Calquence

— THERAPEUTIC CATEGORIES —
  • Leukemias, lymphomas, and other hematologic cancers
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Calquence Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Acalabrutinib 100mg; caps or tabs.

    Pharmacological Class

    Bruton tyrosine kinase (BTK) inhibitor.

    How Supplied

    Caps, Tabs—60

    How Supplied

    Calquence is supplied in 100 mg, hard gelatin capsules with yellow body and blue cap, marked in black ink with ‘ACA 100 mg’.

    • 60-count bottle

    Calquence is supplied as a 100 mg, orange, oval, biconvex tablet, with
    debossment ‘ACA100’ on one side and plain on the reverse.

    • 60-count bottle

    Storage

    Store at 20°-25° C (68°-77° F); excursions permitted to 15°-30°C (59°-86° F).

    Manufacturer

    AstraZeneca Pharmaceuticals

    Generic Availability

    NO

    Mechanism of Action

    Acalabrutinib is a small-molecule inhibitor of BTK. Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B cell antigen receptor (BCR) and cytokine receptor pathways. In B cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. 

    Calquence Indications

    Indications

    Mantle cell lymphoma (MCL) in adults who have received at least one prior therapy. Chronic lymphocytic leukemia (CLL). Small lymphocytic lymphoma (SLL).

    Calquence Dosage and Administration

    Adult

    Swallow whole with water. 100mg approx. every 12hrs until disease progression or unacceptable toxicity. In combination with obinutuzumab (CLL/SLL): initiate acalabrutinib at Cycle 1 of each 28-day cycle, then initiate obinutuzumab at Cycle 2 for a total of 6 cycles; give acalabrutinib prior to obinutuzumab if given on same day. Concomitant moderate CYP3A inhibitors: 100mg once daily. Concomitant strong CYP3A inducers: avoid; if needed, increase dose to 200mg every 12hrs. Dose modifications: see full labeling.

    Children

    Not established.

    Administration

    Advise patients to swallow whole with water. 

    Advise patients not to open, break or chew.

    Acalabrutinib may be taken with or without food.

    If a dose of acalabrutinib is missed by more than 3 hours, it should be skipped and the next dose should be taken at its regularly scheduled time. Extra doses of acalabrutinib should not be taken to make up for a missed dose.

    Calquence Contraindications

    Not Applicable

    Calquence Boxed Warnings

    Not Applicable

    Calquence Warnings/Precautions

    Warnings/Precautions

    Risk of serious hemorrhagic events (monitor); consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery. Monitor for infections; consider prophylaxis if at risk for opportunistic infections. Monitor for cytopenias; obtain CBCs regularly. Risk of second primary malignancies (eg, skin cancer or other carcinomas); advise patients to protect from sun exposure. Monitor for atrial fibrillation/flutter; manage appropriately. Severe hepatic impairment: not recommended. Advise females of reproductive potential to use effective contraception during and for ≥1 week after the last dose. Pregnancy: exclude status prior to initiation (potential risk of fetal harm and dystocia). Nursing mothers: not recommended (during and for ≥2 weeks after the last dose).

    Warnings/Precautions

    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%). 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 jiroveci 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.

    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. 
    • 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 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

    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.
    • Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.

    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. 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.  

    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. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection.
    • Monitor for symptoms of arrhythmia (eg, palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

    Pregnancy Considerations

    • Based on findings in animals, Calquence may cause fetal harm and dystocia when administered to a pregnant woman. There is no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus.
    • Pregnancy testing is recommended for females of reproductive potential prior to initiating Calquence therapy.
    • 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.

    Nursing Mother Considerations

    • 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.

    Pediatric Considerations

    The safety and efficacy of Calquence in pediatric patients have not been established.

    Geriatric Considerations

    No clinically relevant differences in efficacy were observed between patients ≥65 years and younger.

    Hepatic Impairment Considerations

    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.

    Calquence Pharmacokinetics

    Absorption

    The geometric mean absolute bioavailability of acalabrutinib was 25%. Median [min, max] time to peak acalabrutinib plasma concentrations (Tmax) was 0.9 [0.5, 1.9] hours, and 1.6 [0.9, 2.7] hour for ACP-5862.

    Distribution

    Reversible binding to human plasma protein was 97.5% for acalabrutinib and 98.6% for ACP-5862. The in vitro mean blood-to-plasma ratio was 0.8 for acalabrutinib and 0.7 for ACP-5862. The geometric mean (% CV) steady-state volume of distribution (Vss) was ~101 (52%) L for acalabrutinib and 67 (32%) L for ACP-5862.

    Metabolism

    Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent, by glutathione conjugation and amide hydrolysis, based on in vitro studies. 

    Elimination

    The geometric mean (% CV) terminal elimination half-life (t1/2) was 1 (59%) hour for acalabrutinib and 3.5 (24%) hours for ACP-5862.

    Following administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine, with <2% of the dose excreted as unchanged acalabrutinib in urine and feces.

    Calquence Interactions

    Interactions

    Avoid concomitant strong CYP3A inhibitors (eg, itraconazole); if short-term use (eg, anti-infectives for ≤7days), interrupt acalabrutinib therapy. Concomitant moderate CYP3A inhibitors, strong CYP3A inducers (eg, rifampin): see Adults. Increased risk of hemorrhage with concomitant antithrombotics; consider benefit/risk. Caps formulation: antagonized by gastric acid reducing agents (eg, PPI [avoid], H2-receptor antagonist, or antacid); if needed, consider ranitidine, famotidine, or calcium carbonate. Separate dosing by at least 2hrs with antacids. Take acalabrutinib 2hrs before H2-receptor antagonist use.

    Interactions

    Strong CYP3A Inhibitors

    • Co-administration of Calquence with a strong CYP3A inhibitor (eg, itraconazole) increased acalabrutinib plasma concentrations.
    • Increased acalabrutinib concentrations may result in increased toxicity.
    • Avoid co-administration of strong CYP3A inhibitors with Calquence.
    • Alternatively, if the inhibitor will be used short-term, interrupt Calquence.

    Moderate CYP3A Inhibitors

    • Co-administration of Calquence with a moderate CYP3A inhibitor may increase acalabrutinib plasma concentrations.
    • Increased acalabrutinib concentrations may result in increased toxicity.
    • When Calquence is co-administered with moderate CYP3A inhibitors, reduce acalabrutinib dose to 100 mg once daily.

    Strong CYP3A Inducers

    • Co-administration of Calquence with a strong CYP3A inducer (eg, rifampin) decreased acalabrutinib plasma concentrations.
    • Decreased acalabrutinib concentrations may reduce Calquence activity.
    • Avoid co-administration of strong CYP3A inducers with Calquence.
    • If a strong CYP3A inducer cannot be avoided, increase the acalabrutinib dose to 200 mg approximately every 12 hours.

    Gastric Acid Reducing Agents

    • Co-administration of Calquence with a proton pump inhibitor, H2-receptor antagonist, or antacid may decrease acalabrutinib plasma concentrations.
    • Decreased acalabrutinib concentrations may reduce Calquence activity.
    • If treatment with a gastric acid reducing agent is required, consider using a H2- receptor antagonist (eg, ranitidine or famotidine) or an antacid (eg, calcium carbonate).
    • Proton pump inhibitors:
      • Avoid co-administration. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with Calquence.
    • H2-receptor antagonists:
      • Take Calquence 2 hours before taking the H2-receptor antagonist. 
    • Antacids:
      • Separate dosing by at least 2 hours.

    Increased risk of hemorrhage with concomitant antithrombotics (see Warnings/Precautions). 

    Calquence Adverse Reactions

    Adverse Reactions

    Anemia, neutropenia, thrombocytopenia, upper RTI, headache, diarrhea, musculoskeletal pain; hemorrhage, infections, second primary malignancy, atrial fibrillation/flutter.

    Adverse Reactions

    Mantle Cell Lymphoma

    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.

    Chronic Lymphocytic Leukemia

    The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea.  

    Calquence Clinical Trials

    Clinical Trials

    Mantle Cell Lymphoma 

    • The efficacy of Calquence was based upon Trial LY-004 titled “An Open-label, Phase 2 Study of ACP-196 in Subjects with Mantle Cell Lymphoma” (NCT02213926). Trial LY-004 enrolled a total of 124 patients with MCL who had received at least one prior therapy.
    • At baseline, 93% of patients had an ECOG performance status of 0 or 1. The median time since diagnosis was 46.3 months and the median number of prior treatments was 2 (range 1-5), including 18% with prior stem cell transplant. The most common prior regimens were CHOP-based (52%) and ARA-C (34%). At baseline, 37% of patients had at least one tumor with a longest diameter ≥ 5 cm, 73% had extra nodal involvement including 51% with bone marrow involvement. 
    • Calquence was administered orally at 100 mg approximately every 12 hours until disease progression or unacceptable toxicity. The median dose intensity was 98.5%. The major efficacy outcome of Trial LY004 was overall response rate and the median follow-up was 15.2 months.
    • Results showed that patients treated with Calquence achieved an ORR of 81% (95% CI, 73-87) with 40% of those having complete response and 41% having partial response. The median time to best response was 1.9 months. 

    Chronic Lymphocytic Leukemia 

    • The efficacy of Calquence in patients with CLL was demonstrated in two randomized, controlled trials. The indication for acalabrutinib includes patients with SLL because it is the same disease.

    Chronic Lymphocytic Leukemia: ELEVATE-TN trial

    • The efficacy of Calquence was evaluated in the ELEVATE-TN trial, a randomized, multicenter, open-label, actively controlled, 3 arm trial of Calquence in combination with obinutuzumab, Calquence monotherapy, and obinutuzumab in combination with chlorambucil in 535 patients with previously untreated chronic lymphocytic leukemia (NCT02475681).
    • Patients were randomly assigned in a 1:1:1 ratio into 3 arms to receive: 
      • Calquence plus obinutuzumab (Calquence+G): Calquence 100 mg was administered approximately every 12 hours starting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1000 mg on Day 1 of Cycles 3 up to 7. Each cycle was 28 days.
      • Calquence monotherapy: Calquence 100 mg was administered approximately every 12 hours until disease progression or unacceptable toxicity.
      • Obinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered intravenously on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 followed by 1000 mg on Day 1 of Cycles 2 to 6. Chlorambucil 0.5 mg/kg was administered orally on Days 1 and 15 of Cycles 1 to 6. Each cycle was 28 days.
    • Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median duration of follow-up was 28.3 months (range: 0.0-40.8 months).
    • Results showed that patients who received Calquence had a longer PFS compared with those who received obinutuzumab plus chlorambucil. In the Calquence combination arm, risk of disease progression or death was reduced by 90% (hazard ratio [HR] 0.10; 95% CI, 0.06-0.17, P <.0001) and in the monotherapy arm it was reduced by 80% (HR 0.20; 95% CI, 0.13-0.30, P <.0001). 
    • With a median follow-up of 28.3 months, median overall survival was not reached in any arm, with fewer than 10% of patients experiencing an event.

    Chronic Lymphocytic Leukemia: ASCEND Trial

    • The efficacy of Calquence in patients with relapsed or refractory CLL was based upon a multicenter, randomized, open-label trial (ASCEND; NCT02970318). The trial enrolled 310 patients with relapsed or refractory CLL after at least 1 prior systemic therapy.
    • Patients were randomly assigned in a 1:1 ratio to receive either: 
      • Calquence 100 mg approximately every 12 hours until disease progression or unacceptable toxicity, or
      • Investigator’s choice: Idelalisib plus a rituximab product (IR) or bendamustine plus a rituximab product (BR).
    • In the Calquence arm, the median treatment duration was 15.7 months, with 94% of patients treated for at least 6 months and 86% of patients treated for at least 1 year. In the investigator’s choice arm, the median treatment duration was 8.4 months, with 59% of patients treated for at least 6 months and 37% treated for at least 1 year.
    • Efficacy was based on PFS as assessed by an IRC, with a median follow-up of 16.1 months (range 0.03-22.4 months). In this trial, treatment with Calquence resulted in longer PFS compared with the other standard treatments (HR 0.31; 95% CI, 0.20-0.49; P <.0001). There was no statistically significant difference in overall response rates between the two treatment arms.
    • With a median follow up of 16.1 months, median overall survival was not reached in either arm, with fewer than 11% of patients experiencing an event.

    Calquence Note

    Not Applicable

    Calquence Patient Counseling

    Patient Counseling

    Serious and Opportunistic Infections 

    • Inform patients of the possibility of serious infection and to report signs or symptoms suggestive of infection.

    Hemorrhage 

    • Inform patients to report signs or symptoms of bleeding. Inform patients that Calquence may need to be interrupted for major surgeries.

    Cytopenias 

    • Inform patients that they will need periodic blood tests to check blood counts during treatment with Calquence. 

    Second Primary Malignancies 

    • Inform patients that other malignancies have been reported in patients who have been treated with Calquence, including skin cancer and other solid tumors. Advise patients to use sun protection. 

    Atrial Fibrillation and Flutter 

    • Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath. 

    Pregnancy Complication 

    • Calquence may cause fetal harm and dystocia. Advise women to avoid becoming pregnant during treatment and for at least 1 week after the last dose of Calquence. 

    Lactation 

    • Advise females not to breastfeed during treatment with Calquence and for at least 2 weeks after the final dose.

    Drug Interactions 

    • Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins and herbal products.

    Cost Savings Program

    The Calquence savings program is available here.

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