Laboratory
Abnormality
VENCLEXTA +
Rituximab
N=194
Grade 3
All
or 4
Grades a
(%)
(%)
Bendamustine +
Rituximab
N=188
All
Grade 3
Grades a
or 4
(%)
(%)
Chemistry
Hypocalcemia
62
5
51
2
Hypophosphatemia
57
14
35
4
AST/SGOT
46
2
31
3
increased
Hyperuricemia
36
36
33
33
Alkaline
phosphatase
35
1
20
1
increased
Hyperbilirubinemia
33
4
26
3
Hyponatremia
30
6
20
3
Hypokalemia
29
6
18
3
Hyperkalemia
24
3
19
2
Hypernatremia
24
1
13
0
Hypoglycemia
16
2
7
0
a Includes laboratory abnormalities that were new or worsening, or with
worsening from baseline unknown.
New Grade 4 laboratory abnormalities reported in ≥2% of patients treated
with VEN+R included neutropenia (31%), lymphopenia (16%), leukopenia
(6%), thrombocytopenia (6%), hyperuricemia (4%), hypocalcemia (2%),
hypoglycemia (2%), and hypermagnesemia (2%).
Monotherapy Studies (M13-982, M14-032, and M12-175)
The safety of single agent VENCLEXTA at the 400 mg recommended daily
dose following a dose ramp-up schedule is based on pooled data from
three single-arm trials (M13-982, M14-032, and M12-175). In the pooled
dataset, consisting of 352 patients with previously treated CLL or SLL, the
median age was 66 years (range: 28 to 85 years), 93% were white, and
68% were male. The median number of prior therapies was 3 (range:
0 to 15). The median duration of treatment with VENCLEXTA at the time of
data analysis was 14.5 months (range: 0 to 50 months). Fifty-two percent
of patients received VENCLEXTA for more than 60 weeks.
Fatal adverse reactions that occurred in the absence of disease
progression and within 30 days of venetoclax treatment were reported in
2% of patients in the VENCLEXTA monotherapy studies, most commonly
(2 patients) from septic shock. Serious adverse reactions were reported
in 52% of patients, with the most frequent (≥5%) being pneumonia (9%),
febrile neutropenia (5%), and sepsis (5%).
Adverse reactions led to treatment discontinuation in 9% of patients,
dose reduction in 13%, and dose interruption in 36%. The most frequent
adverse reactions leading to drug discontinuation were thrombocytopenia
and autoimmune hemolytic anemia. The most frequent adverse reaction
(≥5%) leading to dose reductions or interruptions was neutropenia (8%).
Adverse reactions identified in these trials of single-agent VENCLEXTA are
presented in Table 5.
Table 5. Adverse Reactions Reported in ≥10% (Any Grade) or ≥5%
(Grade ≥3) of Patients with Previously Treated CLL/SLL (VENCLEXTA
Monotherapy)
Body System
Blood and lymphatic
system
disorders
Gastrointestinal
disorders
General disorders and
administration site
conditions
Infections and
infestations
Musculoskeletal and
connective tissue
disorders
Nervous system
disorders
Adverse Reaction
Neutropenia a
Anemia a
Thrombocytopenia a
Lymphopenia a
Febrile neutropenia
Diarrhea
Nausea
Abdominal pain a
Vomiting
Constipation
Mucositis a
Fatigue a
Edema a
Pyrexia
Upper respiratory tract
infection a
Pneumonia a
Lower respiratory tract
infection a
Musculoskeletal pain a
Any Grade Grade ≥3
(%)
(%)
N=352
N=352
50
45
33
18
29
20
11
7
6
6
43
3
42
1
18
3
16
1
16
<1
13
<1
32
4
22
2
18
<1
36 1
14 8
11 2
29 2
Arthralgia 12 <1
Headache
Dizziness a
Cough a 18
14
22 <1
0
0
Respiratory, thoracic,
and
a
13
1
mediastinal disorders Dyspnea
Skin and subcutaneous Rash a
18
<1
tissue disorders
Adverse Reactions graded using NCI Common Terminology Criteria for
Adverse Events version 4.0.
a Includes multiple adverse reaction terms.
Laboratory Abnormalities
Table 6 describes common laboratory abnormalities reported throughout
treatment that were new or worsening from baseline. The most common
(>5%) Grade 4 laboratory abnormalities observed with VENCLEXTA
monotherapy were hematologic laboratory abnormalities, including
neutropenia (33%), leukopenia (11%), thrombocytopenia (15%), and
lymphopenia (9%).
Table 6. New or Worsening Laboratory Abnormalities with VENCLEXTA
Monotherapy (≥40% Any Grade or ≥10% Grade 3 or 4)
All Grades a
(%)
N=352
Grade 3 or 4
(%)
Laboratory Abnormality
N=352
Hematology
Leukopenia
89
42
Neutropenia
87
63
Lymphopenia
74
40
Anemia
71
26
Thrombocytopenia
64
31
Chemistry
Hypocalcemia
87
12
Hyperglycemia
67
7
Hyperkalemia
59
5
AST increased
53
3
Hypoalbuminemia
49
2
Hypophosphatemia
45
11
Hyponatremia
40
9
a Includes laboratory abnormalities that were new or worsening, or
worsening from baseline unknown.
Important Adverse Reactions
Tumor Lysis Syndrome
Tumor lysis syndrome is an important identified risk when initiating
VENCLEXTA.
CLL14
The incidence of TLS was 1% (3/212) in patients treated with VEN+G
[see Warnings and Precautions]. All three events of TLS resolved and did
not lead to withdrawal from the study. Obinutuzumab administration was
delayed in two cases in response to the TLS events.
MURANO
In the open-label randomized phase 3 study, the incidence of TLS was
3% (6/194) in patients treated with VEN+R. After 77/389 patients were
enrolled in the study, the protocol was amended to incorporate the current
TLS prophylaxis and monitoring measures. All events of TLS occurred
during the VENCLEXTA ramp-up period and were resolved within two days.
All six patients completed the ramp-up and reached the recommended
daily dose of 400 mg of VENCLEXTA. No clinical TLS was observed in
patients who followed the current 5-week ramp-up schedule and TLS
prophylaxis and monitoring measures. Rates of laboratory abnormalities
relevant to TLS for patients treated with VEN+R are presented in Table 4.
Monotherapy Studies (M13-982 and M14-032)
In 168 patients with CLL treated according to recommendations, the rate
of TLS was 2%. All events either met laboratory TLS criteria (laboratory
abnormalities that met ≥2 of the following within 24 hours of each other:
potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L,
or phosphorus >1.5 mmol/L); or were reported as TLS events. The
events occurred in patients who had a lymph node(s) ≥5 cm and/or
ALC ≥25 x 10 9 /L. All events resolved within 5 days. No TLS with clinical
consequences such as acute renal failure, cardiac arrhythmias or sudden
death and/or seizures was observed in these patients. All patients
had CLcr ≥50 mL/min. Laboratory abnormalities relevant to TLS were
hyperkalemia (17% all Grades, 1% Grade ≥3), hyperphosphatemia (14% all
Grades, 2% Grade ≥3), hypocalcemia (16% all Grades, 2% Grade ≥3), and
hyperuricemia (10% all Grades, <1% Grade ≥3).
In the initial Phase 1 dose-finding trials, which had shorter (2-3 week)
ramp-up phase and higher starting doses, the incidence of TLS was 13%
(10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and
3 events of acute renal failure, 1 requiring dialysis. After this experience,
TLS risk assessment, dosing regimen, TLS prophylaxis and monitoring
measures were revised.
Clinical Trial Experience with Acute Myeloid Leukemia
The safety of VENCLEXTA (400 mg daily dose) in combination with
azacitidine (n=67) or decitabine (n= 13) and VENCLEXTA (600 mg daily
dose) in combination with low-dose cytarabine (n= 61) is based on two
non-randomized trials of patients with newly-diagnosed AML. The median
duration of exposure for patients taking VENCLEXTA in combination with
azacitidine and decitabine was 6.5 months (range: 0.1 to 31.9 months) and
8.4 months (range: 0.5 to 22.3 months), respectively. The median duration
of exposure for patients taking VENCLEXTA in combination with low dose
cytarabine was 3.9 months (range: 0.2 to 29.2 months).
VENCLEXTA in Combination with Azacitidine or Decitabine
Azacitidine
The most common adverse reactions (≥30%) of any grade were nausea,
diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage,
peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia.
Serious adverse reactions were reported in 75% of patients. The most
frequent serious adverse reactions (≥5%) were febrile neutropenia,
pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure,
and multiple organ dysfunction syndrome.
The incidence of fatal adverse drug reactions was 1.5% within 30 days of
starting treatment. No reaction had an incidence of ≥2%.
Discontinuations due to adverse reactions occurred in 21% of patients.
The most frequent adverse reactions leading to drug discontinuation (≥2%)
were febrile neutropenia and pneumonia (excluding fungal).
Dosage interruptions due to adverse reactions occurred in 61% of patients.
The most frequent adverse reactions leading to dose interruption (≥5%)
were neutropenia, febrile neutropenia, and pneumonia (excluding fungal).
Dosage reductions due to adverse reactions occurred in 12% of patients.
The most frequent adverse reaction leading to dose reduction (≥5%) was
neutropenia.
Decitabine
The most common adverse reactions (≥30%) of any grade were febrile
neutropenia, constipation, fatigue, thrombocytopenia, abdominal pain,
dizziness, hemorrhage, nausea, pneumonia (excluding fungal), sepsis
(excluding fungal), cough, diarrhea, neutropenia, back pain, hypotension,
myalgia, oropharyngeal pain, peripheral edema, pyrexia, and rash.
Serious adverse reactions were reported in 85% of patients. The most
frequent serious adverse reactions (≥5%) were febrile neutropenia, sepsis
(excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue,
cellulitis, and localized infection.
One (8%) fatal adverse drug reaction of bacteremia occurred within
30 days of starting treatment.
Discontinuations due to adverse reactions occurred in 38% of patients. The
most frequent adverse reaction leading to drug discontinuation (≥5%) was
pneumonia (excluding fungal).
Dosage interruptions due to adverse reactions occurred in 62% of patients.
The most frequent adverse reactions leading to dose interruption (≥5%)
were febrile neutropenia, neutropenia, and pneumonia (excluding fungal).
Dosage reductions due to adverse reactions occurred in 15% of patients.
The most frequent adverse reaction leading to dose reduction (≥5%) was
neutropenia.
Adverse reactions reported in patients with newly-diagnosed AML using
VENCLEXTA in combination with azacitidine or decitabine are presented
in Table 7.
Table 7. Adverse Reactions Reported in ≥30% (Any Grade) or
≥5% (Grade ≥3) of Patients with AML Treated with VENCLEXTA in
Combination with Azacitidine or Decitabine
Body System
Adverse
Reaction
Thrombo-
cytopenia a
Neutropenia a
Febrile
neutropenia
Anemia a
Nausea
Diarrhea
Gastrointestinal Constipation
disorders
Vomiting a
Abdominal
pain a
Peripheral
edema a
General
Fatigue a
disorders
Pyrexia
and
administration Cachexia
site
Multiple organ
conditions
dysfunction
syndrome
Pneumonia
(excluding
fungal) a
Sepsis
(excluding
Infections and fungal) a
infestations
Urinary tract
infection
Cellulitis
Localized
infection
Musculoskeletal Back pain
and connective
a
tissue disorders Myalgia
Blood and
lymphatic
system
disorders
VENCLEXTA in
Combination
with
Decitabine
Any
Any
Grade ≥3
Grade ≥3
Grade
Grade
(%)
(%)
(%)
(%)
N = 13
N = 67
N = 13
N = 67
VENCLEXTA in
Combination with
Azacitidine
49 45 54 54
49 49 38 38
36 36 69 69
30
58
54
49
40 30
1
3
3
0 15
46
38
62
23 15
0
8
0
0
22 4 46 0
46 1 31 0
36
21
0 7
3
0 62
31
8 15
0
8
6 6 0 0
27 25 46 31
13 13 46 46
16 6 23 0
6 0 15 8
0 0 8 8
15 0 31 0
10 0 31 0
Nervous system Dizziness a
28
1
46
0
disorders
Skin and
subcutaneous Rash a
33
1
31
0
tissue disorders
a
25
0
38
0
Cough
Respiratory,
Hypoxia
18
6
15
0
thoracic and
mediastinal
Oropharyngeal
9
0
31
0
disorders
pain
46
7
46
0
Hemorrhage a
Vascular
21
6
31
0
Hypotension a
disorders
Hypertension
12
7
15
8
Adverse Reactions graded using NCI Common Terminology Criteria for
Adverse Events version 4.0.
a Includes multiple adverse reaction terms.
Laboratory Abnormalities
Table 8 describes common laboratory abnormalities reported throughout
treatment that were new or worsening from baseline.