A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF VEMURAFENIB (RO5185426) ADJUVANT THERAPY IN PATIENTS WITH SURGICALLY RESECTED, CUTANEOUS BRAF-MUTANT MELANOMA AT HIGH RISK FOR RECURRENCE

Melanoma is one of the most deadly skin cancers. Detection and surgical
treatment of early-stage disease seem to prevent progression in most cases.
However, patients with deep primary tumors or tumors that metastasize to
regional lymph nodes frequently develop distant metastases. The primary
treatment modality for localized cutaneous melanoma is surgery. The only widely
approved adjuvant therapy for melanoma patients at high risk for recurrence is
interferon-alpha-2b with a high-dose regimen (PDR Network 2010). However, there
is currently no international consensus regarding the dose, duration, or use of
interferon-alpha-2b for the treatment of melanoma in the adjuvant setting
(Hauschild et al. 2008). There is no generally accepted standard of care for
adjuvant therapy in patients with resected cutaneous melanoma at high risk for
recurrence that is both effective and well tolerated (Balch et al. 2009; Dummer
et al. 2010). Recent advances in the understanding of the biology of melanoma
have identified the role of BRAF kinase, a serine-threonine kinase downstream
of RAS within the mitogenactivated protein kinase (MAPK) pathway. BRAF
mutations have been identified in 50%*68% of metastatic melanomas, specifically
melanomas that arise from intermittent sun-exposed skin (e.g., in superficial
spreading and nodular melanomas) (Maldonado et al. 2003; Beeram et al. 2005;
Curtin et al. 2005; Lang and MacKie 2005). Vemurafenib (formerly, RO5185426) is
a low molecular weight, orally available inhibitor of the oncogenic form of the
BRAF kinase commonly found in melanoma. It is a potent and highly selective
inhibitor of V600-mutant BRAF. The clinical pharmacokinetics and safety of
vemurafenib are based on data available from five studies in patients who
received the commercial (microprecipitated bulk powder) formulation: NP22676, a
cytochrome P450 (CYP) metabolism study in patients with BRAFV600
mutation-positive Stage IV melanoma (Genentech, data on file); NP25158, a mass
balance study in patients with BRAFV600 mutation-positive Stage IV melanoma
(Genentech, data on file); NP25163, a dose-escalation study in patients with
BRAFV600 mutation*positive unresectable Stage IIIC or Stage IV melanoma
(Genentech, data on file); NP22657, a Phase II, open-label study in patients
with BRAFV600 mutation*positive Stage IV melanoma, in which the effects of
vemurafenib on the QT interval were evaluated (Genentech, data on file); and
NO25026, a Phase III, randomized, controlled study in patients with BRAFV600
mutation*positive unresectable Stage IIIC or Stage IV melanoma (Genentech, data
on file). Efficacy was assessed in the following studies: PLX06-02, NP22657,
NO25026. More detailed information on the findings of these studies can be
found in the Vemurafenib Investigator*s Brochure. This Study (GO27826) is
designed to evaluate the efficacy of vemurafenib adjuvant treatment
administered over a 52-week period in patients with completely resected
BRAFV600 mutation*positive, cutaneous melanoma, as measured by disease-free
survival (DFS).

Please see section 1 (Background) of the protocol for additional study
background information and section 10 (References) for cited references.

Primary Objective
The primary objective of this study is as follows:
* To evaluate the efficacy of vemurafenib adjuvant treatment administered over
a 52-week period in patients with completely resected BRAFV600 mutation*
positive, cutaneous melanoma, as measured by disease-free survival (DFS)
Secondary Objectives
The secondary objectives of this study are as follows:
* To evaluate the efficacy of vemurafenib adjuvant treatment administered over
a 52-week period, as measured by overall survival (OS)
* To evaluate the efficacy of vemurafenib adjuvant treatment administered over
a 52-week period, as measured by distant metastasis-free survival (DMFS)
* To evaluate the safety and tolerability of vemurafenib in the adjuvant setting
* To assess quality of life as measured by European Organisation for Research
and Treatment of Cancer (EORTC) QLQ-C30
* To describe the pharmacokinetics of vemurafenib in the adjuvant setting,
assess between-patient variability of pharmacokinetic (PK) parameters, and
explore and quantify potential covariates that may contribute to
between-patient differences in PK parameters, using a population PK approach
Exploratory Objectives
The exploratory objectives of this study are as follows:
* To assess the efficacy outcomes and safety profile of vemurafenib adjuvant
treatment in patients whose melanomas harbor non*E mutations of BRAF kinase at
amino acid position 600, as detected by DNA sequencing methods
* To assess the relationship between vemurafenib exposure and the risk of
melanoma recurrence, the occurrence of serious adverse events, and
abnormalities in safety laboratory parameters
* To assess the relationship between biomarkers and risk of melanoma recurrence
* To characterize the biomarkers

Study GO27826 is a Phase III, international, multicenter, double-blind,
randomized, placebo-controlled study of patients with completely resected,
BRAFV600 mutation*positive melanoma, as detected by the cobas® BRAF V600
Mutation Test, at high risk for recurrence.
* Cohort 1 (approximately 300 patients) will include patients with completely
resected Stage IIC, IIIA (patients with one or more nodal metastasis > 1 mm in
diameter), or IIIB cutaneous melanoma as defined by the American Joint
Committee on Cancer (AJCC)
Classification, v. 7 (Balch et al. 2009).
* Cohort 2 (approximately 225 patients) will include patients with Stage IIIC
cutaneous melanoma as defined by this classification scheme.
The primary and secondary efficacy and safety objectives of this study will be
evaluated separately for each cohort.
Eligible patients will be randomized (1:1) to receive placebo or vemurafenib
over a 52-week period, with randomization stratified by pathologic stage (Stage
IIC, Stage IIIA, Stage IIIB) and region (North America; Australia/New
Zealand/South Africa/Latin America; rest of the world)
in Cohort 1 and by region (North America; Australia/New Zealand/South
Africa/Latin America; rest of the world) in Cohort 2.
Within each cohort, patients will receive study treatment according to one of
the following treatment arms:
* Arm A: placebo orally, twice daily (BID) for 52 weeks (thirteen, 28-day
cycles)
* Arm B: vemurafenib 960 mg orally, BID for 52 weeks (thirteen, 28-day cycles)

* Cohort 1 (approximately 300 patients) will include patients with completely
resected Stage IIC, IIIA (patients with one or more nodal metastasis > 1 mm in
diameter), or IIIB cutaneous melanoma as defined by the American Joint
Committee on Cancer (AJCC)
Classification, v. 7 (Balch et al. 2009).
* Cohort 2 (approximately 225 patients) will include patients with Stage IIIC
cutaneous melanoma as defined by this classification scheme.

Eligible patients will be randomized (1:1) to receive placebo or vemurafenib
over a 52-week period, with randomization stratified by pathologic stage (Stage
IIC, Stage IIIA, Stage IIIB) and region (North America; Australia/New
Zealand/South Africa/Latin America; rest of the world)
in Cohort 1 and by region (North America; Australia/New Zealand/South
Africa/Latin America; rest of the world) in Cohort 2.
Within each cohort, patients will receive study treatment according to one of
the following treatment arms:
* Arm A: placebo orally, twice daily (BID) for 52 weeks (thirteen, 28-day
cycles)
* Arm B: vemurafenib 960 mg orally, BID for 52 weeks (thirteen, 28-day cycles)

There is no consensus on standard care for adjuvant therapy for this
patiengroup. And previous research with vemurafenib resulted in progression
free survival. Because Vemurafenib demonstrated to be benificial in metastatic
melanoma it might also be identified in patients with resected cutaneous
melanoma who are at high risk for recurrence.