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

PDR001 is a high-affinity, ligand-blocking, humanized anti-PD-1 IgG4 antibody
that blocks the binding of PD-L1 and PD-L2 to PD-1. PDR001 shows functional
activity in vitro/ex vivo. The first in human study is ongoing. By the end of
December 2015, a total of 58 patients had been treated in the study at the dose
levels of 1, 3 and 10 mg/kg every 2 weeks and 3 and 5 mg/kg every 4 weeks. No
patient experienced a dose limiting toxicity and the toxicity profile appears
to be similar to that of marketed inhibitors of PD-1. The PK data support the
use of flat dosing for PDR001 of 400 mg every 4 weeks.
Agents that enhance anti-tumor immunity are not effective in all cancer types,
responses are often not durable, and many patients receive little or no benefit
from treatment. Inhibitors of the PD-1/PD-L1 interaction are well tolerated and
active across a range of cancer types, and will likely be one component of
combination therapies that increase the response rate and durability of
treatment.

* Safety Run in
To determine the recommended regimen of PDR001 in combination with dabrafenib
and trametinib for the randomized part (part 3)

* Biomarker cohort
To evaluate changes in the immune microenvironment and biomarker modulations
upon treatment with PDR001 in combination with dabrafenib and trametinib

* 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

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)

Netherlands is not participating in Part 1.

All participant will be treated with :

Dabrafenib, oral, 150mg BID
Trametinib, oral, 2 mg QD

Biomarker part
Combination with dabrafenib and trametinib and PDR001 infusion 400mg. Depending
of the recommended dose in the safety part, it is expected that this infusion
will be either once every 4 weeks, or once every 8 weeks.

randomized part
> Arm 1: PDR001 infusion in combination with trametinib and dabrafenib
> Arm 2: placebo in combination with dabrafenib and trametinib

RISK: adverse events of treatment with dabrfenib and trametinib, with placebo
or PDR001
Burden: Cycles of 4 weeks, Cycle 1,2,3: 2 visits, from cycle 4 onwards one visit
Infusion with PDR001, approx. 30 minutes
Physical examination: once per cycle.
Blooddraws : at meast once per cycle, on PK days more frequent (max 3)
ECG: every cycle up to cycle 3. Cycle 1 2 12leadECGs, 1 ECG 12lead during cycle
2 and 3 and every 3rd cycle afterwards
MUGA scan during screening, cycle 1 and every 12 weeks afterwards
0-3 tumor biopsies: depending on the studie part. optional additional biopsies
are possible.
CT-/MRI-scan: during screening, cycle 4, every 8 weeks during first 6 months
and every 12 weeks thereafter.
Skin photographs in case of skin lesions.
Questionnaires EORTC QLQ-C30, EQ-5D-5L, FACT-M : screening, cycle 3, every 8
weeks aferwards during first year, afterwards every 3 months.
ophthamological assessments: on screening and cycle 2 day 1