An open-label, single-arm, phase II, multicenter study to evaluate;the efficacy of vemurafenib in metastatic melanoma patients with brain metastases

Melanoma is the third most common tumor to metastasize to the brain, after lung
and
breast cancer. The reported incidence of brain metastases in patients with
malignant
melanoma is 10% to 40%, but many patients may have subclinical brain
metastases, as
evidenced by a higher reported incidence at autopsy (12-73%) and the frequent
discovery
of asymptomatic brain metastases on brain imaging studies.

Current management strategies for melanoma brain metastases are ineffective, as
brain
metastases contribute to death in nearly 95% of patients. The median survival of
patients is only weeks without treatment and less than 1 year with treatment,
although a
few long-term survivors have been reported.
The majority of patients with melanoma brain metastases die a neurological
death, although the incidence varies
depending on the extent of extracranial metastases.
Moreover,CNS metastases are associated with severe pain and progressive
neurological
deterioration, and have a tremendous impact on QoL.

In general, management strategies for melanoma brain metastases currently
include
neurosurgery, stereotactic radiosurgery (SRS), whole brain radiation therapy
(WBRT),
and chemotherapy.
As described above, these approaches are typically associated with dismal
outcomes. An extraordinary clinical need therefore exits for new treatments in
patients with melanoma brain metastases.
Vemurafenib is a highly selective inhibitor of the oncogenic BRAF kinase that
has been
identified in a large number of malignant melanomas. Results from Phase I and
Phase II
studies have shown that vemurafenib induces exceptionally high response rates in
patients with metastatic melanoma carrying the BRAF V600 mutation.
A pilot safety study (MO25653) of vemurafenib in patients with BRAF V600
mutation positive
metastatic melanoma with brain metastases is currently ongoing. Preliminary
data from
this study indicate the safety profile is consistent with previously reported
vemurafenib
trials. Furthermore, another highly selective inhibitor of oncogenic BRAF
kinase,
GSK2118436, was studied in a small cohort of patients with brain metastases. The
activity of this latter BRAF kinase inhibitor was very high in this patient
population, with
a reported response rate of 80%. This response was also correlated with the
extracranial
response. Given the similarities of GSK2118436 and vemurafenib with regard to
the mechanism of action, it is expected that vemurafenib will be of benefit in
metastatic
melanoma patients with brain metastases.
The biochemical specificity and high activity of vemurafenib in Phase I and
Phase II
trials, coupled with the high clinical need for new melanoma brain metastases
treatments,
makes it of significant interest to assess whether vemurafenib is effective and
safe in this
patient population.

The primary objective of this trial is to evaluate the efficacy of vemurafenib
using Best
Overall Response Rate (BORR), as assessed by an Independent Review Committee
(IRC)
using RECIST, v1.1 criteria in the brain of metastatic melanoma patients with
previously
untreated brain metastases.

This trial is an open-label, single-arm, phase II, multicenter study in adult
patients with
histologically-confirmed metastatic melanoma harboring the BRAF V600 mutation,
as
determined by the cobas® 4800 BRAF V600 Mutation Test, and with brain
metastases.
The study will include two Cohorts that will start simultaneously:
• Cohort 1: Patients who have not received previous treatment for brain
metastases, i.e.,
have never received brain SRT, WBRT, surgery, or any other treatment for their
brain
metastases. Prior systemic therapy for metastatic melanoma is allowed.
• Cohort 2: Patients who have been previously treated with brain SRT, WBRT, or
surgery for their brain metastases and have progressed following this
treatment. For
patients treated with SRT, or surgery, a new RECIST-assessable brain lesion must
have developed following this prior therapy.

Patients with or without symptoms due to their brain metastases are allowed in
both
cohorts. Patients who are on steroids prior to starting vemurafenib must be on
a stable or
decreasing dose of steroids for at least one week (7 days). Anti-seizure
medications are
allowed.

The trial will consist of a Screening/Baseline period (Day -28 to *1), a
Treatment Period,
an End-of-Treatment Visit occurring when vemurafenib is discontinued for any
reason,
and a Follow-Up Visit occurring 28 days after the last dose of vemurafenib. In
addition,
after the Follow-Up Visit, there will be a Survival Follow-Up Period, during
which
patient survival and new anticancer medication use will be monitored. Day 1 of
the study
will be defined as the first day a patient receives vemurafenib. One cycle of
therapy will
be defined as 28 days of treatment. Patients will be asked to attend clinic
visits at regular
intervals during the study for safety and efficacy assessments.

Enrolled patients will receive continuous oral dosing of vemurafenib at 960 mg
twice
daily (b.i.d) until the development of progressive disease in or outside of the
brain
(whichever occurs first), unacceptable toxicity, consent withdrawal, protocol
violation,
death, reasons deemed by the Investigator, or study termination by the Sponsor.
Patients
who develop suspected disease progression either in or outside of the brain
and, in the
opinion of the Investigator, would still benefit from continuing study drug may
continue
treatment with vemurafenib after discussion with the Sponsor; vemurafenib must
be
discontinued at a subsequent visit if there is objective evidence of disease
progression
either in or outside of the brain.

Patients who discontinue vemurafenib for any reason (i.e., disease progression,
an AE,
etc.) other than withdrawal of consent will continue to be followed for
survival and new
anti cancer therapy every 3 months after last dose until death or for a maximum
of 24
months, withdrawal of consent, or lost to follow-up, whichever occurs first.

Patients take orally 2x daily 4 tablets RO5185426.

The following assessments are done during the study:

Screening/Baseline

• Informed Consent
• Submission of tumor tissue for the BRAF V600 mutation screening using the
cobas®
4800 BRAF V600 Mutation Test, except for patients who have been previously
tested
cobas® 4800 BRAF V600 Mutation Test during screening for enrollment in another
study with vemurafenib and were found to be BRAF V600 mutation-positive
• Demographics, including age, sex, race, and self-reported ethnicity
• Medical history, including all clinically significant diseases, previous
surgeries, prior
skin cancer history, prior skin cancer therapies and procedures, responses to
prior
therapies, and all medications used by the patient within 14 days preceding the
screening visit.
• Serum pregnancy test (within 7 days prior to commencement of dosing)
• ECOG Performance Status
• Hematology, including hemoglobin, hematocrit, platelet count, white blood
cell count
(WBC), and absolute neutrophil count (ANC)
o If it is necessary to repeat these blood tests, the results must be known
before the patient receives the first dose of vemurafenib (to ensure
inclusion/exclusion criteria related to these tests are met)
• Physical examination, including the evaluation of the head, eyes, ears, nose,
and
throat (HEENT); cardiovascular, dermatological, musculoskeletal, respiratory,
gastrointestinal, and a thorough neurological systems examination; and height
and
weight (height will only be measured during screening)
• Biochemistry, including glucose, blood urea nitrogen (BUN), creatinine or
creatinine
clearance (CrCl), sodium, potassium, calcium, magnesium, bicarbonate (if
routinely
performed on venous blood samples), total bilirubin with fractionation into
direct and
indirect (if total bilirubin elevated), alkaline phosphatase, AST (SGOT), ALT
(SGPT), and lactate dehydrogenase (LDH)
• Vital signs, including blood pressure, temperature (°C), pulse, and
respiratory rate
• 12-lead ECG, including heart rate, PR interval, QRS duration, QT and QTc
intervals,
and ECG findings
• Brain MRI and tumor assessments (chest, abdomen and pelvis [C/A/P] CT or MRI,
and bone scan if clinically indicated) in the 28-day period prior to Day 1,
Cycle 1.
• Dermatology evaluation by a dermatologist.
• Head and neck examination, as part of the evaluation for SCC.
Chest CT for evaluation of SCC
• AEs (including SAEs caused by a protocol-mandated intervention only)
• Concomitant medications
• Corticosteroids and narcotic pain analgesics daily dose

Treatment Period
Visits during the Treatment Period are to be completed on Day 1 of every 28-day
cycle
until Cycle 8 and then every 12 weeks thereafter. During Day 15 occuring after
the first
dose of study medication, a ± 3-day window is allowed. A window of 4 days prior
to the
scheduled visit date (-4 days/ +1 day) is allowed for each visit from Cycle 2
onwards,
except for tumor evaluations for which a window of +/- 5 days will
apply. The following assessments should be performed during the Treatment
Period.
• FACT-M questionnaire
o Should be completed prior to any other assessments or
physician/investigator consultations and before the patient has been
informed of his/her disease status
o Collected on Day 1 (prior to study drug administration), after 4, 8, 12, 16
weeks on treatment, and every 12 weeks thereafter until study drug
discontinuation
• VAS pain assessment
o Should be administered after the patient has completed the FACT-M
questionnaire for QoL, prior to any other assessments or
physician/investigator consultations, and before the patient has been
informed of his/her disease status
o Collected on Day 1 (prior to study drug administration) and after 4, 8, 12,
16 weeks on treatment, and every 12 weeks thereafter until study drug
discontinuation
• Physician*s Assessment of Global Performance Status 7-Point Scale
o Collected on Day 1 (prior to study drug administration), after 4, 8, 12, 16,
weeks on treatment, and every 12 weeks thereafter until study drug
discontinuation
• ECOG performance status
o Collected on Day 1, after 4, 8, 12, 16, 20, 24 and 28 weeks on treatment,
and every 12 weeks thereafter until study drug discontinuation
• Hematology as previously described
o Performed on Day 1, after 4, 8, 12, 16, 20, 24, and 28 weeks on treatment,
and every 12 weeks thereafter until study drug discontinuation
o Hematology assessments do not need to be repeated on Day 1 if performed
within 7 days of first vemurafenib administration
• Physical examination as previously described
o Performed on Day 1, after 2, 4, 8, 12, 20 and 28 weeks on treatment
• Biochemistry as previously described
o Performed after Day 1 (if not performed within the last 7 days), 4, 8, 12,
16, 20, 24, 28 weeks on treatment and 12 weeks thereafter until study drug
discontinuation
• Vital signs as previously described
o Collected on Day 1, after 2, 4, 8, 12, 16, 20, 24, 28 weeks on treatment
and every 12 weeks thereafter until study drug discontinuation
• 12-lead ECG as previously described
o Mandatory ECG monitoring, with a focus on the QTc interval, should
occur after 2, 4, 8, 12, and 16 weeks on treatment and every 12 weeks
thereafter until study drug discontinuation
• Tumor assessments
o MRI of the brain after 4 and 8 weeks of treatment and every 8 weeks
thereafter
o Chest/abdomen/pelvis (C/A/P) CT/MRI after 8 weeks of treatment and
every 8 weeks thereafter. The same imaging technique (CT or MRI)
should be used for each patients through our the study
o Bone scan, when clinically indicated
• Dermatology evaluation by a dermatologist (as described in section 5.3.8.4)
o Performed after 4 weeks of treatment and every 12 weeks thereafter until
discontinuation
• Head & neck examination, as part of the evaluation for SCC (as described in
section 5.3.8.4)
o Performed after 4 weeks of treatment and every 12 weeks thereafter until
discontinuation
• Chest CT for evaluation of SCC after 24 weeks of therapy
• AEs (including SAEs) throughout the Treatment Period
• Concomitant medications throughout the Treatment Period
• Corticosteroids and narcotic pain analgesics daily dose (patient diaries will
be used)
throughout the Treatment Period
• Drug dispensing and accountability throughout the Treatment Period
• Review of the Drug Dosing Exception Diary throughout the Treatment Period
• Vemurafenib administration throughout the Treatment Period
Some patients may develop suspected disease progression either in or outside
the brain
and, in the opiion of the Investigator, would still benefit from continuing
study drug may
continue treatment with vemurafenib after discussion with the Sponsor until
abjective
disease progression.

End-of-Treatment Visit
The End-of-Treatment Visit will occur when the patient discontinues vemurafenib
for
any reason, unless the patient withdraws consent and refuses, or is lost to
follow up. The
following assessments will be conducted at the End-of-Treatment Visit:
• ECOG Performance Status
• Hematology, including hemoglobin, hematocrit, platelet count, WBC, and ANC
• Physical examination, including the evaluation of the head, eyes, ears, nose,
and
throat (HEENT); cardiovascular, dermatological, musculoskeletal, respiratory,
gastrointestinal, and neurological systems; and weight
• Biochemistry, including glucose, BUN, creatinine or CrCl, sodium, potassium,
calcium, magnesium, bicarbonate (if routinely performed on venous blood
samples),
total bilirubin with fractionation into direct and indirect (if total bilirubin
elevated),
alkaline phosphatase, AST (SGOT), ALT (SGPT), and LDH
• Vital signs, including blood pressure, temperature (°C), pulse, and
respiratory rate
• 12-lead ECG, including heart rate, PR interval, QRS duration, QT and QTc
intervals,
and ECG findings
o Mandatory ECG monitoring, with a focus on the QTc interval
• Dermatology evaluation by a dermatologist (as described in section 5.3.8.4)
if not
done within the previous 12 weeks
• Head & neck examination, as part of the evaluation for SCC (as described in
section 5.3.8.4) if not done within the previous 12 weeks
• AEs (including SAEs)
• Concomitant medications
• Drug accountability
• Review of the Drug Dosing Exception Diary
• Tumour assessments as described previously (if not done within the last 8
weeks)
• Survival status

Follow-Up Visit
The Follow-Up Visit(s) will occur 28 (± 5) days after discontinuation of
vemurafenib.
The following assessments will be conducted at the Follow-Up Visit.
• Overall survival (status of patients, death/alive, date of death, date of
last contact)
• FACT-M questionnaire
o Should be completed prior to any other assessments or
physician/investigator consultations and before the patient has been
informed of his/her disease status
• VAS pain assessment and Physician*s Assessment of Global Performance Status 7-
Point Scale
• Physical examination and vital signs as described previously
• ECOG Performance Status
• 12-lead ECG as previously described
o Mandatory ECG monitoring, with a focus on the QTc interval
• Dermatology evaluation by a dermatologist (as described in section 5.3.8.4)
• Head & neck examination as part of evaluation for SCC (as described in
section 5.3.8.4)
• CT of the chest for evaluation of SCC must be performed within 6 months
following study drug discontinuation
• Follow up for disease progression for those patients who haves discontinued
study
drug for any reason (i.e., AEs, etc.) other than disease progression
• AEs (including SAEs)
• Concomitant therapy including corticosteroids and narcotic pain analgesics
(for
corticosteroids and narcotic analgesics, patient diaries will be used)
• New anticancer therapy

Survival Follow-Up Period
The following assessments will be conducted during the Survival Follow-Up
Period:
• Survival status every 3 months after the last dose until death or for a
maximum of 24
months, withdrawal of consent, or lost to follow-up (whichever occurs first).
• New anticancer therapy

More than 500 adult patients with BRAF V600 mutation-positive metastatic
melanoma treated within a large Phase III trial, as well as a phase II study.
The most common side effects that have occurred in at least 10% of patients
(very common), 1-10% of patients (common), 0.1-1% of patients (uncommon) are:

Very Common
(>= 1/10)

SCC of the skin, seborrheic keratosis, skin papilloma (see below)
Decreased appetite
Headache, dysgeusia (Change in sense of taste)


Cough
Diarrhoea, vomiting, nausea (sickness), constipation
Actinic keratosis (scaly skin), rash maculo-papular, rash papular,
photosensitivity reaction (sensitive to light), pruritus (itchiness),
hyperkeratosis, erythema, alopecia (hair loss), dry skin, sunburn
Arthralgia (joint pain), myalgia (muscle pain), pain in extremity,
musculoskeletal pain, back pain
Fatigue (tiredness), pyrexia (fever) , oedema peripheral (swelling of tissues
in lower limb), asthenia (lacking physical strength and vigour)
GGT increase (increase of a liver test)

Common
(>= 1/100 to < 1/10)
Folliculitis (inflammation of hair follicles)
Basal cell carcinoma (a type of skin cancer)
7th nerve paralysis (paralysis of facial nerves)
Uveitis (inflamation of the eye)
Erythema nodosum, keratosis pilaris, palmar-plantar erythrodysaesthesia
syndrome (hand-foot syndrome, redness, skin peeling or blisters on hands and
feet)
Arthritis (inflammation of the joints)
ALT increase, alkaline phosphatase increase, bilirubin increase (elevation of
liver tests), weight decreased

Uncommon
(>= 1/1,000 to < 1/100)
Neuropathy peripheral (Problem with the nerves that can produce pain, loss of
sensation and/or muscle weakness)
Retinal vein occlusion (Blockage of blood flow to part of the eye)
Vasculitis ( inflammation of blood vessels)
Stevens-Johnson syndrome and toxic epidermal necrolysis (allergic reaction)
AST increase (elevation of a liver test)

The study drug can cause high sensitivity of the skin to sunlight and you may
suffer sunburn more easily than usual, therefore you should avoid prolonged
exposure to sunlight while taking the study drug and for 5-10 days after you
stop taking the study drug. In addition you should use a broad-spectrum
sun-screen and lip balm of at least SPF30, re-applied every 2-3 hours to help
protect against sunburn for at least 5-10 days after you stop taking the study
drug.
The study drug can cause an alteration of the heart activity called
prolongation of the QTc interval. This is a prolongation of the heart cycle
and can be recognized in the electrocardiogram (ECG). It is not clear if such
a prolongation can cause any additional serious side effects concerning the
electrical activity of the heart, e.g. dysarrhythmia (irregular heart beat),
especially if you are also taking other medications which may have an affect
on the QTc interval. Therefore your heart activity will be closely monitored
during the study. You should report and discuss with the study doctor any other
medication(s) you are taking while you are treated with the study drug, so that
he/she can take action to prevent any such potential drug interactions.

New Primary Melanomas and Other Cancers
New primary melanomas have been reported in clinical trials. Cases suspected to
be new primary melanomas (possible additional cancerous growth) have been
reported in patients treated with vemurafenib. Cases were managed with
excision, and patients continued treatment without dose adjustment. During this
study, you will be evaluated by a dermatologist to check for early signs of SCC
and any other cancerous growth. If you notice changes in your skin, you should
inform the study doctor right away.
Two patients treated with vemurafenib in excess of 300 days while on another
clinical trial, developed SCC of the head and neck (a malignant head and neck
cancer.) Therefore you will also have regular head and neck exams and CT scans
of your chest.
Two patients who were treated with vemurafenib for more than 2 years developed
intestinal polyps (fleshy benign tumor growths occurring on the lining of
gastrointestinal tract).


Also side effects with are currently unknown might occur during the study.


Participation in the study may help patients in the future by giving important
information about vemurafenib and the treatment of metastatic melanoma in the
brain. Also the medical condition of the patients included in this trial might
improve, but this cannot be guaranteed.