ASH Clinical News ACN_4.14_Full Issue_web | Page 159

others in the U.S. and across Europe,
has compared survival outcomes in AYA
patients treated at either pediatric or adult
centers and “found pretty consistently that
the survival outcomes were about 15 to 20
percent better in pediatric institutions,”
Dr. Gupta reported. In a review of 15- to
21-year-old patients diagnosed with ALL
between 1992 and 2011, he and coauthors
found that five-year event-free survival
and overall survival was 72 percent and
82 percent for patients treated at pediatric
centers, but 56 percent and 64 percent for
those treated at adult centers (p=0.03 and
p<0.001 for comparisons). 9
This finding was replicated once again
in a 2018 study led by Lori Muffly, MD,
MS, from the Stanford University Depart-
ment of Medicine. The study examined
the patterns of care and outcomes in
IMPORTANT SAFETY INFORMATION (cont’d)
6 stools per day over baseline) or asymptomatic (Grade 1)
colitis, initiate supportive care with antidiarrheal agents,
continue COPIKTRA at the current dose, and monitor the
patient at least weekly until the event resolves. If the diarrhea is
unresponsive to antidiarrheal therapy, withhold COPIKTRA and
initiate supportive therapy with enteric acting steroids (e.g.,
budesonide). Monitor the patient at least weekly. Upon
resolution of the diarrhea, consider restarting COPIKTRA
at a reduced dose. For patients presenting with abdominal pain,
stool with mucus or blood, change in bowel habits, peritoneal
signs, or with severe diarrhea (Grade 3) (i.e., >6 stools per day
over baseline), withhold COPIKTRA and initiate supportive
therapy with enteric acting steroids (e.g., budesonide) or
systemic steroids. A diagnostic work-up to determine etiology,
including colonoscopy, should be performed. Monitor at least
weekly. Upon resolution of the diarrhea or colitis, restart
COPIKTRA at a reduced dose. For recurrent Grade 3 diarrhea or
recurrent colitis of any grade, discontinue COPIKTRA.
Discontinue COPIKTRA for life-threatening diarrhea or colitis.
Pneumonitis: Serious, including fatal (1/442; <1%),
pneumonitis without an apparent infectious cause occurred in
5% of patients receiving COPIKTRA 25 mg BID (N=442).
Median time to onset of any grade pneumonitis was 4 months
(range: 9 days to 27 months), with 75% of cases occurring
within 9 months. The median event duration was 1 month, with
75% of cases resolving by 2 months. Withhold COPIKTRA in
patients with new or progressive pulmonary signs and
symptoms such as cough, dyspnea, hypoxia, interstitial
infi ltrates on a radiologic exam, or a decline by more than 5% in
oxygen saturation, and evaluate for etiology. If the pneumonitis
is infectious, patients may be restarted on COPIKTRA at the
previous dose once the infection, pulmonary signs and
symptoms resolve. For moderate non-infectious pneumonitis
(Grade 2), treat with systemic corticosteroids and resume
COPIKTRA at a reduced dose upon resolution. If non-infectious
pneumonitis recurs or does not respond to steroid therapy,
discontinue COPIKTRA. For severe or life-threatening
non-infectious pneumonitis, discontinue COPIKTRA and
treat with systemic steroids.
Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation
developed in 8% and 2%, respectively, of patients receiving
COPIKTRA 25 mg BID (N=442). Two percent of patients had
both an ALT or AST > 3 X ULN and total bilirubin > 2 X ULN.
Median time to onset of any grade transaminase elevation was
2 months (range: 3 days to 26 months), with a median event
duration of 1 month (range: 1 day to 16 months). Monitor
hepatic function during treatment with COPIKTRA. For Grade 2
ALT/AST elevation (> 3 to 5 X ULN), maintain COPIKTRA dose
and monitor at least weekly until return to < 3 X ULN. For Grade
3 ALT/AST elevation (> 5 to 20 X ULN), withhold COPIKTRA
and monitor at least weekly until return to < 3 X ULN. Resume
COPIKTRA at the same dose (fi rst occurrence) or at a reduced
Copyright © 2018 Verastem, Inc.
All rights reserved.
PM-US-DUV-18-0074
survival (hazard ratio [HR] = 0.53; 95%
CI 0.37-0.76; p=0.001), as well as higher
leukemia-specific survival (HR=0.51; 95%
CI 0.35-0.74; p<0.001).
“This finding was so significant that
it suggests that perhaps the age limit for
treating this particular disease at pediatric
centers should be increased to at least 25,”
commented Dr. Muffly.
Treatment at a National Cancer Institute
dose for subsequent occurrences. For grade 4 ALT/AST
elevation (> 20 X ULN), discontinue COPIKTRA.
Neutropenia: Grade 3 or 4 neutropenia occurred in 42% of
patients receiving COPIKTRA 25 mg BID (N=442), with Grade
4 neutropenia occurring in 24% of all patients. Median time to
onset of grade ≥3 neutropenia was 2 months. Monitor
neutrophil counts at least every 2 weeks for the fi rst 2 months
of COPIKTRA therapy, and at least weekly in patients with
neutrophil counts < 1.0 Gi/L (Grade 3-4). Withhold COPIKTRA
in patients presenting with neutrophil counts < 0.5 Gi/L
(Grade 4). Monitor until ANC is > 0.5 Gi/L, then resume
COPIKTRA at same dose for the fi rst occurrence or at a
reduced dose for subsequent occurrences.
Embryo-Fetal Toxicity: Based on fi ndings 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. Conduct pregnancy testing
before initiating COPIKTRA treatment. 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.
ADVERSE REACTIONS
B-cell Malignancies Summary
Fatal adverse reactions within 30 days of the last dose occurred
in 8% (36/442) of patients treated with COPIKTRA 25 mg BID.
Serious adverse reactions were reported in 289 patients (65%).
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 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.
CLL/SLL
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%;
60/158) and diarrhea or colitis (23%; 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%), most often due to diarrhea or colitis and rash.
The most common adverse reactions with COPIKTRA (≥20%
of patients) were diarrhea or colitis, neutropenia, pyrexia, upper
respiratory tract infection, pneumonia, rash, fatigue, nausea,
anemia and cough.
DRUG INTERACTIONS
CYP3A Inducers: Coadministration with a strong CYP3A
inducer may reduce COPIKTRA effi cacy. Avoid coadministration
with strong CYP3A4 inducers.
CYP3A Inhibitors: Coadministration with a strong CYP3A
inhibitor may increase the risk of COPIKTRA toxicities. Reduce
COPIKTRA dose to 15 mg BID when coadministered with a
strong CYP3A4 inhibitor.
CYP3A Substrates: Coadministration of COPIKTRA with
sensitive CYP3A4 substrates may increase the risk of toxicities
of these drugs. Consider reducing the dose of the sensitive
CYP3A4 substrate and monitor for signs of toxicities of the
coadministered sensitive CYP3A substrate.
INDICATIONS AND USAGE
COPIKTRA™ (duvelisib) is indicated for: The treatment of adult
patients with relapsed or refractory CLL or SLL after at least
two prior therapies.
Please see brief summary of full Prescribing Information
on the following pages.
REFERENCES: 1. COPIKTRA Prescribing Information, Verastem, Inc. 2. Data on
fi le, Verastem Oncology.
Printed in USA | November 2018
Cutaneous Reactions: Serious, including fatal (2/442; <1%),
cutaneous reactions occurred in 5% of patients receiving
COPIKTRA 25 mg BID (N=442). Fatal cases included drug
reaction with eosinophilia and systemic symptoms (DRESS) and
toxic epidermal necrolysis (TEN). Median time to onset of any
grade cutaneous reaction was 3 months (range: 1 day to
29 months, 75 th percentile: 6 months) with a median event
duration of 1 month (range: 1 day to 37 months, 75 th percentile:
2 months). Presenting features for the serious events were
primarily described as pruritic, erythematous, or maculo-
papular. Less common presenting features include exanthem,
desquamation, erythroderma, skin exfoliation, keratinocyte
necrosis, and papular rash. Advise patients to report new or
worsening cutaneous reactions. Review all concomitant
medications and discontinue any medications potentially
contributing to the event. For patients presenting with mild or
moderate (Grade 1-2) cutaneous reactions, continue COPIKTRA
at the current dose, initiate supportive care with emollients,
antihistamines (for pruritus), or topical steroids, and monitor the
patient closely. Withhold COPIKTRA for severe (Grade 3)
cutaneous reaction until resolution. Initiate supportive care with
steroids (topical or systemic) or antihistamines (for pruritus).
Monitor at least weekly until resolved. Upon resolution of the
event, restart COPIKTRA at a reduced dose. Discontinue
COPIKTRA if severe cutaneous reaction does not improve,
worsens, or recurs. For life-threatening cutaneous reactions,
discontinue COPIKTRA. In patients with SJS, TEN, or DRESS
of any grade, discontinue COPIKTRA.
AYA patients newly diagnosed with ALL
between 2004 and 2014 identified from the
California Cancer Registry. 10 Even after
controlling for age and examining the data
in multiple analyses, researchers found
that those patients who were treated at
pediatric centers had significantly better
outcomes: Compared with those treated in
adult settings, patients treated in pediatric
settings had significantly higher overall