34
Latest & Greatest
Pivotal Phase III VALOR
Trial Fails to Meet Its
Primary Endpoint
VALOR is a phase III, randomized,
double-blind, placebo-controlled, trial
comparing cytarabine with or without
vosaroxin, the study agent, in 711 patients
with relapsed or refractory acute myeloid
leukemia (AML). The trial did not meet its
primary endpoint (statistically significant
improvement in overall survival), with a
median overall survival of 7.5 months for
vos aroxin and cytarabine – compared with
6.1 months for placebo and cytarabine
(HR=0.865; p=0.06). When an analysis of
overall survival was censored for stem cell
transplantation, however, vosaroxin resulted
in better median overall survival than
placebo and cytarabine (6.7 months vs. 5.3
months [HR=0.809; p=0.02]). The trial also
demonstrated a clinically significant benefit
in complete remission rate (30.1% vs. 16.3%;
p=0.0000148), the secondary endpoint. In
terms of safety, patients taking vosaroxin
experienced serious adverse events more often than the placebo arm (55.5% vs. 35.7%);
these results were consistent with those
observed in previous company trials. Vosaroxin also has been granted “fast track”
designation by the FDA for the potential
treatment of relapsed or refractory AML in
combination with cytarabine.
Source: Sunesis Pharmaceuticals, Inc. press release. Accessed from http://
ir.sunesis.com/phoenix.zhtml?c=194116&p=irol-newsArticle&ID=1974155
FDA Approves New
Treatment for Acquired
Hemophilia A
Obizur™ (antihemophilic factor [recombinant], porcine sequence) was recently
approved for the treatment of bleeding
episodes in adults with acquired hemophilia A (acquired Factor VIII [FVIII]
deficiency). This approval was based on
T:7”
T:10”
5.9 Tumor Lysis Syndrome
Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE
Fatal instances of tumor lysis syndrome have been reported during
(in at least 2 patients) in Mantle Cell Lymphoma
treatment with lenalidomide. The patients at risk of tumor lysis syndrome
All AEs1
Grade 3/4 AEs2
are those with high tumor burden prior to treatment. These patients should
System Organ Class/Preferred Term
(N=134)
(N=134)
be monitored closely and appropriate precautions taken.
n (%)
n (%)
5.10 Tumor Flare Reaction
Musculoskeletal and connective tissue disorders
Tumor flare reaction has occurred during investigational use of
lenalidomide for CLL and lymphoma, and is characterized by tender lymph
Back pain
18 (13)
2 (1)
node swelling, low grade fever, pain and rash. REVLIMID is not indicated
Muscle spasms
17 (13)
1 (<1)
and not recommended for use in CLL outside of controlled clinical trials.
Arthralgia
11 (8)
2 (1)
Monitoring and evaluation for tumor flare reaction (TFR) is recommended
Muscular weakness$
8 (6)
2 (1)
in patients with MCL. Tumor flare reaction may mimic progression of
disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR;
Respiratory, thoracic and mediastinal disorders
all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1
Cough
38 (28)
1 (<1)
and one patient developed TFR again in cycle 11. Lenalidomide may be
Dyspnea$
24 (18)
8 (6)
continued in patients with Grade 1 and 2 TFR without interruption or
modification, at the physician’s discretion. Patients with Grade 1 and 2
Pleural Effusion
10 (7)
2 (1)
TFR may also be treated with corticosteroids, non-steroidal antiHypoxia
3 (2)
2 (1)
inflammatory drugs (NSAIDs) and/or narcotic analgesics for management
Pulmonary embolism
3 (2)
2 (1)
of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended
to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1.
Respiratory distress$
2 (1)
2 (1)
Patients with Grade 3 or 4 TFR may be treated for management of symptoms
Oropharyngeal pain
13 (10)
0
per the guidance for treatment of Grade 1 and 2 TFR.
Infections and infestations
6 ADVERSE REACTIONS
Pneumonia@ $
19 (14)
12 (9)
The following adverse reactions are described in detail in other sections of
the prescribing information:
Upper respiratory tract infection
17 (13)
0
• Embryo-Fetal Toxicity [see Boxed Warnings, Warnings and
Cellulitis$
3 (2)
2 (1)
Precautions (5.1, 5.2)]
Bacteremia$
2 (1)
2 (1)
• Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings
and Precautions (5.3)]
Staphylococcal sepsis$
2 (1)
2 (1)
• Venous and arterial thromboembolism [see Boxed Warnings,
Urinary tract infection$
5 (4)
2 (1)
Warnings and Precautions (5.4)]
Skin and subcutaneous tissue disorders
• Increased Mortality in Patients with CLL [see Warnings and
Precautions (5.5)]
Rash +
30 (22)
2 (1)
• Second Primary Malignancies [see Warnings and Precautions (5.6)]
Pruritus
23 (17)
1 (<1)
• Hepatotoxicity [see Warnings and Precautions (5.7)]
Blood and lymphatic system disorders
• Allergic Reactions [see Warnings and Precautions (5.8)]
content
• Tumor lysis syndrome [see Warnings and Precautions Print-only Neutropenia
(5.9)]
65 (49)
58 (43)
• Tumor flare reactions [see Warnings and Precautions (5.10)]
Thrombocytopenia% $
48 (36)
37 (28)
Because clinical trials are conducted under widely varying conditions,
Anemia$
41 (31)
15 (11)
adverse reaction rates observed in the clinical trials of a drug cannot be
Leukopenia$
20 (15)
9 (7)
directly compared to rates in the clinical trials of another drug and may
not reflect the rates observed in practice.
Lymphopenia
10 (7)
5 (4)
6.3 Clinical Trials Experience in Mantle Cell Lymphoma
Febrile neutropenia$
8 (6)
8 (6)
In the MCL trial, a total of 134 patients received at least 1 dose of
Metabolism and nutrition disorders
REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%)
Decreased appetite
19 (14)
1 (<1)
were Caucasian, 108/134 (81%) were males and 82/134 (61%) had
duration of MCL for at least 3 years.
Hypokalemia
17 (13)
3 (2)
Table 7 summarizes the most frequently observed adverse reactions
Dehydration$
10 (7)
4 (3)
regardless of relationship to treatment with REVLIMID. Across the 134
Hypocalcemia
4 (3)
2 (1)
patients treated in this study, median duration of treatment was 95 days
(1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of
Hyponatremia
3 (2)
3 (2)
therapy, 53 patients (40%) received 6 or more cycles, and 26 patients
Renal and urinary disorders
(19%) received 12 or more cycles. Seventy-six patients (57%) underwent
Renal failure$
5 (4)
2 (1)
at least one dose interruption due to adverse events, and 51 patients
(38%) underwent at least one dose reduction due to adverse events.
Vascular disorders
Twenty-six patients (19%) discontinued treatment due to adverse events.
Hypotension@ $
9 (7)
4 (3)
Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE
Deep vein thrombosis$
5 (4)
5 (4)
(in at least 2 patients) in Mantle Cell Lymphoma
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
1
2
All AEs
Grade 3/4 AEs
Tumor flare
13 (10)
0
System Organ Class/Preferred Term
(N=134)
(N=134)
Squamous cell carcinoma of skin$
4 (3)
4 (3)
n (%)
n (%)
Investigations
General disorders and administration site conditions
Weight decreased
17 (13)
0
Fatigue
45 (34)
9 (7)
1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects
Pyrexia$
31 (23)
3 (2)
2-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or
Edema peripheral
21 (16)
0
more subjects
$
Asthenia
19 (14)
4 (3)
$-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects
@ - AEs where at least one resulted in a fatal outcome
General physical health deterioration
3 (2)
2 (1)
% - AEs where at least one was considered to be Life Threatening (if the
Gastrointestinal disorders
outcome of the event was death, it is included with death cases)
Diarrhea$
42 (31)
8 (6)
# - All PTs under SOC of Infections except for rare infections of Public Health
$
Nausea
40 (30)
1 (<1)
interest will be considered listed
+ - All PTs under HLT of Rash will be considered listed
Constipation
21 (16)
1 (<1)
The following adverse events which have occurred in other indications
Vomiting$
16 (12)
1 (<1)
and not described above have been reported (5-10%) in patients treated
Abdominal pain$
13 (10)
5 (4)
with REVLIMID monotherapy for mantle cell lymphoma.
(continued)