CALQUENCE: Package Insert and Label Information

CALQUENCE- acalabrutinib tablet, film coated
AstraZeneca Pharmaceuticals LP

1 INDICATIONS AND USAGE

1.1 Mantle Cell Lymphoma

CALQUENCE is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

1.2 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

CALQUENCE as Monotherapy

For patients with MCL, CLL, or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity.

CALQUENCE in Combination with Obinutuzumab

For patients with previously untreated CLL or SLL, the recommended dosage of CALQUENCE is 100 mg taken orally approximately every 12 hours until disease progression or unacceptable toxicity. Start CALQUENCE at Cycle 1 (each cycle is 28 days). Start obinutuzumab at Cycle 2 for a total of 6 cycles and refer to the obinutuzumab prescribing information for recommended dosing. Administer CALQUENCE prior to obinutuzumab when given on the same day.

Advise patients to swallow tablet whole with water. Advise patients not to chew, crush, dissolve, or cut the tablets. CALQUENCE may be taken with or without food. If a dose of CALQUENCE is missed by more than 3 hours, it should be skipped and the next dose should be taken at its regularly scheduled time. Extra tablets of CALQUENCE should not be taken to make up for a missed dose.

2.2 Recommended Dosage for Drug Interactions

Dosage Modifications for Use with CYP3A Inhibitors or Inducers

These are described in Table 1 [see Drug Interactions (7)].

Table 1: Recommended Dosage Modifications for Use with CYP3A Inhibitors or Inducers

CYP3A	Co-administered Drug	Recommended CALQUENCE use
Inhibition	Strong CYP3A inhibitor	Avoid co-administration. If these inhibitors will be used short-term (such as anti‑infectives for up to seven days), interrupt CALQUENCE. After discontinuation of strong CYP3A inhibitor for at least 24 hours, resume previous dosage of CALQUENCE.
	Moderate CYP3A inhibitor	Reduce the CALQUENCE 100 mg every 12 hours dosage to 100 mg once daily.
Induction	Strong CYP3A inducer	Avoid co-administration. If co-administration is unavoidable, increase CALQUENCE dosage to 200 mg approximately every 12 hours.

2.3 Dosage Modifications for Adverse Reactions

Recommended dosage modifications of CALQUENCE for Grade 3 or greater adverse reactions are provided in Table 2.

Table 2: Recommended Dosage Modifications for Adverse Reactions

Event	Adverse Reaction Occurrence	Dosage Modification (Starting dose = 100 mg approximately every 12 hours)
Grade 3 or greater non-hematologic toxicities, Grade 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia or Grade 4 neutropenia lasting longer than 7 days	First and Second	Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at 100 mg approximately every 12 hours.
	Third	Interrupt CALQUENCE. Once toxicity has resolved to Grade 1 or baseline level, CALQUENCE may be resumed at a reduced frequency of 100 mg once daily.
	Fourth	Discontinue CALQUENCE.
Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

Refer to the obinutuzumab prescribing information for management of obinutuzumab toxicities.

3 DOSAGE FORMS AND STRENGTHS

Tablets:100 mg acalabrutinib, orange, oval, film-coated, biconvex, debossed with ‘ACA 100’ on one side and plain on the other.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Serious and Opportunistic Infections

Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.

Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%) [see Adverse Reactions (6.1)]. These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jirovecii pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.

5.2 Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients [see Adverse Reactions (6.1)].

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

5.3 Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients [see Adverse Reactions (6.1)]. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted [see Dosage and Administration (2.3)].

5.4 Second Primary Malignancies

Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials [see Adverse Reactions (6.1)]. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure.

5.5 Atrial Fibrillation and Flutter

Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients [see Adverse Reactions (6.1)]. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

•

Serious and Opportunistic Infections [see Warnings and Precautions (5.1)]

•

Hemorrhage [see Warnings and Precautions (5.2)]

•

Cytopenias [see Warnings and Precautions (5.3)]

•

Second Primary Malignancies [see Warnings and Precautions (5.4)]

•

Atrial Fibrillation and Flutter [see Warnings and Precautions (5.5)]

6.1 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 [see Clinical Studies (14.1)]. 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 (%)
* Per NCI CTCAE version 4.03. † Bruising: Includes all terms containing ‘bruise,’ ‘contusion,’ ‘petechiae,’ or ‘ecchymosis’ ‡ Rash: Includes all terms containing ‘rash’ § Hemorrhage: Includes all terms containing ‘hemorrhage’ or ‘hematoma’
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
Bruising †	21	–
Rash ‡	18	0.8
Vascular disorders
Hemorrhage §	8	0.8
Respiratory, thoracic and mediastinal disorders
Epistaxis	6	–

Table 4: Hematologic Adverse Reactions Reported in ≥ 20% of Patients with MCL in Trial LY-004

* Per NCI CTCAE version 4.03; based on laboratory measurements and adverse reactions.
Hematologic Adverse Reactions *	CALQUENCE Monotherapy N=124
	All Grades (%)	Grade ≥ 3 (%)
Hemoglobin decreased	46	10
Platelets decreased	44	12
Neutrophils decreased	36	15

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 [see Clinical Studies (14.2)].

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 [see Clinical Studies (14.2)].

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 ObinutuzumabN=178		CALQUENCE Monotherapy N=179		Obinutuzumab plus Chlorambucil N=169
	All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)
* 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 ¶ Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection # Derived from adverse reaction and laboratory data Þ Includes neutropenia, neutrophil count decreased, and related laboratory data ß Includes anemia, red blood cell count decreased, and related laboratory data à Includes thrombocytopenia, platelet count decreased, and related laboratory data è Includes lymphocytosis, lymphocyte count increased, and related laboratory data ð Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain ø Includes asthenia, fatigue, and lethargy ý Includes bruise, contusion, and ecchymosis £ Includes rash, dermatitis, and other related terms ¥ Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis
Infections
Infection †	69	22‡	65	14‡	46	13‡
Upper respiratory tract infection §	39	2.8	35	0	17	1.2
Lower respiratory tract infection ¶	24	8	18	4.5	7	1.8
Urinary tract infection	15	1.7	15	2.8	5	0.6
Blood and lymphatic system disorders #
Neutropenia Þ	53	37	23	13	78	50
Anemia ß	52	12	53	10	54	14
Thrombocytopenia à	51	12	32	3.4	61	16
Lymphocytosis è	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 pain ð	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
Fatigue ø	34	2.2	23	1.1	24	1.2
Skin and subcutaneous tissue disorders
Bruising ý	31	0	21	0	5	0
Rash £	26	2.2	25	0.6	9	0.6
Vascular disorders
Hemorrhage ¥	20	1.7	20	1.7	6	0

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 * †	CALQUENCE plus Obinutuzumab N=178		CALQUENCE Monotherapy N=179		Obinutuzumab plus Chlorambucil N=169
	AllGrades (%)	Grade ≥ 3 (%)	AllGrades (%)	Grade ≥ 3 (%)	AllGrades (%)	Grade ≥ 3 (%)
* Per NCI CTCAE version 4.03 † Excludes electrolytes
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

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 (14.2)]. 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
	AllGrades (%)	Grade ≥ 3 (%)	AllGrades (%)	Grade ≥ 3 (%)	AllGrades (%)	Grade ≥ 3 (%)
* 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 ¶ Includes pneumonia, lower respiratory tract infection, bronchitis, bronchiolitis, tracheitis, and lung infection. # Derived from adverse reaction and laboratory data Þ Includes neutropenia, neutrophil count decreased, and related laboratory data ß Includes anemia, red blood cell decreased, and related laboratory data à Includes thrombocytopenia, platelet count decreased, and related laboratory data è Includes lymphocytosis, lymphocyte count increased and related laboratory data ð Includes colitis, diarrhea, and enterocolitis ø Includes hemorrhage, hematoma, hemoptysis, hematuria, menorrhagia, hemarthrosis, and epistaxis ý Includes asthenia, fatigue, and lethargy £ Includes back pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal discomfort, pain in extremity, myalgia, spinal pain and bone pain
Infections
Infection †	56	15‡	65	28‡	49	11
Upper respiratory tract infection §	29	1.9	26	3.4	17	2.9
Lower respiratory tract infection ¶	23	6	26	15	14	6
Blood and lymphatic system disorders #
Neutropenia Þ	48	23	79	53	80	40
Anemia ß	47	15	45	8	57	17
Thrombocytopenia à	33	6	41	13	54	6
Lymphocytosis è	26	19	23	18	2.9	2.9
Nervous system disorders
Headache	22	0.6	6	0	0	0
Gastrointestinal disorders
Diarrhea ð	18	1.3	49	25	14	0
Vascular disorders
Hemorrhage ø	16	1.3	5	1.7	6	2.9
General disorders
Fatigue ý	15	1.9	13	0.8	31	6
Musculoskeletal and connective tissue disorders
Musculoskeletal pain £	15	1.3	15	1.7	2.9	0

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 *	CALQUENCE N=154		Idelalisib plus Rituximab Product N=118		Bendamustine plus Rituximab Product N=35
	AllGrades (%)	Grade ≥ 3 (%)	AllGrades (%)	Grade ≥ 3 (%)	AllGrades (%)	Grade ≥ 3 (%)
* Excludes electrolytes
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

Increases in creatinine to 1.5 to 3 times ULN occurred in 1.3% of patients who received CALQUENCE.