ASH News Daily - Sunday, December 11, 2011 - (Page A-4)
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Sickle Cell
«« From Page A-1
as a screening test to be applied
to all patients with SCD” and thus
the benefit of screening asymptomatic
adult patients and children is
uncertain and the treatment for
pulmonary hypertension is yet to
be defined. The randomized, placebo-controlled
Treatment of Pulmonary
Hypertension and SCD
With Sildenafil Trial was stopped
early due to increased pain in the
treatment arm. However, Dr. Hassell
stated that, “despite finding
that the use of sildenafil may be associated
with increased pain, other
experience suggests that sickle cell
ZELBORAF™ (vemurafenib) tablet, oral
Initial U.S. Approval: 2011
This is a brief summary of information about TRADENAME. Before
prescribing, please refer to the full Prescribing Information.
1 INDICATIONS AND USAGE
ZELBORAF™ is indicated for the treatment of patients with unresectable
or metastatic melanoma with BRAFV600E
FDA-approved test.
mutation as detected by an
Limitation of Use: ZELBORAF is not recommended for use in patients
with wild-type BRAF melanoma.
5 WARNINGS AND PRECAUTIONS
5.1 Cutaneous Squamous Cell Carcinoma (cuSCC)
Cases of cuSCC, including both SCCs of the skin and keratoacanthomas,
have been reported in patients treated with ZELBORAF [see Adverse
Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients
in Trial 1 was 24%. CuSCC usually occurred early in the course
of treatment with a median time to the first appearance of 7 to 8
weeks. Of the patients who experienced cuSCC, approximately 33%
experienced > 1 occurrence with median time between occurrences
of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF
clinical studies included age (≥ 65 years), prior skin cancer, and chronic
sun exposure. In the clinical trials, cases of cuSCC were managed with
excision, and patients were able to continue treatment without dose
adjustment.
It is recommended that all patients receive a dermatologic evaluation
prior to initiation of therapy and every two months while on therapy. Any
suspicious skin lesions should be excised, sent for dermatopathologic
evaluation and treated as per standard of care. Monitoring should be
considered for 6 months following discontinuation of ZELBORAF.
5.2 Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylaxis, have been
reported in association with ZELBORAF and upon re-initiation of
treatment. Severe hypersensitivity reactions included generalized rash
and erythema or hypotension. In patients who experience a severe
hypersensitivity reaction, ZELBORAF treatment should be permanently
discontinued.
5.3 Dermatologic Reactions
Severe dermatologic reactions have been reported in patients receiving
ZELBORAF, including one case of Stevens-Johnson syndrome and one
case of toxic epidermal necrolysis in Trial 1. In patients who experience
a severe dermatologic reaction, ZELBORAF treatment should be
permanently discontinued.
5.4 QT Prolongation
Pharmacology (12.3)]. QT prolongation may lead to an increased risk
of ventricular arrhythmias, including Torsade de Pointes. Treatment
with ZELBORAF is not recommended in patients with uncorrectable
electrolyte abnormalities, long QT syndrome, or who are taking
medicinal products known to prolong the QT interval.
mutation-positive metastatic melanoma [see Clinical
ECG and electrolytes, including potassium, magnesium, and calcium,
should be monitored before treatment with ZELBORAF and after dose
modification. Monitoring of ECGs should occur 15 days after treatment
initiation and then monthly during the first 3 months of treatment,
followed by every 3 months thereafter or more often as clinically
indicated. Initiation of treatment with ZELBORAF is not recommended
in patients with QTc > 500 ms. If during treatment the QTc exceeds
500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily
interrupted, electrolyte abnormalities should be corrected, and
cardiac risk factors for QT prolongation (e.g., congestive heart failure,
bradyarrhythmias) should be controlled. Re-initiation of treatment
should occur at a lower dose once the QTc decreases below 500 ms
[see Dosage and Administration (2.2)]. Permanent discontinuation of
ZELBORAF treatment is recommended if after correction of associated
risk factors, the QTc increase meets values of both > 500 ms and
> 60 ms change from pre-treatment values.
5.5 Liver Laboratory Abnormalities
Liver laboratory abnormalities have occurred with ZELBORAF (Table 3)
[see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline
phosphatase) and bilirubin should be monitored before initiation of
treatment and monthly during treatment, or as clinically indicated.
Laboratory abnormalities should be managed with dose reduction,
treatment interruption, or treatment discontinuation [see Dosage and
Administration (2.2)].
5.6 Photosensitivity
Mild to severe photosensitivity was reported in patients treated with
ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients
should be advised to avoid sun exposure while taking ZELBORAF. While
taking the drug, patients should be advised to wear protective clothing
and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30)
when outdoors to help protect against sunburn.
For intolerable grade 2 (tender erythema covering 10 - 30% body surface
area) or greater photosensitivity, dose modifications are recommended
[see Dosage and Administration (2.2)].
5.7 Ophthalmologic Reactions
In Trial 1, five cases of uveitis have been reported in patients treated
with ZELBORAF. Treatment with steroid and mydriatic ophthalmic
drops may be required to manage uveitis. Patients should be routinely
monitored for signs and symptoms of uveitis. Additionally, there were
five patients with blurry vision, five patients with iritis and six patients
with photophobia. There was one case of retinal vein occlusion in Trial 2.
5.8 New Primary Malignant Melanoma
There were eight skin lesions in seven patients reported as new primary
malignant melanoma in Trial 1. Cases were managed with excision,
and patients continued treatment without dose adjustment. Monitoring
for skin lesions should occur as outlined above [see Warnings and
Precautions (5.1)].
5.9 Use in Pregnancy
Pregnancy Category D
ZELBORAF may cause fetal harm when administered to a pregnant
woman based on its mechanism of action. There are no adequate and
well-controlled studies in pregnant women. If this drug is used during
pregnancy or if the patient becomes pregnant while taking this drug, the
patient should be apprised of the potential hazard to a fetus [see Use in
Specific Populations (8.1)].
5.10 BRAFV600E
Testing
an FDA-approved test is required for selection of patients for ZELBORAF
therapy because these are the only patients studied and for whom benefit
has been shown. For patients in ZELBORAF clinical studies, including
Trial 1 and Trial 2, all enrolled patients tested positive when their tumor
tissue was assessed with the cobas®
Confirmation of BRAFV600E mutation-positive melanoma as detected by
[see Clinical Studies (14)]. This test is designed to detect BRAFV600E
mutations in DNA isolated from formalin-fixed, paraffin-embedded
4800 BRAF V600 Mutation Test
Exposure-dependent QT prolongation was observed in an uncontrolled,
open-label Phase 2 QT sub-study in previously treated patients
with BRAFV600E
Skin and
subcutaneous
tissue disorders
Rash
Photosensitivity
reaction
Alopecia
Pruritis
Hyperkeratosis
Rash maculopapular
Actinic keratosis
Dry skin
Rash papular
Erythema
Musculoskeletal
and connective
tissue
disorders
Arthralgia
Myalgia
Musculoskeletal
pain
Back pain
General disorders
and administration
site conditions
Fatigue
Asthenia
Gastrointestinal
disorders
Nausea
Diarrhea
Vomiting
Constipation
Nervous system
disorders
Headache
Dysgeusia
Neoplasms
benign, malignant
and unspecified
(includes cysts
and polyps)
Skin papilloma
Cutaneous SCC†#
Seborrheic
keratosis
Investigations
Gamma-
glutamyltransferase
increased
Metabolism and
nutrition disorders
Decreased appetite 18
Respiratory,
thoracic and
mediastinal
disorders
Cough
Injury, poisoning
and procedural
complications
Sunburn
-
-
8 <1
-
21
-
-
53 4
13 <1
Pain in extremity 18 <1
8
-
8 <1
Edema peripheral 17 <1
Pyrexia
38 2
19 <1
11 <1
35 2
28 <1
18 1
12 <1
23 <1
-
14
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1
3 <1
-
6 2
4 <1
5 <1
33 2
-
5
9 <1
9 <1
43 2
13 <1
26 1
-
24
10
3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
67 8
24 <1
-
9
11
-
11 <1
54 4
-
23
2
17 2
-
37 2
29 <1
26 2
-
16
27
11
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
37 8
33 3
-
-
45 <1 -
23 1
24 1
-
9 2
8
-
19 -
5 <1 -
14 -
-
-
2
4
2
1
3
1
-
-
-
-
-
- <1 -
- <1 -
-
2
-
-
-
-
- 52 7
- 49 3
- 36 -
- 30 2
- 28 -
- 21 6
- 17 -
- 16 -
- 13 -
-
8
-
-
-
-
-
-
-
-
-
-
-
ZELBORAF
n= 336
ADRs
All
Grades
(%)
Grade
3
(%)
Grade
4
(%)
Dacarbazine
n= 287
All
Grades
(%)
Grade
3
(%)
Grade
4
(%)
All
Grades
(%)
patients with true pulmonary hypertension
may have significant
benefit from this treatment and may
elect to risk some increase in pain.”
This underscores the importance
of asking patients what risk they
would accept for potential benefit.
Dr. Michael DeBaun, Monroe
Carell Jr. Children’s Hospital at
Vanderbilt, then discussed secondary
prevention of overt stroke. He
critically reviewed the literature
regarding secondary prevention
of overt strokes, concluding that
treatment for overt stroke is yet to
be defined. He noted that transfusions
are the current treatment for
overt stroke, although they are not
a definitive treatment for secondary
Safety:7"
human melanoma tissue. The safety and efficacy of ZELBORAF have
not been evaluated in patients whose melanoma tested negative by the
cobas®
FDA approved test kits,for detailed information.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
4800 BRAF V600 Mutation Test. Refer to the package inserts of
Because clinical studies are conducted under widely varying conditions,
adverse reaction rates observed in the clinical studies of a drug cannot
be directly compared to rates in the clinical studies of another drug and
may not predict the rates observed in a broader patient population in
clinical practice.
The adverse drug reactions (ADRs) described in this section were
identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1,
treatment naive patients with unresectable or metastatic melanoma
(n=675) were allocated to ZELBORAF 960 mg orally twice daily or
to dacarbazine 1000 mg/m2
(n=132) patients with metastatic melanoma and failure of at least
one prior systemic therapy received treatment with ZELBORAF
960 mg orally twice daily. Adverse reactions reported in at least 10%
of patients treated with ZELBORAF are presented in Table 2. The most
common adverse reactions of any grade (≥ 30% in either study) reported
in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue,
photosensitivity reaction, nausea, pruritus and skin papilloma. The most
common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The
incidence of Grade 4 adverse reactions was ≤ 4% in both studies.
The incidence of adverse events resulting in permanent discontinuation
of study medication in Trial 1 was 7% for the ZELBORAF arm and 4%
for the dacarbazine arm. In Trial 2, the incidence of adverse events
resulting in permanent discontinuation of study medication was 3% in
ZELBORAF-treated patients. The median duration of study treatment
was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in
Trial 1, and 5.7 months for ZELBORAF in Trial 2.
Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated
with ZELBORAF*
Trial 1: Treatment Naive Patients
Trial 2: Patients with
Failure of at Least
One Prior Systemic
Therapy
ZELBORAF
n= 132
Grade
3
(%)
Grade
4
(%)
intravenously every 3 weeks. In Trial 2,
“Despite finding that the use
of sildenafil may be associated
with increased pain, other
experience suggests that
sickle cell patients with true
pulmonary hypertension may
have significant benefit from
this treatment and may elect
to risk some increase in pain.”
prevention based on the available literature.
When determining optimal
stroke treatment, Dr. DeBaun also
conveyed that patient and family
preference is critical but difficult to
measure. Dr. DeBaun communicated
his approach to secondary stroke
prevention that includes in order of
preference: 1) HLA-matched sibling
Clinically relevant adverse events reported in < 10% of patients treated
with ZELBORAF in the Phase 2 and Phase 3 studies include:
Skin and subcutaneous tissue disorders: palmar-plantar
erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum,
Stevens-Johnson syndrome
paralysis
Musculoskeletal and connective tissue disorders: arthritis
Nervous system disorders: dizziness, neuropathy peripheral, VIIth
nerve
Neoplasms benign, malignant and unspecified (includes cysts and polyps):
basal cell carcinoma
Infections and infestations: folliculitis
Investigations: weight decreased
Eye disorders: retinal vein occlusion, uveitis
Vascular disorders: vasculitis
Cardiac disorders: atrial fibrillation
Table 3 shows the incidence of worsening liver laboratory abnormalities
in Trial 1 summarized as the proportion of patients who experienced a
shift from baseline to Grade 3 or 4.
Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities*
Change From Baseline to Grade 3/4
Parameter
GGT
AST
ALT
Alkaline phosphatase
Bilirubin
ZELBORAF (%)
11.5
0.9
2.8
2.9
1.9
Dacarbazine (%)
8.6
0.4
1.9
0.4
-
* For ALT, alkaline phosphatase and bilirubin, there were no patients
with a change to grade 4 in either treatment arm.
7 DRUG INTERACTIONS
7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes
Results from an in vivo drug-drug interaction study in patients with cancer
demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak
CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)].
Concomitant use of ZELBORAF with agents with narrow therapeutic
windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is
not recommended as ZELBORAF may alter their concentrations. If
coadministration cannot be avoided, exercise caution and consider a
dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug.
Coadministration of vemurafenib resulted in an 18% increase in
AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology
(12.3)]. Exercise caution and consider additional INR monitoring when
ZELBORAF is used concomitantly with warfarin.
7.2 Drugs that Inhibit or Induce CYP3A4
Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin,
atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir,
nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine,
rifampin, rifabutin, rifapentine, phenobarbital) should be used with
caution when coadministered with ZELBORAF.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.9)].
ZELBORAF may cause fetal harm when administered to a pregnant
woman based on its mechanism of action.
There are no adequate and well controlled studies in pregnant women.
Women of childbearing potential and men should be advised to use
appropriate contraceptive measures during ZELBORAF therapy and for
at least 2 months after discontinuation of ZELBORAF. If this drug is used
during pregnancy or if the patient becomes pregnant while taking this
drug, the patient should be apprised of the potential hazard to a fetus.
8.3 Nursing Mothers
It is not known whether vemurafenib is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for
serious adverse reactions from ZELBORAF in nursing infants, a decision
should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and efficacy in pediatric patients below the age of 18 have not
been established.
8.5 Geriatric Use
Ninety-four (28%) of 336 patients with unresectable or metastatic
melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly
patients (≥ 65 years) may be more likely to experience some adverse
reactions, including cutaneous squamous cell carcinoma, nausea,
decreased appetite, peripheral edema, keratoacanthoma and atrial
fibrillation. The effects of ZELBORAF on overall survival, progressionfree
survival and best overall response rate were similar in the elderly as
compared to younger patients.
8.6 Gender
The Grade 3 adverse events reported more frequently in females than
males were rash, arthralgia, photosensitivity and increased creatinine.
The Grade 3 adverse events reported more frequently in males than
females were keratoacanthoma, increased alkaline phosphatase and
increased total bilirubin.
8.7 Hepatic Impairment
21 <1
24 22
10 <1
5
3
-
-
-
<1
-
-
<1 <1
1
-
1
-
-
-
-
-
30
-
24 24
14
-
15
6
-
-
-
4
No adjustment to the starting dose is needed for patients with
pre-existing mild and moderate hepatic impairment. ZELBORAF should
be used with caution in patients with pre-existing severe hepatic
impairment [see Clinical Pharmacology (12.3)].
8.8 Renal Impairment
No adjustment to the starting dose is needed for patients with
pre-existing mild and moderate renal impairment.
ZELBORAF should be used with caution in patients with pre-existing
severe renal impairment [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
There is no specific antidote for overdosage of ZELBORAF. Patients
who develop adverse reactions should receive appropriate symptomatic
treatment. In case of suspected overdose, ZELBORAF should be
withheld and supportive care instituted.
8
10
-
-
-
-
7
-
-
-
- 12 -
-
14
-
-
-
* Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE
v 4.0 (NCI common toxicity criteria) for assessment of toxicity.
† Includes both squamous cell carcinoma of the skin and keratoacanthoma.
#
All cases of cutaneous squamous cell carcinoma were to be reported as
Grade 3 per instructions to study investigators and no dose modification
or interruption was required.
Manufactured by:
Genentech, Inc.
1 DNA Way
donor hematopoietic stem cell transplantation
(if available), 2) regular
transfusion therapy, and 3) less than
optimal treatment may be selected
based on patient and parent preference.
Dr. DeBaun concluded his talk,
stating, “We need consolidation of
the SCD community to answer alternative
therapy options for secondary
prevention of strokes.” These alternative
therapy options include experimental
hematopoietic stem cell
transplantation, revascularization
procedures, and continued careful
monitoring for those patients that
continue on hydroxyurea.
Dr. Alexis Thompson from Chil-
dren’s Memorial Hospital in Chicago
concluded by summarizing the data
supporting primary prophylaxis in
SCD emphasizing both the acceptability
and feasibility of primary prophylaxis.
Data presented included
the role of consistent penicillin prophylaxis
to reduce infectious complications
in children with SCD and the
role that transcranial doppler screening
combined with chronic transfusions
has had in the dramatic reduction
of the incidence of first overt
stroke. However, in the recent Pediatric
Hydroxyurea Phase III Clinical
Trial (BABY HUG), hydroxyurea
did not show a benefit for primary
prevention of reduced splenic or renal
function. Dr. Thompson also affirmed
Dr. Hassell’s discussions that
research into SCD pulmonary complications
has left us with the need
for better tools to assess pulmonary
status in young children in order to
fully understand the natural history
of SCD-related lung complications
and to develop more effective interventions.
“The lung is likely one of
the most challenging organs to consider
for primary prophylaxis” Dr.
Thompson stated.
It is truly amazing that the sub-
stitution of valine for glutamic acid
on the sixth position of the β-globin
gene leads to significant multi-organ
phenotypic disease variability
and a century of research that leaves
us with potentially more questions
than answers – albeit much more
informed questions. Certainly, the
need to answer these questions is
what keeps all of us striving for additional
scientific discovery.
Drs. Brandow and Panepinto indicated
no relevant conflicts of interest.
WiFi Supporters
The ASH Annual Meeting is a
free WiFi hot spot thanks to the
support from:
Bristol-Myers Squibb
Incyte
Millennium
South San Francisco, CA
94080-4990
Initial U.S. Approval: August 2011
© 2011 Genentech, Inc
BRF0000422000
Novartis Molecular Diagnostics
Seattle Genetics
ASH NEWS DAILY
Sunday, December 11, 2011
Safety:10"
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