ASH_6.9_full issue | Page 35

CALQUENCE ® (acalabrutinib) capsules, for oral use
2
Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE (CALQUENCE in
combination with obinutuzumab and monotherapy) included:
• Neoplasms: second primary malignancy (10%), non-melanoma skin cancer (5%)
• Cardiac disorders: atrial fibrillation or flutter (3.6%), hypertension (5%)
• Infection: herpesvirus infection (6%)
Table 6: Select Non-Hematologic Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline
in Patients Receiving CALQUENCE (ELEVATE-TN)
Laboratory
Abnormality* ,a
CALQUENCE plus
Obinutuzumab
N=178
All
Grades (%)
Grade ≥ 3
(%)
CALQUENCE
Monotherapy
N=179
All
Grades (%)
Grade ≥ 3
(%)
Obinutuzumab plus
Chlorambucil
N=169
All
Grades (%)
Grade ≥ 3
(%)
Uric acid increase 29 29 22 22 37 37
ALT increase 30 7 20 1.1 36 6
AST increase 38 5 17 0.6 60 8
Bilirubin increase 13 0.6 15 0.6 11 0.6
*Per NCI CTCAE version 4.03
a
Excludes electrolytes
Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 3.9% and 2.8% of patients in the
CALQUENCE combination arm and monotherapy arm, respectively.
ASCEND
The safety of CALQUENCE in patients with relapsed or refractory CLL was evaluated in a randomized, open-label study
(ASCEND) [see Clinical Studies (14.2) in the full Prescribing Information]. The trial enrolled patients with relapsed
or refractory CLL after at least one prior therapy and required hepatic transaminases ≤ 2 times upper limit of normal
(ULN), total bilirubin ≤ 1.5 times ULN, and an estimated creatinine clearance ≥ 30 mL/min. The trial excluded patients
having an absolute neutrophil count < 500/μL, platelet count < 30,000/μL, prothrombin time or activated partial
thromboplastin time > 2 times ULN, significant cardiovascular disease, or a requirement for strong CYP3A inhibitors or
inducers. Patients were allowed to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonist.
In ASCEND, 154 patients received CALQUENCE (100 mg approximately every 12 hours until disease progression or
unacceptable toxicity), 118 received idelalisib (150 mg approximately every 12 hours until disease progression or
unacceptable toxicity) with up to 8 infusions of a rituximab product, and 35 received up to 6 cycles of bendamustine
and a rituximab product. The median age overall was 68 years (range: 32-90); 67% were male; 92% were white; and
88% had an ECOG performance status of 0 or 1.
In the CALQUENCE arm, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5%
of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within
30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies
and infection.
In recipients of CALQUENCE, permanent discontinuation due to an adverse reaction occurred in 10% of patients, most
frequently due to second primary malignancies followed by infection. Adverse reactions led to dosage interruptions
of CALQUENCE in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and dose
reduction in 3.9% of patients.
Selected adverse reactions are described in Table 7 and non-hematologic laboratory abnormalities are described in
Table 8. These tables reflect exposure to CALQUENCE with median duration of 15.7 months with 94% of patients on
treatment for greater than 6 months and 86% of patients on treatment for greater than 12 months. The median duration
of exposure to idelalisib was 11.5 months with 72% of patients on treatment for greater than 6 months and 48% of
patients on treatment for greater than 12 months. Eighty-three percent of patients completed 6 cycles of bendamustine
and rituximab product.
Table 7: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ASCEND)
Infections
Body System
Adverse Reaction*
CALQUENCE
N=154
All Grades
(%)
Grade ≥ 3
(%)
Idelalisib plus
Rituximab Product
N=118
All Grades
(%)
Grade ≥ 3
(%)
Bendamustine plus
Rituximab Product
N=35
All Grades
(%)
Grade ≥ 3
(%)
Infection † 56 15 ‡ 65 28 ‡ 49 11
Upper respiratory tract infection a 29 1.9 26 3.4 17 2.9
Lower respiratory tract infection b 23 6 26 15 14 6
Blood and lymphatic system disorders §
Neutropenia c 48 23 79 53 80 40
Anemia d 47 15 45 8 57 17
Thrombocytopenia e 33 6 41 13 54 6
Lymphocytosis f 26 19 23 18 2.9 2.9
Nervous system disorders
Headache 22 0.6 6 0 0 0
Gastrointestinal disorders
Diarrhea g 18 1.3 49 25 14 0
Vascular disorders
Hemorrhage h 16 1.3 5 1.7 6 2.9
General disorders
Fatigue i 15 1.9 13 0.8 31 6
Musculoskeletal and connective tissue disorders
Musculoskeletal pain j 15 1.3 15 1.7 2.9 0
*Per NCI CTCAE version 4.03
†
Includes any adverse reactions involving infection or febrile neutropenia
‡
Includes 1 fatal case in the CALQUENCE monotherapy arm and 1 fatal case in the Idelalisib plus Rituximab arm
§
Derived from adverse reaction and laboratory data
a
Upper respiratory tract infection, rhinitis and nasopharyngitis
b
Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection.
c
Includes neutropenia, neutrophil count decreased, and related laboratory data
d
Includes anemia, red blood cell decreased, and related laboratory data
e
Includes thrombocytopenia, platelet count decreased, and related laboratory data
f
Includes lymphocytosis, lymphocyte count increased and related laboratory data
g
Includes colitis, diarrhea, and enterocolitis
h
Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis
i
Includes asthenia, fatigue, and lethargy
j
Includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal
pain and bone pain
Table 8: Select Non-Hematologic Laboratory Abnormalities (≥ 10% Any Grade), New or Worsening from Baseline
in Patients Receiving CALQUENCE (ASCEND)
Laboratory
Abnormality a
CALQUENCE
N=154
All
Grades (%)
Grade
≥ 3 (%)
Idelalisib plus
Rituximab Product
N=118
All
Grades (%)
Grade
≥ 3 (%)
Bendamustine plus
Rituximab Product
N=35
All
Grades (%)
Grade
≥ 3 (%)
Uric acid increase 15 15 11 11 23 23
ALT increase 15 1.9 59 23 26 2.9
AST increase 13 0.6 48 13 31 2.9
Bilirubin increase 13 1.3 16 1.7 26 11
Per NCI CTCAE version 5
a
Excludes electrolytes
Increases in creatinine to 1.5 to 3 times ULN occurred in 1.3% of patients who received CALQUENCE.
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant
woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction
studies, administration of acalabrutinib to animals during organogenesis resulted in dystocia in rats and reduced fetal
growth in rabbits at maternal exposures (AUC) 2 times exposures in patients at the recommended dose of 100 mg
approximately every 12 hours (see Data). Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All
pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population,
the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and
15-20%, respectively.
Data
Animal Data
In a combined fertility and embryo-fetal development study in female rats, acalabrutinib was administered orally
at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No effects on
embryo-fetal development and survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately
9-times the AUC in patients at the recommended dose of 100 mg approximately every 12 hours. The presence of
acalabrutinib and its active metabolite were confirmed in fetal rat plasma.
In an embryo-fetal development study in rabbits, pregnant animals were administered acalabrutinib orally at doses
up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Administration of acalabrutinib at doses
≥ 100 mg/kg/day produced maternal toxicity and 100 mg/kg/day resulted in decreased fetal body weights and delayed
skeletal ossification. The AUC at 100 mg/kg/day in pregnant rabbits was approximately 2-times the AUC in patients at
100 mg approximately every 12 hours.
In a pre- and postnatal development study in rats, acalabrutinib was administered orally to pregnant animals during
organogenesis, parturition and lactation, at doses of 50, 100, and 150 mg/kg/day. Dystocia (prolonged or difficult
labor) and mortality of offspring were observed at doses ≥ 100 mg/kg/day. The AUC at 100 mg/kg/day in pregnant rats
was approximately 2-times the AUC in patients at 100 mg approximately every 12 hours. Underdeveloped renal papilla
was also observed in F1 generation offspring at 150 mg/kg/day with an AUC approximately 5-times the AUC in patients
at 100 mg approximately every 12 hours.
Lactation
Risk Summary
No data are available regarding the presence of acalabrutinib or its active metabolite in human milk, its effects on the
breastfed child, or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating
rats. Due to the potential for adverse reactions in a breastfed child from CALQUENCE, advise lactating women not to
breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.
Females and Males of Reproductive Potential
Pregnancy
Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy.
Contraception
Females
CALQUENCE may cause embryo-fetal harm and dystocia when administered to pregnant women [see Use in Specific
Populations (8.1) in the full Prescribing Information]. Advise female patients of reproductive potential to use effective
contraception during treatment with CALQUENCE and for at least 1 week following the last dose of CALQUENCE. If
this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
informed of the potential hazard to a fetus.
Pediatric Use
The safety and efficacy of CALQUENCE in pediatric patients have not been established.
Geriatric Use
Of the 929 patients with CLL or MCL in clinical trials of CALQUENCE, 68% were 65 years of age or older, and 24%
were 75 years of age or older. Among patients 65 years of age or older, 59% had Grade 3 or higher adverse reactions
and 39% had serious adverse reactions. Among patients younger than age 65, 45% had Grade 3 or higher adverse
reactions and 25% had serious adverse reactions. No clinically relevant differences in efficacy were observed between
patients ≥ 65 years and younger.
Hepatic Impairment
Avoid administration of CALQUENCE in patients with severe hepatic impairment. The safety of CALQUENCE has
not been evaluated in patients with moderate or severe hepatic impairment [see Recommended Dosage for Hepatic
Impairment (2.2) and Clinical Pharmacology (12.3) in the full Prescribing Information].
Distributed by:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
CALQUENCE is a registered trademark of the AstraZeneca group of companies.
©AstraZeneca 2019
11/19 US-34118 12/19
Other clinically relevant adverse reactions (all grades incidence < 15%) in recipients of CALQUENCE included:
• Skin and subcutaneous disorders: bruising (10%), rash (9%)
• Neoplasms: second primary malignancy (12%), non-melanoma skin cancer (6%)
• Musculoskeletal and connective tissue disorders: arthralgia (8%)
• Cardiac disorders: atrial fibrillation or flutter (5%), hypertension (3.2%)
• Infection: herpesvirus infection (4.5%)