CLINICAL NEWS
Pre-emptive Rituximab Prevents Long-Term Relapses in Immune-
Mediated TTP
Patients with immune-mediated thrombotic
thrombocytopenic purpura (iTTP) who have
persistent, severe ADAMTS13 deficiency have
a high likelihood of relapse, but pre-emptive
treatment with rituximab reduced the long-
term relapse risk by maintaining normal
ADAMTS13 activity, according to research
published in Blood, led by Mathieu Jestin,
MD, from the Hôpital Saint-Antoine in Paris,
reported.
“We established that the number of patients
needed to treat to prevent a clinical relapse
is only two, suggesting that our pre-emptive
strategy using this B-cell depleting therapy is
5.7 Embryo-Fetal Toxicity
Based on findings in animals and its mechanism of action, COPIKTRA can cause fetal
harm when administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential and males with
female partners of reproductive potential to use effective contraception during
treatment and for at least 1 month after the last dose [see Use in Specific Populations
(8.1, 8.3), Clinical Pharmacology (12.1, 12.3)].
Summary of Clinical Trial Experience in B-cell Malignancies
The data described below reflect exposure to COPIKTRA in two single-arm, open-
label clinical trials, one open-label extension clinical trial, and one randomized,
open-label, actively controlled clinical trial totaling 442 patients with previously
treated hematologic malignancies primarily including CLL/SLL (69%) and FL (22%).
Patients were treated with COPIKTRA 25mg BID until unacceptable toxicity or
progressive disease. The median duration of exposure was 9 months (range 0.1 to 53
months), with 36% (160/442) of patients having at least 12 months of exposure. For
the 442 patients, the median age was 67 years (range 30 to 90 years), 65% were
male, 92% were White, and 93% had an Eastern Cooperative Oncology Group
(ECOG) performance status of 0 to 1. Patients had a median of 2 prior therapies. The
trials required hepatic transaminases at least ≤ 3 times upper limit of normal (ULN),
total bilirubin ≤1.5 times ULN, and serum creatinine ≤ 1.5 times ULN. Patients were
excluded for prior exposure to a PI3K inhibitor within 4 weeks. Fatal adverse
reactions within 30 days of the last dose occurred in 36 patients (8%) treated with
COPIKTRA 25mg BID. Serious adverse reactions were reported in 289 (65%) patients.
The most frequent serious adverse reactions that occurred were infection (31%),
diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%).
Adverse reactions resulted in treatment discontinuation in 156 patients (35%), most
often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in
104 patients (24%) due to adverse reactions, most often due to diarrhea or colitis
and transaminase elevation. The median time to first dose modification or
discontinuation was 4 months (range 0.1 to 27 months), with 75% of patients having
their first dose modification or discontinuation within 7 months.
Common Adverse Reactions
Table 1 summarizes common adverse reactions in patients receiving COPIKTRA
25mg BID, and Table 2 summarizes the treatment-emergent laboratory abnormalities.
The most common adverse reactions (reported in ≥ 20% of patients) were diarrhea
or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory
infection, pneumonia, musculoskeletal pain, and anemia.
Grade ≥ 3
n (%)
Blood and lymphatic
system disorders
Neutropenia †
Anemia †
Thrombocytopenia † 151 (34)
90 (20)
74 (17) 132 (30)
48 (11)
46 (10)
Gastrointestinal disorders
Diarrhea or colitis †a
Nausea †
Abdominal pain
Vomiting
Mucositis
Constipation 222 (50)
104 (24)
78 (18)
69 (16)
61 (14)
57 (13) 101 (23)
4 (< 1)
9 (2)
6 (1)
6 (1)
1 (< 1)
General disorders and
administration site conditions
Fatigue †
Pyrexia 126 (29)
115 (26) 22 (5)
7 (2)
Hepatobiliary disorders
Transaminase elevation †b 67 (15) 34 (8)
Grade ≥ 3
n (%)
Infections and infestations
Upper respiratory tract infection †
Pneumonia †c
Lower respiratory tract infection † 94 (21)
91 (21)
46 (10) 2 (< 1)
67 (15)
11 (3)
Metabolism and nutrition
disorders
Decreased appetite
Edema †
Hypokalemia † 63 (14)
60 (14)
45 (10) 2 (< 1)
6 (1)
17 (4)
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain †
Arthralgia 90 (20)
46 (10) 6 (1)
1 (< 1)
Nervous system disorders
Headache † 55 (12) 1 (< 1)
Respiratory, thoracic and
mediastinal disorders
Cough †
Dyspnea † 111 (25)
52 (12) 2 (< 1)
8 (2)
Skin and subcutaneous
tissue disorders
Rash †d 136 (31) 41 (9)
Grouped term for reactions with multiple preferred terms
a
Diarrhea or colitis includes the preferred terms: colitis, enterocolitis, colitis microscopic, colitis ulcerative,
diarrhea, diarrhea hemorrhagic
b
Transaminase elevation includes the preferred terms: alanine aminotransferase increased, aspartate
aminotransferase increased, transaminases increased, hypertransaminasemia, hepatocellular injury,
hepatotoxicity
c
Pneumonia includes the preferred terms: All preferred terms containing “pneumonia” except for “pneumonia
aspiration”; bronchopneumonia, bronchopulmonary aspergillosis
d
Rash includes the preferred terms: dermatitis (including allergic, exfoliative, perivascular), erythema (including
multiforme), rash (including exfoliative, erythematous, follicular, generalized, macular & papular, pruritic,
pustular), toxic epidermal necrolysis and toxic skin eruption, drug reaction with eosinophilia and systemic
symptoms, drug eruption, Stevens-Johnson syndrome
Grade 4 adverse reactions occurring in ≥ 2% of recipients of COPIKTRA included
neutropenia (18%), thrombocytopenia (6%), sepsis (3%), hypokalemia and increased
lipase (2% each), and pneumonia and pneumonitis (2% each).
Table 2 Most Common New or Worsening Laboratory Abnormalities (≥ 20%
Any Grade) in Patients with B-cell Malignancies Receiving COPIKTRA
Laboratory Parameter
a
COPIKTRA 25 mg BID
(N = 442)
Any Grade
n (%) Any Grade
n (%)
†
Table 1 Common Adverse Reactions (≥ 10% Incidence) in Patients with
B-cell Malignancies Receiving COPIKTRA
Adverse Reactions
COPIKTRA 25 mg BID
(N = 442)
Adverse Reactions
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely variable conditions, adverse
reaction rates observed in clinical trials of a drug cannot be directly compared with
rates in clinical trials of another drug and may not reflect the rates observed in
practice.
an attractive strategy to prevent most clini-
cal relapses of iTTP,” study coauthor Paul
Coppo, MD, PhD, also from the Hôpital
Saint-Antoine, told ASH Clinical News. “This
treatment strategy should profoundly modify
the epidemiology of this disease.”
The study included 92 patients with iTTP
COPIKTRA 25 mg BID
(N = 442)
Any Grade
n (%) b Grade ≥ 3
n (%) b
Hematology abnormalities
Neutropenia
Anemia
Thrombocytopenia
Lymphocytosis
Leukopenia
Lymphopenia 276 (63)
198 (45)
170 (39)
132 (30)
129 (29)
90 (21) 184 (42)
66 (15)
65 (15)
92 (21)
34 (8)
39 (9)
Chemistry abnormalities
ALT increased
AST increased
Lipase increased
Hypophosphatemia
ALP increased
Serum amylase increased
Hyponatremia
Hyperkalemia
Hypoalbuminemia
Creatinine increased
Hypocalcemia 177 (40)
163 (37)
133 (36)
136 (31)
128 (29)
101 (28)
116 (27)
114 (26)
111 (25)
106 (24)
100 (23) 34 (8)
24 (6)
58 (16)
23 (5)
7 (2)
16 (4)
30 (7)
14 (3)
7 (2)
7 (2)
12 (3)
Includes laboratory abnormalities that are new or worsening in grade or with worsening from baseline
unknown.
Percentages are based on number of patients with at least one post-baseline assessment; not all patients
were evaluable.
a
b
Grade 4 laboratory abnormalities developing in ≥ 2% of patients included neutropenia
(24%), thrombocytopenia (7%), lipase increase (4%), lymphocytopenia (3%), and
leukopenia (2%).