1 Name of Medicine
Acalabrutinib maleate monohydrate.
2 Qualitative and Quantitative Composition
Each film-coated tablet contains acalabrutinib maleate monohydrate equivalent to 100 mg of acalabrutinib.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
The Calquence 100 mg film-coated tablet is an orange, 7.5 x 13 mm, oval, biconvex tablet, debossed with 'ACA 100' on one side and plain on the reverse.
4.1 Therapeutic Indications
Calquence is indicated for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.
This indication is approved via the provisional approval pathway, based on overall response rate. Full registration for this indication depends on verification and description of clinical benefit in confirmatory trials.
Calquence is indicated for the treatment of patients with chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL).
4.2 Dose and Method of Administration
Treatment with Calquence should be initiated and supervised by a physician experienced in the use of anticancer therapies.
Recommended dosage (18 years and above).
Mantle cell lymphoma (MCL).
The recommended dose of Calquence for the treatment of MCL is 100 mg (1 tablet) twice daily.
Chronic lymphocytic leukemia (CLL).
The recommended dose of Calquence for the treatment of CLL is 100 mg (1 tablet) twice daily, either as monotherapy or in combination with obinutuzumab. Administer Calquence prior to obinutuzumab when given on the same day. Refer to the obinutuzumab product information for recommended obinutuzumab dosing information (for details of the combination regimen, see Section 5.1 Pharmacodynamic Properties).
Doses should be separated by approximately 12 hours.
Treatment with Calquence should continue until disease progression or unacceptable toxicity.
Missed dose.
If a patient misses a dose of Calquence by more than 3 hours, instruct the patient to take the next dose at its regularly scheduled time. Extra tablets of Calquence should not be taken to make up for a missed dose.
Dose adjustments.
Adverse reactions.
Recommended dose modifications of Calquence for Grade 3 or greater adverse reactions are provided in Table 1.
Dose adjustments for use with CYP3A inhibitors or inducers.
Recommended dose adjustments are described in Table 2 (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Special patient populations.
Renal impairment.
No dose adjustment is recommended in patients with mild to moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics and safety of Calquence in patients with severe renal impairment (eGFR < 29 mL/min/1.73 m2) or end-stage renal disease have not been studied (see Section 5.2 Pharmacokinetic Properties).
Hepatic impairment.
No dose adjustment is recommended in patients with mild or moderate hepatic impairment (Child-Pugh A, Child-Pugh B, or total bilirubin between 1.5-3 times the upper limit of normal [ULN] and any AST). It is not recommended to administer Calquence in patients with severe hepatic impairment (Child-Pugh C or total bilirubin > 3 times ULN and any AST) (see Section 5.2 Pharmacokinetic Properties).
Severe cardiac disease.
Patients with severe cardiovascular disease were excluded from Calquence clinical studies.
Use in the elderly.
No dose adjustment is necessary based on age (see Section 5.2 Pharmacokinetic Properties).
Paediatric use.
The safety and efficacy of Calquence in children and adolescents aged less than 18 years have not been established.
Method of administration.
Calquence should be swallowed whole with water at approximately the same time each day. Calquence can be taken with or without food. The tablet should not be chewed, crushed, dissolved, or divided.4.3 Contraindications
None.
4.4 Special Warnings and Precautions for Use
Haemorrhage.
Serious haemorrhagic events, including fatal events, have occurred in the combined safety database of 1040 patients with hematologic malignancies treated with Calquence monotherapy. Major haemorrhage (Grade 3 or higher bleeding events, serious, or any central nervous system events) occurred in 3.6% of patients, with fatalities occurring in 0.1% of patients. Overall, bleeding events including bruising and petechiae of any grade occurred in 46% of patients with haematological malignancies.
The mechanism for the bleeding events is not well understood. Use of antithrombotic agents concomitantly with Calquence may increase the risk of haemorrhage. In Calquence clinical trials, 3% of patients taking Calquence without antithrombotic agents experienced major haemorrhage. The addition of antithrombotic agents increased the percentage to 4.3%. Consider the risks and benefits of antithrombotic agents when co-administered with Calquence. Patients should be monitored 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.
Infection.
Serious infections (bacterial, viral or fungal), including fatal events have occurred in the combined safety database of 1040 patients with haematologic malignancies treated with Calquence monotherapy. Consider prophylaxis in patients who are at increased risk for opportunistic infections.
Grade 3 or higher infections occurred in 18% of these patients. The most frequently reported Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation, aspergillosis, and progressive multifocal leukoencephalopathy (PML) have occurred. Monitor patients for signs and symptoms of infection and treat as medically appropriate.
Cytopenias.
In the combined safety database of 1040 patients with haematologic malignancies, patients treated with Calquence monotherapy experienced Grade 3 or 4 cytopenias, including neutropenia (21%), anaemia (10%) and thrombocytopenia (7%) based on laboratory measurements. Monitor complete blood counts as medically appropriate during treatment.
Second primary malignancies.
Second primary malignancies, including non-skin cancers, occurred in 12% of patients with haematologic malignancies treated with Calquence monotherapy in the combined safety database of 1040 patients. The most frequent second primary malignancy was skin cancer, which occurred in 7% of patients. Monitor patients for the appearance of skin cancers. Advise protection from sun exposure.
Atrial fibrillation and flutter.
In the combined safety database of 1040 patients with haematologic malignancies treated with Calquence monotherapy, Grade 3 atrial fibrillation and atrial flutter occurred in 1% of patients and Grade 1 or 2 in 3% of patients. Monitor for symptoms (e.g. palpitations, dizziness, syncope, chest pain, dyspnoea) of atrial fibrillation and atrial flutter and obtain an ECG as appropriate.
Use in the elderly.
Of the 1040 patients in clinical trials of Calquence monotherapy, 41% were ≥ 65 years of age and less than 75 years of age, and 22% were 75 years of age or older. No clinically relevant differences in safety or efficacy were observed between patients ≥ 65 years and younger.
Paediatric use.
The safety and efficacy of Calquence in children and adolescents aged less than 18 years have not been established.
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
Interactions with CYP3A inhibitors and inducers.
The clinical impact and prevention or management of interactions with CYP3A inhibitors or inducers are provided in Table 3. Also see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.
Effects of acalabrutinib and its active metabolite, ACP-5862, on CYP450 and UGT enzymes.
In vitro data indicate no relevant inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, UGT1A2 or UGT2B7 by acalabrutinib or ACP-5862 at therapeutic concentrations. Acalabrutinib is a weak inducer of CYP1A2, CYP2B6 and CYP3A4; ACP-5862 weakly induces CYP3A4.
Effects of acalabrutinib and its active metabolite, ACP-5862, on drug transport systems.
Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g. methotrexate) by inhibition of intestinal BCRP.
ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g. metformin) by inhibition of MATE1.
In vitro, acalabrutinib and ACP-5862 are substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Acalabrutinib is not a substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OATP1B1 and OATP1B3. ACP-5862 is not a substrate of OATP1B1 or OATP1B3. Acalabrutinib and ACP-5862 do not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, OATP1B3 and MATE2-K at clinically relevant concentrations.
Effect of food on acalabrutinib.
In healthy subjects, administration of a single 100 mg dose of acalabrutinib tablet with a high fat, high calorie meal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat, and 39 grams protein) did not affect the mean AUC as compared to dosing under fasted conditions. Resulting Cmax decreased by 54% and Tmax was delayed 1-2 hours.
Gastric acid reducing medications.
Acalabrutinib tablets can be co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists, antacids).4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
In a fertility study in rats, there were no effects of acalabrutinib on fertility in male rats at exposures 16 times, or in female rats at exposures 14 times the AUC observed in patients at the recommended dose of 100 mg twice daily.
(Category C)
Based on findings in animals, Calquence may cause fetal harm 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 pregnant rabbits during organogenesis resulted decreased fetal body weights and delayed skeletal ossification at maternal exposures (AUC) approximately 3.6 times exposures in patients at the recommended dose of 100 mg twice daily. This dose was maternotoxic. Dystocia was observed in a rat study (see below). Advise pregnant women of the potential risk to a fetus.
In a combined fertility and embryofetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting prior to mating through the period of organogenesis. No effects on embryofetal development or survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 16 times the AUC in patients at the recommended dose of 100 mg twice daily. The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma.
In a rat reproductive study involving dosing animals from implantation throughout gestation, parturition and lactation, dystocia (prolonged/difficult labour) was observed at ≥ 100 mg/kg/day, yielding exposures > 3.5 times the clinical exposure at 100 mg twice daily. Dystocia was not observed in rats at 50 mg/kg/day, associated with exposures approximately equivalent to the clinical exposure at 100 mg twice daily.
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.4.7 Effects on Ability to Drive and Use Machines
Calquence has no or negligible influence on the ability to drive and use machines. However, during treatment with acalabrutinib fatigue and dizziness have been reported and patients who experience these symptoms should observe caution when driving or using machines.
4.8 Adverse Effects (Undesirable Effects)
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. Clinical trials with acalabrutinib were studied with the acalabrutinib capsule formulation.
Mantle cell lymphoma (MCL).
The safety data described in this section reflect exposure to Calquence (100 mg twice daily) in 124 patients with previously treated MCL in ACE-LY-004 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). 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 anaemia, thrombocytopenia, headache, neutropenia, diarrhoea, fatigue, myalgia, and bruising. Grade 1 severity for the non-haematologic, most common events were as follows: headache (25%), diarrhoea (16%), fatigue (20%), myalgia (15%), and bruising (19%). The most common Grade ≥ 3 non-haematological adverse reaction (reported in at least 2% of patients) was diarrhoea.
Dose reductions and discontinuation due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively.
Table 4 and Table 5 present the frequency category of adverse reactions observed in patients with MCL treated with Calquence.
Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.
Chronic lymphocytic leukemia (CLL).
The safety data described below reflect exposure to Calquence (100 mg twice daily) in two randomized controlled clinical trials (ELEVATE-TN and ASCEND) in patients with CLL (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The most common adverse reactions (≥ 20%) of any grade were infection, neutropenia, anaemia, thrombocytopenia, headache, diarrhoea, musculoskeletal pain, bruising, and nausea. The most commonly reported Grade ≥ 3 adverse reactions were infection, neutropenia, and anaemia.
ELEVATE-TN (patients with previously untreated CLL). The safety of Calquence plus obinutuzumab (Calquence+G), Calquence monotherapy, and obinutuzumab plus chlorambucil (GClb) was evaluated in a randomized, multicentre, open-label, Phase 3 study, in 526 patients with previously untreated CLL. Details of the study treatment are described in Section 5.1 Pharmacodynamic Properties, Clinical trials.
In the Calquence+G arm, adverse events led to regimen discontinuation in 11% of patients and a dose reduction of Calquence in 8% of patients. In the Calquence monotherapy arm, adverse events led to discontinuation in 9% and dose reduction in 3% of patients. In the GClb arm, adverse events led to regimen discontinuation in 14% of patients and a dose reduction of chlorambucil in 28% of patients. There were no dose reductions for obinutuzumab.
The adverse reactions described in Table 6 and Table 7 reflect exposure to Calquence in the Calquence+G and Calquence monotherapy arms with a median duration of exposure of 27.7 months in patients with previously untreated CLL. The median duration of exposure in the GClb arm was 5.6 months.
Tumour lysis syndrome.
Tumour lysis syndrome (TLS) was reported in 2% of patients treated with Calquence+G. No patients experienced TLS in the Calquence monotherapy arm.
Atrial fibrillation/atrial flutter.
Atrial fibrillation/atrial flutter was reported in patients treated with Calquence+G and Calquence monotherapy with an incidence of 3% and 4%, respectively, including 1% with ≥ Grade 3 atrial fibrillation/atrial flutter in the Calquence+G arm. No patients experienced ≥ Grade 3 atrial fibrillation/atrial flutter in the Calquence monotherapy arm.
Infusion related reaction.
Infusion related reaction was reported in 14% and 40% of patients in the Calquence+G and GClb arms, respectively.
ASCEND (patients with CLL who received at least one prior therapy). The safety of Calquence versus investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab was evaluated in a randomized, multicentre, open-label, Phase 3 study, in 307 patients with relapsed or refractory CLL. Details of the study treatment are described in Section 5.1 Pharmacodynamic Properties, Clinical trials.
In the Calquence arm, adverse events led to discontinuation in 10% and dose reduction in 3% of patients. In patients receiving idelalisib plus rituximab, adverse events led to regimen discontinuation in 9% of patients and a dose reduction of idelalisib in 24%. In patients receiving bendamustine plus rituximab, adverse events led to regimen discontinuation in 9% of patients and a dose reduction of bendamustine in 14% of patients. There were no dose reductions of rituximab.
The adverse reactions described in Table 8 and Table 9 reflect exposure to Calquence with a median duration of 15.7 months, exposure to idelalisib with a median duration of 11.5 months, exposure to rituximab with a median duration of 5.5 months, and exposure to bendamustine and a median duration of 5.6 months in patients with relapsed or refractory CLL.
Tumour lysis syndrome.
TLS was reported in patients treated with Calquence and idelalisib plus rituximab with an incidence of 1% in both arms. The one patient experiencing TLS treated with Calquence had Grade 3 TLS and bulky disease.
Post-marketing experience.
The following adverse reactions have been identified during post-approval use of Calquence. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Vascular disorders.
Hypertension.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.4.9 Overdose
There is no specific treatment for acalabrutinib overdose and symptoms of overdose have not been established. In the event of an overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Acalabrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (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 signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signalling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and tumour growth in mouse xenograft models.
Pharmacodynamics.
In patients with B-cell malignancies dosed with 100 mg twice daily, median steady state BTK occupancy of ≥ 95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval.
Cardiac electrophysiology.
The effect of acalabrutinib on the QTc interval was evaluated in a randomized, double-blind, double-dummy, placebo- and positive-controlled, 4-way crossover thorough QTc study in 48 healthy adult subjects. Administration of a single dose of acalabrutinib that is the 4-fold maximum recommended single dose did not prolong the QTc interval to any clinically relevant extent (i.e. ≥ 10 ms).
Clinical trials.
Clinical trials with acalabrutinib were studied with the acalabrutinib capsule formulation.
Mantle cell lymphoma (MCL). The safety and efficacy of Calquence in MCL were evaluated in an open-label, multi-centre, single-arm Phase 2 study (ACE-LY-004) of 124 previously treated patients. All patients received Calquence 100 mg orally twice daily until disease progression or unacceptable toxicity. The trial did not include patients who received prior treatment with BTK inhibitors. The primary endpoint was investigator-assessed overall response rate (ORR) per the Lugano classification for non-Hodgkin's lymphoma (NHL). Duration of Response (DoR) was an additional outcome measure. Efficacy results are presented in Table 10.
The median age was 68 (range 42 to 90) years, 79.8% were male and 74.2% were Caucasian. At baseline, 92.8% 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 to 5), including 17.7% with prior stem cell transplant. The most common prior regimens were CHOP-based (51.6%) and ARA-C (33.9%). At baseline, 37.1% of patients had at least one tumour with a longest diameter ≥ 5 cm, 72.6% had extra nodal involvement including 50.8% with bone marrow involvement. The simplified MIPI score (which includes age, ECOG score, and baseline lactate dehydrogenase and white cell count) was intermediate in 43.5% and high in 16.9% of patients. The median dose intensity was 98.5%.
Lymphocytosis. Upon initiation of Calquence, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count (ALC) increased ≥ 50% from baseline and a post baseline assessment ≥ 5 x 109) in 31.5% of patients in ACE-LY-004. The median time to onset of lymphocytosis was 1.1 weeks and the median duration of lymphocytosis was 6.7 weeks.
Chronic lymphocytic leukemia (CLL). Patients with previously untreated CLL.
The safety and efficacy of Calquence in previously untreated CLL were evaluated in a randomised, multi-centre, open-label Phase 3 study (ELEVATE-TN) of 535 patients. Patients received Calquence plus obinutuzumab, Calquence monotherapy, or obinutuzumab plus chlorambucil. Patients 65 years of age or older or between 18 and 65 years of age with coexisting medical conditions were included in ELEVATE-TN. The trial also allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists.
Patients were randomised in a 1:1:1 ratio into 3 arms to receive:
Calquence plus obinutuzumab (Calquence+G): Calquence 100 mg was administered twice daily 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 twice daily 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 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 up to 6. Chlorambucil 0.5 mg/kg was administered on Days 1 and 15 of Cycles 1 up to 6. Each cycle was 28 days.
Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and geographic region (North America and Western Europe versus Other). After confirmed disease progression, 45 patients randomised on the GClb arm crossed over to Calquence monotherapy. Table 11 summarizes the baseline demographics and disease characteristics of the study population.
The primary endpoint was progression-free survival (PFS) of Calquence+G arm versus GClb arm as assessed by an Independent Review Committee (IRC) per International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012). With a median follow-up of 28.3 months, PFS by IRC indicated a 90% statistically significant reduction in the risk of disease progression or death for previously untreated CLL patients in the Calquence+G arm compared to the GClb arm. At the time of analysis, median overall survival had not been reached in any arm with a total of 37 deaths: 9 (5%) in the Calquence+G arm, 11 (6.1%) in the Calquence monotherapy arm, and 17 (9.6%) in the GClb arm. Efficacy results are presented in Table 12. The Kaplan-Meier curves for PFS are shown in Figure 1.
PFS results for Calquence with or without obinutuzumab were consistent across subgroups, including high risk features. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation, and unmutated IGHV), the PFS HRs of Calquence with or without obinutuzumab versus obinutuzumab plus chlorambucil was 0.08 [95% CI (0.04, 0.15)] and 0.15 [95% CI (0.09, 0.25)], respectively.
Patients with CLL who received at least one prior therapy.
The safety and efficacy of Calquence in relapsed or refractory CLL were evaluated in a randomised, multi-centre, open-label Phase 3 study (ASCEND) of 310 patients who received at least one prior therapy. Patients received Calquence monotherapy or investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab. The trial allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists.
Patients were randomised 1:1 to receive either:
Calquence 100 mg twice daily until disease progression or unacceptable toxicity, or
Investigator's choice: idelalisib 150 mg twice daily until disease progression or unacceptable toxicity in combination with ≤ 8 infusions of rituximab (375 mg/m2/500 mg/m2) on Day 1 of each 28-day cycle for up to 6 cycles.
Bendamustine 70 mg/m2 (Day 1 and 2 of each 28-day cycle) in combination with rituximab (375 mg/m2/500 mg/m2) on Day 1 of each 28-day cycle for up to 6 cycles.
Patients were stratified by 17p deletion mutation status (presence versus absence), ECOG performance status (0 or 1 versus 2) and number of prior therapies (1 to 3 versus ≥ 4). After confirmed disease progression, 35 patients randomised on investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab crossed over to Calquence. Table 13 summarizes the baseline demographics and disease characteristics of the study population.
The primary endpoint was PFS as assessed by IRC IWCLL 2008 criteria with incorporation of the clarification for treatment-related lymphocytosis (Cheson 2012). With a median follow-up of 16.1 months, PFS indicated a 69% statistically significant reduction in the risk of death or progression for patients in the Calquence arm. At the time of analysis, median overall survival had not been reached in any arm with a total of 33 deaths: 15 (9.7%) in the Calquence monotherapy arm and 18 (11.6%) in the investigator's choice of either idelalisib plus rituximab or bendamustine plus rituximab arm. Efficacy results are presented in Table 14. The Kaplan-Meier curve for PFS is shown in Figure 2.
PFS results for Calquence were consistent across subgroups, including high risk features. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation, and unmutated IGHV), the PFS HR was 0.27 [95% CI (0.17, 0.44)].
5.2 Pharmacokinetic Properties
The pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862 were studied in healthy subjects and patients with B-cell malignancies. Acalabrutinib exhibits dose-proportionality, and both acalabrutinib and ACP-5862 exhibit almost linear PK across a dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dose). Population PK modelling suggests that the PK of acalabrutinib and ACP-5862 does not differ significantly in patients with different B-cell malignancies. At the recommended dose of 100 mg twice daily in patients with B-cell malignancies (including MCL and CLL), the geometric mean steady state daily area under the plasma drug concentration over time curve (AUC24h) and maximum plasma concentration (Cmax) of acalabrutinib were 1893 nanogram.h/mL and 466 nanogram/mL, respectively, and for ACP-5862 were 4091 nanogram.h/mL and 420 nanogram/mL, respectively.
Calquence tablets and Calquence capsules have been demonstrated to be bioequivalent. Geometric mean PK exposures (Cmax and AUClast or AUCinf) of acalabrutinib and ACP-5862 were similar (< 4% difference) between the tablet and capsule, with the 90% confidence intervals for geometric mean ratios within the pre-defined bioequivalence margin of 80% and 125%.
Absorption.
The median (min-max) time to peak plasma concentrations (Tmax) was 0.5 (0.2, 3.0) hours for acalabrutinib, and 0.75 (0.5, 4.0) hours for ACP-5862, following administration of acalabrutinib tablet. The absolute bioavailability of Calquence was 25% following oral administration of acalabrutinib capsule.
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 mean steady state volume of distribution (Vss) was approximately 34 L for acalabrutinib.
Metabolism.
In vitro, acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent by glutathione conjugation and amide hydrolysis. ACP-5862 was identified as the major metabolite in plasma with a geometric mean exposure (AUC) that was approximately 2- to 3-fold higher than the exposure of acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib with regard to BTK inhibition.
Acalabrutinib may inhibit intestinal BCRP substrates (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), while ACP-5862 may inhibit MATE1 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) at clinically relevant concentrations. Acalabrutinib does not inhibit MATE1, while ACP-5862 does not inhibit BCRP at clinically relevant concentrations.
Excretion.
Following a single oral dose of 100 mg acalabrutinib tablet, the median terminal elimination half-life (t1/2) of acalabrutinib was 1.3 (range: 0.8 to 9.0) hours. The median t1/2 of the active metabolite, ACP-5862, was 7.3 hours (range: 2.5 to 10.1) hours.
The mean apparent oral clearance (CL/F) was 70 L/hr for acalabrutinib and 13 L/hr for ACP-5862, with similar PK between patients and healthy subjects, based on population PK analysis.
Following administration of a single 100 mg radiolabelled [14C]-acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the faeces and 12% of the dose was recovered in the urine, with less than 2% of the dose excreted as unchanged acalabrutinib in urine and faeces.
Specific populations.
Age, race, and body weight.
Age (32 to 90 years), sex, race (Caucasian, African American), and body weight (40 to 149 kg) did not have clinically meaningful effects on the PK of acalabrutinib and its active metabolite, ACP-5862, based on population PK analysis.
Renal impairment.
Acalabrutinib undergoes minimal renal elimination. Based on population PK analysis, no clinically relevant PK difference was observed in 543 patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2, as estimated by MDRD (modification of diet in renal disease equation)). Acalabrutinib PK has not been evaluated in patients with severe renal impairment (eGFR < 29 mL/min/1.73 m2, MDRD) or renal impairment requiring dialysis.
Hepatic impairment.
Acalabrutinib is metabolized in the liver. In hepatic impairment studies, compared to subjects with normal liver function (n = 6), acalabrutinib exposure (AUC) was increased by 1.9-fold, 1.5-fold, and 5.3-fold in subjects with mild (n = 6) (Child-Pugh A), moderate (n = 6) (Child-Pugh B) and severe (n = 8) (Child-Pugh C) hepatic impairment, respectively. Based on a population PK analysis, no clinically relevant PK difference was observed in subjects with mild (n = 79) or moderate (n = 6) hepatic impairment (total bilirubin between 1.5 to 3 times the upper limit of normal [ULN] and any AST) relative to subjects with normal (n = 651) hepatic function (total bilirubin and AST within ULN).
Drug interaction studies.
Effect of CYP3A inhibitors on acalabrutinib.
Co-administration with a strong CYP3A inhibitor (200 mg itraconazole once daily for 5 days) increased the acalabrutinib Cmax by 3.9-fold and AUC by 5.1-fold in healthy subjects.
Physiologically based pharmacokinetic (PBPK) simulations with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) showed that co-administration increased acalabrutinib Cmax and AUC increased by 2- to almost 3-fold (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Effect of CYP3A inducers on acalabrutinib.
Co-administration with a strong CYP3A inducer (600 mg rifampin once daily for 9 days) decreased acalabrutinib Cmax by 68% and AUC by 77% in healthy subjects (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Gastric acid reducing medicines.
Co-administration of acalabrutinib tablet with a proton pump inhibitor (20 mg rabeprazole, twice daily for 3 days) increased AUC by 17% (up to 31% increase, based on upper limit of 90% confidence interval) and decreased Cmax by 24% (up to 45% decrease, based on lower limit of 90% confidence interval), with a delay in Tmax (up to 1 hour, approximately).
5.3 Preclinical Safety Data
Genotoxicity.
Acalabrutinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or in an in vivo rat bone marrow micronucleus assay.
Carcinogenicity.
Carcinogenicity studies have not been conducted with acalabrutinib.6 Pharmaceutical Particulars
6.1 List of Excipients
Tablet core.
Mannitol, microcrystalline cellulose, hyprolose, and sodium stearylfumarate.
Tablet coating.
Hypromellose, copovidone, titanium dioxide, macrogol 3350, medium chain triglycerides, iron oxide yellow, iron oxide red.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 30°C.
6.5 Nature and Contents of Container
Polyamide-aluminium-polyvinylchloride/aluminium blisters. Cartons of 56 tablets.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Acalabrutinib maleate monohydrate is a white to pale brown powder with pH-dependent solubility. It is freely soluble in water at pH values below 3 and practically insoluble at pH values above 6.
Chemical structure.
The chemical name is 4-{8-Amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (2Z)-2-butenedioic acid hydrate (1:1:1).
Molecular formula: C26H23N7O2.C4H4O4.H2O.
Molecular weight: 599.59.
CAS number.
CAS 2641500-53-8.7 Medicine Schedule (Poisons Standard)
Prescription only medicine (Schedule 4).
Summary Table of Changes
