Calquence

The Calquence 100 mg tablet is an orange, 7.5 x 13 mm, oval, biconvex tablet, debossed with 'ACA 100' on one side and plain on the reverse.
Each film-coated tablet contains acalabrutinib maleate equivalent to 100 mg of acalabrutinib.
Excipients/Inactive Ingredients: Tablet Core: mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate.
Tablet Coating: hypromellose, copovidone, titanium dioxide, macrogol 3350, triglycerides (medium-chain), iron oxide yellow (E172), iron oxide red (E172), purified water.

ATC Code: L01EL02.
Pharmacology: Pharmacodynamics: Mechanism of action: Acalabrutinib is a selective small-molecule inhibitor of Bruton tyrosine kinase (BTK). BTK is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in B-cell survival and proliferation, and is required for cellular adhesion, trafficking, and chemotaxis.
Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to irreversible inactivation of BTK (IC₅₀ ≤5 nM) with minimal off-target interactions. In a screen of 380 mammalian wild-type kinases, the only additional kinase interactions at clinically relevant concentrations of acalabrutinib and ACP-5862 were with BMX and ERBB4, with 3- to 4-fold less potency than BTK.
In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signalling proteins CD86 and CD69, inhibited malignant B-cell proliferation and survival, and had minimal activity on other immune cells (T cells and NK cells).
Pharmacodynamic effects: 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: In a dedicated QT study, at a dose 4 times the maximum recommended dose, CALQUENCE does not prolong the QT/QTc interval to any clinically relevant extent (e.g., not greater than or equal to 10 ms).
Clinical efficacy and safety in patients: MCL: Patients with MCL who received at least one prior therapy - ACE-LY-004: 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 1.
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. (See Table 1.)

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Based on investigator assessment, 92% of responders achieved a response by cycle 2, with a median time to documented response of 1.9 months. The median DoR had not been reached at 15.2 months median follow-up from treatment initiation. Seventy two percent (72%) of patients had an ongoing response at 12 months per Kaplan-Meier estimate. The ORR was consistent across all pre-specified subgroups including age, performance status, disease stage, and number of prior therapies.
Lymphocytosis: Upon initiation of CALQUENCE, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count increased ≥50% from baseline and a post baseline assessment ≥5 x 10⁹) have been reported in 30.6% of patients in ACE-LY-004. The median time to onset of lymphocytosis was 1.1 weeks and the median duration of lymphocytosis was 5.6 weeks.
54-month final analysis of ACE-LY-004: The efficacy results at 54-month final analysis after the median follow-up of 38.1 months are presented in Table 2. At the final analysis the mPFS was 22 months (95% CI: 16.6, 33.3) and the mOS was 59.2 months (95% CI: 36.5, NE). (See Table 2.)

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Patients with previously untreated MCL - ECHO: The safety and efficacy of CALQUENCE in patients with previously untreated MCL was evaluated in ECHO, a randomised, double-blind, placebo controlled, multicentre phase 3 study. ECHO included 598 patients 65 years of age and older with confirmed MCL that was previously untreated. Patient randomisation was stratified by geographic region (North America versus Western Europe versus Other) and simplified MIPI (Mantle Cell Lymphoma International Prognostic Index) score (0-3 versus 4-5 versus 6-11). The study enrolled patients during the COVID-19 pandemic.
Patients were randomised in 1:1 ratio in 2 arms to receive: CALQUENCE plus bendamustine and rituximab (CALQUENCE+BR) arm: CALQUENCE 100 mg was administered twice daily from Day 1 of Cycle 1, continuously. Bendamustine, 90 mg/m², was intravenously administered over 30 minutes on Days 1 and 2 of each of six 28-day cycles; and rituximab, 375 mg/m², was intravenously administered on Day 1 of each cycle of six 28-day cycle. CALQUENCE+BR was administered for a maximum of 6 treatment cycles (induction treatment).
Placebo plus bendamustine and rituximab (Placebo+BR) arm: Placebo was administered twice daily from Day 1 of Cycle 1, continuously. Bendamustine, 90 mg/m², was intravenously administered over 30 minutes on Days 1 and 2 of each of six 28-day cycles; and rituximab, 375 mg/m², was intravenously administered on Day 1 of each cycle of six 28-day cycles. BR was administered for a maximum of 6 treatment cycles (induction treatment).
CALQUENCE or placebo was administered continuously until disease progression or unacceptable toxicity. After the induction treatment, patients in the placebo+BR arm that were achieving a response (PR or CR) received rituximab maintenance at 375 mg/m² on Day 1 of every other cycle for maximum of 12 additional doses up to Cycle 30. Patients randomised to placebo+BR arm, who had confirmed PD were eligible to cross over to CALQUENCE monotherapy at 100 mg twice daily dose until their second disease progression or unacceptable toxicity.
The median age was 71 years (65-86), 70.7% were males, 78.3% were White, 93.1% had an ECOG performance status of 0-1. The simplified MIPI score was low (0-3) in 33.1%, intermediate (4-5) in 42.8% and high (6-11) in 24.1% of patients. A total of 37.7% of patients had tumour bulk ≥5 cm and 86% had Ann Arbor stage IV disease. Aggressive variants of MCL such as blastoid and pleomorphic forms were seen in 7.7% and 5.5% of patients respectively. A total of 47.8% patients had Ki-67 score of ≥30%. The baseline characteristics were similar between both treatment arms.
The primary endpoint was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) per Lugano Classification for NHL in subjects with previously untreated MCL. Additional efficacy endpoints were Investigator-assessed (INV) PFS, INV and IRC assessed overall response rate (ORR), IRC and INV assessed duration of response (DOR) and overall survival (OS).
With a median follow-up of 46.1 months in the CALQUENCE+BR arm and 44.4 months in the Placebo+BR arm, IRC-assessed PFS demonstrated 27% statistically significant reduction in risk of disease progression or death in patients treated with CALQUENCE+BR compared to Placebo+BR. At the time of PFS analysis, median OS had not been reached in any arm with a total of 203 deaths: 97 (32.4%) in the CALQUENCE+BR arm, 106 (35.5%) in the Placebo+BR arm. Efficacy results are presented in Table 3. The Kaplan-Meier curves for PFS are shown in Figure 1. (See Table 3 and Figure 1.)

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CLL: Patients with Previously Untreated CLL - ELEVATE-TN: 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 1,000 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 1,000 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 1,000 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 1,000 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 4 summarizes the baseline demographics and disease characteristics of the study population. (See Table 4.)

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The primary endpoint was progression-free survival (PFS) 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 5. The Kaplan-Meier curves for PFS are shown in Figure 2. (See Table 5 and Figure 2.)

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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 0.13 [95% CI (0.08, 0.21)], respectively.
With long term data, the median follow-up was 58.2 months for CALQUENCE+G arm, 58.1 months for Calquence arm and 58.2 months for the GClb arm. The median investigator-assessed PFS for CALQUENCE+G and CALQUENCE monotherapy was not reached; and was 27.8 months in GClb arm. At the time of most recent data cut off, a total of 72 patients (40.7%) originally randomised to the GClb arm crossed over to CALQUENCE monotherapy. The median overall survival had not been reached in any arm with a total of 76 deaths: 18 (10.1%) in the CALQUENCE+G arm, 30 (16.8%) in the CALQUENCE monotherapy arm, and 28 (15.8%) in the GClb arm. The time to next treatment was prolonged for CALQUENCE+G arm (HR=0.14 [95% CI: 0.09, 0.21]; 0<0.0001) and Calquence only arm (HR=0.27 [95% CI: 0.19, 0.38]; 0<0.0001) compared to GClb arm. (See Table 6 and Figure 3.)

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Patients with Previously Untreated CLL-Fixed duration therapy - AMPLIFY: The safety and efficacy of CALQUENCE in combination with venetoclax with or without obinutuzumab in previously untreated CLL was evaluated in a randomised, multi-centre, open-label Phase 3 study (AMPLIFY) of 867 patients. Patients received CALQUENCE plus venetoclax, CALQUENCE plus venetoclax and obinutuzumab, or Investigator's choice of chemoimmunotherapy, either FCR (fludarabine plus cyclophosphamide plus rituximab) or BR (bendamustine plus rituximab). AMPLIFY included patients previously untreated for CLL without del(17p) or TP53 mutation that were 18 years of age and older. The trial also allowed patients to receive antithrombotic agents other than warfarin or equivalent vitamin K antagonists. The study enrolled patients during the COVID-19 pandemic.
Patients were randomised in a 1:1:1 ratio into 3 arms to receive: CALQUENCE plus venetoclax (AV): CALQUENCE 100 mg was administered twice daily starting on Cycle 1 Day 1 for a total of 14 cycles or until disease progression or unacceptable toxicity. On Cycle 3 Day 1 patients started the venetoclax 5-week dose-titration schedule, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Venetoclax was administered for a total of 12 cycles. Each cycle was 28 days.
CALQUENCE plus venetoclax plus obinutuzumab (AVO): CALQUENCE 100 mg was administered twice daily starting on Cycle 1 Day 1 for a total of 14 cycles or until disease progression or unacceptable toxicity. On Cycle 3 Day 1 patients started the venetoclax 5-week dose-titration schedule, starting at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Venetoclax was administered for a total of 12 cycles. Obinutuzumab 1,000 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 1,000 mg on Day 1 of Cycles 3-7. Each cycle was 28 days.
Investigator's choice of chemoimmunotherapy (FCR/BR): Fludarabine plus cyclophosphamide plus rituximab (FCR): Fludarabine (25 mg/m²) and cyclophosphamide (250 mg/m²) were administered on Days 1-3 up to a maximum of 6 cycles. Rituximab was administered at a dose of 375 mg/m² on Day 1 Cycle 1 and 500 mg/m² on Day 1 of Cycles 2 up to 6. Each cycle was 28 days.
Bendamustine plus rituximab (BR): Bendamustine 90 mg/m² was administered on Days 1 and 2 up to maximum of 6 cycles. Rituximab was administered at a dose of 375 mg/m² on Day 1 Cycle 1 and 500 mg/m² on Day 1 of Cycles 2 up to 6. Each cycle was 28 days.
Patients were stratified by age (>65 years or ≤65 years), IGHV mutational status (mutated versus unmutated), Rai stage (high risk [≥3] versus non-high risk) and geographic region (North America and Western Europe versus other). Table 7 summarises the baseline demographics and disease characteristics of the study population. (See Table 7.)

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The primary endpoint was IRC-assessed PFS for AV versus Investigator's choice of chemoimmunotherapy (FCR/BR) arm as assessed by IWCLL 2018 criteria. Additional efficacy endpoints were IRC-assessed PFS of AVO versus Investigator's choice (FCR/BR) arm and OS in both AV arm vs. Investigator's choice (FCR/BR) arm and AVO vs Investigator's choice (FCR/BR) arm.
With a median follow-up of 41.3 months, IRC-assessed PFS indicated a 35% statistically significant reduction in risk of disease progression or death in patients treated with AV compared to FCR/BR.
With a median follow-up of 42.0 months, IRC-assessed PFS indicated a 58% statistically significant reduction in risk of disease progression or death in patients treated with AVO compared to FCR/BR.
At the time of primary analysis, the OS HR was 0.33 [95% CI (0.18, 0.56)] for AV arm compared to the FCR/BR arm, with a total of 60 death events; 18 (6.2%) in AV arm and 42 (14.5%) in FCR/BR arm.
At the time of primary analysis, the OS HR was 0.76 [95% CI (0.49, 1.18)] for AVO arm compared to the FCR/BR arm, with a total of 79 death events; 37 (12.9%) in AVO arm and 42 (14.5%) in FCR/BR arm.
Efficacy results are presented in Table 8. The Kaplan-Meier curve for IRC-PFS is shown in Figure 4. (See Table 8 and Figure 4.)

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The benefit of CALQUENCE in combination with venetoclax with or without obinutuzumab on PFS risk reduction was consistent across all clinically relevant subgroups, including higher risk CLL patients (unmutated IGHV). In patients with unmutated IGHV, the PFS HRs of CALQUENCE in combination with venetoclax or CALQUENCE in combination with venetoclax and obinutuzumab versus FCR/BR arm were 0.69 [95% CI (0.48, 0.97)] and 0.35 [95% CI (0.23, 0.53)], respectively.
Patients with CLL who received at least one prior therapy - ASCEND: 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 9 summarizes the baseline demographics and disease characteristics of the study population. (See Table 9.)

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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 10. The Kaplan-Meier curve for PFS is shown in Figure 5. (See Table 10 and Figure 5.)

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At the final analysis, with a median follow-up of 46.5 months for CALQUENCE and 45.3 months for the IR/BR, 72% reduction in risk of investigator-assessed disease progression or death was observed for patients in the CALQUENCE arm. The median investigator-assessed PFS was not reached in CALQUENCE and was 16.8 months in IR/BR. The median investigator-assessed PFS in patients with 17p deletion per IWCLL criteria was not reached in CALQUENCE arm and was 13.8 months in IR/BR arm.
At the time of final analysis, median overall survival had not been reached in any arm with a total of 95 deaths: 41 (26.5%) in the CALQUENCE monotherapy arm and 54 (34.8%) in the IR/BR arm. (See Table 11 and Figure 6.)

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Investigator assessed PFS results for CALQUENCE at final analysis were consistent across subgroups, including high risk features and were consistent with the primary analysis. In the high risk CLL population (17p deletion, 11q deletion, TP53 mutation, and unmutated IGHV), the investigator assessed PFS HR was 0.26 [95% CI (0.19, 0.37)]. (See Table 12.)

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Pharmacokinetics: 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. 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 (AUC_24h) and maximum plasma concentration (C_max) of acalabrutinib were 1,893 ng·h/mL and 466 ng/mL, respectively, and for ACP-5862 were 4,091 ng·h/mL and 420 ng/mL, respectively.
CALQUENCE tablets and CALQUENCE capsules have been demonstrated to be bioequivalent.
Absorption: The median (min, max) time to peak plasma concentrations (T_max) was 0.5 (0.2, 3.0) hours, and 0.75 (0.5, 4.0) hours for ACP-5862. The absolute bioavailability of CALQUENCE was 25%.
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 (V_ss) was approximately 34 L for acalabrutinib.
Biotransformation/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.
In vitro, acalabrutinib is a weak inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C19, CYP2D6, UGT1A1, and UGT2B7. ACP-5862 is a weak inhibitor of CYP2C8, CYP2C9 and CYP2C19, but does not inhibit CYP1A2, CYP2B6, CYP2D6, CYP3A4/5, UGT1A1, and UGT2B7 in vitro. Acalabrutinib is a weak inducer of CYP1A2, CYP2B6 and CYP3A4 mRNA; ACP-5862 weakly induces CYP3A4.
Interactions with transport proteins: In vitro, acalabrutinib and its active metabolite, 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, in vitro. 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.
Acalabrutinib may inhibit intestinal BCRP substrates (see Interactions), while ACP-5862 may inhibit MATE1 (see Interactions) at clinically relevant concentrations. Acalabrutinib does not inhibit MATE1, while ACP-5862 does not inhibit BCRP at clinically relevant concentrations.
Elimination: Following a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life (t_1/2) of acalabrutinib was 1.3 (range: 0.8 to 9.0) hours. The median t_1/2 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.
Pharmacokinetics in Special Populations: Based on population PK analysis, age, sex, race (Caucasian, African American), and body weight did not have clinically meaningful effects on the PK of acalabrutinib and its active metabolite, ACP-5862.
Renal Impairment: Acalabrutinib undergoes minimal renal elimination. A pharmacokinetic study in patients with renal impairment has not been conducted.
Based on population PK analysis, no clinically relevant PK difference was observed in 433 patients with mild renal impairment (eGFR between 60 and 89 mL/min/1.73m² as estimated by MDRD), 110 patients with moderate renal impairment (eGFR between 30 and 59 mL/min/1.73m²) relative to 204 patients with normal renal function (eGFR greater than or equal to 90 mL/min/1.73m²). The pharmacokinetics of acalabrutinib has not been characterised in patients with severe renal impairment (eGFR less than 29 mL/min/1.73m²) or renal impairment requiring dialysis. Patients with creatinine levels greater than 2.5 times the institutional ULN were not included in the clinical trials (see Dosage & Administration).
Hepatic Impairment: Acalabrutinib is metabolized in the liver. In dedicated 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 difference was observed between subjects with mild (n=79) or moderate (n=6) hepatic impairment (total bilirubin between 1.5 to 3 times ULN and any AST) relative to subjects with normal (n=651) hepatic function (total bilirubin and AST within ULN).
Toxicology: Preclinical safety data: Carcinogenicity: Carcinogenicity studies have not been conducted with acalabrutinib.
Genotoxicity/Mutagenicity: Acalabrutinib was not mutagenic in a bacterial reverse mutation assay, in an in vitro chromosome aberration assay, or in an in vivo mouse bone marrow micronucleus assay.
Repeat-dose toxicity: Daily oral administration of acalabrutinib for up to 6 months duration in rats and 9 months in dogs was tolerated at exposure levels that exceed human therapeutic exposures at the recommended dose (2.5-fold in rats, 8.2-fold in dogs, based on AUC).
In rats, renal effects including tubular degeneration were observed at exposures 4.2 times or greater than that of the recommended human dose. Renal effects were reversible with complete recovery in rats exposed at levels 4.2 times the recommended human dose and partial recovery in rats at the higher exposures (6.8-fold or greater).
In rats, dose-responsive reversible liver findings including individual hepatocyte necrosis were observed after exposures 4.2 times or greater than that of the recommended human dose.
Cardiac toxicities (myocardial haemorrhage, inflammation, necrosis) were observed in rats that died during the study and at exposures equivalent to 6.8 times or greater than that of the human recommended dose. Reversibility for the heart findings could not be assessed as these findings were only observed at doses above the maximum tolerated dose (MTD). At exposures representing 4.2 times the human recommended dose, no cardiac toxicities were observed.
Reproductive toxicology: No effects on fertility were observed in male or female rats at exposures 10 or 9 times the human AUC exposure at the recommended dose, respectively.
In a combined fertility and embryofoetal development study in female rats, acalabrutinib was administered orally at doses up to 200 mg/kg/day starting 14 days prior to mating through gestational day [GD] 17. No effects on embryofoetal development and survival were observed. The AUC at 200 mg/kg/day in pregnant rats was approximately 9-times the AUC in patients at the recommended dose of 100 mg twice daily. The presence of acalabrutinib and its active metabolite were confirmed in foetal rat plasma.
In an embryofoetal study in pregnant rabbits, acalabrutinib was administered orally at doses up to 200 mg/kg/day during the period of organogenesis (from GD 6-18). Acalabrutinib produced no maternal toxicity and no evidence of teratogenicity or foetal development, growth, or survival at doses of 50 mg/kg/day (approximately equivalent to the human AUC exposure at the recommended dose). Decreased foetal body weight and delayed ossification were observed at exposure levels that produced maternal toxicity (doses ≥100 mg/kg/day), which were 2.4-times greater than the human exposure levels at the recommended dose.
In a rat reproductive study, dystocia (prolonged/difficult labour) was observed at exposures >2.3-times the clinical exposure at 100 mg twice daily.

Mantle Cell Lymphoma (MCL): CALQUENCE as monotherapy is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
CALQUENCE in combination with bendamustine and rituximab (BR) is indicated for the treatment of adult patients with previously untreated MCL who are ineligible for autologous stem cell transplant (ASCT).
Chronic Lymphocytic Leukaemia (CLL)/Small Lymphocytic Lymphoma (SLL): CALQUENCE is indicated: in combination with obinutuzumab or as monotherapy for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
In combination with venetoclax with or without obinutuzumab for the treatment of patients with previously untreated CLL/SLL.
As monotherapy for the treatment of patients with CLL/SLL who have received at least one prior therapy.

Treatment with CALQUENCE should be initiated and supervised by a physician experienced in the use of anticancer therapies.
Posology: MCL: The recommended dose of CALQUENCE in monotherapy or in combination with other medicinal products is 100 mg (1 tablet) twice daily. For the combination regimens, refer to the prescribing information of each of the medicinal product for dosing information. For details of the combination regimens, see Pharmacology: Pharmacodynamics under Actions.
CALQUENCE in combination with bendamustine and rituximab: CALQUENCE should be administered on Day 1 on Cycle 1 (each cycle is 28 days) until disease progression or unacceptable toxicity. Bendamustine should be administered at 90 mg/m² on Days 1 and 2 of each cycle for a total of 6 cycles. Rituximab should be administered at 375 mg/m² on Day 1 each cycle for a total of 6 cycles. Patients achieving a response (partial response [PR] or complete response [CR]) after the first 6 cycles, may receive maintenance rituximab at 375 mg/m² on Day 1 of every other cycle for a maximum of 12 additional doses, starting on Cycle 8 up to Cycle 30.
CLL/SLL: The recommended dose of CALQUENCE for the treatment of CLL/SLL is 100 mg (1 tablet) twice daily, either as monotherapy or in combination. Refer to the prescribing information of each of the combination medicinal products for recommended dosing information (for details of the combination regimen, see Pharmacology: Pharmacodynamics under Actions).
CALQUENCE doses should be separated by approximately 12 hours.
Treatment with CALQUENCE monotherapy or in combination with obinutuzumab should continue until disease progression or unacceptable toxicity. Treatment with CALQUENCE in combination with venetoclax with or without obinutuzumab, should continue until disease progression, unacceptable toxicity or completion of 14 cycles of treatment (each cycle is 28 days).
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 adverse reactions in patients receiving CALQUENCE monotherapy and CALQUENCE in combination with obinutuzumab or in combination with venetoclax with or without obinutuzumab are provided in Table 13.
Temporarily interrupt CALQUENCE to manage a Grade ≥3 non-haematological treatment-related adverse reaction, Grade 3 thrombocytopenia with significant bleeding, Grade 4 thrombocytopenia, or Grade 4 neutropenia lasting longer than 7 days. Upon resolution of the adverse reaction to Grade 1 or baseline (recovery), restart CALQUENCE as recommended in Table 13. (See Table 13.)

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Dose modifications for adverse reactions in patients receiving CALQUENCE in combination with bendamustine and rituximab are listed in Table 14. (See Table 14.)

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Refer to the prescribing information of each of the medicinal products used in combination with CALQUENCE for additional information for management of toxicities. (See Table 15.)

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Acalabrutinib tablets can be co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists, antacids), unlike acalabrutinib capsules which show impaired uptake when given with acid reducing agents (see Interactions).
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, dissolved, or opened.
Special patient populations: Elderly (≥65 years): No dose adjustment is necessary based on age (see Pharmacology: Pharmacokinetics under Actions).
Renal Impairment: No dose adjustment is recommended in patients with mild to moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73m² as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics and safety of CALQUENCE in patients with severe renal impairment (eGFR less than 29 mL/min/1.73m²) or end-stage renal disease have not been studied (see Pharmacology: Pharmacokinetics under Actions).
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). Avoid administration of CALQUENCE in patients with severe hepatic impairment (Child-Pugh C or total bilirubin >3 times ULN and any AST) (see Pharmacology: Pharmacokinetics under Actions).
Severe Cardiac Disease: Patients with severe cardiovascular disease were excluded from CALQUENCE clinical studies.
Paediatric and adolescents: The safety and efficacy of CALQUENCE in children and adolescents aged less than 18 years have not been established.

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.

Hypersensitivity to acalabrutinib or to any of the excipients in the formulation.

Haemorrhage: Serious haemorrhagic events, including fatal events, have occurred in patients with haematologic malignancies (n=1,478) treated with CALQUENCE monotherapy. Major haemorrhage (Grade 3 or higher bleeding events, serious, or any central nervous system events) occurred in 5.5% of patients, with fatalities occurring in 0.1% of patients. Overall, bleeding events including bruising and petechiae of any grade occurred in 46.1% of patients with haematological malignancies.
The mechanism for the bleeding events is not well understood.
Patients receiving antithrombotic agents may be at increased risk of haemorrhage. Use caution with antithrombotic agents and consider additional monitoring for signs of bleeding when concomitant use is medically necessary.
Consider the benefit-risk of withholding CALQUENCE for at least 3 days pre- and post-surgery.
Infections: Serious infections (bacterial, viral or fungal), including fatal events have occurred in patients with haematologic malignancies (n=1,478) treated with CALQUENCE monotherapy. Grade 3 or higher infections occurred in 26.4% 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.
Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat as medically appropriate.
Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia (17.5%), anaemia (9.5%) and thrombocytopenia (6.2%), occurred in patients with haematologic malignancies (n=1,478) treated with CALQUENCE monotherapy.
Monitor complete blood counts as medically appropriate.
Second Primary Malignancies: Second primary malignancies, including non-skin cancers, occurred in 17.6% of patients with haematologic malignancies (n=1,478) treated with CALQUENCE monotherapy. The most frequent second primary malignancy was skin cancer, which occurred in 9.9% of patients. Monitor patients for the appearance of skin cancers.
Atrial Fibrillation: In patients with haematologic malignancies (n=1,478) treated with CALQUENCE monotherapy, atrial fibrillation/flutter of any grade occurred in 7.4% of patients and Grade 3 or higher occurred in 2.3% 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.
Tumour lysis syndrome: Tumour lysis syndrome (TLS) has been reported with CALQUENCE therapy. Patients considered at risk for TLS (e.g., presence of bulky disease at baseline) should be assessed for possible risk of TLS and closely monitored as clinically indicated.
Interstitial lung disease/pneumonitis: Interstitial lung disease (ILD)/pneumonitis has been reported in patients treated with CALQUENCE in combination with bendamustine and rituximab in MCL. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g., cough, dyspnoea or hypoxia) and manage ILD/pneumonitis as clinically indicated.
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.

Pregnancy: CALQUENCE should not be used during pregnancy and women of childbearing potential should be advised to avoid becoming pregnant while receiving CALQUENCE. There are insufficient clinical data on CALQUENCE use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Based on findings from animal studies, there may be a risk to the foetus from exposure to acalabrutinib during pregnancy. Administration of acalabrutinib to pregnant rabbits at exposures 2.4-times the human AUC at the recommended dose was associated with reduced foetal growth (see Pharmacology: Toxicology: Preclinical safety data under Actions). Dystocia was observed in a rat study involving dosing animals from implantation throughout gestation, parturition and lactation at exposures >2.3-times the human AUC at the recommended dose (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Lactation: It is not known whether acalabrutinib is excreted in human milk. There are no data on the effect of acalabrutinib on the breast-fed infant or on milk production. Acalabrutinib and its active metabolite were present in the milk of lactating rats. A risk to the suckling child cannot be excluded. Breast-feeding mothers are advised not to breast-feed during treatment with CALQUENCE and for 2 days after receiving the last dose.
Fertility: There are no data on the effect of CALQUENCE on human fertility. In a nonclinical study of acalabrutinib in male and female rats, no adverse effects on fertility parameters were observed (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Overall Summary of Adverse Drug Reactions: CALQUENCE Monotherapy: The overall safety profile of acalabrutinib monotherapy is based on pooled data from 1,478 patients with haematologic malignancies receiving acalabrutinib monotherapy. The median duration of acalabrutinib monotherapy treatment across the pooled dataset was 38.2 months.
The most common (≥20%) adverse drug reactions (ADRs) of any grade reported in patients receiving acalabrutinib monotherapy were infection, diarrhoea, headache, musculoskeletal pain, bruising, arthralgia, fatigue, nausea, leukopenia and rash.
The most commonly reported (≥5%) Grade ≥3 adverse drug reactions were infection , leukopenia, neutropenia, anaemia, second primary malignancies, thrombocytopenia and second primary malignancies excluding non-melanoma skin.
Dose reductions due to adverse events were reported in 5.9% of patients. Discontinuation due to adverse events were reported in 14.6% of the patients. The median dose intensity was 98.2%.
The adverse drug reactions for patients receiving acalabrutinib monotherapy are listed in Table 16.
CALQUENCE in combination with obinutuzumab: The overall safety profile of acalabrutinib in combination with obinutuzumab is consistent with the known safety profile of acalabrutinib monotherapy and that of obinutuzumab.
CALQUENCE in combination with bendamustine and rituximab: The overall safety profile of acalabrutinib in combination with bendamustine and rituximab is based on pooled data from 297 patients receiving acalabrutinib in combination with bendamustine and rituximab. The median duration of CALQUENCE exposure in patients treated with CALQUENCE in combination with bendamustine and rituximab was 28.6 months.
The most common (≥20%) adverse drug reactions (ADRs) of any grade reported in patients receiving acalabrutinib in combination with bendamustine and rituximab were infection, leukopenia, neutropenia, nausea, rash, diarrhoea, musculoskeletal pain, headache, fatigue, vomiting, constipation, anaemia and thrombocytopenia.
The most commonly reported (≥5%) Grade ≥3 adverse drug reactions were leukopenia, neutropenia, infection, rash, thrombocytopenia, anaemia, second primary malignancies and second primary malignancies excluding non-melanoma skin.
Dose reductions due to adverse events were reported in 10.1% of patients. Discontinuation due to adverse events were reported in 42.8% of the patients. The median dose intensity was 96.3%.
The adverse drug reactions for patients receiving acalabrutinib in combination with bendamustine or rituximab are listed in Table 18.
CALQUENCE in combination with venetoclax with or without obinutuzumab: The overall safety profile of acalabrutinib in combination with venetoclax with or without obinutuzumab is based on pooled data from 291 patients receiving acalabrutinib in combination with venetoclax and 284 patients receiving acalabrutinib in combination with venetoclax and obinutuzumab. The median duration of CALQUENCE exposure in patients treated with CALQUENCE in combination with venetoclax with or without obinutuzumab was 12.9 months.
The most common (≥20%) adverse drug reactions (ADRs) of any grade reported in patients receiving acalabrutinib in combination with venetoclax were infection, leukopenia, neutropenia, headache, diarrhoea, musculoskeletal pain and bruising.
The most commonly reported (≥5%) Grade ≥3 adverse drug reactions in patients receiving acalabrutinib in combination with venetoclax were neutropenia and infection.
Acalabrutinib dose reductions in patients due to adverse events were reported in 5.8% of patients receiving acalabrutinib in combination with venetoclax. Discontinuation due to adverse events were reported in 7.6% of the patients. The median dose intensity was 99.5%.
The most common (≥20%) adverse drug reactions (ADRs) of any grade reported in patients receiving acalabrutinib in combination with venetoclax and obinutuzumab were infection, leukopenia, neutropenia, diarrhoea, headache, nausea, musculoskeletal pain and bruising.
The most commonly reported (≥5%) Grade ≥3 adverse drug reactions in patients receiving acalabrutinib in combination with venetoclax and obinutuzumab were leukopenia, neutropenia, infection and thrombocytopenia.
Acalabrutinib dose reductions due to adverse events were reported in 6.3% of patients receiving acalabrutinib in combination with venetoclax and obinutuzumab. Discontinuation due to adverse events were reported in 13.7% of the patients. The median dose intensity was 98.1%.
The adverse drug reactions for patients receiving acalabrutinib in combination with venetoclax with or without obinutuzumab are listed in Table 20.
Tabulated list of adverse reactions: The following tables present adverse drug reactions (ADRs) identified in clinical studies with patients receiving CALQUENCE monotherapy or combination therapy for haematological malignancies.
Adverse drug reactions are listed according to system organ class (SOC) in MedDRA. Within each system organ class, the adverse drug reactions are sorted by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each ADR is based on the CIOMS III convention and is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data). (See Tables 16, 17, 18, 19, 20 and 21.)

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Special populations: Elderly: Of the 1,478 patients in clinical trials of CALQUENCE monotherapy, 42% were 65 years of age or older and less than 75 years of age and 20.6% were 75 years of age or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 years and younger.

Active substances that may increase acalabrutinib plasma concentrations: CYP3A Inhibitors: Co-administration with a strong CYP3A inhibitor (200 mg itraconazole once daily for 5 days) increased acalabrutinib C_max and AUC by 3.7-fold and 5.1-fold in healthy subjects (n=17), respectively.
When accounting for both acalabrutinib and its active metabolite, ACP-5862, physiologically based pharmacokinetic (PBPK) simulations with strong, moderate, and weak CYP3A inhibitors show no meaningful change in total AUC of active components.
Avoid co-administration of strong CYP3A inhibitors with CALQUENCE. Alternatively, if the strong CYP3A inhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir, posaconazole, voriconazole) will be used short-term, interrupt CALQUENCE.
Active substances that may decrease acalabrutinib plasma concentrations: CYP3A Inducers: Co-administration of a strong CYP3A inducer (600 mg rifampin once daily for 9 days) decreased acalabrutinib C_max and AUC by 68% and 77% in healthy subjects (n=24), respectively.
When accounting for both acalabrutinib and its active metabolite, ACP-5862, PBPK simulations with strong CYP3A inducers showed a 21-51% decrease in total AUC of active components. Simulations with a moderate CYP3A inducer (efavirenz) showed a 25% decrease in total AUC of active components.
Avoid co-administration of strong inducers of CYP3A activity (e.g., phenytoin, rifampin, carbamazepine) with CALQUENCE. Avoid St. John's wort which may unpredictably decrease acalabrutinib plasma concentrations. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg twice daily.
Gastric Acid Reducing Medications: No clinically significant differences in acalabrutinib pharmacokinetics were observed when a 100 mg acalabrutinib tablet was used concomitantly with rabeprazole (20 mg twice daily for 3 days), a proton pump inhibitor. Acalabrutinib tablets can be co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists, antacids), unlike acalabrutinib capsules which show impaired uptake when given with acid reducing agents.
Active substances whose plasma concentrations may be altered by CALQUENCE: CYP3A Substrates: Based on in vitro data and PBPK modelling, no interaction with CYP substrates is expected at the clinically relevant concentrations (see Pharmacology: Pharmacokinetics under Actions).
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 (see Pharmacology: Pharmacokinetics under Actions).
ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of MATE1 (see Pharmacology: Pharmacokinetics under Actions).
Effect of food on acalabrutinib: In healthy subjects, administration of a single 100 mg dose of acalabrutinib 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 C_max decreased by 73% and T_max was delayed 1-2 hours.

Incompatibilities: Not applicable.
Instructions for use, handling and disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Special precautions for storage: Do not store above 30°C.

Targeted Cancer Therapy

L01EL02 - acalabrutinib ; Belongs to the class of Bruton's tyrosine kinase (BTK) inhibitors. Used in the treatment of cancer.

POM