CALQUENCE SIDE EFFECTS
- Generic Name: acalabrutinib capsules
- Brand Name: Calquence
- Drug Class: Antineoplastic Tyrosine Kinase Inhibitors
SIDE EFFECTS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
- Serious and Opportunistic Infections
- Hemorrhage
- Cytopenias
- Second Primary Malignancies
- Atrial Fibrillation and Flutter
Clinical Trials Experience
As clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data in the Warnings and Precautions reflect exposure to CALQUENCE 100 mg approximately every 12 hours in 1029 patients with hematologic malignancies. Treatment includes CALQUENCE monotherapy in 820 patients in 6 trials, and CALQUENCE with obinutuzumab in 209 patients in 2 trials. Among these recipients of CALQUENCE, 88% were exposed for at least 6 months and 79% were exposed for at least one year. In this pooled safety population, adverse reactions in ≥ 30% of 1029 patients were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain.
Mantle Cell Lymphoma
The safety data described in this section reflect exposure to CALQUENCE (100 mg approximately every 12 hours) in 124 patients with previously treated MCL in Trial LY-004. The median duration of treatment with CALQUENCE was 16.6 (range: 0.1 to 26.6) months. A total of 91 (73.4%) patients were treated with CALQUENCE for ≥ 6 months and 74 (59.7%) patients were treated for ≥ 1 year.
The most common adverse reactions (≥ 20%) of any grade were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising. Grade 1 severity for the non-hematologic, most common events were as follows: headache (25%), diarrhea (16%), fatigue (20%), myalgia (15%), and bruising (19%). The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea.
Dose reductions and discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.
Tables 3 and 4 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE.
Table 3: Non-Hematologic Adverse Reactions in ≥ 5% (All Grades) of Patients with MCL in Trial LY-004
Body System Adverse Reactions* |
CALQUENCE Monotherapy N=124 |
|
All Grades (%) | Grade ≥ 3 (%) | |
Nervous system disorders | ||
Headache | 39 | 1.6 |
Gastrointestinal disorders | ||
Diarrhea | 31 | 3.2 |
Nausea | 19 | 0.8 |
Abdominal pain | 15 | 1.6 |
Constipation | 15 | – |
Vomiting | 13 | 1.6 |
General disorders | ||
Fatigue | 28 | 0.8 |
Musculoskeletal and connective tissue disorders | ||
Myalgia | 21 | 0.8 |
Skin and subcutaneous tissue disorders | ||
Bruisinga | 21 | – |
Rashb | 18 | 0.8 |
Vascular disorders | ||
Hemorrhagec | 8 | 0.8 |
Respiratory, thoracic and mediastinal disorders | ||
Epistaxis | 6 | – |
* Per NCI CTCAE version 4.03. a Bruising: Includes all terms containing ‘bruise,’ ‘contusion,’ ‘petechiae,’ or ‘ecchymosis’ b Rash: Includes all terms containing ‘rash’ c Hemorrhage: Includes all terms containing ‘hemorrhage’ or ‘hematoma’ |
Table 4: Hematologic Adverse Reactions Reported in ≥ 20% of Patients with MCL in Trial LY-004
Hematologic Adverse Reactions* | CALQUENCE Monotherapy N=124 |
|
All Grades (%) | Grade ≥ 3 (%) | |
Hemoglobin decreased | 46 | 10 |
Platelets decreased | 44 | 12 |
Neutrophils decreased | 36 | 15 |
* Per NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions. |
Increases in creatinine to 1.5 to 3 times the upper limit of normal (ULN) occurred in 4.8% of patients.
Chronic Lymphocytic Leukemia
The safety data described below reflect exposure to CALQUENCE (100 mg approximately every 12 hours, with or without obinutuzumab) in 511 patients with CLL from two randomized controlled clinical trials].
The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea.
ELEVATE-TN
The safety of CALQUENCE plus obinutuzumab (CALQUENCE+G), CALQUENCE monotherapy, and obinutuzumab plus chlorambucil (GClb) was evaluated in a randomized, multicenter, open-label, actively controlled trial in 526 patients with previously untreated CLL.
Patients randomized to the CALQUENCE+G arm were treated with CALQUENCE and obinutuzumab in combination for six cycles, then with CALQUENCE as monotherapy until disease progression or unacceptable toxicity. Patients initiated obinutuzumab on Day 1 of Cycle 2, continuing for a total of 6 cycles. Patient randomized to CALQUENCE monotherapy received CALQUENCE approximately every 12 hours until disease progression or unacceptable toxicity. The trial required age ≥ 65 years of age or 18 to < 65 years of age with a total Cumulative Illness Rating Scale (CIRS) > 6 or creatinine clearance of 30 to 69 mL/min, hepatic transaminases ≤ 3 times ULN and total bilirubin ≤1.5 times ULN, and allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists.
During randomized treatment, the median duration of exposure to CALQUENCE in the CALQUENCE+G and CALQUENCE monotherapy arms was 27.7 months (range 0.3 to 40 months), with 95% and 92% and 89% and 86% of patients with at least 6 months and 12 months of exposure, respectively. In the obinutuzumab and chlorambucil arm, the median number of cycles was 6 with 84% of patients receiving at least 6 cycles of obinutuzumab, 70% of patients received at least 6 cycles of chlorambucil. Eighty-five percent of patients in the CALQUENCE+G arm received at least 6 cycles of obinutuzumab.
In the CALQUENCE+G and CALQUENCE monotherapy arms, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE+G arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (2.8% to 7%).
In the CALQUENCE+G arm, adverse reactions led to treatment discontinuation in 11% of patients and a dose reduction of CALQUENCE in 7% of patients. In the CALQUENCE monotherapy arm, adverse reactions led to discontinuation in 10% and dose reduction in 4% of patients.
Tables 5 and 6 present adverse reactions and laboratory abnormalities identified in the ELEVATE-TN trial.
Table 5: Common Adverse Reactions (≥ 15% Any Grade) with CALQUENCE in Patients with CLL (ELEVATE-TN)
Body System Adverse Reaction* |
CALQUENCE plus Obinutuzumab N=178 |
CALQUENCE Monotherapy N=179 |
Obinutuzumab plus Chlorambucil N=169 |
|||
All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
Infections | ||||||
Infection† | 69 | 22* | 65 | 14* | 46 | 13* |
Upper respiratory tract infection§ | 39 | 2.8 | 35 | 0 | 17 | 1.2 |
Lower respiratory tract infectiona | 24 | 8 | 18 | 4.5 | 7 | 1.8 |
Urinary tract infection | 15 | 1.7 | 15 | 2.8 | 5 | 0.6 |
Blood and lymphatic system disordersb | ||||||
Neutropeniac | 53 | 37 | 23 | 13 | 78 | 50 |
Anemiad | 52 | 12 | 53 | 10 | 54 | 14 |
Thrombocytopeniae | 51 | 12 | 32 | 3.4 | 61 | 16 |
Lymphocytosisf | 12 | 11 | 16 | 15 | 0.6 | 0.6 |
Nervous system disorders | ||||||
Headache | 40 | 1.1 | 39 | 1.1 | 12 | 0 |
Dizziness | 20 | 0 | 12 | 0 | 7 | 0 |
Gastrointestinal disorders | ||||||
Diarrhea | 39 | 4.5 | 35 | 0.6 | 21 | 1.8 |
Nausea | 20 | 0 | 22 | 0 | 31 | 0 |
Musculoskeletal and connective tissue disorders | ||||||
Musculoskeletal paingg | 37 | 2.2 | 32 | 1.1 | 16 | 2.4 |
Arthralgia | 22 | 1.1 | 16 | 0.6 | 4.7 | 1.2 |
General disorders and administration site conditions | ||||||
Fatigueh | 34 | 2.2 | 23 | 1.1 | 24 | 1.2 |
Skin and subcutaneous tissue disorders | ||||||
Bruisingi | 31 | 0 | 21 | 0 | 5 | 0 |
Rashj | 26 | 2.2 | 25 | 0.6 | 9 | 0.6 |
Vascular disorders | ||||||
Hemorrhagek | 20 | 1.7 | 20 | 1.7 | 6 | 0 |
* Per NCI CTCAE version 4.03 † Includes any adverse reactions involving infection or febrile neutropenia ‡ Includes 3 fatal cases in the CALQUENCE plus obinutuzumab arm, 3 fatal cases in the CALQUENCE monotherapy arm and 1 fatal case in the obinutuzumab plus chlorambucil arm § Includes upper respiratory tract infection, nasopharyngitis and sinusitis a Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection b Derived from adverse reaction and laboratory data c Includes neutropenia, neutrophil count decreased, and related laboratory data d Includes anemia, red blood cell count 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 back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain h Includes asthenia, fatigue, and lethargy i Includes bruise, contusion, and ecchymosis j Includes rash, dermatitis, and other related terms k Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis |
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 |
CALQUENCE Monotherapy N=179 |
Obinutuzumab plus Chlorambucil N=169 |
|||
All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | 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 aExcludes electrolytes |
Increases in creatinine to 1.5 to 3 times ULN 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]. The trial enrolled patients with relapsed or refractory CLL after at least one prior therapy and required hepatic transaminases ≤ 2 times 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)
Body System Adverse Reaction* |
CALQUENCE N=154 |
Idelalisib plus Rituximab Product N=118 |
Bendamustine plus Rituximab Product N=35 |
|||
All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
Infections | ||||||
Infection† | 56 | 15* | 65 | 28* | 49 | 11 |
Upper respiratory tract infection§ | 29 | 1.9 | 26 | 3.4 | 17 | 2.9 |
Lower respiratory tract infectiona | 23 | 6 | 26 | 15 | 14 | 6 |
Blood and lymphatic system disordersb | ||||||
Neutropeniac | 48 | 23 | 79 | 53 | 80 | 40 |
Anemiad | 47 | 15 | 45 | 8 | 57 | 17 |
Thrombocytopeniae | 33 | 6 | 41 | 13 | 54 | 6 |
Lymphocytosisf | 26 | 19 | 23 | 18 | 2.9 | 2.9 |
Nervous system disorders | ||||||
Headache | 22 | 0.6 | 6 | 0 | 0 | 0 |
Gastrointestinal disorders | ||||||
Diarrheag | 18 | 1.3 | 49 | 25 | 14 | 0 |
Vascular disorders | ||||||
Hemorrhageh | 16 | 1.3 | 5 | 1.7 | 6 | 2.9 |
General disorders | ||||||
Fatiguei | 15 | 1.9 | 13 | 0.8 | 31 | 6 |
Musculoskeletal and connective tissue disorders | ||||||
Musculoskeletal painj | 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 § Includes upper respiratory tract infection, rhinitis and nasopharyngitis a Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection b Derived from adverse reaction and laboratory data 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 |
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%)
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 |
Idelalisib plus Rituximab Product N=118 |
Bendamustine plus Rituximab Product N=35 |
|||
All Grades (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | 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.
SRC: NLM .