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in clinical remission who were prospectively
enrolled in the French Reference Center for
Thrombotic Microangiopathies network.
Evaluable patients also had severe immune-
mediated ADAMTS13 deficiency (<10%).
To determine the effects of the pre-
emptive treatment strategy, the researchers
compared the median number of iTTP epi-
sodes and the median cumulative incidence
of annual relapses in the 54 months (range =
45-82 months) preceding and the 35.8 months
(range = 23.3-68) following pre-emptive
rituximab.
Pre-emptive rituximab was administered
at the following doses: 500 mg/m 2 per infusion
(n=13) or 375 mg/m 2 per infusion (n=79).
In the period before pre-emptive rituximab
was initiated, 37 patients had more than one
iTTP episode (median = 3; range not reported),
for a median cumulative relapse incidence of
0.33 episodes per year (range = 0.23-0.66).
After initiating the pre-emptive rituximab
therapy, this incidence decreased to 0 episodes
per year (range = 0-1.32; p<0.001).
The investigators also monitored ADAMTS13
activity starting 30 days after the first ritux-
imab infusion and then systematically
measured levels every three months until 24
months of follow-up. Patients were deemed
unresponsive to therapy if they continued to
demonstrate persistent severe ADAMTS13
deficiency for at least six months after the first
rituximab infusion.
Summary of Clinical Trial Experience in CLL/SLL
Study 1
The safety data below reflects exposure in a randomized, open-label, actively
controlled clinical trial for adult patients with CLL or SLL who received at least one
prior therapy. Of 313 patients treated, 158 received COPIKTRA monotherapy and 155
received ofatumumab. The 442-patient safety analysis above includes patients from
Study 1. COPIKTRA was administered at 25 mg BID in 28-day treatment cycles until
unacceptable toxicity or progressive disease. The comparator group received 12
doses of ofatumumab with an initial dose of 300 mg intravenous (IV) on Day 1
followed a week later by 7 weekly doses of 2000 mg IV, followed 4 weeks later by
2000 mg IV every 4 weeks for 4 doses. In the total study population, the median age
was 69 years (range: 39 to 90 years), 60% were male, 92% were White, and 91%
had an ECOG performance status of 0 to 1. Patients had a median of 2 prior therapies,
with 61% of patients having received 2 or more prior therapies. The trial required a
hemoglobin ≥ 8 g/dL and platelets ≥ 10,000 μL with or without transfusion support,
hepatic transaminases ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5
times ULN, and serum creatinine ≤ 2 times ULN. The trial excluded patients with
prior autologous transplant within 6 months or allogeneic transplant, prior exposure
to a PI3K inhibitor or a Bruton’s tyrosine kinase (BTK) inhibitor, and uncontrolled
autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura. During
randomized treatment, the median duration of exposure to COPIKTRA was 11.6
months with 72% (114/158) exposed for ≥ 6 months and 49% (77/158) exposed for ≥
1 year. The median duration of exposure to ofatumumab was 5.3 months, with 77%
(120/155) receiving at least 10 of 12 doses. Fatal adverse reactions within 30 days of
the last dose occurred in 12% (19/158) of patients treated with COPIKTRA and in 4%
(7/155) of patients treated with ofatumumab. Serious adverse reactions were
reported in 73% (115/158) of patients treated with COPIKTRA and most often
involved infection (38% of patients; 60/158) and diarrhea or colitis (23% of patients;
36/158). COPIKTRA was discontinued in 57 patients (36%), most often due to
diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 46 patients
(29%) due to adverse reactions, most often due to diarrhea or colitis and rash.
Common Adverse Reactions
Table 3 summarizes selected adverse reactions in Study 1, and Table 4 summarizes
treatment-emergent laboratory abnormalities. The most common adverse reactions
with COPIKTRA (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia,
pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia
and cough.
Table 3. Common Nonhematologic Adverse Reactions (≥ 10% Incidence) in
Patients with CLL/SLL Receiving COPIKTRA (Study 1)
COPIKTRA
N = 158
Adverse Reactions
Gastrointestinal disorders
Diarrhea or colitis †a
Nausea †
Constipation
Abdominal pain
Vomiting
General disorders and
administration site
conditions
Pyrexia
Fatigue †
Ofatumumab
N = 155
Any
Grade
(%) Grade
≥ 3
(%) Any
Grade
(%) Grade
≥ 3
(%)
57
23
17
16
15 25
0
<1
3
0 14
11
8
7
7 2
0
0
0
0
29
25 3
4 10
23 <1
4
Hepatobiliary disorders
Transaminase
elevation †d 11 6 4 <1
Infections and infestations
Upper respiratory tract
infection †
Pneumonia †b
Lower respiratory tract
infection † 28
27 0
22 16
8 <1
3
18 4 10 1
Investigations
Weight decreased 11 0 2 0
Metabolism and nutrition
disorders
Decreased appetite
Edema † 13
11 0
1 3
5 <1
0
COPIKTRA
N = 158
Adverse Reactions
Ofatumumab
N = 155
Any
Grade
(%) Grade
≥ 3
(%) Any
Grade
(%) Grade
≥ 3
(%)
Musculoskeletal and
connective tissue
disorders
Musculoskeletal pain † 17 1 12 <1
Respiratory, thoracic and
mediastinal disorders
Cough †
Dyspnea 23
12 1
3 16
7 0
0
Skin and subcutaneous
tissue disorders
Rash †c 27 11 15 <1
Grades were obtained per CTCAE version 4.03.
†
Grouped term for reactions with multiple preferred terms
a
Diarrhea or colitis includes the preferred terms: colitis, enterocolitis, colitis microscopic, colitis ulcerative,
diarrhea
b
Pneumonia includes the preferred terms: All preferred term containing “pneumonia” except for “pneumonia
aspiration”; bronchopneumonia, bronchopulmonary aspergillosis
c
Rash includes the preferred terms: dermatitis (including allergic, exfoliative, perivascular), erythema (including
multiforme), rash (including exfoliative, erythematous, follicular, generalized, macular & papular, pruritic,
pustular), toxic skin eruption, drug eruption
d
Transaminase elevation includes the preferred terms: alanine aminotransferase increased, aspartate
aminotransferase increased, transaminases increased, hepatotoxicity
Table 4. Most Common New or Worsening Laboratory Abnormalities (≥ 20%
Any Grade) in Patients with CLL/SLL Receiving COPIKTRA (Study 1)
COPIKTRA
N = 158
Laboratory Parameter
Ofatumumab
N = 155
Any
Grade
(%) Grade
≥ 3
(%) Any
Grade
(%) Grade
≥ 3
(%)
Hematology abnormalities
Neutropenia
Anemia
Thrombocytopenia
Lymphocytosis 67
55
43
30 49
20
16
22 52
36
34
11 37
7
8
6
Chemistry abnormalities
ALT increased
Lipase increased
AST increased
Phosphate decreased
Hyperkalemia
Hyponatremia
Amylase increased
Hypoalbuminemia
Creatinine increased
Alkaline phosphatase increased
Hypocalcemia
Hypokalemia 42
37
36
34
31
31
31
31
29
27
25
20 7
12
3
3
4
7
5
2
1
0
1
8 12
15
14
20
24
18
10
15
31
14
17
8 0
3
1
3
1
3
1
1
0
0
1
0
Grades were obtained per CTCAE version 4.03.
Grade 4 laboratory abnormalities that developed in ≥ 2% of COPIKTRA treated
patients included neutropenia (32%), thrombocytopenia (6%), lymphopenia (3%),
and hypokalemia (2%).
The data above are not an adequate basis for comparison of rates between the study
drug and the active control.
Summary of Clinical Trial Experience in FL
The data described below reflect the exposure to COPIKTRA 25 mg BID in 96 patients
with relapsed or refractory FL. These patients were included in the 442-patient
safety analysis presented above. The median duration of treatment was 24 weeks,
with 46% of patients exposed for ≥ 6 months and 19% exposed for ≥ 1 year. The
median age was 64 years (range: 30 to 82 years), and 93% had an ECOG performance
status of 0 to 1. Patients had a median of 3 prior systemic therapies. Serious adverse
reactions were reported in 58% and most often involved diarrhea or colitis,
pneumonia, renal insufficiency, and sepsis. The most common adverse reactions
(≥ 20% of patients) were diarrhea or colitis, nausea, fatigue, musculoskeletal pain,
rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain,
vomiting, transaminase elevation, and thrombocytopenia. Adverse reactions
resulted in COPIKTRA discontinuation in 29% of patients, most often due to diarrhea
or colitis and rash. COPIKTRA was dose reduced in 23% due to adverse reactions, most
often due to transaminase elevation, diarrhea or colitis, lipase increased and infection.