FEATURE
Dr. Stock agreed that the key to
improved outcomes among AYA patients
treated at pediatric centers is practitioners’
experience level. “A number of studies
have now demonstrated better outcomes
with pediatric protocols delivered at pedi-
atric centers,” she said. “That’s partly be-
cause pediatricians are treating pediatric
patients in one specific way, while adult
patients at adult centers are treated with a
wider variety of protocols.”
With Age Comes Wisdom
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.
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)
Grade ≥ 3
n (%)
Any Grade
n (%)
†
Table 1 Common Adverse Reactions (≥ 10% Incidence) in Patients with
B-cell Malignancies Receiving COPIKTRA
Any Grade
n (%)
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.
Adverse Reactions
analyses have translated to the clinic.
For instance, two-thirds of AYAs in
their study received treatment at adult
settings, “despite this being the most com-
mon pediatric cancer and a very, very rare
cancer in adults,” Dr. Muffly said.
Also, just one-quarter of these patients
were receiving pediatric-directed regimens
at adult centers, though the treatment land-
scape may have changed since 2014, when
data collection ended. “Our data don’t
While Dr. Muffly’s study relied on
population-level data to give researchers
a glimpse of real-world practice outside
of the realm of clinical trials, she noted
that the inclusion of registry data meant
that the authors were unable to account
for a number of variables that may have
affected patients during their treatment.
It is difficult to determine whether the ideas
supported by clinical trials and retrospective
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%).
necessarily mean that this will hold true for
2019 and beyond, but it shows us where we
may need more answers and guidance.”
Does that mean adult centers should
embrace pediatric protocols? Perhaps,
according to Dr. Muffly, but adult centers
may be reticent to head in that direction.
It may make more sense for pediatric
centers to take on older patients.
“There’s a big learning curve to under-
standing how to use pediatric regimens