6.1 Clinical Trial Experience with CLL/SLL
MURANO
The safety of VENCLEXTA in combination with rituximab (VEN+R) versus bendamustine in combination with rituximab (B+R), was evaluated in an open-label randomized study, in patients with CLL who had received at least one prior therapy.
Patients randomized to VEN+R completed the scheduled ramp-up (5 weeks) and received VENCLEXTA 400 mg once daily in combination with rituximab for 6 cycles followed by single agent VENCLEXTA for a total of 24 months after ramp-up. Patients randomized to B+R received 6 cycles (28 days per cycle) for a total of 6 months. Details of the study treatment are described in Section 14 [see Clinical Studies (14.1)].
At the time of analysis, the median duration of exposure was 22 months in the VEN+R arm compared with 6 months in the B+R arm.
In the VEN+R arm, fatal adverse reactions that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of last rituximab were reported in 2% (4/194) of patients. Serious adverse reactions were reported in 46% of patients in the VEN+R arm, with most frequent (≥5%) being pneumonia (9%).
In the VEN+R arm, adverse reactions led to treatment discontinuation in 16% of patients, dose reduction in 15%, and dose interruption in 71%. In the B+R arm, adverse reactions led to treatment discontinuation in 10% of patients, dose reduction in 15%, and dose interruption in 40%. In the VEN+R arm, neutropenia led to dose interruption of VENCLEXTA in 46% of patients and discontinuation in 3%, and thrombocytopenia led to discontinuation in 3% of patients.
Table 9 and Table 10 present adverse reactions and laboratory abnormalities, respectively, identified in the MURANO trial. The MURANO trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for VEN+R as compared with B+R, for any specific adverse reaction or laboratory abnormality.
Table 9. Common (≥10%) Adverse Reactions Reported with ≥5% Higher All-Grade or ≥2% Higher Grade ≥3 Incidence in Patients Treated with VEN+R Compared with B+R
Adverse Reaction by Body System |
VENCLEXTA + Rituximab Followed by Single Agent VENCLEXTA (N = 194) |
Bendamustine + Rituximab (N = 188) |
All Grades (%) |
Grade ≥3 (%) |
All Grades (%) |
Grade ≥3 (%) |
Blood & lymphatic system disorders |
Neutropeniaa |
65 |
62 |
50 |
44 |
Gastrointestinal disorders |
Diarrhea |
40 |
3 |
17 |
1 |
Infections & infestations |
Upper respiratory tract infectiona |
39 |
2 |
23 |
2 |
Lower respiratory tract infectiona |
18 |
2 |
10 |
2 |
Musculoskeletal and connective tissue disorders |
Musculoskeletal paina |
19 |
1 |
13 |
0 |
Metabolism and nutrition disorders |
Tumor lysis syndrome |
3 |
3 |
1 |
1 |
aIncludes multiple adverse reaction terms. |
Other adverse reactions (all Grades) reported in ≥10% of patients in the VEN+R arm in MURANO, and other important adverse reactions are presented below:
Blood & lymphatic system disorders: anemia (16%), thrombocytopenia (15%), febrile neutropenia (4%)
Gastrointestinal disorders: nausea (21%), constipation (14%), abdominal pain (13%), mucositis (10%), vomiting (8%)
Respiratory disorders: cough (22%)
General disorders and administration site conditions: fatigue (22%), pyrexia (15%)
Skin disorders: rash (13%)
Nervous system and psychiatric disorders: headache (11%), insomnia (11%)
Infections & infestations: pneumonia (10%)
During treatment with single agent VENCLEXTA after completion of VEN+R combination treatment, the most common all grade adverse reactions (≥10% patients) reported were upper respiratory tract infection (21%), diarrhea (19%), neutropenia (16%), and lower respiratory tract infections (11%).The most common grade 3 or 4 adverse reaction (≥2% patients) were neutropenia (12%) and anemia (3%).
Laboratory Abnormalities
Table 10 describes common treatment-emergent laboratory abnormalities identified in the MURANO trial.
Table 10. Common (≥10%) New or Worsening Laboratory Abnormalities Occurring at ≥5% (Any Grade) or ≥2% (Grade 3 or 4) Higher Incidence with VEN+R Compared with B+R
|
VENCLEXTA + Rituximab N=194 |
Bendamustine + Rituximab N=188 |
Laboratory Abnormality |
All Gradesa (%) |
Grade 3 or 4 (%) |
All Gradesa (%) |
Grade 3 or 4 (%) |
Hematology |
Leukopenia |
89 |
46 |
81 |
35 |
Lymphopenia |
87 |
56 |
79 |
55 |
Neutropenia |
86 |
64 |
84 |
59 |
Chemistry |
Hypocalcemia |
62 |
5 |
51 |
2 |
Hypophosphatemia |
57 |
14 |
35 |
4 |
AST/SGOT increased |
46 |
2 |
31 |
3 |
Hyperuricemia |
36 |
36 |
33 |
33 |
Alkaline phosphatase increased |
35 |
1 |
20 |
1 |
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 |
aIncludes 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 11.
Table 11. Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade ≥3) of Patients with Previously Treated CLL/SLL (VENCLEXTA Monotherapy)
Body System |
Adverse Reaction |
Any Grade (%) N=352 |
Grade ≥3 (%) N=352 |
Blood and lymphatic system disorders |
Neutropeniaa |
50 |
45 |
Anemiaa |
33 |
18 |
Thrombocytopeniaa |
29 |
20 |
Lymphopeniaa |
11 |
7 |
Febrile neutropenia |
6 |
6 |
Gastrointestinal disorders |
Diarrhea |
43 |
3 |
Nausea |
42 |
1 |
Abdominal paina |
18 |
3 |
Vomiting |
16 |
1 |
Constipation |
16 |
<1 |
Mucositisa |
13 |
<1 |
General disorders and administration site conditions |
Fatiguea |
32 |
4 |
Edemaa |
22 |
2 |
Pyrexia |
18 |
<1 |
Infections and infestations |
Upper respiratory tract infectiona |
36 |
1 |
Pneumoniaa |
14 |
8 |
Lower respiratory tract infectiona |
11 |
2 |
Musculoskeletal and connective tissue disorders |
Musculoskeletal paina |
29 |
2 |
Arthralgia |
12 |
<1 |
Nervous system disorders |
Headache |
18 |
<1 |
Dizzinessa |
14 |
0 |
Respiratory, thoracic, and mediastinal disorders |
Cougha |
22 |
0 |
Dyspneaa |
13 |
1 |
Skin and subcutaneous tissue disorders |
Rasha |
18 |
<1 |
Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0. aIncludes multiple adverse reaction terms. |
Laboratory Abnormalities
Table 12 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 12. New or Worsening Laboratory Abnormalities with VENCLEXTA Monotherapy (≥40% Any Grade or ≥10% Grade 3 or 4)
Laboratory Abnormality |
All Gradesa (%) N=352 |
Grade 3 or 4 (%) 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 |
aIncludes 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.
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 described in sections 2.1 and 2.2 [see Dosage and Administration (2.1, 2.2)]. 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 described in sections 2.1 and 2.2 [see Dosage and Administration (2.1, 2.2)]. Rates of laboratory abnormalities relevant to TLS for patients treated with VEN+R are presented in Table 10.
Monotherapy Studies (M13-982 and M14-032)
In 168 patients with CLL treated according to recommendations described in sections 2.1 and 2.2, the rate of TLS was 2% [see Dosage and Administration (2.1, 2.2)]. 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 109/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 [see Dosage and Administration (2.1, 2.2)].
6.2 Clinical Trial Experience with AML
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 [see Clinical Studies (14.3)]. 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 13.
Table 13. 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 |
VENCLEXTA in Combination with Azacitidine |
VENCLEXTA in Combination with Decitabine |
Any Grade (%) N = 67 |
Grade ≥3 (%) N = 67 |
Any Grade (%) N = 13 |
Grade ≥3 (%) N = 13 |
Blood and lymphatic system disorders |
Thrombocytopeniaa |
49 |
45 |
54 |
54 |
Neutropeniaa |
49 |
49 |
38 |
38 |
Febrile neutropenia |
36 |
36 |
69 |
69 |
Anemiaa |
30 |
30 |
15 |
15 |
Gastrointestinal disorders |
Nausea |
58 |
1 |
46 |
0 |
Diarrhea |
54 |
3 |
38 |
8 |
Constipation |
49 |
3 |
62 |
0 |
Vomitinga |
40 |
0 |
23 |
0 |
Abdominal paina |
22 |
4 |
46 |
0 |
General disorders and administration site conditions |
Peripheral edemaa |
46 |
1 |
31 |
0 |
Fatiguea |
36 |
7 |
62 |
15 |
Pyrexia |
21 |
3 |
31 |
0 |
Cachexia |
0 |
0 |
8 |
8 |
Multiple organ dysfunction syndrome |
6 |
6 |
0 |
0 |
Infections and infestations |
Pneumonia (excluding fungal)a |
27 |
25 |
46 |
31 |
Sepsis (excluding fungal)a |
13 |
13 |
46 |
46 |
Urinary tract infection |
16 |
6 |
23 |
0 |
Cellulitis |
6 |
0 |
15 |
8 |
Localized infection |
0 |
0 |
8 |
8 |
Musculoskeletal and connective tissue disorders |
Back pain |
15 |
0 |
31 |
0 |
Myalgiaa |
10 |
0 |
31 |
0 |
Nervous system disorders |
Dizzinessa |
28 |
1 |
46 |
0 |
Skin and subcutaneous tissue disorders |
Rasha |
33 |
1 |
31 |
0 |
Respiratory, thoracic and mediastinal disorders |
Cougha |
25 |
0 |
38 |
0 |
Hypoxia |
18 |
6 |
15 |
0 |
Oropharyngeal pain |
9 |
0 |
31 |
0 |
Vascular disorders |
Hemorrhagea |
46 |
7 |
46 |
0 |
Hypotensiona |
21 |
6 |
31 |
0 |
Hypertension |
12 |
7 |
15 |
8 |
Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0. aIncludes multiple adverse reaction terms. |
Laboratory Abnormalities
Table 14 describes common laboratory abnormalities reported throughout treatment that were new or worsening from baseline.
Table 14. New or Worsening Laboratory Abnormalities with VENCLEXTA Reported in ≥40% (Any Grade) or ≥10% (Grade 3 or 4) of Patients with AML Treated with VENCLEXTA in Combination with Azacitidine or Decitabine
Laboratory Abnormality |
VENCLEXTA in Combination with Azacitidine |
VENCLEXTA in Combination with Decitabine |
Any Gradea (%) N = 67 |
Grade 3 or 4a (%) N = 67 |
Any Gradea (%) N = 13 |
Grade 3 or 4a (%) N = 13 |
Hematology |
Neutropenia |
100 |
100 |
100 |
100 |
Leukopenia |
100 |
98 |
100 |
100 |
Thrombocytopenia |
91 |
78 |
83 |
83 |
Lymphopenia |
88 |
73 |
100 |
92 |
Anemia |
57 |
57 |
69 |
69 |
Chemistry |
Hyperglycemia |
75 |
12 |
69 |
0 |
Hypocalcemia |
58 |
7 |
85 |
0 |
Hypoalbuminemia |
52 |
4 |
38 |
8 |
Hypokalemia |
49 |
7 |
46 |
0 |
Hyponatremia |
49 |
4 |
38 |
0 |
Hypophosphatemia |
46 |
15 |
23 |
8 |
Hyperbilirubinemia |
45 |
9 |
46 |
15 |
Hypomagnesemia |
21 |
0 |
54 |
8 |
aIncludes laboratory abnormalities that were new or worsening, or worsening from baseline unknown. |
VENCLEXTA in Combination with Low-Dose Cytarabine
The most common adverse reactions (≥30%) of any grade were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation, and dyspnea.
Serious adverse reactions were reported in 95% of patients. The most frequent serious adverse reactions (≥5%) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal), and device-related infection.
The incidence of fatal adverse drug reactions was 4.9% within 30 days of starting treatment with no reaction having an incidence of ≥2%.
Discontinuations due to adverse reactions occurred in 33% of patients. The most frequent adverse reactions leading to drug discontinuation (≥2%) were hemorrhage and sepsis (excluding fungal).
Dosage interruptions due to adverse reactions occurred in 52% of patients. The most frequent adverse reactions leading to dose interruption (≥5%) were thrombocytopenia, neutropenia, and febrile neutropenia.
Dosage reductions due to adverse reactions occurred in 8% of patients. The most frequent adverse reaction leading to dose reduction (≥2%) was thrombocytopenia.
Adverse reactions reported in patients with newly-diagnosed AML receiving VENCLEXTA in combination with low-dose cytarabine are presented in Table 15.
Table 15. Adverse Reactions Reported in ≥30% (Any Grade) or ≥5% (Grade ≥3) of Patients with AML Treated with VENCLEXTA in Combination with Low-Dose Cytarabine
Body System |
Adverse Reaction |
Any Grade (%) N = 61 |
Grade ≥3 (%) N = 61 |
Blood and lymphatic system disorders |
Thrombocytopeniaa |
59 |
59 |
Neutropeniaa |
46 |
46 |
Febrile neutropenia |
46 |
44 |
Anemiaa |
26 |
26 |
Gastrointestinal disorders |
Nausea |
64 |
2 |
Diarrhea |
44 |
3 |
Constipation |
33 |
0 |
General disorders and administration site conditions |
Fatiguea |
44 |
10 |
Infections and infestations |
Sepsisa |
20 |
18 |
Pneumoniaa |
18 |
16 |
Device related infection |
13 |
11 |
Urinary tract infection |
8 |
7 |
Metabolic and nutritional disorders |
Decreased appetitea |
28 |
7 |
Respiratory disorders |
Dyspneaa |
31 |
3 |
Vascular disorders |
Hemorrhagea |
49 |
15 |
Hypotensiona |
21 |
7 |
Hypertension |
15 |
8 |
Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version 4.0. aIncludes multiple adverse reaction terms. |
Laboratory Abnormalities
Table 16 describes common laboratory abnormalities reported throughout treatment that were new or worsening from baseline.
Table 16. New or Worsening Laboratory Abnormalities with VENCLEXTA Reported in ≥40% (Any Grade) or ≥10% (Grade 3 or 4) of Patients with AML Treated with VENCLEXTA in Combination with Low-Dose Cytarabine
Laboratory Abnormality |
All Gradesa (%) N = 61 |
Grade 3 or 4a (%) N = 61 |
Hematology |
Thrombocytopenia |
100 |
96 |
Neutropenia |
96 |
96 |
Leukopenia |
96 |
96 |
Lymphopenia |
93 |
66 |
Anemia |
61 |
59 |
Chemistry |
|
|
Hyperglycemia |
85 |
8 |
Hypocalcemia |
79 |
16 |
Hyponatremia |
62 |
11 |
Hyperbilirubinemia |
57 |
3 |
Hypoalbuminemia |
59 |
5 |
Hypokalemia |
56 |
20 |
Hypophosphatemia |
51 |
21 |
Hypomagnesemia |
46 |
0 |
Blood creatinine increased |
46 |
3 |
Blood bicarbonate decreased |
41 |
0 |
aIncludes laboratory abnormalities that were new or worsening, or worsening from baseline unknown. |
Tumor Lysis Syndrome
Tumor lysis syndrome is an important risk when initiating treatment in patients with AML. The incidence of TLS was 3% (2/61) with VENCLEXTA in combination with low-dose cytarabine with implementation of dose ramp-up schedule in addition to standard prophylaxis and monitoring measures. All events were laboratory TLS, and all patients were able to reach the target dose.