimen -1b)
Parameter
Prior distribution
µ313
N(mean = logit(0.1), sd = 2)
µ323
N(mean = logit(0.5), sd=1)
313
log-normal(mean = 0.50, sd = log(2)/1.96)
323
log-normal(mean = 0.25, sd = log(2)/1.96)
ρ33
uniform(-1,1)


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Historical data for PDR001
The dose-DLT data of PDR001 single agent from the following clinical study are considered as 
relevant information (Table 14-12) and were used to derive the prior distribution for the BLRM 
parameters (log(α3k), log(β3k)) for model k (k = 1, 2, 3).
•
CPDR001X201: open-label, multi-center, phase I/II study of the safety and efficacy of 
PDR001 administered to patients with advanced malignancies
The DLT observation window in the phase I dose escalation part of this trial was 4 weeks. A 
review of AE records of the patients did not indicate any significant additional toxicity in the 
2nd cycle of treatment, suggesting data from the 1 cycle DLT evaluation period of study 
CPDR001X2101 is also information for a 2 cycle DLT evaluation period. Assuming the average 
weight of a patients is 80 kg, each dose level in the historical data dQ4W[mg/kg] can be converted 
to a flat dose level, using the following:
dQ4W [mg] = dQ4W[mg/kg] * 80[kg]
Table 14-12
Historical data from PDR001 Q4W single agent clinical study
Dosing schedule
Dose level 
(mg/kg)
Converted to dose 
level in Q4W (mg)
Number of evaluable 
patients
Number of DLTs
q4w
3
240
6
0
q4w
5
400
10
0
Robustification component of PDR001
To take into account the potential situation that PDR001 in combination is substantially more 
toxic than when administered as single agent, and that the longer DLT period of 8 weeks (56 
days) may increase the chance of experiencing toxicity, a second prior component with vague 
bivariate normal distribution centered around a higher toxicity is added to improve the 
robustness of the final prior. The parameters of this weakly information prior distribution are 
described below:
•
The mean (log(α3k), log(β3k)) = (logit(0.33), 0), i.e. the median DLT rate at the reference 
dose (400 mg), was assumed to be 0.33 and doubling in dose was assumed to double odds 
of DLT.
•
To complete the specification, the prior standard deviation, sd(log(α3k), log(β3k)), was set 
equal to (2,1) which allows for considerable prior uncertainty for the dose/toxicity profile.
•
The correlation, corr(log(α3k), log(β3k)), was set equal to 0.
14.2.3.2 Prior distribution for interaction parameters
Based on the available information, there is a possibility of an antagonistic or synergistic 
interaction between dabrafenib and trametinib that will be taken into account for model 1 
(dosing regimen 1) and model 2 (dosing regimen -1a). For model 3 (dosing regimen -1b), the 
interaction is centered at a 0% increase in odds of DLT, given that DLT’s for the triple 
combination in this dosing regimen will be assessed after a 4 week run-in with dabrafenib an 
and trametinib. No interaction is expected for the other two-way combinations, and for the 
three-way combination no interaction is expected over and above what is already described. 
However, in all cases, considerable uncertainty remains as to the true interaction, and normal 


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priors are used that allow for both synergistic and antagonistic toxicity. The following 
assumptions will be used for interaction parameters for model k (k = 1, 2, 3).
Dabrafenib and trametinib for model 1 (dosing regimen 1) and 2 (dosing regimen -1a):
•
ƞ12k is normally distributed and centered at 1.2, i.e. a 20% increase in odds of DLT over 
independence at the combination starting dose
•
97.5th percentile is log(3), i.e. a 3-fold increase in odds of DLT over independence at the 
combination starting dose
Dabrafenib and trametinib for model 3 (dosing regimen -1b):
•
ƞ123 is normally distributed and centered at 0, i.e. a 0% increase in odds of DLT over 
independence at the combination starting dose
•
97.5th percentile is log(2), i.e. a 2-fold increase in odds of DLT over independence at the 
combination starting dose
Dabrafenib and PDR001 for all 3 models:
•
ƞ13k is normally distributed and centered at 0, i.e. a 0% increase in odds of DLT over 
independence at the combination starting dose
•
97.5th percentile is log(2), i.e. a 2-fold increase in odds of DLT over independence at the 
combination starting dose
Trametinib and PDR001 for all 3 models:
•
ƞ23k is normally distributed and centered at 0, i.e. a 0% increase in odds of DLT over 
independence at the combination starting dose
•
97.5th percentile is log(2), i.e. a 2-fold increase in odds of DLT over independence at the 
combination starting dose
Dabrafenib, trametinib and PDR001 for all 3 models:
•
ƞ123k is normally distributed and centered at 0, i.e. a 0% increase in odds of DLT over 
independence at the combination starting dose
•
97.5th percentile is log(1.5), i.e. a 1.5-fold increase in odds of DLT over independence at 
the combination starting dose
14.2.3.3 Additional historical data for the combination of dabrafenib and 
trametinib
The dose-DLT data for the combination of dabrafenib and trametinib from the following clinical 
studies are considered as relevant information (Table 14-13) and will be incorporated into the 
prior model using discounted weighting.
•
BRF113220: open-label, multi-center phase I/II dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamics, and clinical activity of dabrafenib in 
combination with trametinib in subjects with BRAF mutant melanoma
•
MEK115306 (COMBI-d): randomized, double-blind, phase III study comparing the 
combination of dabrafenib and trametinib to dabrafenib and placebo as first-line therapy in 
subjects with unresectable (Stage IIIc) or metastatic (Stage IV) BRAF V600E/K mutation-
positive cutaneous melanoma


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•
MEK116513 (COMBI-v): randomized, open-label, phase III study comparing the 
combination of dabrafenib and trametinib to vemurafenib in subjects with unresectable 
(Stage IIIc) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous 
melanoma
The DLT observation window in the phase I dose escalation trial was 3 weeks.
As DLT’s weren’t formally assessed in the phase III’s studies, a post-hoc analysis was 
conducted to estimate the number of patients who met DLT criteria in the first 8 weeks of 
combination treatment.
Data from these studies will be incorporated into the prior model using discounted weighting, 
where weight is determined as:
weight = 1 / (1 + (2*n*τ2)/(sd2), where n refers to study sample size and  and sd correspond to 
the assumed mean and standard deviation for between-trial heterogeneity. In this case, a 
substantial between-trial heterogeneity is assumed (= 0.50, sd = 2).
Table 14-13
Historical data for combination of dabrafenib and trametinib
Study
Dose level of dabrafenib and 
trametinib (mg/kg)
Number of 
evaluable 
patients
Number of 
DLTs
Weight to be 
used in prior 
model
75 mg BID + 1 mg QD
4
0
150 mg BID + 1 mg QD
4
0
150 mg BID + 1.5 mg QD
4
0
BRF113220
150 mg BID + 2 mg QD
4
1
0.33
MEK115306 (COMBI-d)
150 mg BID + 2 mg QD
209
23
0.037
MEK116513 (COMBI-v)
150 mg BID + 2 mg QD
350
51
0.022
14.2.3.4 Summary of prior distributions
The prior distributions of the model parameters and prior summaries for DLT rates for model 1 
(dosing regimen 1) are summarized in Table 14-14 and Table 14-15.


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Table 14-14
Prior distribution for model parameters: model 1 (dosing regimen 1)
Parameter
mean
Standard deviations
Correlation
weight
Dabrafenib single agent MAP prior
(log(α11), log(β11)) ~ BVN
MAP component
(-3.049, 0.190)
(0.880, 0.835)
-0.284
N/A
Trametinib single agent MAP prior
(log(α21), log(β21)) ~ BVN
MAP component
(-3.708, 0.052)
(1.090, 0.943)
-0.381
N/A
PDR001 single agent model
(log(α31), log(β31)) ~ BVN
MAP component
(-3.983, 0.058)
(1.361, 1.011)
0.063
0.95
Robustification component
(-0.708, 0)
(2, 1)
0
0.05
Interaction parameters ~ Normal
ƞ121
0.182
0.468
N/A
N/A
ƞ131
0
0.354
N/A
N/A
ƞ231
0
0.354
N/A
N/A
ƞ1231
0
0.207
N/A
N/A
Dosing regimen 1: 400 mg i.v. PDR001 Q4W, 150 mg BID dabrafenib, and 2 mg QD trametinib
Table 14-15
Summary of prior distribution of DLT rates (with dabrafenib fixed at 
150 mg BID and trametinib fixed at 2 mg QD) for model 1 (dosing 
regimen 1)
Prior probabilities that P(DLT) is in 
the interval:
Quantiles
PDR dose 
(regimen)
[0, 0.16)
[0.16, 0.33)
[0.33,1]
Mean
SD
2.5%
50%
97.5%
400 mg (Q4W)
0.555
0.326
0.120
0.185
0.146
0.033
0.144
0.594
Table 14-15 shows that the prior model for dosing regimen 1 results in a probability of excessive 
toxicity (i.e. DLT rate of ≥ 33%) with the triple combination of 12% which satisfies the EWOC 
criteria (< 25%).
The prior distributions of the model parameters and prior summaries for DLT rates for model 2 
(dosing regimen -1a) are summarized in Table 14-16 and Table 14-17.


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Table 14-16
Prior distribution for model parameters: model 2 (dosing regimen -1a)
Parameter
mean
Standard deviations
Correlation
weight
Dabrafenib single agent MAP prior
(log(α12), log(β12)) ~ BVN
MAP component
(-3.049, 0.190)
(0.880, 0.835)
-0.284
N/A
Trametinib single agent MAP prior
(log(α22), log(β22)) ~ BVN
MAP component
(-3.708, 0.052)
(1.090, 0.943)
-0.381
N/A
PDR001 single agent model
(log(α32), log(β32)) ~ BVN
MAP component
(-3.946, 0.051)
(1.500, 1.045)
0.061
0.95
Robustification component
(-0.708, 0)
(2, 1)
0
0.05
Interaction parameters ~ Normal
ƞ122
0.182
0.468
N/A
N/A
ƞ132
0
0.354
N/A
N/A
ƞ232
0
0.354
N/A
N/A
ƞ1232
0
0.207
N/A
N/A
Dosing regimen -1a: 400 mg i.v. PDR001 Q8W, 150 mg BID dabrafenib, and 2 mg QD trametinib
Table 14-17
Summary of prior distribution of DLT rates (with dabrafenib fixed at 
150 mg BID and trametinib fixed at 2 mg QD) for model 2 (dosing 
regimen -1a)
Prior probabilities that P(DLT) is in 
the interval:
Quantiles
PDR dose 
(regimen)
[0, 0.16)
[0.16, 0.33)
[0.33,1]
Mean
SD
2.5%
50%
97.5%
400 mg (Q8W*)
0.639
0.301
0.060
0.157
0.117
0.037
0.129
0.467
*Per PK simulations, it is reasonable to assume that 400 mg Q8W is approximately equivalent to 230 mg Q4W. 
Results are therefore shown for 230 mg Q4W.
Table 14-17 shows that the prior model for dosing regimen -1a results in a probability of 
excessive toxicity with the triple combination of 6% which satisfies the EWOC criteria.
The prior distributions of the model parameters and prior summaries for DLT rates for model 3 
(dosing regimen -1b) are summarized in Table 14-18 and Table 14-19.


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Table 14-18
Prior distribution for model parameters: model 3 (dosing regimen -1b)
Parameter
mean
Standard deviations
Correlation
weight
Dabrafenib single agent MAP prior
(log(α13), log(β13)) ~ BVN
MAP component
(-3.049, 0.190)
(0.880, 0.835)
-0.284
N/A
Trametinib single agent MAP prior
(log(α23), log(β23)) ~ BVN
MAP component
(-3.708, 0.052)
(1.090, 0.943)
-0.381
N/A
PDR001 single agent model
(log(α33), log(β33)) ~ BVN
MAP component
(-3.946, 0.051)
(1.500, 1.045)
0.061
0.95
Robustification component
(-0.708, 0)
(2, 1)
0
0.05
Interaction parameters ~ Normal
ƞ123
0
0.354
N/A
N/A
ƞ133
0
0.354
N/A
N/A
ƞ233
0
0.354
N/A
N/A
ƞ1233
0
0.207
N/A
N/A
Dosing regimen -1b: 4 weeks of 150 mg dabrafenib and 2 mg QD trametinib, followed by 400 mg i.v. PDR001 
Q4W, 150 mg BID dabrafenib, and 2 mg QD trametinib
Table 14-19
Summary of prior distribution of DLT rates (with dabrafenib fixed at 
150 mg BID and trametinib fixed at 2 mg QD) for model 3 (dosing 
regimen -1b)
Prior probabilities that P(DLT) is in 
the interval:
Quantiles
PDR dose 
(regimen)
[0, 0.16)
[0.16, 0.33)
[0.33,1]
Mean
SD
2.5%
50%
97.5%
400 mg (Q4W*)
0.608
0.291
0.102
0.173
0.145
0.030
0.132
0.601
*Q4W after a 4 week run-in with dabrafenib and trametinib.
Table 14-19 shows that the prior model for dosing regimen -1b results in a probability of 
excessive toxicity with the triple combination of 10% which satisfies the EWOC criteria.
14.2.3.5 Incorporating trial data into models 1, 2, and 3
When incorporating trial data from the first dosing regimen into model 1, a weight of 1 will be 
used. If the updated results for model 1 indicate that dosing regimen 1 is not tolerated, then new 
patients will be enrolled into dosing regimens -1a and -1b simultaneously. In this case:
•
For model 2 (dosing regimen -1a): when incorporating trial data from dosing regimen -1a, 
a weight of 1 will be used. For data from regimen 1 and -1b, a discounted weighting 
approach will be used.
•
For model 3 (dosing regimen -1b): when incorporating trial data from dosing regimen -1b, 
a weight of 1 will be used. For data from regimen 1 and -1a, a discounted weighting 
approach will be used.
Discounted weighting will be determined as:


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•
Weight = 1 / (1 + 2*n*τ2) / (sd2), where n refers to the number of patients with data for a 
particular dosing regimen and  and sd correspond to the assumed mean and standard 
deviation for between-trial heterogeneity.
•
For model 2 (dosing regimen -1a): a substantial between-trial heterogeneity is assumed ( 
= 0.50, sd = 2). Assuming data are evaluable for 6 patients per dosing regimen, weight is 
equal to 0.571.
•
For model 3 (dosing regimen -1b): as less information is known about Q4W dosing of 
PDR001 after a 4 week run-in of dabrafenib and trametinib, large between-trial 
heterogeneity is assumed ( = 1, sd = 2). Assuming data are evaluable for 6 patients per 
dosing regimen, weight is equal to 0.25.
14.2.4
Hypothetical scenarios
To illustrate the performance of the Bayesian model used to guide dosing decisions for PDR001 
in combination with dabrafenib and trametinib, hypothetical scenarios following the provisional 
dose regimens specified in Section 6.2.2 are displayed in Table 14-20 and Table 14-21. In each 
case, the recommended next dosing regimen is determine using the model-based assessment of 
the risk of DLT in future patients and the dosing rules as described in Section 6.2.3. In practice, 
a dose below the recommended dosing regimen might be chosen based on additional safety, 
PK, or PD information.
Table 14-20
Hypothetical scenarios (with dabrafenib fixed at 150 mg BID and 
trametinib fixed at 2 mg QD) for all 3 dosing regimens, given 0-6 DLT’s 
are observed in the first 6 patients receiving dosing regimen 16-6
Next dose level (regimen)#
Scenario
PDR001 
Regimen
Number of 
patients
Number of 
DLTs
Dose level: 
(regimen)#
Median 
P(DLT)
P(excessive 
toxicity)#
1
Q4W
Q8W^
Q4W*
6
0
1 (Q4W)
0.097
0.010
2
Q4W
Q8W^
Q4W*
6
1
1 (Q4W)
0.145
0.050
3
Q4W
Q8W^
Q4W*
6
2
1 (Q4W)
0.208
0.166
4
Q4W
Q8W^
Q4W*
6
3
-1A (Q8W),
-1B (Q4W*)
0.189
0.177
0.122
0.166
5
Q4W
Q8W^
Q4W*
6
4
-1A (Q8W),
-1B (Q4W*)
0.230
0.206
0.246
0.240
6
Q4W
Q8W^
Q4W*
6
5
Stop
7
Q4W
Q8W^
Q4W*
6
6
Stop


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Next dose level (regimen)#
^Per PK simulations, it is reasonable to assume that 400 mg Q8W is approximately equivalent to 230 mg Q4W. 
Results are therefore shown for 230 mg Q4W.
* Q4W after a 4 week run-in with dabrafenib and trametinib.
# Results for Q4W come from Model 1; Q8W come from Model 2; Q4W* come from Model 3.
Dosing regimen 1 (Q4W): weight for incorporating data from dosing regimen 1 = 1.
Dosing regimen -1A (Q8W): weight for incorporating data from dosing regimen 1 = 0.571.
Dosing regimen -1B (Q4W*): weight for incorporating data from dosing regimen 1 = 0.25.
Table 14-20 shows that:
•
If 0, 1, or 2 DLT’s are observed in the first 6 patients who receive dosing regimen 1 (Q4W 
of PDR001), the probability of excessive toxicity (i.e. DLT rate ≥ 33%) with dosing 
regimen 1 is < 25%, satisfying the EWOC criteria. In this case, it would be recommended 
to continue with Q4W dosing of PDR001.
•
If 3 or 4 DLT’s are observed in the first 6 patients, the probability of excessive toxicity 
with dosing regimen 1 does not satisfy the EWOC criteria. In this case, it would be 
recommended to test dosing regiments -1a (Q8W of PDR001) and -1b (Q4W of PDR001, 
after 4 week run-in of dabrafenib and trametinib).
•
If 5 or 6 DLT’s are observed in the first 6 patients, the probability of excessive toxicity for 
all 3 dosing regimens do not satisfy the EWOC criteria. In this case, it would be 
recommended to stop the study.
Table 14-21
Hypothetical scenarios (with dabrafenib fixed at 150 mg BID and 
trametinib fixed at 2 mg QD) for cohorts -1a and -1b, given 3 DLT’s are 
observed in first 6 patients receiving dosing regimen 1
Next dose level (regimen)#
Scenario
PDR001 
Regimen
Number of 
patients
Number of 
DLTs
Dose level: 
(regimen)#
Median 
P(DLT)
Next dose level: 
(regimen)#
1
Q8W^
Q4W*
6
6
0
0
-1A (Q8W)
-1B (Q4W*)
0.123
0.109
0.004
0.013
2
Q8W^
Q4W*
6
6
0
1
-1A (Q8W)
-1B (Q4W*)
0.141
0.156
0.009
0.059
3
Q8W^
Q4W*
6
6
1
0
-1A (Q8W)
-1B (Q4W*)
0.152
0.118
0.015
0.019
4
Q8W^
Q4W*
6
6
1
1
-1A (Q8W)
-1B (Q4W*)
0.171
0.167
0.032
0.071
5
Q8W^
Q4W*
6
6
0
2
-1A (Q8W)
-1B (Q4W*)
0.157
0.216
0.020
0.175
6
Q8W^
Q4W*
6
6
2
0
-1A (Q8W)
-1B (Q4W*)
0.184
0.126
0.050
0.024
7
Q8W^
Q4W*
6
6
1
2
-1A (Q8W)
-1B (Q4W*)
0.189
0.226
0.051
0.198
8
Q8W^
Q4W*
6
6
2
1
-1A (Q8W)
-1B (Q4W*)
0.205
0.176
0.088
0.087
9
Q8W^
Q4W*
6
6
2
2
-1A (Q8W)
-1B (Q4W*)
0.228
0.239
0.139
0.236
10
Q8W^
Q4W*
6
6
0
3
-1A (Q8W)
Stop
0.175
0.039
11
Q8W^
Q4W*
6
6
3
0
-1A (Q8W)
-1B (Q4W*)
0.219
0.135
0.120
0.031


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Next dose level (regimen)#
12
Q8W^
Q4W*
6
6
1
3
-1A (Q8W)
Stop
0.211
0.102
13
Q8W^
Q4W*
6
6
3
1
-1A (Q8W)
-1B (Q4W*)
0.244
0.187
0.190
0.107
14
Q8W^
Q4W*
6
6
2
3
-1A (Q8W)
Stop
0.251
0.215
15
Q8W^
Q4W*
6
6
3
2
Stop
16
Q8W^
Q4W*
6
6
3
3
Stop
^Per PK simulations, it is reasonable to assume that 400 mg Q8W is approximately equivalent to 230 mg Q4W. 
Results are therefore shown for 230 mg Q4W.
*Q4W after a 4 week run-in with dabrafenib and trametinib.
#Results for Q8W come from Model 2; results for Q4W* come from Model 3.
Dosing regimen -1A (Q8W): weight for incorporating data from dosing regimen -1A = 1; weight for incorporating 
data from dosing regimen 1 and -1B data = 0.571.
Dosing regimen -1B (Q4W*): weight for incorporating data from regimen -1B = 1; weight for incorporating data 
from dosing regimen 1 and -1A data = 0.25.
Table 14-21 shows that in the case that 3 DLT’s are observed in the first 6 patients who receive 
dosing regimen 1:
•
If 0, 1, or 2 DLT’s are observed in the first 6 patients who receive dosing regimen -1a 
(Q8W of PDR001) and 0, 1, or 2 DLT’s are observed in the first 6 patients who receive 
dosing regimen -1b (Q4W of PDR001, after 4 week run-in of dabrafenib and trametinib), 
the probability of excessive toxicity (i.e. DLT rate ≥ 33%) for both dosing regimens 
satisfy the EWOC criteria. In this case, it would be recommended to continue with either 
dosing regimen -1a or -1b. Final probability values for both regimens, along with 
additional safety and PK data, would be used to decide which regimen should be selected.
•
If 0, 1, or 2 DLT’s are observed in the first 6 patients who receive dosing regimen -1a and 
3 DLT’s are observed in the first 6 patients who receive dosing regimen -1b, only the 
probability of excessive toxicity for dosing regimen -1a satisfies the EWOC criteria. In 
this case, it would be recommended to continue with dosing regimen -1a.
•
If 3 DLT’s are observed in the first 6 patients who receive dosing regimen -1a and 0 or 1 
DLT is observed in the first 6 patients who receive dosing regimen -1b, the probability of 
excessive toxicity for both dosing regimens satisfy the EWOC criteria. In this case, it 
would be recommended to continue with either dosing regimen -1a or -1b. Final 
probability values for both regimens, along with additional safety and PK data, would be 
used to decide which regimen should be selected.
•
If ≥ 3 DLT’s are observed in the first 6 patients who receive dosing regimen -1a and ≥ 2 
DLT’s are observed in the first 6 patients who receive dosing regimen -1b, the probability 
of excessive toxicity for both dosing regimens do not satisfy the EWOC criteria. In this 
case, it would be recommended to stop the study.
Note that the actual number of evaluable patients per cohort is variable (see Section 6.2.3). 
Recommendations during the study will depend on the number of evaluable patients at each 
dosing regimen and the observed number of DLT’s.


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Overall, from the examples illustrated above, it can be seen that the BLRM leads to decisions 
that make clinical sense.
14.2.5
References
Neuenschwander B, Matano A, Tang Z, et al (2014). A Bayesian Industry Approach to Phase 
I Combination Trials in Oncology. In Statistical Methods in Drug Combination Studies. Zhao 
W and Yang H (eds), Chapman & Hall/CRC


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14.3
Appendix 3: Safety follow up flow chart


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14.4
AJCC Melanoma Staging System (Edition 8)
Table 14-22
Definition of primary tumor (T)
T category
Thickness
Ulceration status
TX: not assessable
N/A
N/A
T0: No evidence of primary tumor 
(e.g, unknown)
N/A
N/A
Tis (melanoma in situ)
N/A
N/A
T1
≤1.0 mm
Unknown or unspecified
T1a
<0.8 mm
Without ulceration
<0.8 mm
With ulceration
T1b
0.8 to 1 mm
With or without ulceration
T2
>1 to 2 mm
Unknown or unspecified
T2a
>1 to 2 mm
Without ulceration
T2b
>1 to 2 mm
With ulceration
T3
>2 to 4 mm
Unknown or unspecified
T3a
>2 to 4 mm
Without ulceration
T3b
>2 to 4 mm
With ulceration
T4
>4 mm
Unknown or unspecified
T4a
>4 mm
Without ulceration
T4b
>4 mm
With ulceration


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Table 14-23
Definition of Regional Lymph Node (N)
N category
Number of tumor-involved regional lymph node(s)
Presence of in-transit, 
satellite, and/or 
microsatellite 
metastases
NX
Regional nodes not assessed (eg, SLN biopsy not performed, 
regional nodes previously removed for another reason).
Exception: Pathological N category is not required for T1 
melanomas, use cN.
No
N0
No regional metastases detected
No
N1
One tumor-involved node or in-transit, satellite, and/or 
microsatellite metastases with no tumor-involved nodes
 
N1a
One clinically occult (ie, detected by SLN biopsy)
No
N1b
One clinically detected
No
N1c
No regional lymph node disease
Yes
N2
Two or three tumor-involved nodes or in-transit, satellite, and/or 
microsatellite metastases with one tumor-involved node
 
N2a
Two or three clinically occult (ie, detected by SLN biopsy)
No
N2b
Two or three, at least one of which was clinically detected
No
N2c
One clinically occult or clinically detected
Yes
N3
Four or more tumor-involved nodes or in-transit, satellite, and/or 
microsatellite metastases with two or more tumor-involved 
nodes, or any number of matted nodes without or with in-transit, 
satellite, and/or microsatellite metastases
 
N3a
Four or more clinically occult (ie, detected by SLN biopsy)
No
N3b
Four or more, at least one of which was clinically detected, or 
presence of any number of matted nodes
No
N3c
Two or more clinically occult or clinically detected and/or 
presence of any number of matted nodes
Yes


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Protocol No. CPDR001F2301
Table 14-24
Definition of Distant Metastasis (M)
M Category
Anatomic site
LDH level
M0
No evidence of distant 
metastasis
Not applicable
M1
Evidence of distant metastasis
See below
M1a
Not recorded or unspecified
M1a(0)
Not elevated
M1a(1)
Distant metastasis to skin, soft 
tissue including muscle, and/or 
non-regional lymph node
Elevated
M1b
Not recorded or unspecified
M1b(0)
Not elevated
M1b(1)
Distant metastasis to lung with or 
without M1a sites of disease
Elevated
M1c
Not recorded or unspecified
M1c(0)
Not elevated
M1c(1)
Distant metastasis to non-CNS 
visceral sites with or without M1a 
or M1b sites of disease
Elevated
M1d
Not recorded or unspecified
M1d(0)
Normal
M1d(1)
Distant metastasis to CNS with 
or without M1a, M1b, or M1c 
sites of disease
Elevated


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Protocol No. CPDR001F2301
Table 14-25
Pathological (pTNM)
When T is...
And N is...
And M is...
Then the pathological stage group is...
Tis
N0
M0
0
T1a
N0
M0
IA
T1b
N0
M0
IA
T2a
N0
M0
IB
T2b
N0
M0
IIA
T3a
N0
M0
IIA
T3b
N0
M0
IIB
T4a
N0
M0
IIB
T4b
N0
M0
IIC
T0
N1b, N1c
M0
IIIB
T0
N2b, N2c, N3b, or N3c
M0
IIIC
T1a/b-T2a
N1a or N2a
M0
IIIA
T1a/b-T2a
N1b/c or N2b
M0
IIIB
T2b/T3a
N1a-N2b
M0
IIIB
T1a-T3a
N2c or N3a/b/c
M0
IIIC
T3b/T4a
Any N ≥N1
M0
IIIC
T4b
N1a-N2c
M0
IIIC
T4b
N3a/b/c
M0
IIID
Any T, Tis
Any N
M1
IV