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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).

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).

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)

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)

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

Placebo is administered via intravenous infusion over 30 minutes once every 4 weeks

Placebo

Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.

Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions

Novartis Pharmaceuticals

To evaluate the safety and efficacy of the combination of an anti-PD-1 antibody (Spartalizumab (PDR001)), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in unresectable or metastatic BRAF V600 mutant melanoma

This study is designed as a Phase III, multi-center study consisting of three parts:

* Part 1, known as the Safety Run-in, is an open-label part aimed at determining the recommended Phase III regimen (RP3R) of spartalizumab in combination with dabrafenib and trametinib for previously untreated subjects with BRAF V600 mutant unresectable or metastatic melanoma (Stage IIIC/IV per AJCC edition 7). In Part 1, 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, referred to as the Biomarker Cohort, is an open-label section focused on characterizing the kinetics of immune biomarkers and potential immune resistance mechanisms. 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 receive PDR001 (spartalizumab) at a dosage of 400 mg Q4W, in combination with dabrafenib (150 mg BID) and trametinib (2 mg QD).
* Part 3 is a double-blind, randomized, placebo-controlled phase that compares 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 is 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 discontinue study treatment without disease progression as per RECIST 1.1 continue 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 enter 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).

Part 1 and Part 2 are open- label. Part 3 is double-blind and randomized.

A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma

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

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

DLT was defined as an adverse event or abnormal laboratory value that was unrelated to disease, disease progression, inter-current illness, or concomitant medications and occured within 8 weeks of treatment with spartalizumab in combination with dabrafenib and trametinib. The DLT criteria included Grade 4 hematological adverse events, Grade 4 bilirubin elevation, specific gastrointestinal adverse events, symptomatic serum amylase or lipase elevation, Grade 3 or higher hypertension, Grade 3 or higher cardiac events, Grade 2 or higher pneumonitis, Grade 3 or higher immune-related toxicities, infusion-related reactions, other clinically significant adverse events, and toxicities leading to a dosing delay of over 12 weeks. NCI CTCAE v4.03 was used for grading DLTs

Change from baseline in PD-L1 expression (as determined by immunohistochemistry in tissue samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2

Change from baseline in CD8+ cells (as determined by flow cytometry in blood samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2

Progression-free survival was defined as the time from the date of first dose to the date of the first documented radiological progression per investigator's assessment according to RECIST 1.1 or death due to any cause. The distribution of PFS was estimated using the Kaplan-Meier (KM) method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment.

Overall survival is defined as the time from date of randomization to date of death due to any cause

ORR was defined as the percentage of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1.

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 PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters

DOR was defined as the time from first documented response of CR or PR to date of first documented progression or death, according to RECIST 1.1 criteria. The distribution of DOR was estimated using the KM method.

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 PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters

DCR was defined as the percentage of participants with CR or PR or subjects with stable disease (SD) lasting for a duration of at least 24 weeks as per local review according to RECIST 1.1 criteria.

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 PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.

The EORTC QLQ-C30 was a 30-item questionnaire that patients complete, consisting of both multi-item scales and single-item measures. It included five functional scales, three symptom scales, six single items, and a Global Health Status/Quality of Life (GHS/QoL) scale.

The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life.

The change from baseline in GHS/QoL scores was calculated. A positive change from baseline indicated improvement in the patient's quality of life.

The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale.

The EORTC QLQ-C30 physical functioning scale measured a patient's ability to carry out daily activities and tasks requiring physical exertion. It consisted of five questions asking patients to rate their level of physical functioning, with response options ranging from 1="not at all" to 4="very much". The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating better physical functioning.

The change from baseline in physical functioning scale scores was calculated. A positive change from baseline indicated improvement in physical functioning.

The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale.

The EORTC QLQ-C30 pain symptom scale was one of the symptom scales in the questionnaire, which measured the severity of pain experienced by the patient. The pain symptom scale consisted of two items, one measuring the severity of pain and the other measuring the use of painkillers. The items were rated on a 4-point scale ranging from 1="not at all" to 4="very much". The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating more severe pain.

The change from baseline in pain symptom scale scores was calculated. A negative change from baseline indicated improvement.

The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale.

The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life.

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 GHS/QoL score or death due to any cause. If a subject had not had an event, the time to deterioration was censored at the date of the last adequate assessment. The distribution was estimated using KM method.

The Functional Assessment of Cancer Therapy-Melanoma (FACT-M) quality of life questionnaire was composed of the FACT-General (FACT-G) plus the Melanoma Subscale and the Melanoma Surgery Subscale, which complemented the general scale with items specific to quality of life (QoL) in melanoma.

The Melanoma Subscale of FACT-M included 16 questions, with response options of 0= "Not at all", 1= "a little bit", 2= "somewhat", 3= "quite a bit" and 4= "very much". The FACT-M melanoma subscale score ranged from 0 to 64, with higher scores indicating a higher quality of life in relation to melanoma.

The change from baseline in melanoma subscale scores was calculated. A positive change from baseline indicated improvement.

The EQ-5D-5L is a standardized questionnaire used to assess health-related quality of life, and it includes a Visual Analog Scale (VAS). The VAS score is obtained by asking the individual to rate their current health status on a scale from 0 to 100, where 0 represents the worst possible health state and 100 represents the best possible health state.

The change from baseline in EQ-5D-5L VAS score was calculated. A positive change from baseline indicates improvement in the health status.

PFS was defined as the time from the date of first dose to the date of the first documented radiological progression as per investigator's assessment using RECIST 1.1 response criteria or death due to any cause. The distribution of PFS was estimated using the KM method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment.

PFS analysis was performed by PD-L1 status (positive, negative) where a positive status was defined as having ≥ 1% expression and a negative status was defined as having \< 1% expression.

OS is defined as the time from date of randomization to date of death due to any cause.

OS analysis 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.

Spartalizumab ADA prevalence at baseline was calculated as the percentage of participants who had an spartalizumab ADA positive result at baseline.

Spartalizumab ADA incidence was calculated as the percentage of participants who were treatment-induced spartalizumab ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted spartalizumab ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer)

Ctrough for spartalizumab refers to the serum concentration of spartalizumab immediately prior to the administration of a dose of spartalizumab on Day 1 of Cycle 2 and later cycles.

Plasma concentration of dabrafenib immediately prior to the administration of a dose of dabrafenib.

Plasma concentration of trametinib immediately prior to the administration of a dose of trametinib.

Number of participants with dose interruptions for spartalizumab, dabrafenib and trametinib

Number of patients with dose reductions for spartalizumab, dabrafenib and trametinib

Relative dose intensity for spartalizumab, dabrafenib and trametinib computed as the ratio of dose intensity and planned dose intensity

Treatment-emergent Adverse Events: Any sign or symptom that occured during the study treatment plus 30 days post treatment in the Safety Set (treated patients only). All-Cause Mortality is using the Full Analysis Set, including all participants to whom study treatment was assigned by randomization (Part 3) and all participants to whom study treatment was assigned and who received at least one one of any study treatment (Part 1 and 2)

Deaths were collected in the pre-treatment period (from day of patient's informed consent to the day before first administration of study treatment )

All Participants (Pre-treatment)

AEs during on-treatment period and post-treatment safety follow-up (up to 150 days post-treatment)

Part 1: Safety run-in Cohort (On-treatment and Post-treatment Safety FU)

Deaths collected in the post-treatment survival follow-up period (starting from day 151 post- treatment). No AEs were collected during this period

Part 1: Safety run-in Cohort (Post-treatment Survival FU)

Part 2: Biomarker Cohort (On-treatment and Post-treatment Safety FU)

Part 2: Biomarker Cohort (Post-treatment Survival FU)

Part 3- Arm 1: Spartalizumab + Dabrafenib + Trametinib (On-treatment and Post-treatment Safety FU)

Part 3- Arm 1: Spartalizumab + Dabrafenib +Trametinib (Post-treatment Survival FU)

Part 3- Arm 2: Placebo + Dabrafenib + Trametinib (On-treatment and Post-treatment Safety FU)

Part 3- Arm 2: Placebo + Dabrafenib + Trametinib (Post-treatment Survival FU)

In Part 1, participants are treated with spartalizumab 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD).

Part 1- Safety run-in: Spartalizumab 400 mg Q4W + Dabrafenib 150 mg BID + Trametinib 2 mg QD

Part 2- Biomarker Cohort: Spartalizumab 400 mg Q4W + Dabrafenib 150 mg BID + Trametinib 2 mg QD

Part 3- Arm 1: Spartalizumab 400 mg Q4W + Dabrafenib 150 mg BID + Trametinib 2 mg QD

Part 3- Arm 2: Placebo + Dabrafenib 150 mg BID + Trametinib 2 mg QD

Total

Age, Categorical

Sex: Female, Male

Race/Ethnicity, Customized

Study Director

Dose-Determining Set (DDS) including all subjects in Part 1 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 spartalizumab in combination with dabrafenib and trametinib dosing.

Safety Run-In (Part 1): Number of Participants With Dose Limiting Toxicities (DLTs)

Cycle 1 Day 15

Cycle 3 Day 1

Participants in Part 2 who received at least one dose of study treatment and with evaluable data at the pre-specified time points

Biomarker Cohort (Part 2): Change From Baseline in Programmed Cell Death-ligand 1 (PD-L1) Expression Upon Treatment With Spartalizumab in Combination With Dabrafenib and Trametinib

Biomarker Cohort (Part 2): Change From Baseline in CD8+ Cells Upon Treatment With Spartalizumab in Combination With Dabrafenib and Trametinib

All participants in Part 3 to whom study treatment was assigned by randomization regardless of whether or not treatment was administered.

Randomized (Part 3): Progression-Free Survival (PFS) as Per Investigator's Assessment by RECIST 1.1

Overall Survival (OS)

For Part 1 and 2: all subjects to whom study treatment was assigned and who received at least one dose of any study treatment.

For Part 3: all subjects to whom study treatment was assigned by randomization, regardless of whether or not treatment was administered.

Overall Response Rate (ORR) as Per Investigator's Assessment by RECIST 1.1

For Part 1 and 2: all subjects to whom study treatment was assigned and who received at least one dose of any study treatment for whom best overall response was CR or PR.

For Part 3: all subjects to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) for whom best overall response was CR or PR.

Duration of Response (DOR) as Per Investigator's Assessment by RECIST 1.1

Disease Control Rate (DCR) as Per Investigator's Assessment by RECIST 1.1

Cycle 4 Day 1

Cycle 6 Day 1

Cycle 8 Day 1

Cycle 10 Day 1

Cycle 12 Day 1

Cycle 14 Day 1

Cycle 16 Day 1

Cycle 18 Day 1

Cycle 20 Day 1

Cycle 22 Day 1

Cycle 25 Day 1

Cycle 28 Day 1

Cycle 31 Day 1

Cycle 34 Day 1

30 days post-progression

60 days post-progression

All participants in Part 3 to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) and with available data at the pre-specified time points

Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status Scores

Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Physical Functioning Scale Scores

Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Pain Symptom Scale Scores

Randomized (Part 3): Time to 10 Point Definitive Deterioration in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status

Randomized (Part 3): Change From Baseline in Function Assessment Cancer Therapy-melanoma (FACT-M) Melanoma Subscale Score

Randomized (Part 3): Change From Baseline in EuroQoL 5-level Instrument (EQ-5D-5L)- Visual Analog Scale (VAS) Score

PD-L1 negative (<1%)

PD-L1 positive (>=1%)

All participants in Part 3 to whom study treatment was assigned by randomization (regardless of whether or not treatment was administered) with an evaluable PD-L1 assessment.

Randomized (Part 3): PFS as Per Investigator's Assessment by RECIST 1.1 by PD-L1 Expression

Randomized (Part 3): OS by PD-L1 Expression

Part 1 and 2: All subjects to whom study treatment was assigned and who received any study treatment with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample. Part 3: All subjects randomized to spartalizumab with dabrafenib and trametinib with a determinant baseline immunogenicity sample and at least one determinant post-baseline immunogenicity sample. Determinant sample: sample that is neither ADA-inconclusive nor unevaluable

Spartalizumab Anti-drug Antibody (ADA) Prevalence at Baseline

Spartalizumab ADA Incidence

Cycle 2

Cycle 3

Cycle 4

Cycle 5

Cycle 6

Cycle 7

Cycle 8

Cycle 9

Cycle 10

Cycle 11

Cycle 12

All subjects who provided at least one evaluable spartalizumab PK concentration at the specified time points.

Trough Concentration (Ctrough) for Spartalizumab

Cycle 18

Cycle 24

Cycle 30

Cycle 36

All subjects who provided at least one evaluable dabrafenib PK concentration at the specified time points.

Pre-dose Plasma Concentration for Dabrafenib

All subjects who provided at least one evaluable trametinib PK concentration at the specified time points.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma	NCT02967692	Melanoma	Spartalizumab Placebo Dabrafenib Trametinib	18 Years -	Novartis
A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma	NCT02967692	Melanoma	Spartalizumab Placebo Dabrafenib Trametinib	18 Years -	Novartis

Spots Global Cancer Trial Database for metastatic braf v600 mutated melanoma