Adolescent and Young Adult Leukemia
(NCI)-designated center or Children’s
Oncology Group (COG) center also was
associated with higher overall survival,
compared with treatment at community
hospitals (HR=0.80; 95% CI 0.66-0.96;
p=0.019). However, both studies were ret-
rospective and may not have accounted for
all factors that influenced outcome.
“Physicians and treatment teams in pe-
diatric and NCI-designated cancer settings
may be more experienced in caring for
AYA patients with ALL,” Dr. Muffly said,
“and this in part may explain why we are
seeing better outcomes in these centers.”
This idea was supported by the fact
that, when adult centers used the pediatric
ALL regimen, there was no significant
difference in survival outcomes, compared
with adult centers that used the adult regi-
men. However, she noted that these data
were collected only from 2009 through
2014; due to the complex nature of the
pediatric regimen, adult centers who
used the pediatric protocol included in
the study may have still been adjusting to
the protocol.
The U.S. adult intergroup trial, C10403,
also examined survival outcomes among
AYA patients who received a pediatric-
inspired regimen in an adult setting. 11 Early
results from the trial presented at the 2014
ASH Annual Meeting, which included 296
patients, revealed that two-year event-free
COPIKTRA (duvelisib) Capsules, for oral use
BRIEF SUMMARY OF PRESCRIBING INFORMATION - CONSULT PACKAGE
INSERT FOR FULL PRESCRIBING INFORMATION
WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA
OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS
• Fatal and/or serious infections occurred in 31% of COPIKTRA-treated patients.
Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is
suspected [see Warnings and Precautions (5.1)].
• Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated
patients. Monitor for the development of severe diarrhea or colitis. Withhold
COPIKTRA [see Warnings and Precautions (5.2)].
• Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated
patients. Withhold COPIKTRA [see Warnings and Precautions (5.3)].
• Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients.
Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA
[see Warnings and Precautions (5.4)].
1. INDICATIONS AND USAGE
1.1 Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory
CLL or SLL after at least two prior therapies.
1.2 Follicular Lymphoma (FL)
COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory
FL after at least two prior systemic therapies. This indication is approved under
accelerated approval based on overall response rate (ORR) [see Clinical Studies
(14.2)]; continued approval for this indication may be contingent upon verification
and description of clinical benefit in confirmatory trials.
3 DOSAGE FORMS AND STRENGTHS
Strength Description
25 mg White to off-white opaque and Swedish orange opaque
capsule printed in black ink with “duv 25 mg”
15 mg
Pink opaque capsule printed in black ink with “duv 15 mg”
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Infections
Serious, including fatal (18/442; 4%), infections occurred in 31% of patients
receiving COPIKTRA 25 mg BID (N = 442). The most common serious infections were
pneumonia, sepsis, and lower respiratory infections. Median time to onset of any
grade infection was 3 months (range: 1 day to 32 months), with 75% of cases
occurring within 6 months. Treat infections prior to initiation of COPIKTRA. Advise
patients to report any new or worsening signs and symptoms of infection. For grade
3 or higher infection, withhold COPIKTRA until infection has resolved. Resume
COPIKTRA at the same or reduced dose [see Dosage and Administration (2.3)].
Serious, including fatal, Pneumocystis jirovecii pneumonia (PJP) occurred in 1% of
patients taking COPIKTRA. Provide prophylaxis for PJP during treatment with
COPIKTRA. Following completion of COPIKTRA treatment, continue PJP prophylaxis
until the absolute CD4+ T cell count is greater than 200 cells/μL. Withhold COPIKTRA
in patients with suspected PJP of any grade, and permanently discontinue if PJP is
confirmed. CMV reactivation/ infection occurred in 1% of patients taking COPIKTRA.
Consider prophylactic antivirals during COPIKTRA treatment to prevent CMV
infection including CMV reactivation. For clinical CMV infection or viremia, withhold
COPIKTRA until infection or viremia resolves. If COPIKTRA is resumed, administer
the same or reduced dose and monitor patients for CMV reactivation by PCR or
antigen test at least monthly [see Dosage and Administration (2.3)].
5.2 Diarrhea or Colitis
Serious, including fatal (1/442; <1%), diarrhea or colitis occurred in 18% of patients
receiving COPIKTRA 25 mg BID (N = 442). The median time to onset of any grade
diarrhea or colitis was 4 months (range: 1 day to 33 months), with 75% of cases
occurring by 8 months. The median event duration was 0.5 months (range: 1 day to
29 months; 75 th percentile: 1 month). Advise patients to report any new or worsening
diarrhea. For non-infectious diarrhea or colitis, follow the guidelines. For patients
presenting with mild or moderate diarrhea (Grade 1-2) (i.e. up to 6 stools per day over
baseline) or asymptomatic (Grade 1) colitis, initiate supportive care with antidiarrheal
agents as appropriate, 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
and overall survival rates were 66 percent
and 78 percent, which compared favorably
with historic controls.
According to Dr. Advani, one of the
study’s coauthors, these numbers also
were comparable to AYA survival rates
when patients were treated at pediatric
centers. “At least on the C10403 trial,
outcomes looked equally good if AYA
patients were treated at either adult or
pediatric centers,” she said.
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 [see
Dosage and Administration (2.3)].
5.3 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 any 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,
anti-histamines (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 anti-histamines (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 [see Dosage and Administration (2.3)].
5.4 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
who present with new or progressive pulmonary signs and symptoms such as cough,
dyspnea, hypoxia, interstitial infiltrates 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
[see Dosage and Administration (2.3)].
5.5 Hepatotoxicity
Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, in
patients receiving COPIKTRA 25 mg BID (N=442). Two percent of patients had both
an ALT or AST greater than 3 x ULN and total bilirubin greater than 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 (greater than 3 to 5 × ULN), maintain COPIKTRA dose and monitor at least
weekly until return to less than 3 × ULN. For Grade 3 ALT/AST elevation (greater than
5 to 20 × ULN), withhold COPIKTRA and monitor at least weekly until return to less
than 3 × ULN. Resume COPIKTRA at the same dose (first occurrence) or at a reduced
dose for subsequent occurrence. For grade 4 ALT/AST elevation (greater than 20 ×
ULN) discontinue COPIKTRA [see Dosage and Administration (2.3)].
5.6 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. The median
time to onset of Grade ≥ 3 neutropenia was 2 months (range: 3 days to 31 months),
with 75% of cases occurring within 4 months. Monitor neutrophil counts at least
every 2 weeks for the first 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, resume COPIKTRA at same dose for the first occurrence or a reduced dose
for subsequent occurrence [see Dosage and Administration (2.3)].